Gastroenterology – various disorders

acetyl cysteine – for abdominal complications

abdominal pain, constipation, distal intestinal obstruction syndrome (DIOS)

appendicitis

intestinal inflammation, fecal microbiome. gut-Lung Axis

bacterial overgrowth,  Clostridium difficile

Helicobacter pylori

fibrosing colonopathy

gastroesophageal reflux

effect of modulators GI function

transplant complications

other intestinal CF abnormalities – current changes

Acetyl cysteine – for abdominal complications

1964 Meeker IAJr. Acetyl cysteine used to liquefy inspissated meconium causing intestinal obstruction in the newborn. Surgery 1964; 56:419-425. [PubMed] 100ml 0f 20% acetyl cysteine and equal parts of 1% hydrogen peroxide were introduced into the lumen of the bowel where it remains for 30 minutes. Bowel resection was then not necessary.

1967 Lillibridge CB, Docter JM, Eidelman S. Oral administration of n-acetyl cysteine in the prophylaxis of “meconium ileus equivalent”. J Pediatr 1967; 71:887-889.[PubMed] An adult with CF was chronically disabled by frequent abdominal pain and episodes of faecal impaction. Treatment with oral acetyl cysteine 30ml three time daily led to almost complete cessation of the attacks. The patients gained weight and became fully employed. This is the first report of this treatment in an older patient with CF.

1969 Gracey M, Burke V, Anderson CM. Treatment of abdominal pain in cystic fibrosis by oral administration of n-acetyl cysteine. Arch Dis Child 1969; 44:404-405. [PubMed]

For patients with troublesome abdominal pain, 5 ml of a 20% solution N-acetyl cysteine with 50% water was given four times daily. Five of the six patients ceased having pain within a week – the other patient refused to take the treatment. The authors were prompted to try the treatment by the case of a 26 year old man with CF reported by Lillibridge CB et al,(J Pediatr 1967; 71:887-889. [PubMed]) whose abdominal pain responded impressively with N-acetylcysteine 30 ml three times daily by mouth. Gracey later confirmed in 1975 that “this troublesome complaint may be relieved by giving n-acetyl cysteine by mouth and further personal experience confirms the value of this form of therapy. Sometimes up to 15ml of a 20% solution 3 or 4 times a day may be necessary at first”

A particularly useful report at the time as the results of surgery for meconium ileus equivalent were still poor.

1976 Hodson ME, Mearns MB, Batten JC. Meconium ileus equivalent in adults with cystic fibrosis of pancreas: a report of six cases. Br Med J 1976; 2(6039):790-791. [PubMed]
Eleven episodes of “meconium ileus equivalent” have been seen in six adults with cystic fibrosis of the pancreas. Three patients were initially treated surgically; one died and the other two developed serious postoperative chest infections. Six episodes were successfully treated medically with acetylcysteine orally and by enema, nasogastric suction, and intravenous fluids. Operation should be avoided if possible, and maintenance treatment with acetylcysteine may be necessary to prevent relapse.

Abdominal pain, constipation, distal intestinal obstruction syndrome (DIOS)

1951 Levy E. A case of fibrocystic disease of the pancreas with intestinal obstruction. Arch Dis Child 1951; 26:335-339. [PubMed]
The first of many reports of late intestinal obstruction which has proved to be an important and frequent complication as the age of survival has increased (also Fisher 1954 below). A seven month old infant underwent laparotomy for a presumed intussusception. The plum-coloured distended small bowel was obstructed by putty like material with haemorrhages at the root of the mesentery. The colon was empty and contracted. No surgery was done and the infant died the next day.

1954 Fisher OD. Intestinal obstruction as a late complication of fibrocystic disease of pancreas (Mucosis). Arch Dis Child 1954; 29:262-264. [PubMed]
From the Royal Belfast Children’s Hospital, the second report of late obstruction (first was Levy, 1951 above), on this occasion in an infant aged 13 months with CF, which closely followed cessation of pancreatin therapy the supply of which had run out five days before admission. The whole bowel was intermittently obstructed by masses of putty-like material and material like liquid rubber was removed via an incision, pancreatin was restarted and the infant recovered. Fisher observed rather strangely “Suggesting use of pancreatin as a form of replacement therapy”.

Shwachman commented he had seen six such patients already, three were surgically treated. He mentions the presence of a palpable abdominal mass in lower right quadrant and material which was “rock-like” – the right iliac fossa hard mass was later recognised as a relatively common feature of children and adults with distal intestinal obstruction syndrome (DIOS) as more older children and adults attended CF clinics. Those clinicians who examine the abdomen as a routine (not all do!) will notice these right iliac fossa masses occaisionally in asymptomatic patients with CF.

1962 Jensen KG. Meconium ileus equivalent in a 15-year old patient with mucoviscidosis. Acta Paediatr Scand 1962; 51:344-345. [PubMed]
This report, often incorrectly quoted as first description of meconium ileus equivalent, describes the condition in a boy aged 15 years – however, it was the first time the term “meconium ileus equivalent” was used. Already Levy (1951 above) and Fischer (1954 above) and others had reported post neonatal intestinal obstruction. Also Fanconi (Helvet Paediat Acta 1960; 15:566-579) had used the term “post-neonatal meconium ileus”. This present patient of Jensen’s had an ileostomy through which pancreatin was infused which relieved the obstruction.

1976 Hodson ME, Mearns MB, Batten JC. Meconium ileus equivalent in adults with cystic fibrosis of pancreas: a report of six cases. BMJ 1976; 2:790-791. [PubMed]
Eleven episodes of meconium ileus equivalent (MIE) are described in six adult patients, four of whom were diabetic. Three were surgically treated with one fatality and there were two serious postoperative complications. Treatment with intravenous fluids, nasogastric suction, enemas and oral acetylcysteine was recommended followed by maintenance treatment with oral acetylcysteine.

–   A repeated complaint of CF physicians was of people with CF being admitted with acute gastrointestinal symptoms to a general surgical unit and undergoing unnecessary operations as the staff were unfamiliar with this condition. The use of gastrografin for the treatment of MIE had not yet been published from the Liverpool CF unit (O’Halloran SM et al. 1986 below). It is perhaps relevant that four of the six patients were diabetic and possibly could have been sub clinically slightly dehydrated. Later work reported that a positive effort to increase hydration by drinking more water significantly reduced the incidence of meconium ileus equivalent in people with cystic fibrosis (Obideen et al, 2006 below)

1983 Bali A, Stableforth DE, Asquith P. Prolonged small-intestinal transit time in cystic fibrosis. BMJ 1983; 287: 1011-1013. [PubMed]

A lactulose hydrogen breath test was used to measure small intestinal transit time in patients with CF and controls. Seven of 10 CF individuals had high fasting breath hydrogen levels (25-170ppm; normals <20ppm) that fell to normal after prolonged fasting; this indicates bacterial colonisation of the small bowel and was the first report of this occurring in cystic fibrosis. Seven of the 10 patients had prolonged small intestinal transit times (160-390 minutes) compared with controls (50-150 minutes). Again, the first documentation of the prolonged small bowel transit time in CF which was confirmed in subsequent studies.

–   Increased fasting breath hydrogen and after glucose (Bond JH, Levitt MD. J Clin Invest 1972; 51:1219-1225.[PubMed]) or lactulose (Rhodes JM et al, Scand J Gastroenterol 1979; 14:333-336. [PubMed]) indicates small bowel bacterial over growth. A later-than-normal rise after oral lactulose indicates prolonged small bowel transit time as the non-absorbable sugar is fermented by the bacteria in the large bowel at a later stage.
Although these were interesting first reports of small bowel bacterial colonisation and slow transit in CF, the results did not have a major impact on practical management as interest in most CF centres was focused on the chest infection. Fortunately, in recent years there is increasing interest in these matters – both bacterial contamination and inflammation of the small bowel wall which appears to be a relatively frequent occurrence (Smyth et al, 2000 below; Werlin S et al, 2008 below).

1986 O’Halloran SM, Gilbert J, McKendrick OM, Carty HML, Heaf DP. Gastrografin in acute meconium ileus equivalent. Arch Dis Child 1986; 61:128-130. [PubMed]
Gastrografin is a radiological contrast medium containing sodium diatrizoate, meglutamine diatrizoate and iodine plus flavoring and wetting agents. It is hypertonic with minimal absorption from the intestine. This is the first description from the Liverpool CF unit of the use of gastrografin as an effective and subsequently widely used treatment for distal intestinal obstruction syndrome, which, for some reason, was particularly common in the Liverpool CF clinic affecting 37% of the children.

In one year 37 of 40 episodes were treated with a single oral dose of gastrografin with an 81% success rate.
It is interesting, and unexplained, that fibrosing colonopathy was later described in Liverpool children (Smyth et al, 1993 below) where it was more common than in any other UK CF centre.

1995 Littlewood JM. Abdominal pain in cystic fibrosis. J R Soc Med 1995; 88 (Suppl): 9-17. [PubMed]

A detailed review of the causes, investigation and treatment of abdominal pain in CF summarising experience with over 600 patients with CF seen at the Leeds Regional Paediatric CF Centre. As sub-specialisation increased in paediatrics in the UK, the majority of paediatricians working in CF centres were primarily interested in the treatment of the chest – understandably as most people with CF died from this cause. So the gastrointestinal aspects were relatively under-investigated although a significant number of patients had, and still do have, abdominal symptoms.

In this study recurrent abdominal pain occurred in 11% of children receiving their care at the Leeds centre (where there was considerable interest in and investigation of gastrointestinal problems) and in 31% of those referred for Comprehensive CF Assessment from other hospitals – admittedly a selected group.
It was interesting that the prevalence of recurrent abdominal pain differed greatly with the mode of presentation e.g. meconium ileus 38%, respiratory 39%, malabsorption 47%, presence of a CF sibling 30% but only in 4% in those diagnosed by neonatal screening and treated from the age of a few weeks (Littlewood JM J R Soc Med 1992; 85 (Suppl 18):13-19).

2000 Smyth RL, Croft NM, O’Hea U, Marshall TG, Ferguson A. Intestinal inflammation in cystic fibrosis. Arch Dis Child 2000; 82:394-399. [PubMed]

To determine whether there is increased inflammation in the gastrointestinal tract of CF children who had developed fibrosing colonopathy, whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF who had had fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, alpha1-antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin1beta) were measured.
Compared to controls, all the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1beta, and interleukin 8. Similar values were obtained for the CF patients who had had fibrosing colonopathy.

–   Whole gut lavage is essentially washing out the gut and counting the inflammatory cells in the washings as an indication of the degree of intestinal inflammation. These data suggest that there is immune activation in the gastrointestinal mucosa of all children with cystic fibrosis, which may result from the basic cellular defect perhaps with secondary bacterial infection of the gut. Certainly the children who had previously had fibrosing colonopathy did not appear to have more signs of inflammation than those who had not had the complication.

The finding of evidence of intestinal inflammation is not unexpected as it has been reported, and confirmed, that small bowel bacterial overgrowth affects some 70% of people with CF which is likely to be related to these findings (Bali et al, 1983 above). Also more recent work using capsule endoscopy showed that many patients had diffuse areas of inflammation in the small bowel associated with very high caloprotectin levels confirming the inflammatory response (253+/- 97 ug/g Normal <50) (Werlin S et al. Pediatr Pulmonol 2008; Suppl 31:Poster 610:422; Werlin SL et al. J Pediatr Gastro Nutr 2010; 51:304-308. [PubMed]). Subsequently interest in this area increased progressively throughout the decade.

2006 Obideen K, Wehbi M, Hoteit M, Cai Q. Nocturnal hydration an effective modality to reduce recurrent abdominal pain and recurrent pancreatitis in patients with adult-onset cystic fibrosis. Dig Dis & Sci 2006; 51:1744-1748.[PubMed]
The proportion of older people with CF who have recurrent troublesome abdominal symptoms is as high as 20-30% in some clinics. In this study patients were encouraged to “drink plenty of water through the night” and assessed with regard to abdominal symptoms for 3 months before and after starting this regimen. The frequency and severity of pain was reduced as was the medication required, emergency room visits and hospitalisations and even episodes of acute pancreatitis.

This is a simple measure which would be likely to reduce the pain which, in our experience, is commonly due to constipation and faecal accumulation in the lower ileum and colon even though the patient does not complain of constipation i.e. defined as the passage of infrequent hard stools.

So this suggestion of increasing fluid intake is simple, cheap and potentially very useful measure to reduce the incidence of abdominal pain in adults with CF. An extremely economical, and apparently effective, way of improving quality of life.
An additional reason for persisting abdominal symptoms could be the presence of inflammation of the bowel which has been shown in a number of recent studies by breath tests, inflammatory markers in the stools, endoscopic means and most recently by capsule visualisation)

2010 van der Doef HP, Kook FT, Seek FJ, Wontedness JW, Ferruling SP, Houwen RH. Constipation in pediatric cystic fibrosis patients: an underestimated medical condition. J Cyst Fibros 2010; 9:59-63. [PubMed]
The aims of this study were to determine prevalence, risk factors and treatment of constipation in patients with cystic fibrosis, as well as the diagnostic value of abdominal radiography. A cohort of 214 pediatric CF patients was investigated. Furthermore, 106 abdominal radiographs of CF patients with or without constipation were independently assessed by three observers on two separate occasions using the Barr and Leech scores. The prevalence of constipation was 47%. Low total fat absorption and meconium ileus were independent risk factors for constipation in CF, while fiber and fluid intake were not associated. In CF patients the inter and intra observer variabilities of the Barr and Leech scores were poor to moderate.

The authors concluded that constipation is a significant medical issue in CF and was associated with low total fat absorption and a history of meconium ileus. Finally, they consider that abdominal radiography seems of little value in the regular follow-up of CF patients.

–   I would maintain that abdominal radiography is of value in the follow up of those CF patients who are complaining of abdominal symptoms – particularly abdominal pain which may affect over 20% of patients in some CF clinics. By definition, constipation implies the infrequent passage of hard stools and this is not synonymous with colonic overloading which is common in people with CF. In my experience much of the pain experienced by people with CF is related to colonic overloading (figure) but the patient may not complain of “constipation” or any disturbance of bowel habit as in the child in figure 10 above (Littlewood et al, Pediatr Pulmonol 2006; 41:34-49.[PubMed]).

2010 Houwen RH, van der Doef HP, Sermet I, Munck A, Hauser B, Walkowiak J, Robberecht E, Colombo C, Sinaasappel M, Wilschanski M. ESPGHAN Cystic Fibrosis Working Group. Defining DIOS and constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, and treatment of DIOS. J Pediatr Gastroenterol Nutr 2010; 50:38-42. [PubMed]
The aims of this study were to seek consensus on the definitions for DIOS and constipation in patients with CF and to determine the incidence, characteristics, and treatment of DIOS in a cohort of paediatric patients with CF. During the 2005 European Society for Paediatric Gastroenterology, Hepatology, and Nutrition meeting in Porto a group of paediatric gastroenterologists discussed the definition of DIOS and constipation in CF. Subsequently, all patients younger than or equal to 18 years with complete DIOS according to the definition agreed upon and diagnosed during the years 2001 to 2005 in 8 CF centres were studied.

Distal intestinal obstruction syndrome was defined as an acute complete or incomplete faecal obstruction in the ileocaecum, whereas constipation was defined as gradual faecal impaction of the total colon. Fifty-one episodes of DIOS in 39 patients were recorded, giving an overall incidence of 6.2 (95% confidence interval, 4.4-7. 9) episodes per 1000 patient-years. Of the 39 patients with DIOS, 20% experienced a relapse, 92% were pancreatic insufficient, 44% had a history of meconium ileus at birth, and 82% had a severe genotype. Conservative treatment was effective in 49 of 51 DIOS episodes (96%).

The European Society for Paediatric Gastroenterology, Hepatology, and Nutrition CF Working Group definitions of DIOS and constipation in CF are specific and make a clear distinction between these 2 entities. The incidence of DIOS in the present study was considerably higher than reported previously.

2012 Munck A. Pesle A. Cunin-Roy C. Gerardin M. Ignace I. Delaisi B. Wood C. Recurrent abdominal pain in children with cystic fibrosis: a pilot prospective longitudinal evaluation of characteristics and management. J Cyst Fibros 2012; 11:46-48. [PubMed].

Children with cystic fibrosis commonly experience abdominal pain; however this remains poorly characterised. This prospective cross-sectional study with a longitudinal design, examined the prevalence, causes and effect of pain management via daily diaries, validated questionnaires for pain characteristics, anxiety status and quality of life. One hundred and thirty CF patients aged 8 to 18 years, regularly followed at our centre, were questioned on recurrent abdominal pain. Eight patients fulfilled the criteria; all wished to enter the study. Pain management included behavioural intervention with effective pain relief, and had a positive impact on anxiety and quality of life.

This study is the first one to prospectively assess recurrent abdominal pain in CF.  They documented a very low prevalence of 6%. Ruling out abdominal discomfort, only a minority of CF children presented recurrent abdominal pain with a true negative impact on daily life.

The low prevalence of recurrent abdominal pain in this series from Paris is probably related to the first author’s interest in gastrointestinal problems in CF and the management the patients receive in the clinic.

2013 Stoltz DA. Rokhlina T. Ernst SE. Pezzulo AA. Ostedgaard LS. Karp PH. Samuel MS. Reznikov LR. Rector MV. Gansemer ND. Bouzek DC. Alaiwa MH. Hoegger MJ. Ludwig PS. Taft PJ. Wallen TJ. Wohlford-Lenane C. McMenimen JD. Chen JH. Bogan KL. Adam RJ. Hornick EE. Nelson GA 4th. Hoffman EA. Chang EH. Zabner J. McCray PB Jr. Prather RS. Meyerholz DK. Welsh MJ. Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs.J Clin Invest 2013; 123:2685-2693. [PubMed]
Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesised that transgenic expression of porcine CF transmembrane conductance regulator (pCFTR) cDNA under control of the intestinal fatty acid-binding protein (iFABP) promoter would alleviate the meconium ileus. We produced 5 CFTR-/-;TgFABP>pCFTR lines. In 3 lines, intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype. In contrast, these pigs still had pancreatic destruction, liver disease, and reduced weight gain, and within weeks of birth, they developed sinus and lung disease, the severity of which varied over time.

These data indicate that expressing CFTR in intestine, without pancreatic or hepatic correction, is sufficient to rescue meconium ileus. Comparing CFTR expression in different lines revealed that approximately 20% of wild-type CFTR mRNA largely prevented meconium ileus. This model may be of value for understanding CF pathophysiology and testing new preventions and therapies

2014 Farrelly PJ. Charlesworth C. Lee S. Southern KW. Baillie CT. Gastrointestinal surgery in cystic fibrosis: a 20-year review. J Pediatr Surg 2014; 49(2):280-3. [PubMed]
The purpose of this study was to evaluate outcomes of the surgical management for meconium ileus (MI) and Distal Intestinal Obstruction Syndrome (DIOS) in children born between 1990 and 2010.
Seventy-five of 376 neonates presented with meconium ileus. Fifty-four (92%) required laparotomy. Contrast enema decompression was attempted in nineteen. There were no post-operative deaths. Thirty-nine (72%) neonates with MI were managed with stomas. LOS was longer in those managed with stomas (p=0.001) and in complex MI (p=0.002).
Thirty-five patients were treated for DIOS. Twenty-five patients were managed with gastrografin. Ten patients underwent surgical management of DIOS. Overall, MI did not predispose to later development of DIOS. There was a significantly greater incidence of laparotomy for DIOS in children who had MI.
The proportion of neonates with complex meconium ileus was high (49%) and may explain the infrequent utilisation of radiological decompression. Complex MI or management with stomas both significantly increase LOS. Re-laparotomy rate is high (22%) in MI irrespective of the type of management. DIOS is not a benign condition, particularly when the child has had previous abdominal surgery. Early referral to a surgical team is essential in these children.

A recent 20 year review of intestinal obstruction in cystic fibrosis from Liverpool, the source of much early work on the treatment of MI, the first use of gastrografin and later the first description of fibrosing colonopathy (see Topics section).

2014 Subhi R. Ooi R. Finlayson F. Kotsimbos T. Wilson J. Lee WR. Wale R. Warrier S. Distal intestinal obstruction syndrome in cystic fibrosis: presentation, outcome and management in a tertiary hospital (2007-2012). ANZ J Surg 2014; 84:740-4. [PubMed]
A retrospective audit of CF patients at the Alfred Hospital, Melbourne from January 2007 to February 2012 who had DIOS. Forty-five encounters of 35 patients were extracted. Twenty-five (83%) patients were homozygous for the delta F508 mutations, 29 (85%) had pancreatic insufficiency and 15 (44%) had a lung transplant. Patients presented with abdominal pain (96% of encounters), nausea (76% of encounters) and vomiting (67% of encounters). Computed tomography (CT) was performed in 20 episodes. Compared with CT, abdominal X-ray had a sensitivity of 63% (95% confidence interval (CI) 30-89%) and specificity of 33% (95% CI 8-70%) for detecting DIOS with obstruction. Forty-one (91%) encounters resolved with medical management within 2-3 days. Three patients required surgical intervention in four episodes. Previous laparotomy (odds ratio (OR) 28.5, 95% CI 1.3-624, P = 0.03) and history of meconium ileus (OR 14, 95% CI 1-192, P < 0.05) were statistically significant predictors of progression to surgical management.
The authors concluded that in most patients with DIOS, the obstruction resolves with medical management. Early consultation with a CF service, assessment for a surgical abdomen and involvement of surgeons where appropriate is recommended. A history of previous laparotomy is a risk factor for the need for surgical intervention.

–   A useful record of experience from a major adult unit where only 3 patients required surgical intervention.

2016 Munck A; Alberti C; Colombo C; Kashirskaya N; Ellemunter H; Fotoulaki M; Houwen R; Robberecht E; Boizeau P; Wilschanski M; CF/Pancreas ESPGHAN Working Group and DIOS Study Group. J Cyst Fibros 2016; 5(4):531-9. [PubMed]
Distal intestinal obstruction syndrome (DIOS) is a specific complication of cystic fibrosis. METHODS: A study was performed in 10 countries to prospectively evaluate the incidence, associated factors, and treatment modalities in children and adults. RESULTS: 102 patients presented 112 episodes. The incidence of DIOS was similar in children and adults. Medical treatment failed only in cases of complete DIOS (11%). Children with meconium ileus had a higher rate of surgery for DIOS (15% vs. 2%, p=0.02). Complete DIOS entailed longer hospitalisation (4 [3; 7] days vs. 3 [1; 4], p=0.002). Delayed arrival at hospital and prior weight loss had a significant impact on the time needed for DIOS resolution. Associated CF co-morbidities for DIOS included meconium ileus (40% vs. 18%, p<0.0001), exocrine pancreatic insufficiency (92% vs. 84%, p=0.03), liver disease (22% vs. 12%, p=0.004), diabetes mellitus (49% vs. 25%, p=0.0003), and Pseudomonas aeruginosa (68% vs. 52%, p=0.01); low fibre intake and insufficient hydration were frequently observed. Female gender was associated with recurrent DIOS (75% vs. 52%, p=0.04), constipation with incomplete episodes (39% vs. 11%, p=0.03), and poor patient compliance in taking pancreatic enzyme therapy during complete episodes (25% vs. 3%, p=0.02).

The authors concluded DIOS is a multifactorial condition having a similar incidence in children and adults. They show that delayed arrival at hospital after the initial symptoms causes significant morbidity. Early recognition and treatment would improve the prognosis.

2016 Ooi CY; Jeyaruban C; Lau J; Katz T; Matson A; Bell SC; Adams SE; Krishnan U. High ambient temperature and risk of intestinal obstruction in cystic fibrosis. J Paediatr Child Health 2016; 52(4):430-5. [PubMed]
Distal intestinal obstruction syndrome (DIOS) and constipation in cystic fibrosis (CF) are conditions associated with impaction and/or obstruction by abnormally viscid mucofaecal material within the intestinal lumen. Dehydration has been proposed as a risk factor for DIOS and constipation in CF. A study primarily aimed to determine whether warmer ambient temperature and lower rainfall are risk factors for DIOS and constipation in CF

The authors found that relatively high ambient temperature may play a role in the pathogenesis of DIOS and constipation in CF.

Chee Yee Ooi  is Paediatric Gastroenterologist
 at the Sydney Children’s Hospital and has a particular interest in the field of CF diagnosis, gastrointestinal disease in CF and pancreatitis.

Sherie Smith , Nicola Rowbotham , Gwyneth Davies , Katie Gathercole , Sarah J Collins, Zoe Elliott, Sophie Herbert , Lorna Allen , Christabella Ng, Alan Smyth How can we relieve gastrointestinal symptoms in people with cystic fibrosis? An international qualitative survey. BMJ Open Respir Res  2020 Sep;7(1):e000614.doi: 10.1136/bmjresp-2020-000614. FREE [Pubmed]
Relieving gastrointestinal (GI) symptoms was identified as a ‘top ten’ priority by our James Lind Alliance Priority Setting Partnership in cystic fibrosis (CF). We conducted an online survey to find out more about the effect of GI symptoms in CF
There were 276 respondents: 90 (33%) people with CF (pwCF), 79 (29%) family, 107 (39%) health care professionals (HCPs). The most commonly reported symptoms by lay respondents were stomach cramps/pain, bloating and a ‘combination of symptoms’. The top three symptoms that HCPs said were reported to them were reduced appetite, bloating and constipation. Almost all (94% (85/90)) HCPs thought medications helped to relieve GI symptoms but only 58% (82/141) of lay respondents agreed.
The authors consider their survey has shown that GI symptoms among our participants are prevalent and intrude on daily lives of pwCF. There is a need for well-designed clinical studies to provide better evidence for management of GI symptoms and complications.

Ms. Sherie Smith is a registered nurse and Cochrane Systematic Reviewer in the Faculty of Medicine & Health Science University of Nottingham,

– Although the authors stress the need for clinical studies to provide better evidence for management, it would interesting to find out how nay of these respondents who were still having significant symptoms had been thoroughly investigated from the gastroenterological point of view? Surely a starting point before treatment? Things may be different now but it used to be that people with CF were looked after by chest orientated professionals and often had scant attention given to their gastroenterological problems.

 Birimberg-Schwartz L; Wilschanski M.  Cystic Fibrosis Related Gastrointestinal Manifestations – Moving Forward. Journal of Cystic Fibrosis. 20(4):562-563, 2021 07.[Pubmed]
(No abstract so I have summarised some of the main points of the full version- JML)

With the increase in life expectancy new disease-related manifestations are emerging such as an increased risk of colorectal cancer. Hepato-biliary GI manifestations are quite variable and include exocrine pancreatic disease, meconium ileus, constipation, distal intestinal obstruction syndrome, CF related liver disease, small intestinal bacterial overgrowth and intestinal inflammation.
The authors comment that CF related GI symptoms are not always properly addressed, and patients hesitate to report them to their pulmonologist. They stress the need for a dedicated gastroenterologist to work as part of the CF centre team.
The paucity of high-quality CF-GI studies prompted the CF Foundation to declare recently such studies are a priority. Current knowledge suggests that altered intestinal fluid secretions, dysbiosis and inflammation contribute to gut dysfunction. They also note the lack of GI clinical outcome measures which will be needed with CFTR modulator drug trials.
Nonetheless, the authors are encouraged to see “sprouting of research in the field which will lead the way to improved patient GF-GI disease outcomes”.

Dr Liron Birimberg-Schwartz and Dr Michael Wilschanski are in the  Department of Pediatric Gastroenterology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of  Jerusalem, Israel.

Neele Dellschaft, Caroline Hoad, Luca Marciani, Penny Gowland, Robin Spiller.  Small bowel water content assessed by MRI in health and disease: a collation of single-centre studies.  Aliment Pharmacol Ther 2022 Feb;55(3):327-338. doi: 10.1111/apt.16673. Epub 2021 Oct 30.    [Pubmed]

Background: New developments in MRI have allowed the non-invasive, accurate measurement of the small bowel water content (SBWC).
Aims: To collate studies measuring SBWC following ingestion of a range of foods in both health and disease to provide data for adequately powering future studies in this area.
Methods: This collation brings together 29 studies including 954 participants (530 healthy, 54 diverticulosis, 255 IBS, 53 functional constipation, 12 cystic fibrosis, 15 Crohn’s disease, 20 coeliac disease, 15 scleroderma) which have been carried out in a single centre using comparable study designs.
Results: Fasting SBWC (mean 82 [SD 65] mL) shows high variability with a small decline with advancing age (healthy volunteers only; individual patient data). Fasting values are increased in untreated coeliac disease (202 [290] mL, P = 0.004). Post-prandial SBWC shows less intra-individual variability than fasting values in healthy volunteers. SBWC is increased by eating, most markedly by high fat meals but also by fibre, both viscous and particulate. Indigestible residue accumulates in late post-prandial period but empties soon after ingestion of a high calorie meal which produces a significant drop (by 50 [52] mL) in healthy volunteers. The associated fall in SBWC is abnormal in people with cystic fibrosis (SBWC reduced by 10 [121] mL, P = 0.002) and in people with irritable bowel syndrome with diarrhoea (SBWC reduced by 17 [43] mL, P = 0.007).
Conclusions: SBWC as assessed by MRI is a valuable biomarker indicating the balance of secretion and absorption in health and disease and the impact of treatments.

Dr Neele Dellschaft is a Research Fellow at the Sir Peter Mansfield Imaging Centre, University of Nottingham, Nottingham, UK.  NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK

Appendicitis

1976 Holsclaw DS, Habboushe C. Occult appendiceal abscess complicating cystic fibrosis.J Pediatr Surg. 1976 Apr;11(2):217-21. [PubMed]

Three case histories illustrate the diagnostic dilemma encountered whenever a patient with CF who is receiving antibiotics is evaluated for abdominal pain. Although acute appendicitis with perforation and abscess formation is not a common complication of CF, it occurs more frequently than is generally appreciated. The large number of abdominal situations in CF which can cause pain confused with but not typical of acute appendicitis. The true underlying condition is further masked by the concurrent use of antibiotics for pulmonary infection. A higher index of suspicion is needed to rule out acute appendicitis in a patient with cystic fibrosis and abdominal pain. A greater awaremess of the possibility of occult appendiceal abscess may help to avoid this complication.

This is one of a number of reports most of which emphasise the difficulty experienced in diagnosing appendicitis in a child already receiving antibiotics.

2011 Gilchrist FJ, Doherty CJ, Govan JR, Webb AK, Jones AM. Pseudomonas aeruginosa bacteraemia in an adult with cystic fibrosis and acute appendicitis. J Cyst Fibros 2011; 10(6):477- 8. [PubMed]
The authors report an adult with CF who developed Pseudomonas aeruginosa bacteraemia during an episode of acute appendicitis. The Pseudomonas aeruginosa isolated from the blood culture was confirmed by molecular typing to be the same transmissible strain responsible for the patient’s chronic pulmonary infection. The authors suggest that the bacteraemia was caused by Pseudomonas aerunginosa in swallowed sputum, crossing the inflamed appendiceal wall and entering the blood stream.

–   Despite their high bacterial load, bacteraemia is surprisingly rare in patients with cystic fibrosis (CF) but it is worth noting that it can and does occur on occasion, as in the present case, and not only in those patients who have indwelling intravenous devices which may become become infected.

Intestinal structure, function, inflammation, gut-lung axis

1951 Ayers WB, Stowens D, Ochsner A, Platou RV. Splanchnicectomy for pancreatic fibrosis: analysis of results in 24 patients. Pediatrics 1951; 8:657-663. [PubMed]
It was known that stimulation of various abdominal viscera could cause bronchospasm. So it was suggested that the changes of CF in the pancreas may cause a state of “autonomic dyskinesia” causing more or less persistent bronchospasm and bronchorrhoea. It was argued that interruption of the splanchnic nerves may break the afferent limb of such a reflex; so this rather alarming operation was performed to interrupt these nerves. The procedure in 15 patients with CF showed only temporary improvement in 3 and no change in the others.

–   Mercifully the operation was abandoned although the new and novel treatment caused considerable interest at the time as there was little else to offer many patients (also Ayers WB et al. Am J Dis Child 1951; 82:238-239). Despite the negative results, the authors still believed the operation “may have a place” in controlling distressing respiratory symptoms. Dorothy Andersen said she had not advised the operation and welcomed this frank report from which “we may expect relief from the pressure on the part of referring physicians and referred patients to persuade us to do splanchnicectomies”. She queried the situations, if any, when the operation would be useful – the possibility of the relief of progressive respiratory distress when all else had failed was mentioned. Subsequently little was heard of this treatment.

1958 Blanc WA, Reid JD, Andersen DH. Avitaminosis E in cystic fibrosis of the pancreas: a morphologic study of gastrointestinal and striated muscle. Pediatrics 1958; 22: 494-506.
Ceroid pigment was present in the smooth muscle fibres of the gastrointestinal tract of patients with cystic fibrosis. It was first seen in those dying during the second year of life and present in all after 5 years of age, the amount increasing with age. The only other condition where this pigment is found is biliary atresia and cirrhosis. It was considered as probably due to prolonged and severe vitamin E deficiency. However, alterations in striated muscle are rare and minimal in CF but common in severe vitamin E deficiency (Martin AJP, Moore T. Some effects of prolonged vitamin E deficiency. J Hyg 1939; 39:643; Human occurrence reported in one case of CF by Pappenheimer AM, Victor J. Am J Path 1946; 22:395).

1958 Shwachman H, Fekete E, Kulczycki LL, Foley GE. Effect of long term antibiotic therapy in patients with cystic fibrosis of the pancreas. Antibiot Ann 1958-59; 692-699.

An early (possibly the first) report of severe yellow discolouration of the teeth due to tetracycline (figure) , an antibiotic which had become available between 1948-1950.

Discolouration of the teeth was present in 80% of young children with CF receiving long term tetracycline prophylaxis; many subsequent reports have confirmed the problem (Zegarelli EV et al. Oral Surg Oral Med oral Pathol 1962; 15:929-933.[PubMed]; Appelbaum E et al ibid 1964; 17: 366-367. [PubMed]; Witkop CJ, Wolf RO. JAMA 1963; 185:1008-1011. [PubMed]). Tetracycline is deposited in growing bone by forming complexes with the bone mineral.

1964 Freye HB, Kurtz SM, Spock A, Capp MP. Light and electron microscopic examination of the small bowel of children with cystic fibrosis. J Pediatr 1964; 64:575-579. [PubMed]
Twenty one duodenal/jejunal mucosal biopsies were obtained from children with CF and showed normal villi and cell structure but the surfaces were covered by “a coarse fibrillar substance probably mucus” in those children who had steatorrhoea but not from the one patient that had normal fat absorption. The findings were considered to support the concept of Dische that mucus may contribute to the absorptive defect (Dische Z et al. Pediatrics 1959; 24:74-91.[PubMed]).

–   These were early days for per oral jejunal biopsy in children and this was the first large study in children with cystic fibrosis. Earlier di Sant’Agnese had observed that “the histological picture on peroral biopsy is apparently normal as might be expected” (di Sant’Agnese et al. Rev Nutr Res 1961; 22:29-50. [PubMed]). However, the present findings did not carry matters forward a great deal. My impression was that the intestinal villi were unusually tall in the few children with CF whom we biopsied to exclude coeliac disease.

1959 Marie J, Salet J, Debris P, Hebert S, Corbin JL, Bezri A. Edematous form of cystic fibrosis of pancreas with hypoproteinaemia and anaemia (French). Sem Hop Paris 1959; 35:2140-6.
A report of the oedema and hypoproteinaemia in an infant with CF (also Lee PA et al, 1974; Gunn T et al, 1978 below). Also infants with CF presenting in this manner may have a false negative sweat test (Maclean WC, Tripp RW. J Pediatr 1973; 83:86-88. [PubMed]).

1962 Barbero GJ, Sibinga MS. Enlargement of the submaxillary glands in cystic fibrosis. Pediatrics NY 1962; 29:788-793.[PubMed]

This is the first record of enlarged submandibular glands in CF – a feature which is sometimes quite marked (figure). During their studies on secretory activity of the salivary glands the authors noted many patients had enlarged submandibular glands. The submandibular glands of 300 normal children, 106 with CF and 20 with chronic pulmonary disease were examined. Enlarged submandibular glands were palpated in 92% of children with CF and only 2% of healthy controls and those with chronic pulmonary disorders. The presence of enlargement can be helpful when considering a diagnosis of CF.

1963 Parkins RA, Eidelman S, Rubin CE, Dobbins WO III, Phelps PC. The diagnosis of cystic fibrosis by rectal suction biopsy. Lancet 1963; 38:851-6. [PubMed]

An interesting paper by workers with extensive experience in rectal biopsy. The histological picture was characteristic of CF in many patients. When the histological picture of rectal “mucosis” is present it is specific for CF as shown here (figure 4) and it cannot be confused with any other rectal condition. It was not clear as to the proportion of cases of CF could be diagnosed with certainty – six of 11 patients with CF examined in this study showed definite diagnostic changes. Understandably, rectal biopsy never became popular as an additional diagnostic aid for CF; although ion transport abnormalities in the rectal mucosa were described in number of later studies (Hardcastle J et al, 1991 below)

1971 Holsclaw DS, Rocmans C, Shwachman H. Intussusception in patients with cystic fibrosis. Pediatrics 1971; 48:51-58. [PubMed] Douglas Holsclaw estimated that intussusception occurred in 1% of children with CF with an average age of onset was between nine and 12 years – older than the age of presentation in non-CF children. Compared with non-CF intussusception the onset was less acute and blood was passed rectally in less than a quarter of patients. (also Brown PM et al, NEJM 1960; 263:544; Flux M. South Med J 1967; 60:1184-1186. [PubMed]).

Even with present day treatment an appreciable number of people with CF have intermittent colicky abdominal pain and distal intestinal obstruction syndrome (DIOS). In attacks the concern is always that they have developed either appendicitis or intussusception. Although in later publications ultrasound was recommended as reliably identifying intussusception, I suggest that a contrast enema should be an early investigation and will usually suggest the diagnosis (Littlewood JM. J R Soc Med 1992; 85 Suppl 18:13-19. [PubMed]).

1988 Taylor CJ, Baxter PS, Hardcastle J, Hardcastle PT. Failure to induce secretion in jejunal biopsies from children with cystic fibrosis. Gut 1988; 29:957-962. [PubMed]

In this study by Prof. Chris Taylor (figure) and colleagues from Sheffield, the secretory activity of jejunal biopsies from

children with CF was investigated using a modified Ussing chamber technique. The results showed that the defect in chloride transport observed in other epithelia in CF also exists in the jejunum and could contribute to the intestinal effects of the disease. Similar findings were obtained in a study from Chapel Hill (Berschneider HM, et al. Altered intestinal chloride transport in cystic fibrosis. FASEB J 1988; 2:2625-9.[PubMed]) with the same suggestion that the existence of these abnormalities may contribute to the intestinal problems, such as meconium ileus, distal intestinal obstruction and chronic abdominal pain which are by no means all controlled even with the more effective acid resistant enzyme preparations such as Pancrease and Creon.

–   Prof. Taylor is one of the UK’s leading authorities on CF generally but particularly with regard to the gastroenterological and nutritional aspects. Also he and his scientific colleagues in Sheffield have made major contributions to the scientific aspects of CF concerning membrane function.

1988 Goldstein JL, Nash NT, al-Bazzaz F, Layden TJ, Rao MC. Rectum has abnormal ion transport but normal cAMP-binding proteins in cystic fibrosis. Am J Physiol 1988; 254: C719-24. [PubMed]
In keeping with the small intestinal and colonic electrolyte transport abnormalities in CF, when the authors compared in vivo transrectal potential difference (PD) in CF, the base-line PD was different in normal and CF subjects and was eliminated by amiloride in both groups. However, in response to a Cl-free solution with amiloride, all six CF subjects exhibit less of a change in potential difference. They concluded that the rectum is also an involved epithelium in CF in which the aberration may lie at a point beyond the binding of cAMP to its protein kinase. This is not an unexpected findings as there are obvious histological abnormalities of the rectal epithelium (Parkins et al, 1963 above).

1989 Hill S, Phillips A, Mearns M, Walker-Smith JA. Cows’ milk sensitive enteropathy in cystic fibrosis. Arch Dis Child 1989; 64:1251-1255. [PubMed]
Over 12 years, proximal small intestinal mucosal biopsies were carried out in children with CF who had diarrhoea and failed to thrive in spite of adequate treatment, including pancreatic supplements. Histological examination of eight of the 17 biopsies taken over a period of 12 years from children with CF showed evidence of enteropathy, and accounted for one in 13 (8%) children with cystic fibrosis under 3 years of age attending Margaret Mearns’s CF clinic. Seven children clearly responded to a cows’ milk free diet; the diarrhoea stopped and weight gain increased. One of these responded only when gluten was also excluded from his diet. The eighth child remained on a normal diet and his symptoms did not improve. The enteropathy had resolved in all five patients who had further biopsies taken while receiving treatment, and from 15 months to 3 years of age all the children tolerated a normal diet and continued to thrive.

1989 Gray MA, Harris A, Coleman L, Greenwell JR, Argent BE. Two types of chloride channel on duct cells cultured from human fetal pancreas. Am J Physiol 1989; 257(2 Pt 1):C240-51.[PubMed]

This paper was from a number of the UK’s leading scientific CF researchers – including Michael Gray and Barry Argent  from Newcastle. Using the patch-clamp technique, they identified two types of chloride channel on duct cells cultured from human fetal pancreas. While the physiological role of these channels was not entirely clear, they considered that one, the small-conductance channel, might function in parallel with a Cl- -HCO-3 exchanger to provide a mechanism for electrogenic bicarbonate secretion from the duct cell.

1989 Baxter PS, Wilson AJ, Read NW, Hardcastle J, Hardcastle PT, Taylor CJ. Abnormal jejunal potential difference in cystic fibrosis. Lancet 1989; i: 464-466. [PubMed]
Further work from Chris Taylor’s Sheffield team that had already described failure to induce secretion from CF jejunal biopsies (Taylor et al, 1988 above). Here the transmucosal potential difference (PD) and intraluminal pressure were recorded from the same jejunal site in 15 healthy adult controls and 4 adults with cystic fibrosis. In the controls, runs of contractions were associated with wave-like changes in PD that were absent in patients with cystic fibrosis. Intraluminal boluses of 4 mg pilocarpine, or 0.1 mg prostaglandin E2, caused changes of -4.6 mV and -4.5 mV, respectively, in controls; these responses were not seen in patients with cystic fibrosis. There were no significant differences in basal PD and PD changes caused by altered concentrations of infused saline or glucose between patients and controls.

1991 Hardcastle J, Hardcastle PT, Taylor CJ, Goldhill J. Failure of cholinergic stimulation to induce a secretory response from the rectal mucosa in cystic fibrosis. Gut 1991; 32:1035-1039. [PubMed]
One of many studies from Sheffield on the scientific and clinical aspects of the gut in cystic fibrosis. The secretory response to cholinergic stimulation failed in rectal biopsy specimens from 5 children with CF compared with controls.
Thus, the failure of chloride secretion in the small intestine observed by this group (Taylor CJ et al. 1987 above; Taylor CJ et al, 1988 above) was also present in the rectal mucosa of people with cystic fibrosis.

2007 Fridge JL, Conrad C, Gerson L, Castillo RO, Cox K. Risk factors for small bowel bacterial overgrowth in cystic fibrosis. J Pediatr Gastroenterol Nutr 2007; 44:212-218. [PubMed]
Fifty patients, 25 pancreatic-insufficient CF study patients (mean age, 17 y) and 25 gastrointestinal clinic control patients (mean age, 15 y), completed a glucose-hydrogen breath test after an overnight fast. A positive breath test was defined as a fasting hydrogen > or =15 ppm or a rise of > or =10 ppm hydrogen over baseline during the test.

The prevalence of positive breath tests was higher in the CF study group (56%) than in the control group (20%) (P = 0.02). The mean fasting hydrogen levels of patients in the study and control groups were 22 and 5 ppm (P = 0.0001). The mean QOL questionnaire scores were not significantly different between breath test-positive and -negative study patients. The use of azithromycin was associated with an increased risk of a positive breath test. Use of laxatives and inhaled ipratropium was associated with a decreased risk of a positive breath test.

This study confirmed that patients with CF were more likely to have elevated fasting hydrogen levels compared with controls. This suggests a high prevalence of small bowel bacterial overgrowth in CF patients. Also that medications commonly used by CF patients may influence intestinal health.

2007 Bruzzese E, Raia V, Spagnuolo MI, Volpicelli M, De Marco G. Maiuri L, Guarino A. Effect of Lactobacillus GG supplementation on pulmonary exacerbations in patients with cystic fibrosis. Clinical Nutrition 2007; 26:322-328. [PubMed]
Nineteen children with CF received a probiotic Lactobacillus GG (LGG) for 6 months and then changed to a placebo of oral rehydration solution (ORS) for 6 months; in parallel nineteen received ORS and then changed to LGG. Patients treated with LGG showed a reduction of pulmonary exacerbations (Median 1 vs. 2)  and of hospital admissions (Median 0 vs. 1, range 3 vs. 2,).   LGG resulted in a greater increase in FEV1 (3.6% +/- 5.2 vs. 0.9% +/- 5; p=0.02) and body weight (1.5 kg +/- 1.8 vs. 0.7 kg +/- 1.8; p=0.02).

The authors concluded that Lactobacillus GG reduces pulmonary exacerbations and hospital admissions in patients with CF, that probiotics may delay respiratory impairment and that a relationship exists between intestinal and pulmonary inflammation.

There is an increasing interest on the part of patients, parents and doctors in the role probiotics in treating people with CF (Borowitz D et al, J Pediatr Gastroenterol Nutr 2005; 41:273-285. [PubMed]); however, as yet, few CF clinics advise their routine use – perhaps because the evidence of their value is still sparse but also there are so many other components to treatment that there is reluctance to add yet another medicine to gain a marginal benefit.

2009 Lisowska A, Wójtowicz J, Walkowiak J. Small intestine bacterial overgrowth is frequent in cystic fibrosis: combined hydrogen and methane measurements are required for its detection. Acta Biochimica Polonica. 2009; 56:631-634. [PubMed]
The study aimed to assess the usefulness of combined measurement of hydrogen and methane expiration for the diagnosis of SIBO in CF. The study comprised 62 CF patients aged 5 to 18 years. Three-hundred-ninety subjects assessed due to gastrointestinal symptoms for the presence of SIBO served as a comparative group. In all subjects hydrogen/methane BT using glucose was performed. In 23 (37.1%) CF patients and in 52 (13.3%) subjects from the comparative group abnormal BT results were found. In seven (11.3%) CF patients and 29 (7.4%) of the other subjects studied methane measurement allowed diagnosis of SIBO. The authors confirmed that small intestine bacterial overgrowth is frequent in cystic fibrosis. They advised that for its detection in cystic fibrosis and other gastrointestinal patients, combined hydrogen and methane measurement instead of only the hydrogen breath test should be applied. Without the additional measurement of methane a significant percentage of SIBO will be missed.

There are a number of studies now showing that SIBO is relatively common in people with CF although in most CF centres, where attention is largely directed towards the chest, the knowledge does not seem to excite much interest! The finding can also be considered in the light of reports that the use of probiotics may reduce the frequency of exacerbations of chest infection (Weiss B et al. Pediatr Pulmonol 2010; 45:536-540.[PubMed]).

2010 Lisowska A, Madry E, Pogorzelski A, Szydlowski J, Radzikowski A, Walkowiak J. Small intestine bacterial overgrowth does not correspond to intestinal inflammation in cystic fibrosis. Scand J Clin Lab Invest 2010; 70:322-326. [PubMed]
The authors aimed to assess whether small bowel bacterial overgrowth (SIBO) correlates with the intestinal inflammation in CF patients described by a number of authors. Fecal calprotectin was measured, as an indication of inflammation, in 25 non-sputum producing CF patients and 30 healthy subjects (HS). All CF subjects were tested for the presence of SIBO using the hydrogen-methane breath test (BT). Fecal calprotectin concentrations in CF patients (range: 1. 8-302. 5; median 80. 0 mg/L) were significantly higher (p < 0. 00001) than in healthy subjects (not detectable-15. 5; 2. 5 mg/L). Calprotectin levels were abnormal in 21 (84%) studied CF subjects and none of HS. Abnormal BT results were found in 10 (40. 0%) of CF patients. Calprotectin concentrations in SIBO positive and negative patients did not differ.

–   Gastrointestinal inflammation is a frequent finding in cystic fibrosis patients. However, small intestine bacterial overgrowth does not seem to be the major or at least is not the only determinant of intestinal inflammation. Indirect measures of intestinal inflammation in CF patients may give false positive results. This is a useful addition to the information available on the intestinal pathology in people with CF that has received more attention in recent years including studies using direct visualisation and biopsy techniques. The present study confirms that there is more to the inflammation, so frequently reported in CF, than the presence of bacteria in the small bowel.

2010 Werlin SL, Benuri-Silbiger I, Kerem E, Adler SN, Goldin E, Zimmerman J, Malka N, Cohen L, Armoni S, Yatzkan-Israelit Y, Bergwerk A, Aviram M, Bentur L, Mussaffi H, Bjarnasson I. Wilschanski M. Evidence of intestinal inflammation in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 2010; 51:304-308. [PubMed]
The aim of the present study was to examine the small intestine of patients with CF without overt evidence of gastrointestinal disease using a capsule endoscopy (CE). Patients with CF received the agile patency capsule and, depending on the result of that procedure, then underwent standard CE using the PillCam SB capsule (Given Imaging, Yokneam, Israel). A stool specimen was taken on the same day as the CE for determination of the calprotectin level. Forty-two patients with CF ages 10 to 36 years were included; 29 had pancreatic insufficiency. One patient failed to excrete the patency capsule after 36 hours and was withdrawn from the study. Pulmonary function was mild to moderate with FEV1 68. 5% +/- 16% predicted. Review of the CE videos showed that most of the patients had varying degrees of diffuse areas of inflammatory findings in the small bowel including edema, erythema, mucosal breaks, and frank ulcerations. There were no adverse events. Fecal calprotectin levels were markedly high in patients with pancreatic insufficiency, 258 microg/g (normal <50).

The authors conclude that small bowel mucosal pathology may be detected using capsule endoscopy in most of the patients with CF. The high fecal calprotectin levels found are suggestive of mucosal inflammation, which may correlate with the capsule endoscopy findings. Additional study is required to examine the possible relation of these mucosal lesions, which may be part of a newly identified enteropathy associated with CF, with persistent intestinal malabsorption in many of these patients.

–    This is an impressive study with some striking pictures of the inflamed small intestinal mucosa in the full paper. Evidence of inflammation had been reported previously but these findings are the first visual support for the lesions which would seem to be one factor in failing to achieve normal absorption in some people with CF despite the use of pancreatic enzymes.

2010 Vincenzi F, Bizzarri B, Ghiselli A, de’ Angelis N, Fornaroli F, de’ Angelis GL. Cystic fibrosis and Crohn’s disease: successful treatment and long term remission with infliximab. World J Gastroenterol 2010; 16:1924-7. [PubMed]
The association of cystic fibrosis and Crohn’s disease (CD) is well known, but to date, there are very few cases in the literature of patients suffering from mucoviscidosis who have required treatment with infliximab. The authors report the case of a 23-year-old patient suffering from cystic fibrosis and severe CD treated successfully with infliximab without any infective complications or worsening of the pulmonary disease and with a long term (2 years) complete remission

–   Infliximab is a monoclonal antibody against tumour necrosis factor alpha used to treat autoimmune disease.  (see also Other Conditions in Topic section)

2013 Gelfond D. Ma C. Semler J. Borowitz D. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci 2013; 58:2275-81.[PubMed]                                                                                                                                               The authors utilized a wireless motility capsule (WMC) to study intestinal pH profile and gastrointestinal transit profile in CF subjects. The studies were done on ten adult CF patients with pancreatic insufficiency (PI) while off acid suppression medication and ten age, gender and BMI matched healthy controls.

A statistically significant difference was observed between mean pH values during the first 23 min of small bowel transit (p < 0.05). In CF subjects, there was a significant delay in time interval required to reach and sustain pH 5.5 and pH 6.0 (p < 0.001), which is required for PERT dissolution. Only small bowel transit in CF subjects was noted to be significantly delayed (p = 0.004) without a compensatory increase in whole gut transit time.

The authors confirmed the findings in a number of previous studies that there is significant delay in the small intestinal transit and a deficient buffering capacity required to neutralize gastric acid in the proximal small bowel of patients with CF. See also two studies from Leeds. One with a pH-sensitive radio telemetry capsule – Gilbert J et al. Ileal pH in cystic fibrosis. Scand J Gastroenterol 1988; 23(Suppl 143):132-134. [PubMed]; this confirmed the acid conditions detrimental to lipid digestion .are confined to the upper small bowel. The length of time that small bowel pH exceeds 6.0 is adequate for dissolution of microencapsulated enzymes and lipid absorption. Also Seal S et al. Stable isotope studies on pancreatic enzyme release in vivo. Postgrad Med J 1996; 72 (Suppl 2):S37-S38. [PubMed]. As part of this investigation the oro-caecal transit time was found to be prolonged (6hrs Range 4.0-7.5 hrs) compared with the normal 1.0-2.0 hrs. Also Bali A et al. Prolonged intestinal transit time in cystic fibrosis. BMJ 1983; 287:1011-1013. [PubMed] was the first documentation of prolonged small bowel transit in CF (see entry in Eighties Clinical above

2013 Shah N, Tan HL, Sebire N, Suri R, Leuven K.The role of endoscopy and biopsy in the management of severe gastrointestinal disease in cystic fibrosis patients.Pediatr Pulmonol 2013; 48:1181-9.[PubMed]
Nine of the 12 CF patients seen at the the GOS combined paediaitric GI clinic had evidence of mucosal inflammation in their biopsies, including duodenitis with eosinophilic infiltrate, chronic non-specific inactive gastritis, enteropathy with partial villous atrophy, and non-specific colitis. Immunosuppressive and anti-inflammatory therapies were commenced in these nine patients, including prednisolone, azathioprine, methotrexate, ketotifen, mesalazine, and sulfasalazine as well as the use of parenteral nutrition and elemental feeds. All the patients clinically responded to therapy. Five of the patients commenced on anti-inflammatory therapy had repeat biopsies 1-5 years following commencement of treatment and all showed histological improvement of the mucosal inflammation. GI endoscopy with mucosal biopsy has a significant role to play in the management of CF children with severe GI disease. In these patients the findings influenced the management in the majority of patients with severe GI symptoms. Furthermore, if GI mucosal inflammation is identified on biopsy, management with immunomodulatory agents may be clinically beneficial

2017 Burke DG, Fouhy F, Harrison MJ, Rea MC, Cotter PD, O’Sullivan O, Stanton C, Hill C, Shanahan F, Plant BJ, Ross RP. The altered gut microbiota in adults with cystic fibrosis. BMC Microbiol. 2017 Mar 9;17(1):58. doi: 10.1186/s12866-017-0968-8. [Pubmed]
The authors compared the gut microbiota of 43 individuals with CF during a period of stability, to that of 69 non-CF controls using 454-pyrosequencing of the 16S rRNA gene. This is one of the largest single-centre studies on gut microbiota in stable adults with CF and demonstrates the significantly altered gut microbiota, including reduced microbial diversity seen in CF patients compared to healthy controls. The data show the impact that CF and it’s management have on gut microbiota, presenting the opportunity to develop CF specific probiotics to minimise microbiota alterations.

–   There is increasing evidence that the situation in the gut can have a significant effect on the respiratory infection.

Arnold CA, Burke AP, Calomeni E, Mayer RC, Rishi A, Singhi AD, Stashek K, Voltaggio L, Tondon R. Brown Bowel Syndrome: A Multi-institutional Case Series. Am J Surg Pathol. 2020 Jan 23. doi: 10.1097/PAS.0000000000001443. [Epub ahead of print][Pubmed]

Brown bowel syndrome (BBS) is a rare condition associated with vitamin E deficiency and defined by prominent lipofuscin deposition in the muscularis propria. Eight unique cases of BBS were identified: 5 men and 3 women (mean age=58.6 y). Pertinent comorbidities included bariatric surgery=2, malnourishment=2, Crohn=2, cystic fibrosis=1, alcohol and cocaine abuse=1, and prior small bowel resections=1.
(Details in full summary)
BBS is important to recognize because it is linked with malnutrition, specifically vitamin E deficiency, and it can (rarely) clinically simulate malignancy. The diagnosis is based on the identification of the lipofuscin pigment in the cytoplasm of smooth muscle cells, which is most easily seen in the muscularis propria of the small bowel

Dr Christina A Arnold is in the Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO.

Meeker SM, Mears KS, Sangwan N, Brittnacher MJ, Weiss EJ, Treuting PM, Tolley N, Pope CE, Hager KR, Vo AT, Paik J, Frevert CW, Hayden HS, Hoffman LR, Miller SI, Hajjar AM.  CFTR dysregulation drives active selection of the gut microbiome. 
PLoS Pathog. 2020 Jan 21;16(1):e1008251. doi: 10.1371/journal.ppat.1008251. eCollection  2020 Jan.Free full text [Pubmed]

Patients with cystic fibrosis (CF) have altered fecal microbiomes compared to those of healthy controls. The magnitude of this dysbiosis correlates with measures of CF gastrointestinal (GI) disease, including GI inflammation and nutrient malabsorption. However, whether this dysbiosis is caused by mutations in the CFTR gene, the underlying defect in CF, or whether CF-associated dysbiosis augments GI disease was not clear.                                                                                                                   To test the relationships between CFTR dysfunction, microbes, and intestinal health, the authors established a germ-free (GF) CF mouse model and demonstrated that CFTR gene mutations are sufficient to alter the GI microbiome. Furthermore, flow cytometric analysis demonstrated that colonized CF mice have increased mesenteric lymph node and spleen TH17+ cells compared with non-CF mice, suggesting that CFTR defects alter adaptive immune responses.

The authors consider their findings demonstrate that CFTR mutations modulate both the host adaptive immune response and the intestinal microbiome.

Dr Stacy M Meeker is in the Department of Comparative Medicine, University of Washington, Seattle, WA, United States of America.

Hayden HS, Eng A, Pope CE, Brittnacher MJ, Vo AT, Weiss EJ, Hager KR, Martin BD, Leung DH⁵, Heltshe SL, Borenstein E, Miller SI, Hoffman LR.  Fecal dysbiosis in infants with cystic fibrosis is associated with early linear growth failure.  Nat Med. 2020 Jan 20. doi: 10.1038/s41591-019-0714-x. [Epub ahead of print] [Pubmed]
Most infants with cystic fibrosis (CF) have pancreatic exocrine insufficiency that results in nutrient malabsorption and requires oral pancreatic enzyme replacement. Newborn screening for CF has enabled earlier diagnosis, nutritional intervention and enzyme replacement for these infants, allowing most infants with CF to achieve their weight goals by 12 months of age. Nevertheless, most infants with CF continue to have poor linear growth during their first year of life. Although this early linear growth failure is associated with worse long-term respiratory function and survival, the determinants of body length in infants with CF have not been defined. Several characteristics of the CF gastrointestinal (GI) tract, including inflammation, maldigestion and malabsorption, may promote intestinal dysbiosis. As GI microbiome activities are known to affect endocrine functions, the intestinal microbiome of infants with CF may also impact growth.

The authors identified an early, progressive fecal dysbiosis that distinguished infants with CF and low length from infants with CF and normal length. This dysbiosis included altered abundances of taxa that perform functions that are important for GI health, nutrient harvest and growth hormone signalling, including decreased abundance of Bacteroidetes and increased abundance of Proteobacteria. Thus, the GI microbiota represent a potential therapeutic target for the correction of low linear growth in infants with CF.

Dr Hilary S Hayden is in the Department of Microbiology, University of Washington, Seattle, WA, USA

Carmen Ribes Koninckx , Ester Donat , Marc A Benninga, Ilse J Broekaert, Frederic Gottrand, et al.  The Use of Fecal Calprotectin Testing in Paediatric Disorders: A Position Paper of the European Society for Paediatric Gastroenterology and Nutrition Gastroenterology Committee.  J Pediatr Gastroenterol Nutr 2021 Apr 1;72(4):617-640.doi: 10.1097/MPG.0000000000003046. [Pubmed]

Objectives: The aim of the study was to review the evidence regarding the clinical use and value of fecal calprotectin (FC) measurements in different gastrointestinal disorders in children.
Methods: A literature search was conducted in the PubMed, MEDLINE, EMBASE, and Cochrane databases until October 31, 2019. Subtopics were identified and each assigned to individual authors.
Results: A total of 28 recommendations were voted on using the nominal voting technique. Recommendations are given related to sampling, measurement methods, and results interpretation. The 14 authors anonymously voted on each recommendation using a 9-point scale (1 strongly disagree to 9 fully agree). Consensus was considered achieved if at least 75% of the authors voted 6, 7, 8, or 9.

Conclusions: Consensus was reached for all recommendations. Limitations for the use of FC in clinical practice include variability in extraction methodology, performance of test kits as well as the need to establish local reference ranges because of the influence of individual factors, such as age, diet, microbiota, and drugs. The main utility of FC measurement at present is in the diagnosis and monitoring of inflammatory bowel disease (IBD) as well as to differentiate it from functional gastrointestinal disorders (FAPDs). FC, however, has neither utility in the diagnosis of infantile colic nor to differentiate between functional and organic constipation. A rise in FC concentration, may alert to the risk of developing necrotizing enterocolitis and help identifying gastrointestinal involvement in children with Henoch-Schönlein purpura. FC measurement is of little value in Cow’s Milk Protein Allergy, coeliac disease (CD), and cystic fibrosis. FC does neither help to distinguish bacterial from viral acute gastroenteritis (AGE), nor to diagnose Helicobacter Pylori infection, small intestinal bacterial overgrowth (SIBO), acute appendicitis (AA), or intestinal polyps.

Dr Carmen Ribes Koninckx is head of the Department of Paediatric Gastroenterology, Hepatology and Nutrition, La Fe University Hospital Valencia, Spain.

– A useful summary of the situations in which estimation of fecal calprotectin may be of use and this appears to be mainly for monitoring of inflammatory bowel disease and differentiating IBD from functional bowel disorders.

Rachel Y Tam  Josie M van Dorst , Isabelle McKay, Michael Coffey, Chee Y Ooi^.    Intestinal Inflammation and Alterations in the Gut Microbiota in Cystic Fibrosis: A Review of the Current Evidence, Pathophysiology and Future Directions.  J Clin Med 2022 Jan 27;11(3):649.doi: 10.3390/jcm11030649   Free PMC article [Pubmed]

Cystic fibrosis (CF) is a life-limiting autosomal recessive multisystem disease. While its burden of morbidity and mortality is classically associated with pulmonary disease, CF also profoundly affects the gastrointestinal (GI) tract. Chronic low-grade inflammation and alterations to the gut microbiota are hallmarks of the CF intestine. The aetiology of these manifestations is likely multifactorial, resulting from cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, a high-fat CF diet, and the use of antibiotics. There may also be a bidirectional pathophysiological link between intestinal inflammation and changes to the gut microbiome. Additionally, a growing body of evidence suggests that these GI manifestations may have significant clinical associations with growth and nutrition, quality of life, and respiratory function in CF. As such, the potential utility of GI therapies and long-term GI outcomes are areas of interest in CF. Further research involving microbial modulation and multi-omics techniques may reveal novel insights. This article provides an overview of the current evidence, pathophysiology, and future research and therapeutic considerations pertaining to intestinal inflammation and alterations in the gut microbiota in CF.

Rachel Y Tam is at the Discipline of Paediatrics & Child Health, Randwick Clinical Campus, School of Clinical Medicine, UNSW Medicine & Health, University of New South Wales, Sydney, NSW 2031, Australia.

Ryan Marsh, Helen Gavillet, Liam Hanson, Christabella Ng, Mandisa Mitchell-Whyte, Giles Major, Alan R Smyth, Damian Rivett, Christopher van der Gast^.   Intestinal function and transit associate with gut microbiota dysbiosis in cystic fibrosis.  J Cyst Fibros 2022 May;21(3):506-513.doi.10.1016/j.jcf.2021.11.014. Epub 2021 Dec 8. [Pubmed]Free article

Background: Most people with cystic fibrosis (pwCF) suffer from gastrointestinal symptoms and are at risk of gut complications. Gut microbiota dysbiosis is apparent within the CF population across all age groups, with evidence linking dysbiosis to intestinal inflammation and other markers of health. This pilot study aimed to investigate the potential relationships between the gut microbiota and gastrointestinal physiology, transit, and health.
Study design: Faecal samples from 10 pwCF and matched controls were subject to 16S rRNA sequencing. Results were combined with clinical metadata and MRI metrics of gut function to investigate relationships.
Results: pwCF had significantly reduced microbiota diversity compared to controls. Microbiota compositions were significantly different, suggesting remodelling of core and rarer satellite taxa in CF. Dissimilarity between groups was driven by a variety of taxa, including Escherichia coli, Bacteroides spp., Clostridium spp., and Faecalibacterium prausnitzii. The core taxa were explained primarily by CF disease, whilst the satellite taxa were associated with pulmonary antibiotic usage, CF disease, and gut function metrics. Species-specific ordination biplots revealed relationships between taxa and the clinical or MRI-based variables observed.

Conclusions: Alterations in gut function and transit resultant of CF disease are associated with the gut microbiota composition, notably the satellite taxa. Delayed transit in the small intestine might allow for the expansion of satellite taxa resulting in potential downstream consequences for core community function in the colon.

Ryan Marsh is a PhD student in the Department of Life Sciences, Manchester Metropolitan University, Manchester, United Kingdom.

Helicobacter pylori

2000 Israel NR, Khanna B, Cutler A, Perry M, Caplan D, Weatherly M, Gold BD. Seroprevalence of Helicobacter pylori infection in cystic fibrosis and its cross-reactivity with anti-Pseudomonas antibodies. J Pediatr Gastroenterol Nutr 2000; 30:426-431. [PubMed]
The seroprevalence of H. pylori in a cohort of patients with CF and its cross-reactivity with Pseudomonas antibodies were investigated using competitive inhibition assay. The research ELISA and 3 commercial tests initially showed H. pylori seropositivity of 47%, 28%, 24%, and 37%, respectively but post adsorption seropositivity declined to 8%, 0%, 0%, and 15%, respectively – and all these positives were confirmed endoscopically to have H. pylori infection. So cross-reactivity between solid-phase H. pyloriantigens and anti-Pseudomonas antibodies occurs in patients with CF. The authors advise that preadsorption of CF sera with Pseudomonas proteins should be used in serologic testing if testing for H. pylori.

–     This was a useful study as there had been confusion about the prevalence of H. pylori in people with CF since the existence of cross reactivity with Pseudomonas antibodies had been reported from Niels Hoiby’s laboratory in Denmark (Johansen HK et al. Clin Diag Lab Immunol 1995; 2:149-155. [PubMed]). One might perhaps have predicted the expected  prevalence of H pylori in people with CF to be low (8-15%) in view of the numerous courses of antibiotics they receive!
This and subsequent studies (Yahav J et al. Dig Dis Sci 2006; 51:2274-2279. [PubMed]) confirm that H. pylori is not a significant problem for people with CF.

2006 Yahav J, Samra Z, Blau H, Dinari G, Chodick G, Shmuely H. Helicobacter pylori and Clostridium difficile in cystic fibrosis patients. Digest Dis Sci 2006; 51:2274-9. [PubMed]
Stool specimens from 30 consecutive patients with CF, aged 1-44, and from 30 healthy similarly aged subjects were tested for the H. pylori antigen by specific monoclonal antibodies and for CD toxins by Tox A/B assay and Tox A assay. CF patients were assessed clinically and tested for specific H. pylori serum antibodies and for mutations. In CF patients, the prevalence of H. pylori antigen was 16.6% (5/30), compared to 30% (9/30) in controls. Of the 26 CF patients with PI, only 2 (7.6%) were infected by H. pylori, compared with 3 of the 4 (75%) patients with PS (P=0.001). H. pylori infection was diagnosed in 3 of 5 (60%) CF patients carrying mild mutations, compared to 1 of 25 (4%) CF patients carrying severe mutations (P=0.01). Fourteen of 30 (46.6%) stool specimens from CF patients tested positive in the ToxA/B assay, and 3 of 14 tested positive for ToxA. No significant differences in antibiotic use, severity of lung disease, PI, chronic abdominal pain, or genotype were found between the two groups. None of the controls was positive for CD toxins. Prevalence of H. pylori infection in CF patients was lower than in similarly aged non-CF controls. CF patients with PI or a history of distal intestinal obstruction syndrome and those carrying mutations associated with a severe phenotype were protected against H. pylori infection. Almost half of the CF patients were asymptomatic carriers of CD producing mostly toxin B. More studies are needed to confirm our results in a larger group of CF patients.

–    This paper confirms the previously reported low incidence of H. pylori in people with CF.

2013 Drzymala-Czyz S. Kwiecien J. Pogorzelski A. Rachel M. Banasiewicz T. Plawski A. Szczawinska-Poplonyk A. Herzig KH. Walkowiak J. Prevalence of Helicobacter pylori infection in patients with cystic fibrosis. J Cyst Fibros 2013; 12:761-765. [PubMed]
Helicobacter pylori (H. pylori) is one of the most common bacterial infections worldwide. The prevalence of Hp infection in cystic fibrosis (CF) is unclear – although there have been a number of previous studies. The aim of this study was to determine the prevalence of H. pylori infection in CF patients and to correlate H. pylori presence with CF expression. The presence of H. pylori infection was assessed using a breath test with isotope-labelled urea in CF 79 patients compared to 302 healthy control subjects (HS).

Fifteen (19.0%) the CF patients were H. pylori positive. No statistical differences in the basic clinical parameters or in their distribution were documented. No clinical factor was an independent risk factor of H. pylori infection. The corrected prevalence of H. pylori infection in pediatric CF patients and HS was 14.4% and 9.8%, respectively.

The authors concluded that the prevalence of H. pylori infection in CF patients is not different from that in healthy subjects.

This confirms previous work that H. pylori does not seem to be a significant problem for people with cystic fibrosis.

2014 Czy S. Stawinska-Witoszynska B. Madry E. Krzywinska-Wiewiorowska M. Szczepanik M. Walkowiak J. Kwiecien J. Non-invasive detection of Helicobacter pylori in cystic fibrosis–the fecal test vs. the urea breath test. Eur Rev Med Pharmacol Sci 2014; 18:2343-8.[PubMed
Recently it has been shown that cystic fibrosis (CF) patients have the same prevalence of Helicobacter pylori (HP infection) as the general population, as well as the same spectrum of changes caused by this pathogen. The two most popular noninvasive tests, the urea breath test (UBT) and the fecal test (FT) were assessed in diagnosing HP infection in CF patients.
There was convincing evidence of divergent UBT and FT results in the CF patients, so the authors suggest that UBT is kept as the standard method for HP detection in this population.

–    The infection has never seemed to be a major practical problem amongst people with cystic fibrosis. But this is useful information and the infection should be considered and not overlooked.

Fibrosing colonopathy

1994 Smyth RL, van Velzen D, Smyth AR, Lloyd DA, Heaf DP. Strictures of the ascending colon in cystic fibrosis and high strength pancreatic enzymes. Lancet 1994; 343:85-86. [PubMed]

The first report of fibrosing colonopathy – a new, unexpected and serious complication subsequently shown to be related to the use of the new high strength pancreatic enzyme preparations that had been introduced during the previous 2 years (Pancrease HL, Creon 25,000, Nutrizym 22). The authors observed five children with CF, who presented over a period of two months, with meconium ileus equivalent that failed to respond to medical management. At surgery, four had a stricture in the ascending colon (figure 5 similar early ), and all had histopathological changes of post-ischemic ulceration repair, with mucosal and submucosal fibrosis (figure 6). The only common change in the management of these children had been a switch from conventional enteric-coated pancreatic enzymes to a high-strength product between 12 and 15 months before presentation.

A survey of 114 CF care centres in the United States revealed 15 cases of colonic stricture all of whom had been taking relatively large dises of the new enzymes (6,700 to 29,100 units /lipase/kg per meal)(Freiman JP, FitzSimmons SC. Colonic strictures in patients with cystic fibrosis: results of a survey of 114 cystic fibrosis care centers in the United States. J Pediatr Gastroenterol Nutr 1996; 22:153-156. [PubMed])

A case controlled study in the UK from Smyth et al, 1995 (below) showed a significant correlation with both a high enzyme dose and the make of preparation – only those enzymes containing a covering of the copolymer eudragit being implicated (Pancrease HL and Nutryzim 22 but not Creon 25,000).

A similar study from the USA confirmed the association with high enzyme dosage but not with the copolymer covering (Freiman JP, FitzSimmons SC. Colonic strictures in patients with cystic fibrosis: results of a survey of 114 cystic fibrosis care centers in the United States. J Pediatr Gastroenterol Nutr 1996; 22:153-156. [PubMed]).

However, no further cases were reported or have since been reported in the UK, in patients taking the high strength Creon 25,000 preparation (which does not contain eudragit) even when given for 3 years in high doses to children (Connett et al, 1999 below).

In the UK the recommendations of the Committee on Safety of Medicines to avoid doses of enzymes in excess of 10,000 IU lipase per kg day and preparations containing the copolymer eudragit in children, abolished the condition in the UK although a few cases continued to occur in the USA. The enzyme content of the various preparations are described in detail elsewhere (Littlewood JM, Wolfe SP, Conway SP. Diagnosis and treatment of malabsorption in cystic fibrosis. Pediatr Pulmonol 2006; 41:35-49. [PubMed]).

1995 Smyth RL, Ashby D, O’Hea U, Burrows E. Lewis P. van Velzen D. Dodge JA. Fibrosing colonopathy in cystic fibrosis. Results of a case controlled study. Lancet 1995; 346:1247-1251. [PubMed]

Fibrosing colonopathy was first described in children with CF in 1994 (Smyth et al, 1994 above). This study confirmed the relationship between fibrosing colonopathy and high doses of lipase and the relation of fibrosing colonopathy with certain brands of high strength enzymes, which contained a copolymer – Eudragit. This is a report of a nested case-control study to identify possible associations with this condition. A case ascertainment within the UK CF population to identify any cases that had occurred between January, 1984, and April, 1994, revealed 14 cases, all less than 14 years and all confirmed by independent histopathological review. All had presented since April, 1993; 12 were boys and six had received some or all of their care in Liverpool. Each child was matched, by date of birth, with four controls from the UK CF Registry. Information was obtained about the cases and the controls from their case records and by a structured interview with the families. In the 12 months before surgery, there was a dose related association between the occurrence of fibrosing colonopathy and use of high-strength pancreatic enzyme preparations. Odds ratio per extra 1000 high-strength capsules was 1.45 (95% CI 1.14-1.84). For use of protease, the odds ratio per million extra units per kg was 1.55 (1.19-2.03). For usage of individual high-strength products at any time during the 12 months before surgery some differences were observed; for Creon 25000 the odds ratio was 0.38 (0.10-1.42), for Nutrizym 22 it was 43.4 (2.51-751), and for Pancrease HL 8.4 (1.95-36.1). These last two confidence intervals are extremely wide and compatible with these two products having the same odds ratios. Laxative use was independently predictive (odds ratio 2.42 [1.20-4.94]).

The authors concluded that there was a definite dose-related association between high-strength pancreatic enzyme preparations and fibrosing colonopathy. (Also Fibrosing colonopathy in children with cystic fibrosis. Proceedings of a conference in Manchester organised by the Cystic Fibrosis Trust, 5th Nov. 1995. Littlewood JM, Hind CRK (eds). Postgrad Med J 1996; 72 (Suppl 2):S1-S64).

1999 Connett GJ, Lucas JS, Atchley JT, Fairhurst JJ, Rolles CJ. Colonic wall thickening is related to age and not dose of high strength pancreatic microspheres in children with cystic fibrosis. Eur J Gastro Hepatol 1999; 11:181-183. [PubMed]
Thirty three children with CF, including 25 who had been receiving high strength pancreatin in the form of Creon 25,000 continuously for 3 years. Median lipase intake was 19,330 u/kg/day (range 0-59,000). There was no relationship between enzyme dosage and colonic wall thickness. The most important relationship of colonic wall thickness appeared to be with age.

–   This was a useful report and reassuring that high doses of pancreatic enzymes, when given in the form of Creon 25,000, did not appear to cause colonic damage. It had already been evident from the UK CF Database that many UK patients were taking more than the recommended equivalent of 10,000 U lipase/kg/day (Mehta A. Lancet 2001; 358:1547-1548). Obviously it would be unwise to translate these findings to other brands of high strength enzymes.

2000 Smyth RL, Croft NM, O’Hea U, Marshall TG, Ferguson A. Intestinal inflammation in cystic fibrosis. Arch Dis Child 2000; 82:394-399. [PubMed]
To determine whether there is increased inflammation in the gastrointestinal tract of CF children who had developed fibrosing colonopathy, whole gut lavage was performed on 21 pancreatic insufficient children with CF, who were clinically well, five children with CF who had had fibrosing colonopathy, and 12 controls. Intestinal outputs of plasma derived proteins (albumin, alpha1-antitrypsin, IgG), secretory immunoglobulins (IgA and IgM), cellular constituents (eosinophil cationic protein and neutrophil elastase), and cytokines (interleukin 8 and interleukin1beta) were measured. Compared to controls, all the 21 CF patients, with no intestinal complications, had increased intestinal outputs of albumin, IgG, IgM, eosinophil cationic protein, neutrophil elastase, interleukin 1beta, and interleukin 8. Similar values were obtained for the CF patients who had had fibrosing colonopathy.

–    Whole gut lavage is essentially washing out the gut and counting the inflammatory cells in the washings as an indication of the degree of intestinal inflammation. These data suggest that there is immune activation in the gastrointestinal mucosa of all children with cystic fibrosis, which may result from the basic cellular defect perhaps with secondary bacterial infection of the gut. Certainly the children who had previously had fibrosing colonopathy did not appear to have more signs of inflammation than in those who had not had the complication.
The finding of evidence of intestinal inflammation is not unexpected as it has been reported, and confirmed, that small bowel bacterial overgrowth affects some 70% of people with CF which is likely to be related to these findings (Bali et al, 1983 above). Also more recent work using capsule endoscopy showed that many patients had diffuse areas of inflammation in the small bowel associated with very high caloprotectin levels confirming the inflammatory response (253+/- 97 ug/g whereas the normal is <50) (Werlin S et al. Pediatr Pulmonol 2008; Suppl 31:Poster 610:422). Interest in this area increased progressively throughout in recent years.

2003 Dialer I, Hundt C, Bertele-Harms RM, Harms HK. Sonographic evaluation of bowel wall thickness in patients with cystic fibrosis. J Clin Gastroenterol 2003; 37:55-60. [PubMed]
Fibrosing colonopathy causing severe thickening of the colon wall was recently described in cystic fibrosis (CF). Since it has been suspected that subclinical colon-wall thickening is a common feature in CF patients, bowel-wall thickness was measured in a series of patients and compared with controls. Additionally, possible clinical factors influencing wall thickness were investigated. STUDY: In 83 CF patients and 31 controls transabdominal ultrasound was performed in the terminal ileum, cecum, ascending and descending colon. The relation of the measured wall thickness to age, sex, pancreatic enzyme intake, and intestinal diseases was analyzed.

In controls, mean wall thickness depending on gut region was 1.1 to 1.3 mm (SD 0.19-0.23). In CF patients, no evidence of severe thickening or stricture was found, but wall thickness was significantly higher than in controls in all measured regions (1.5-1.6 mm; SD 0.31-0.41). Patients with meconium ileus and distal intestinal obstruction syndrome had significantly increased thickness of the terminal ileum compared with patients without these complications. Neither the intake of high-strength enzymes nor enzyme dosage, age or sex were associated with wall thickness.

The authors found no evidence that a subclinical stage of fibrosing colonopathy is prevalent among the CF patients. they considered the slightly thickened gut walls in CF can be interpreted as an expression of glandular dysfunction in the CF intestine.

–    This is a reassuring study failing to reveal significant bowel wall thickening in CF although slightly thicker bowel wall than in controls.

2004 Mack EH, Brett AS, Brown D. Fibrosing colonopathy in an adult cystic fibrosis patient after discontinuing pancreatic enzyme therapy. Southern Med J 2004; 97:901-904. [PubMed]
Fibrosing colonopathy, a complication of cystic fibrosis, has generally been reported in young children with exposure to high doses of pancreatic enzymes. The authors report the case of a 25-year-old male with cystic fibrosis who presented with gradually progressive symptoms of bowel obstruction. Pathologic examination of the right colon revealed findings consistent with fibrosing colonopathy. This case is distinctive because of the adult presentation, and because the patient’s symptoms developed long after he had discontinued taking a high-strength enzyme preparation. The authors suggest this case suggests that multiple etiologic factors, and not simply exposure to pancreatic enzymes, may result in fibrosing colonopathy in adults with cystic fibrosis.

–    There is no need to postulate other factors as the obstruction may have developed on an existing partial obstruction from previous high strength enzymes as we have seen in one patient.

2004 Bruzzese E, Raia V, Gaudiello G, Polito G, Buccigrossi V, Formicola V, Guarino A. Intestinal inflammation is a frequent feature of cystic fibrosis and is reduced by probiotic administration. Aliment Pharmacol Therapeut 2004; 20:813-819. [PubMed]
To assess the incidence of intestinal inflammation in children with cystic fibrosis and to investigate whether probiotics decrease it. Mean faecal calprotectin was significantly higher in the two groups of patients than in controls. Abnormal values were detected in 27 of 30 cystic fibrosis and in 15 of 15 inflammatory bowel disease children. Also mean nitric oxide production was increased in both group of patients, and abnormal values were detected in 19 of 20 cystic fibrosis and in 15 of 15 inflammatory bowel disease children. Calprotectin and nitric oxide concentrations were reduced after probiotics administration. Intestinal inflammation is a major feature of cystic fibrosis and is reduced by probiotics. The latter finding suggests that intestinal microflora play a major role in intestinal inflammation in cystic fibrosis children.

Fortunately the gastrointestinal aspects of CF are receiving more attention. There is increasing evidence that the bowel is inflamed in CF as shown by inflammatory markers in the faeces as in the present paper, by breath tests and endoscopic camera studies. Although, as the authors suggest, the intestinal microflora play a part in the inflammation, although contributory, it is probably not the whole story.

2011 Terheggen G, Dieninghoff D, Rietschel E, Drebber U, Kruis W, Leifeld L. Successful non-invasive treatment of stricturing fibrosing colonopathy in an adult patient. Eur J Med Res 2011; 16:411-4. [PubMed]
Fibrosing colonopathy (FC) is a rare entity associated with cystic fibrosis (CF). Until now, patients with stricturing FC have usually been treated surgically. In this instance,the authors aimed at avoiding surgery by applying a new conservative approach. An adult with CF developed persistent abdominal pain due to a non-passable stricture in the right transverse colon. Histology confirmed fibrosing colonopathy. Initially he was treated with prednisolone pulse therapy and additive antibiotic therapy. For maintenance therapy he received budesonide. The patient underwent clinical, laboratory and endoscopic follow-up over a three-year period. The stricture healed and was easy to pass. A relapse in the cecum at the ileocecal valve again improved under steroid and antibiotic therapy. The authors present this case as a novel therapeutic approach for advanced stricturing FC in an adult patient which successfully avoided surgery (right hemicolectomy) over a three year follow up.

–   Dr Terheggen kindly sent me a copy of the paper. It is important to know the type of enzyme and although the brand of enzyme was not stated in the paper, the patient apparently took a “high strength pancreatic enzyme preparation” during childhood but only “pancreatin 150,000 IU per day” (presumably lipase). Unfortunately there are no full thickness biopsies from surgical specimens – all are endoscopic biopsies.

2008 Infante Pina D, Redecillas Ferreiro S, Torrent Vernetta A, Segarra Cantón O, Maldonado Smith M, Gartner Tizziano L, Hidalgo Albert E. [Improvement of intestinal function in cystic fibrosis patients using probiotics]. [Spanish] Anales de Pediatria 2008; 69:501-505. [PubMed]
The aim of this study is to determine the prevalence of intestinal bacterial overgrowth in cystic fibrosis patients and try to improve the intestinal function with the administration of probiotics. Twenty 20 patients with cystic fibrosis (mean age 10.33, range 5 to 17 years) were included. The expired hydrogen test with a 2 g/kg of 20% dextrose overload was performed on 10 patients. After the test, Lactobacillus rhamnosus LGG 10(11) CFU was administered twice daily for four weeks. Faecal near infrared spectroscopy (FENIR) of water, fat, nitrogen and sugar content in faeces was performed before and after probiotics administration.

Five patients (50%) showed bacterial overgrowth. There was a positive correlation between the hydrogen test and steatorrhea (R = 0.57) and sugar in faeces (R = 0.52). The FENIR results pre-treatment vs post-treatment were: fat 6.2 g +/- 3.3 g vs. 4.9 g +/- 2.1 g (p < 0.05), sugar 6.7 +/- g 3.6 g vs. 5 g +/- 2.6 g (p < 0.05) and nitrogen 0.87 g +/- 0.27 g vs. 0.91 g +/- 0.14 g (NS) respectively. Thirteen patients (81.25%) had improved stool appearance and intestinal comfort and nine (56.25%) decreased the number of daily stools.

The authors concluded that probiotics improved not only clinical but also biochemical intestinal function in cystic fibrosis patients. These could be given as a regular treatment in this type of patients and in those with bacterial overgrowth.

–    One of the few papers on the use of probiotics in people with CF and the number are small and the changes in absorption modest. However, with the increasing evidence of bacterial overgrowth and tissue inflammation in the gut in CF it is likely that probiotics may have a role in treatment of gastrointestinal problems as shown in this study from Spain and others (Bruzzese E et al. 2007 above).

2008 Barker HC, Haworth CS, Williams D, Roberts P, Bilton D. Clostridium difficile pancolitis in adults with cystic fibrosis. J Cyst Fibros 2008; 7:444-447. [PubMed] Three cases of Clostridium difficile pancolitis in adults with cystic fibrosis (CF) in whom the presenting symptoms were atypical. All three required treatment with systemic steroids, in addition to oral vancomycin and metronidazole to achieve resolution of the colitis. This experience suggests that C. difficile colitis should be considered in individuals with CF presenting with non-specific abdominal symptoms.

–   There have been sporadic reports of C difficile infection in people with CF. Some have been in patients who have had lung transplants. Also asymptomatic carriage seems to be relatively common in CF. In a minority the infection leads to serious clinical illness as in the cases reported here.

2010 Lisowska A, Madry E, Pogorzelski A, Szydlowski J, Radzikowski A, Walkowiak J. Small intestine bacterial overgrowth does not correspond to intestinal inflammation in cystic fibrosis. Scand J Clin Lab Invest 2010; 70:322-326. [PubMed]
The authors aimed to assess whether small bowel bacterial overgrowth (SIBO) correlates with the intestinal inflammation in CF patients reported by a number of authors. Fecal calprotectin was measured, as an indication of inflammation, in 25 non-sputum producing CF patients and 30 healthy subjects (HS). All CF subjects were tested for the presence of SIBO using the hydrogen-methane breath test (BT). Fecal calprotectin concentrations in CF patients (range: 1.8-302. 5; median 80.0 mg/L) were significantly higher (p < 0. 00001) than in healthy subjects (not detectable-15.5; 2.5 mg/L). Calprotectin levels were abnormal in 21 (84%) studied CF subjects and none of the healthy subjects. Abnormal BT results were found in 10 (40. 0%) of CF patients. Calprotectin concentrations in SIBO positive and negative patients did not differ.

–    Gastrointestinal inflammation is a frequent finding in cystic fibrosis patients. However, according to these authors, small intestine bacterial overgrowth does not seem to be the major or at least is not the only determinant of intestinal inflammation. Indirect measures of intestinal inflammation in CF patients may give false positive results. This is a useful addition to the information available on the intestinal pathology in people with CF that has received more attention in recent years including studies using direct visualisation and biopsy techniques. The present study confirms that there is more to the inflammation, increasingly reported in CF, than the presence of bacteria in the small bowel.

2010 Werlin SL, Benuri-Silbiger I, Kerem E, Adler SN, Goldin E, Zimmerman J, Malka N, Cohen L, Armoni S, Yatzkan-Israelit Y, Bergwerk A, Aviram M, Bentur L, Mussaffi H, Bjarnasson I. Wilschanski M. Evidence of intestinal inflammation in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 2010; 51:304-308. [PubMed]
The aim of the present study was to examine the small intestine of patients with CF without overt evidence of gastrointestinal disease using a capsule endoscopy (CE). Patients with CF received the agile patency capsule and, depending on the result of that procedure, then underwent standard CE using the PillCam SB capsule (Given Imaging, Yokneam, Israel). A stool specimen was taken on the same day as the CE for determination of the calprotectin level. Forty-two patients with CF ages 10 to 36 years were included; 29 had pancreatic insufficiency. One patient failed to excrete the patency capsule after 36 hours and was withdrawn from the study. Pulmonary function was mild to moderate with FEV1 68. 5% +/- 16% predicted. Review of the CE videos showed that most of the patients had varying degrees of diffuse areas of inflammatory findings in the small bowel including edema, erythema, mucosal breaks, and frank ulcerations. There were no adverse events. Fecal calprotectin levels were markedly high in patients with pancreatic insufficiency, 258 microg/g (normal <50).

The authors conclude that small bowel mucosal pathology may be detected using capsule endoscopy in the majority of people with CF. The high fecal calprotectin levels found are suggestive of mucosal inflammation, which may correlate with the capsule endoscopy findings. Additional study is required to examine the possible relation of these mucosal lesions, which may be part of a newly identified enteropathy associated with CF, with persistent intestinal malabsorption in many of these patients.

–    This is an impressive study with some striking pictures of the inflamed small intestinal mucosa in the full paper. Evidence of inflammation had been reported previously but these findings are the first visual support for the lesions which would seem to be one factor in failing to achieve normal absorption in some people with CF despite the use of pancreatic enzymes.

2011 Gomez Morales L. Garcia Morillo S. Herrera Justiniano JM. Avila Polo R. Fibrosing colonopathy, an increasing complication of cystic fibrosis. Revista Clinica Espanola 2011; 211(1):63-64. [PubMed]
A 30 year old man with CF had repeated episodes of DIOS followed by ileostomy and eventually colectomy histology showed “clear signs of fibrosing colonopathy”. He took 80,000 IU pancreatic supplements (presumably lipase and a small dose) daily but brand not mentioned in the report. The histology in the report is suggestive of fibrosing colonopathy.

–    Undoubtedly there are sporadic cases of fibrosing colonopathy reported in people who are not taking pancreatic enzymes supplements, have never taken such treatment and also in people who do not have CF but who have received mesalazine enteric coated pills for inflammatory bowel disease. There is much evidence, which this writer accepts, to suggest that the coating of these mesalazine pills and the coating of certain brands of pancreatic enzymes, Eudragit L30, are an important factor in the development off fibrosing colonopathy.

2016 Burke DG, Harrison MJ, Fleming C, McCarthy M, Shortt C, Sulaiman I, Murphy DM, Eustace JA, Shanahan F, Hill C, Stanton C, Rea MC, Ross RP, Plant BJ. Clostridium difficile carriage in adult cystic fibrosis (CF); implications for patients with CF and the potential for transmission of nosocomial infection. J Cyst Fibros. 2016 Nov 29. pii: S1569-1993(16)30610-5. doi: 10.1016/j.jcf.2016.09.008. [Epub ahead of print] [PubMed]
Despite increasing carriage rates and the presence of C. difficile toxin in stool, patients with CF rarely appear to develop typical manifestations of C. difficile infection (CDI). C. difficile was detected in 50% (30/60) of patients with CF by culturing for the bacteria. C. difficile toxin was detected in 63% (19/30) of C. difficile-positive stool samples. All toxin-positive stool samples contained toxigenic C. difficile strains harbouring toxin genes, tcdA and tcdB. Despite the presence of C. difficile and its toxin in patient stool, no acute gastrointestinal symptoms were reported. Ribotyping of C. difficile strains revealed 16 distinct ribotypes (RT), 11 of which are known to be disease-causing including the hyper-virulent RT078. Additionally, strains RT002, RT014, and RT015, which are common in non-CF nosocomial infection were described. All strains were CF susceptible to vancomycin, metronidazole, fusidic acid and rifampicin.

No correlation was observed between carriage of C. difficile or any characteristics of isolated strains and any recorded clinical parameters or treatment received. The study demonstrates a high prevalence of hypervirulent, toxigenic strains of C. difficile in asymptomatic patients with CF. This highlights the potential role of asymptomatic patients with CF in nosocomial transmission of C. difficile.

– Further confirmation of the common asymptomatic carriage of C. difficile by people with CF. The authors review the situation regarding the potential for cross infection and also the possible gut-lung axis relationship. They suggest that further studies are needed with regard to the need for eradication.

Deane J, Fouhy F, Ronan NJ, Daly M, Fleming C, Eustace JA, Shanahan F, Flanagan ET, Dupont L, Harrison MJ, Haworth CS, Floto A, Rea MC, Ross RP, Stanton C, Plant BJ.   A multicentre analysis of Clostridium difficile in persons with Cystic Fibrosisdemonstrates that carriage may be transient and highly variable with respect to strain and level: Cystic Fibrosis and Clostridium difficile. J Infect. 2021 Jan 11:S0163-4453(20)30788-X. doi:10.1016/j.jinf.2020.12.027. Online ahead of print [Pubmed]

Clostridium difficile has been reported to occur in the gastrointestinal tract of 50% of Cystic Fibrosis (CF) subjects, however, clinical C. difficile infection (CDI) is a rare occurrence in this cohort despite the presence of toxigenic and hypervirulent ribotypes. Here, we present the first longitudinal, multicentre analysis of C. difficile prevalence among adult CF subjects.
Faecal samples were collected from adults with CF (selected based on confirmed Pseudomonas aeruginosa pulmonary colonisation) from Ireland, UK and Belgium as part of the CFMATTERS clinical research trial (grant No.603038) and from non-CF controls. Faecal samples were collected on enrolment, at three monthly intervals, during pulmonary exacerbation and three months post exacerbation. C. difficile was isolated from faecal samples by ethanol shocking followed by culturing on cycloserine cefoxitin egg yolk agar. Isolates were characterised in terms of ribotype, toxin type and antibiotic susceptibility to antibiotics routinely used in the treatment of CDI (metronidazole and vancomycin) and those implicated in induction of CDI (ciprofloxacin and moxifloxacin).
Results: Prevalence of C. difficile among CF subjects in the three sites was similar ranging from 47-50% at baseline, while the healthy control cohort had a carriage rate of 7.1%. Including subjects who were positive for C. difficile at any time point there was a higher carriage rate of 71.4%, 66.7% and 63.2% in Ireland, UK, and Belgium, respectively. Ribotyping of 80 isolates from 45 CF persons, over multiple time points revealed 23 distinct ribotypes with two ribotypes (046 and 078) shared by all centres. The proportion of toxigenic isolates varied across the sites, ranging from 66.7% in Ireland to 52.9% in Belgium and 100% in the UK. Antibiotic susceptibility rates to vancomycin, metronidazole, ciprofloxacin and moxifloxacin was 100%, 97.5%, 1.3% and 63.8%, respectively.
Conclusions: This study demonstrates the highest carriage rate of C. difficile to date in a CF cohort. Longitudinal data shows that C. difficile can be a transient inhabitant of the CF gut, changing both in terms of strain and excretion rates.

Jennifer Deane is a PhD researcher at Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland; HRB Clinical Research Facility, University College Cork, Cork, Ireland; School of Microbiology, University College Cork, Cork, Ireland.

Gastroesophageal reflux

1975 Feigelson J, Sauvegrain J. Gastro-esophageal reflux in mucoviscidosis. Nouv Presse Med 1975; 4: 2729-2730. [PubMed]

This is the possibly first description of significant gastroesophageal reflux in people with CF detected on radiological examination in 56 patients aged four months to 27 years and showed that 26 (46%) had significant gastro-oesophageal reflux. Attention was drawn to this complication and its effects both on the oesophagus and the respiratory system.

–   Subsequently gastro oesophageal reflux was recognised as a frequent and important complication in people with CF of all ages. There was to be continuing interest in GO reflux both in infants (Malfroot & Dabb, 1991 below) and in relation to physiotherapy practices in CF infants (Button et al, 1997 below); also in adults where GO reflux was shown to be frequent and important in exacerbating respiratory symptoms (Scott RB et al, 1985 below; Ledson MJ et al, 1998 below) and particularly in relation to patients after lung transplantation (Button BM et al. J Heart Lung Transplant 2005; 24:1522-1529). Newer techniques of oesophageal pH monitoring and also fibreoptic endoscopy during the Eighties allowed more frequent recognition and more accurate diagnosis.

1988 Stringer DA, Sprigg A, Joudis E, Corey M, Daneman A, Levison HJ, Durie PR. The association of cystic fibrosis, gastroesophageal reflux and reduced pulmonary function. Can Ass Radiol J 1988; 39:100-1002. [PubMed]
Between 1971 and 1984 fifty seven patients with CF had a barium meal for suspected gastroesophageal reflux which was found to be present in 18 (32%) of those examined – in six the reflux was associated with a hiatus hernia, oesophagitis or stricture. The 18 patients with reflux had significantly worse respiratory function than the other 412 people with CF in the clinic without known reflux.

–   In a number of subsequent publications gastroesophageal reflux was shown to be a frequent and significant problem in both children and adults with CF and other chest problems. The complication was first described by Jean Feigelson (Feigelson J, Sauvegrain J. Reflux gastroesophagien dans la mucoviscidose. N Press Med 1975; 4:2727-2730 above). Other notable contributions included Malfroot A, Dab I. New insights of gastro-oesophageal reflux in cystic fibrosis by longitudinal follow-up. Arch Dis Child 1991; 66:1339-1345 below; Ledson MJ et al. Prevalence and mechanism of gastro-oesophageal reflux in adult cystic fibrosis patients. J R Soc Med 1998; 91:7-9 below).
More recently the association of reflux with head down postural drainage manoeuvres in infants with CF has altered the practice of many physiotherapists by avoiding the head down position (Button BM et al. Postural drainage and gastro-oesophageal reflux in infants with cystic fibrosis. Arch Dis Child 1997; 76:148-150 below).

1991 Malfroot A, Dab I. New insights on gastro-oesophageal reflux in cystic fibrosis by longitudinal follow up. Arch Dis Child 1991; 66:1339-1345. [PubMed]

Gastro oesophageal (GO) reflux was first described as a problem in CF by Jean Feigelson (Feigelson et al, 1975 above) and subsequently the problem was thought to be related to progressive CF in older children. In this Belgian study 21 of 26 (81%) young children with CF aged less than 60 months were studied and 20 confirmed to have reflux by oesophageal pH tracings. Sixteen improved with anti-reflux treatment with improved weight gain, less cough and wheeze but half still had the reflux one year later. The authors concluded the reflux was not caused by the CF chest problems as it improved with time – at the same time as the CF gets worse – hence their title “new insights into GO reflux”.

–    There was to be continuing interest in GO reflux both in respect to physiotherapy practices in CF infants (Button et al, 1997 below) and in adults where GO reflux was shown to be frequent and important in exacerbating respiratory symptoms (Scott RB et al, 1985; Ledson MJ et al, 1998) particularly in relation to patients after lung transplantation (Button BM et al. J Heart Lung Transplant 2005; 24:1522-1529). Newer techniques of oesophageal pH monitoring and also fibreoptic endoscopy allowed more frequent recognition and more accurate diagnosis

1997 Button BM, Heine RG, Catto-Smith AG, Phelan PD, Olinsky A. Postural drainage and gastro-oesophageal reflux in infants with cystic fibrosis. Arch Dis Child 1997; 76:148-150.[PubMed]

First of series of papers from Brenda Button (figure 43 main text), a physiotherapist from Melbourne, Australia, noting the possible dangers of inhalation when infants with CF were in the head down position during postural drainage; infants with CF were known to have an increased incidence of gastro-oesophageal (GO) reflux. Physiotherapy with and without head down tilt were compared using 24 hour pH oesophageal monitoring. Standard physiotherapy with head down tilt was associated with a significant increase in GO reflux in the infants with CF.

–   This was an important study and, with Brenda Button’s subsequent publications, certainly had a major influence on the techniques of physiotherapy recommended for CF infants (see also Malfroot & Dab, 1991 above for earlier studies on reflux in CF infants; Button et al, 2004 also confirmed GO reflux as common and important in adults with CF)

1998 Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastro-oesophageal reflux in adult cystic fibrosis patients. J R Soc Med 1998; 91:7-9.[PubMed]
Fifty adults with CF were surveyed by questionnaire and ten with reflux symptoms had oesophageal manometry and 24 hour pH recording. Forty seven patients (94%) had upper gastrointestinal symptoms: 40 (80%) heartburn (27 worse when supine); 26 (52%) regurgitation; and 28 (56%) dyspepsia. At oesophageal manometry, lower oesophageal sphincter barrier pressure (LOSBP) was subnormal in 6 of the 10 patients and 3 had uncoordinated peristalsis in the mid-oesophagus. Eight patients had significant gastroesophageal reflux. Adult CF patients have high rates of GOR symptoms, diminished LOSBP, and acid reflux.

This study re-emphasised the fact that GOR was a frequent and important problem and a significant cause of symptoms in adults with cystic fibrosis. The complication had been recognised since first described by Jan Feigelson (Feigelson & Sauvegrain, 1975 above) and later by Scott RB et al, 1985 (above); the frequency and importance was again highlighted in this present paper. Brenda Button in Australia had already pointed out the problem of the occurrence of reflux in CF infants in the head down position during physiotherapy (Button et al, 1997 above) – later she also found reflux to be common in adults with CF (Button et al, 2004).

2007 Boesch RP, Acton JD. Outcomes of fundoplication in children with cystic fibrosis. J Pediatr Surg 2007; 42:1341-1344. [PubMed]
Twenty five children with CF underwent fundoplication to treat gastro-oesophageal reflux. 12% had complications that required a subsequent surgical procedure. Although 28% were able to discontinue their anti-reflux medications, no less than 48% developed symptoms of recurrent gastro-oesophageal reflux. Only children who had an FEV1 of less than 60% predicted at the time of fundoplication exhibited an improvement in FEV1 slope.

The complication rate of fundoplication is similar to that reported in large series in children without CF. There is a high rate of recurrent reflux and little apparent benefit for either nutritional or pulmonary outcomes although some children do benefit.

2013 Goralski JL, Lercher DM, Davis SD, Dellon ES. Eosinophilic esophagitis in cystic fibrosis: a case series and review of the literature. [Review] J Cyst Fibros 2013; 12:9-14. [PubMed]
Three patients with eosinophilic esophagitis (EoE) are reported. EoE is a TH-2 driven, allergen-mediated disease which is diagnosed by esophageal biopsies. There have been no prior cases documenting the co-existence of EoE an CF.

2015 Dziekiewicz MA, Banaszkiewicz A, Urzykowska A, Lisowska A, Rachel M, Sands D, Walkowiak J, Radzikowski A, Albrecht P. Gastroesophageal Reflux Disease in Children with Cystic Fibrosis. Exp Med Biol. 2015 Aug 19. [Epub ahead of print] [PubMed]
Gastroesophageal reflux (GER) was diagnosed in 24/44 (54.5%) children with CF. In 14/44 patients typical GER symptoms were present. The authors confirm that the incidence of GER in children with cystic fibrosis is very high but in the majority of patients typical GER symptoms are absent. They emphasise classical pH-metry may not constitute a sufficient diagnostic method in this population because of a relatively high number of proximal reflux episodes indicating an increased risk of aspiration. The pH-impedance diagnostic measurement is advocated when suspecting GER in children with cystic fibrosis.

– The impedance–pH-monitoring test determines if the patient’s symptoms are related either to acid reflux, to non-acid reflux, or not related to reflux of any type.

2016 Hauser B; De Schepper J; Malfroot A; De Wachter E; De Schutter I; Keymolen K; Vandenplas Y.  Gastric emptying and gastro-oesophageal reflux in children with cystic fibrosis. J Cyst Fibros 2016; 15(4):540-7. [PubMed]
The aim of this study was to investigate the relationship between gastric emptying (GE) and GOR in children with CF. Multichannel intraluminal impedance-pH monitoring (MII-pH) to measure GOR and GE breath test (GEBT) to measure GE were performed in 28 children with symptoms suggestive for GOR disease (GORD) (group 1). GEBT was performed in another 28 children with/without GOR symptoms who agreed to undergo GEBT but not MII-pH (group 2).In group 1, there was increased acid GOR (AGOR) in 46.4% and delayed GE (DGE) in 21.4% but no relationship between increased AGOR and DGE. There was no DGE in group 2. We found DGE in 10.7% and rapid GE in 12.5% of the whole group.

The authors concluded almost half of the children with CF and symptoms suggestive for GORD have increased AGOR and almost a quarter has DGE. However, there was no relation between gastro-oesophageal reflux and delayed gastric emptying.

Xochitl Mellor, Terri Schindler, Shahrazad Saab, Erica Roesch, Thomas Sferra, Senthilkumar Sankararaman.Eosinophilic esophagitis in cystic fibrosis: A case series with long-term follow-up.  Pediatr Pulmonol 2022 Jun;57(6):1557-1561.doi: 10.1002/ppul.25912. Epub 2022 Apr 11. [Pubmed]
Challenging mealtime behaviors in young children and difficulties in meeting their dietary intake recommendations are sources of parenting stress and associated with negative quality of life. The gastrointestinal (GI) manifestations of cystic fibrosis (CF) can often present similarly to a GI pathology unrelated to CF. Specifically, this case series focuses on three toddlers with CF who presented with oral aversion and challenging mealtime behaviors and later were diagnosed with eosinophilic esophagitis (EoE). Though EoE often presents with dysphagia, younger patients commonly present with nonspecific GI symptoms such as regurgitation, emesis, abdominal pain, failure to thrive, food intolerance, and oral aversion. Given the overlap of GI manifestations in CF and EoE, it can be challenging for clinicians to diagnose the coexistent EoE in patients with CF. We describe the presenting symptoms, treatment, and successful outcomes of three pediatric patients with CF and EoE. To our knowledge, this is the second case series with a detailed description of EoE in CF.

Xochitl Mellor  is a paediatrician in the Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio, US

Laura Zazzeron , Gianfranco Alicandro , Valeria Daccò , Chiara Lanfranchi, Anna Bulfamante , Calogero Sathya Sciarrabba, Fabiola Corti , Carla Colombo. Effects of prolonged proton pump inhibitor treatment on nutritional status and respiratory infection risk in cystic fibrosis: A matched cohort study. Dig Liver Dis. 2022 Oct 14;S1590-8658(22)00694-6. doi: 10.1016/j.dld.2022.09.005. Online ahead of print.   pubmed.ncbi.nlm.nih.gov/36253246/

Background: Evidence on the effectiveness of proton pump inhibitors (PPI) as adjuvant therapy to improve maldigestion in people with cystic fibrosis (pwCF) is limited and there is increasing concern on possible side effects.
Methods: We conducted a matched cohort study based on paediatric and adult pwCF who received PPI for ≥3 months. Treated patients were matched to a group of patients who never received PPI using a nearest neighbour propensity score matching based on sex, year of birth, CFTR genotype and pancreatic insufficiency.
Results: The study included 160 pwCF: 80 treated and 80 untreated patients. Over a median follow-up of 2 years, no significant differences in changes in BMI z-score were detected between groups (adjusted mean difference: 0.06, 95% CI: -0.17-0.30). At baseline 25% (n = 20) of the treated patients and 22.5% (n = 18) of the untreated patients had a positive culture for P. aeruginosa (Pa). At follow-up percentages of Pa positive cultures increased to 47.5% (n = 38) in the treated group and to 26.3% (n = 21) in the untreated group (adjusted mean difference: 23.1%, 95% CI: 10.8-35.3).

Conclusions: Prolonged PPI therapy should be used cautiously in pwCF since it may increase the risk of respiratory infection by Pa. In addition, such treatment does not seem to improve nutritional status.

Laura Zazzeron is at the Fibrosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda 9, Milano 20122, Italy.

Effect of modulators

Sarah Jane Schwarzenberg , Phuong T Vu, Michelle Skalland , Lucas R Hoffman, Christopher Pope, Daniel Gelfond, et al and the  Promise Study Group. Elexacaftor/tezacaftor/ivacaftor and gastrointestinal outcomes in cystic fibrosis: Report of promise-GI. J Cyst Fibros
. 2022 Oct 21;S1569-1993(22)01384-4. doi: 10.1016/j.jcf.2022.10.003. Online ahead of print. pubmed.ncbi.nlm.nih.gov/36280527/

Background: Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear.
Methods: PROMISE is a 56-center prospective, observational study of ETI in PwCF >12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex.
Results: 438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change.

Conclusions: After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve

Professor Sarah Jane Schwarzenberg at Pediatrics, University of Minnesota Masonic Children’s Hospital, Academic Office Building, 2450 Riverside Ave S AO-201, Minneapolis, MN 55454, USA.

Rectal prolapse

1907 Lockhart-Mummery P. Prolapse of the rectum in children, with fifty cases. Brit Med J 1907; 2:812.

A common disorder among children, writes Mr. Lockhart-Mummery a distinguished London surgeon, “especially that class which attends the surgical practice at a children’s hospital”. He had seen examples of the usually quoted causes of rectal prolapse (phimosis, stone in the bladder, colonic polyps, etc) to be rare but chronic diarrhoea, wasting and general weakness to be common – particularly the removal of fat from around the rectum in such cases.

Unfortunately there is no mention of long term outlook of these children that may have suggested some may have had CF; however, the fact that the average age was 2.56 years perhaps indicated that prior to 1907 most children that had a prolapse due to CF would have already died. Also in 1907 death in early childhood from gastroenteritis was relatively common as was malnutrition and wasting.

Subsequently rectal prolapse was described as a feature of CF (Kulczycki & Shwachman, 1958 below). The lack of fat around the rectum, as suggested by Lockhart-Mummery, is obviously relevant in CF for when this is restored with appropriate pancreatic enzyme treatment the tendency to rectal prolapse diminishes – usually completely. In over 600 people with CF I only recall one teenage girl who still complained of the rectal prolapse occasionally. However, one wonders if persistence of this embarrassing problem is under-reported as was later found to be the case with urinary incontinence in people with cystic fibrosis (Cornacchia et al, 2001 below). (Illustration of severe rectal prolapse in Kulczycki & Shwachman, 1958 below).

1958 Kulczycki LL, Shwachman H. Studies in cystic fibrosis of the pancreas: occurrence of rectal prolapse. N Eng J Med 1958; 259:409-412. [PubMed]

Rectal prolapse (figure) occurred in 22.6% of 386 patients with CF. It appeared to be related to combination of steatorrhoea, poor musculature and chronic coughing. Most frequently between three and six years and more common when the diagnosis is made later. In 16 (4%) patients prolapse was the presenting sign and the authors advised that CF should be excluded in any child with a rectal prolapse.

In a later study Zempsky WT & Rosenstein (Am J Dis Child 1988;142:338-339.[PubMed]) found of 54 children seen for rectal prolapse over 10 years the causes were constipation in 15, acute diarrhoea 11, neurological abnormalities 13 and cystic fibrosis in only six children (11%).

Rectal prolapse in patients with CF virtually always resolves after treatment with pancreatic enzymes. I only recall one adolescent girl, in over 600 patients, who reported occasional persisting problems with prolapse, although it is quite possible other older patients were reluctant to report that rectal prolapse was persisting.

Transplant – GI complications

2003 Gilljam M, Chaparro C, Tullis E, Chan C, Keshavjee S, Hutcheon M. GI complications after lung transplantation in patients with cystic fibrosis. Chest. 2003; 123:37-41. [PubMed] Lung transplantation is now available for patients with cystic fibrosis (CF) and end-stage lung disease. While pulmonary graft function is often considered the major priority following transplantation, the non pulmonary complications of this systemic disease also continue. GI complications after lung transplantation were common in patients with CF, and the authors advised that attention should be paid to the risk for DIOS in the early postoperative period. Prevention and early medical treatment are important in order to avoid acute surgery. Close collaboration with the CF clinic, in order to diagnose and treat CF-related complications, is recommended.

–   The gastrointestinal aspects of treatment may receive insufficient attention if there are serious respiratory problems. This report of extensive experience from Toronto of patient after lung transplantations documents this advice and records experience of 27 of 75 patients. The present writer is aware of an instance where failure to give enzymes in the post operative period resulted in intestinal obstruction then complications resulting from fluid and parenteral nutrition eventually proving fatal.

2006 Dellon ES, Morgan DR, Mohanty SP, Davis K, Aris RM. High incidence of gastric bezoars in cystic fibrosis patients after lung transplantation. Transplantation 2006; 81:1141-6.[PubMed]
Of the 215 patients who received lung transplantation, 17 (7.9%) developed gastric bezoars confirmed by upper endoscopy. Cystic fibrosis was the leading indication for lung transplantation (n=145), and 11% of cystic fibrosis patients (16 of 145) formed gastric bezoars after transplant. Additionally, 94% of patients with bezoars (16 of 17) had cystic fibrosis (P=0.02), with the exception being a subject with primary ciliary dyskinesia. No patient who underwent lung transplant for another indication was found to have a bezoar. The mean time to diagnosis was 34 days, with two-thirds of bezoars diagnosed within one month after transplant. The annual incidence was unchanged during the study period.

Gastric bezoars (figure) are common in  cystic fibrosis patients after lung transplantation. The etiology is likely multifactorial, related to gastric motility, respiratory secretions, and medications. Further investigation is needed to understand the pathogenesis of bezoar formation in this selected population, and strategies for primary prevention may be beneficial.

This complication seems to be relatively common after transplants in people with CF – not altogether unexpected considering the gastrointestinal problems of motility, inflammation and digestion, experienced by people with CF compared with non-CF patients who receive lung transplants.

2011 Meyer KC, Francois ML, Thomas HK, Rad ford KL, Haw es DS, Mack TL, Cornwell RD, Maloney JD, De Olivary NC. Coloncancer in lung transplant recipients with CF: increased risk and results of screening. J Cyst Fibros 2011; 10:366-369. [PubMed]
Four of 70 transplant recipients with CF developed fatal colon carcinoma following transplantation, and the cancer was advanced in all 4 recipients (age 31, 44, 44, 64 yrs) at the time of diagnosis. In contrast, only one of 287 recipients transplanted for non-CF indications developed colon cancer. Of all recipients with CF who did not develop colon cancer, 20 recipients underwent screening colonoscopy at 1 to 12 years following transplantation. Seven (35%) of the screened transplant recipients (ages 36, 38, 40, 41, 43, 49, 51) had colonic polyps in locations ranging from cecum to sigmoid colon and up to 3 cm in diameter. The authors concluded that in contrast to non-CF recipients, patients with CF displayed a significant incidence of colon cancer (4 of 70 recipients; 5.7%) with onset ranging from 246 days to 9.3 years post-transplant, which may be due to a combination of their underlying genetic disorder plus intense, sustained immunosuppression following lung transplantation. Colonoscopic screening may identify patients with pre-malignant colonic lesions and prevent progression to colonic malignancy.

–   This study from the Wisconsin CF Centre confirms the increased risk for developing cancer after transplantations and immunosuppression in people with CF. The finding of colonic polyps in 7 (35%) of transplant recipients is important suggesting the need for colonoscopic screening of such patients.

(See also Topic – Malignancy)

Other related subjects

2009 Perera E, Massie J. Phillips RJ. Treatment of acne with oral isotretinoin in patients with cystic fibrosis. Arch Dis Child 2009; 94:583-586. [PubMed]
Theoretical concerns about liver disease and vitamin A deficiency have limited the use of oral isotretinoin for troublesome acne in adolescents with cystic fibrosis. Oral isotretinoin was administered to nine patients with cystic fibrosis who had troublesome acne unresponsive to antibiotics. All patients were followed for 1-4 years after cessation of treatment. Isotretinoin treatment cleared active acne lesions in all patients. It was well tolerated, and no patient had significant side effects. All nine patients were pleased or delighted with the improvement in their skin. Adolescents with cystic fibrosis and acne can be treated with oral isotretinoin. Oral isotretinoin should be considered for adolescents with cystic fibrosis who have acne associated with scarring, acne not clearing with topical and antibiotic treatment, acne associated with depression or severe cystic acne.

–   This is a helpful paper for those considering the use of isotretinoin but who may have reservations regarding liver toxicity for clearing acne lesions in adolescents has a major effect on their quality of life.

2010 Scotet V, Dugueperoux I, Audrezet MP, Audebert-Bellanger S, Muller M, Blayau M, Ferec C. Focus on cystic fibrosis and other disorders evidenced in fetuses with sonographic finding of echogenic bowel: 16-year report from Brittany, France. Am J Obstet Gynecol 2010; 203:592. e1-6.[PubMed]
Based on the long experience of a region where CF is frequent (Brittany, France), the authors describe disorders diagnosed in fetal echogenic bowel fetuses and assess ultrasonography ability in detecting cystic fibrosis in utero. They reviewed the cases of fetal echogenic bowel diagnosed in pregnant women living in Brittany and referred for CFTR gene analysis over the 1992-2007 period (n = 289). A disorder was diagnosed in 32. 2% of the fetuses, cystic fibrosis being the most commonly identified (7. 6%). They also found digestive malformations (7. 0%), chromosomal abnormalities (3. 7%), and maternofetal infections (3. 7%). Combining these data with their ongoing newborn screening program since 1989 showed that ultrasonography enabled diagnosis of 10. 7% of the cystic fibrosis cases. This study highlights the importance of pregnancy ultrasound examinations and their efficiency in detecting cystic fibrosis

This paper reports valuable extensive experience from France indicating the clinical significance of the finding of an echogenic bowel at antenatal ultrasound

2010 Vincenzi F, Bizzarri B, Ghiselli A, de’ Angelis N, Fornaroli F, de’ Angelis GL. Cystic fibrosis and Crohn’s disease: successful treatment and long term remission with infliximab. World J Gastroenterol 2010; 16:1924-7. [PubMed]
The association of cystic fibrosis and Crohn’s disease (CD) is well known, but to date, there are very few cases in the literature of patients suffering from mucoviscidosis who have required treatment with infliximab. The authors report the case of a 23-year-old patient suffering from cystic fibrosis and severe CD treated successfully with infliximab without any infective complications or worsening of the pulmonary disease and with a long term (2 years) complete remission

–   nfliximab is a monoclonal antibody against tumour necrosis factor alpha used to treat autoimmune disease.

2010 Meyerholz DK, Stoltz DA, Pezzulo AA, Welsh MJ. Pathology of gastrointestinal organs in a porcine model of cystic fibrosis. Am J Pathol 2010; 176:1377-89. [PubMed]
To better understand the initial stages of CF, the authors studied the gastrointestinal pathology of CFTR-/- pigs. By studying newborns, they avoided secondary changes attributable to environmental interactions, infection, or disease progression. Lesions resembling those in humans with CF were detected in intestine, pancreas, liver, gallbladder, and cystic duct. These organs had four common features. First, disease was accelerated compared with that in humans, which could provide a strategy to discover modifying factors. Second, affected organs showed variable hyperplastic, metaplastic, and connective tissue changes, indicating that remodeling was a dynamic component of fetal life. Third, cellular inflammation was often mild to moderate and not always present, which raises new questions as to the role of cellular inflammation in early disease pathogenesis. Fourth, epithelial mucus-producing cells were often increased, producing a striking accumulation of mucus with a layered appearance and resilient structure. Thus, mucus cell hyperplasia and mucus accumulation play prominent roles in early disease. These findings also have implications for CF lung disease, and they lay the foundation for a better understanding of CF pathogenesis.

–   A report of the early changes in the gastrointestinal organs of CF pigs. Just as the CF mice were a major advance in 1992/3 so the porcine CF model is proving of immense value.

2011 Dalgic B, Egritas O. Gray hair and acrodermatitis enteropathica-like dermatitis: an unexpected presentation of cystic fibrosis. Eur J Pediatr 2011; 170:1305-8.[PubMed]
Presentation of cystic fibrosis (CF) with an acrodermatitis enteropathica-like skin rash, anemia, and hypoproteinemia without pulmonary disease is rarely reported before. We describe an 11-month-old boy with rash and edema as the presenting signs of cystic fibrosis. The interesting additional finding in this patient was the graying hair after 3 months of age. A reversal of the gray hair was observed following pancreatic enzyme replacement therapy. In conclusion, acrodermatitis-like eruption and hypoproteinemia can be a presenting sign of CF. Graying hair has not been noticed so far as a sign of CF in these patients

Yet another presentation of CF. The acrodermatitis as the presenting disorder of CF has been described previously, related to the multiple dietary deficiencies in untreated patients, but the greying hair is new and interestingly was reversed after pancreatic enzyme therapy was started.

2011 Ao M, Venkatasubramanian J, Boonkaewwan C, Ganesan N, Syed A, Benya RV, Rao MC. Lubiprostone activates Cl- secretion via cAMP signaling and increases membrane CFTR in the human colon carcinoma cell line, T84. Digest Dis Sci 2011; 56:339-351. [PubMed]
Lubiprostone, used clinically (b.i.d.) to treat constipation, has been reported to increase transepithelial Cl(-) transport in T84 cells by activating ClC-2 channels. To identify the underlying signaling pathway, we explored the effects of short-term and overnight lubiprostone treatment on second messenger signaling and Cl(-) transport. Lubiprostone and the cAMP stimulator, forskolin, caused comparable and maximal increases of I(sc) in T84 cells. Lubiprostone activates Cl(-) secretion in T84 cells via cAMP, protein kinase A, and by increasing apical membrane CFTR protein.

–   The precise action of lubiprostone in CF is still under investigation in the laboratory and also there is a short publication of its use in adults with CF for constipation where there did seem to be some beneficial effect (O’Brien et al. Ann Pharmacother 2011; 45:1061-1066. [PubMed].

2013 Gelfond D. Ma C. Semler J. Borowitz D. Intestinal pH and gastrointestinal transit profiles in cystic fibrosis patients measured by wireless motility capsule. Dig Dis Sci 2013; 58:2275-81.[PubMed]                                                                                                                                                          The authors utilized a wireless motility capsule (WMC) to study intestinal pH profile and gastrointestinal transit profile in CF subjects. The studies were done on ten adult CF patients with pancreatic insufficiency (PI) while off acid suppression medication and ten age, gender and BMI matched healthy controls.

A statistically significant difference was observed between mean pH values during the first 23 min of small bowel transit (p < 0.05). In CF subjects, there was a significant delay in time interval required to reach and sustain pH 5.5 and pH 6.0 (p < 0.001), which is required for PERT dissolution. Only small bowel transit in CF subjects was noted to be significantly delayed (p = 0.004) without a compensatory increase in whole gut transit time.

The authors confirmed the findings in a number of previous studies that there is significant delay in the small intestinal transit and a deficient buffering capacity required to neutralize gastric acid in the proximal small bowel of patients with CF. See also two studies from Leeds. One with a pH-sensitive radio telemetry capsule – Gilbert J et al. Ileal pH in cystic fibrosis. Scand J Gastroenterol 1988; 23(Suppl 143):132-134. [PubMed]; this confirmed the acid conditions detrimental to lipid digestion .are confined to the upper small bowel. The length of time that small bowel pH exceeds 6.0 is adequate for dissolution of microencapsulated enzymes and lipid absorption. Also Seal S et al. Stable isotope studies on pancreatic enzyme release in vivo. Postgrad Med J 1996; 72 (Suppl 2):S37-S38. [PubMed]. As part of this investigation the oro-caecal transit time was found to be prolonged (6hrs Range 4.0-7.5 hrs) compared with the normal 1.0-2.0 hrs. Also Bali A et al. Prolonged intestinal transit time in cystic fibrosis. BMJ 1983; 287:1011-1013. [PubMed] was the first documentation of prolonged small bowel transit in CF (see entry in Eighties Clinical above).

2013 Maisonneuve P, Marshall BC, Knapp EA., Lowenfels AB. Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States. J Nat Cancer Inst 2013; 105:122-9. [PubMed]
From 1990 to 2009, 41,188 patients received care at one of the 250 US CF care centers. Observed number of cancers in nontransplanted and transplanted patients were compared with that expected in the general population. The overall burden of cancer in CF patients remained low in all groups; however they have an increased risk of digestive tract cancer, particularly following transplantation. They also have increased risk of lymphoid leukaemia and testicular cancer, and decreased risk of melanoma.

2013 Cohen-Cymberknoh M. Yaakov Y. Shoseyov D. Shteyer E. Schachar E. Rivlin J. Bentur L. Picard E. Aviram M. Israeli E. Kerem E. Wilschanski M. Evaluation of the intestinal current measurement method as a diagnostic test for cystic fibrosis. Pediatr Pulmonol 2013; 48:229-235. [PubMed]
Intestinal current measurement (ICM) is under consideration as an aid in the diagnosis of CF especially in young children. The aim of this study is to evaluate the diagnostic reliability of ICM. METHODS: Rectal biopsies were obtained from three groups: CF patients, controls, and patients who were suspected for CF. ICMs were performed by mounting the rectal biopsy in an Ussing chamber and sequentially adding secretagogues while recording current changes.
Twenty-one CF patients (aged 3.0+/-3.8 years) and 16 controls (aged 15.6+/-15.1 years) were examined and have remarkably different results (presented as A/cm(2) ): carbachol 16.3+/-6.9, histamine 13.2+/-8.9, and cAMP/forskolin 4.8+/-4.0 for control group and carbachol -1.5+/-5.3 (P<0.0001), histamine -1.5+/-3.1 (P<0.0001), and cAMP/forskolin 0.36+/-0.67 (P<0.0001) for the CF group. Our suggested reference values are: +5.40, +3.52, +2.19 for carbachol, histamine, and cAMP/forskolin, respectively. The combination parameter (the arithmetic sum of carbachol, histamine, and cAMP/forskolin) of +7.19 differentiates normal from abnormal (ROC curve analysis, area under the curve=1.00, both sensitivity and specificity are 100%). This statistical model was applied to 71 patients suspected for CF and revealed that 66 patients had normal ICM results (combination >7.19) and five patients had abnormal ICM results (combination <7.19).

The authors have shown that ICM tests may be useful to differentiate between patients suspected to have CF. These results require confirmation so that ICM may be included in diagnostic algorithms.

–   Further confirmation that intestinal current measurements can be used to differentiate CF and non-CF.

2013 Clancy JP. Szczesniak RD. Ashlock MA. Ernst SE. Fan L. Hornick DB. Karp PH. Khan U. Lymp J. Ostmann AJ. Rezayat A. Starner TD. Sugandha SP. Sun H. Quinney N. Donaldson SH. Rowe SM. Gabriel SE. Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function. PLoS ONE [Electronic Resource]. 8(9):e73905, 2013. [PubMed]
Intestinal current measurements (ICM) from rectal biopsies are a sensitive means to detect cystic fibrosis transmembrane conductance regulator (CFTR) function, but have not been optimized for multicenter use. We piloted multicenter standard operating procedures (SOPs) to detect CFTR activity by ICM and examined key questions for use in clinical trials. SOPs for ICM using human rectal biopsies were developed across three centers and used to characterize ion transport from non-CF and CF subjects (two severe CFTR mutations). All data were centrally evaluated by a blinded interpreter. SOPs were then used across four centers to examine the effect of cold storage on CFTR currents and compare CFTR currents in biopsies from one subject studied simultaneously either at two sites (24 hours post-biopsy) or when biopsies were obtained by either forceps or suction. Rectal biopsies from 44 non-CF and 17 CF subjects were analyzed. Mean differences (A/cm(2); 95% confidence intervals) between CF and non-CF were forskolin/IBMX=102.6(128.0 to 81.1), carbachol=96.3(118.7 to 73.9), forskolin/IBMX+carbachol=200.9(243.1 to 158.6), and bumetanide=-44.6 (-33.7 to -55.6) (P<0.005, CF vs non-CF for all parameters). Receiver Operating Characteristic curves indicated that each parameter discriminated CF from non-CF subjects (area under the curve of 0.94-0.98). CFTR dependent currents following 18-24 hours of cold storage for forskolin/IBMX, carbachol, and forskolin/IBMX+carbachol stimulation (n=17 non-CF subjects) were 44%, 47.5%, and 47.3%, respectively of those in fresh biopsies. CFTR-dependent currents from biopsies studied after cold storage at two sites simultaneously demonstrated moderate correlation (n=14 non-CF subjects, Pearson correlation coefficients 0.389, 0.484, and 0.533). Similar CFTR dependent currents were detected from fresh biopsies obtained by either forceps or suction (within-subject comparisons, n=22 biopsies from three non-CF subjects).

The authors concluded multicentre intestinal current measurement a feasible CFTR outcome measure that discriminates CF from non-CF ion transport, offers unique advantages over other CFTR bioassays, and warrants further development as a potential CFTR biomarker

–  Previous studies were published as far back as 1991 – Veeze HJ, Sinaasappel M, Bijman J, Bouquet J, de Jonge HR. Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis. Gastroenterology 1991; 101:398-403. [PubMed]; Hardcastle J et al. Failure of cholinergic stimulation to induce a secretory response from the rectal mucosa in cystic fibrosis. Gut 1991; 32:1035-1039. [PubMed]; Cohen-Cymberknoh M et al, Pediatr Pulmonol 2013; 48:229-235. [PubMed].

1996 Hayden UL, Carey HV. Cellular localization of cystic fibrosis transmembrane regulator protein in piglet and mouse intestine. Cell Tissue Res. 1996 Feb;283(2):209-13. [PubMed]
Antibodies raised against the cystic fibrosis transmembrane regulator protein (CFTR) were used to localize CFTR in intestinal tissues of piglets and mice. Positive staining for CFTR was detected in goblet cells of both species. A second population of epithelial cells of unknown phenotype was also labeled by anti-CFTR antibodies. The labeling pattern was abolished by preincubation of anti-CFTR antibodies with the immunogen or when non-immune IgG was used in place of anti-CFTR antibodies.

– These results support other studies that suggest that alterations in goblet cell function may be involved in the intestinal abnormalities associated with cystic fibrosis.The date of the paper is correct.

Dr Morgan Green is in the Department of Medicine, University of Alabama at Birmingham, United States

Simon Y Graeber, Constanze Vitzthum, Marcus A Mall.  Potential of Intestinal Current Measurement for Personalized Treatment of Patients with Cystic Fibrosis.  J Pers Med. 2021 May 8;11(5):384.doi: 10.3390/jpm11050384.[Pubmed]Free PMC article

Refinement of personalized treatment of cystic fibrosis (CF) with emerging medicines targeting the CF basic defect will likely benefit from biomarkers sensitive to detect improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function in individual patients. Intestinal current measurement (ICM) is a technique that enables quantitative assessment of CFTR chloride channel function in rectal tissues or other intestinal epithelia. ICM was originally developed to study the CF ion transport defect in the intestine and has been established as a sensitive biomarker of CFTR function and diagnostic test for CF. With the emergence of CFTR-directed therapeutics, ICM has become an important tool to estimate the level of rescue of CFTR function achieved by approved CFTR modulators, both at the level of CFTR genotype groups, as well as individual patients with CF. In combination with preclinical patient-derived cell culture models, ICM may aid the development of targeted therapies for patients with rare CFTR mutations. Here, we review the principles of ICM and examine how this CFTR biomarker may be used to support diagnostic testing and enhance personalized medicine for individual patients with common as well as rare CFTR mutations in the new era of medicines targeting the underlying cause of CF.

Dr Simon Y Graeber is at the Charité-Universitätsmedizin Berlin, Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, 13353 Berlin, Germany.

Birimberg-Schwartz L; Wilschanski M.  Cystic Fibrosis Related Gastrointestinal Manifestations – Moving Forward. Journal of Cystic Fibrosis. 20(4):562-563, 2021 07.[Pubmed]
(No abstract so I have summarised some of the main points of the full version- JML)

With the increase in life expectancy new disease-related manifestations are emerging such as an increased risk of colorectal cancer. Hepato-biliary GI manifestations are quite variable and include exocrine pancreatic disease, meconium ileus, constipation, distal intestinal obstruction syndrome, CF related liver disease, small intestinal bacterial overgrowth and intestinal inflammation.
The authors comment that CF related GI symptoms are not always properly addressed, and patients hesitate to report them to their pulmonologist. They stress the need for a dedicated gastroenterologist to work as part of the CF centre team.
The paucity of high-quality CF-GI studies prompted the CF Foundation to declare recently such studies are a priority. Current knowledge suggests that altered intestinal fluid secretions, dysbiosis and inflammation contribute to gut dysfunction. They also note the lack of GI clinical outcome measures which will be needed with CFTR modulator drug trials.
Nonetheless, the authors are encouraged to see “sprouting of research in the field which will lead the way to improved patient GF-GI disease outcomes”.

Dr Liron Birimberg-Schwartz and Dr Michael Wilschanski are in the  Department of Pediatric Gastroenterology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of  Jerusalem, Israel.

Delphine Ley, Dominique Turck^. Digestive outcomes in Cystic fibrosis.  Best Pract Res Clin Gastroenterol Feb-Mar 2022;56-57:101788.doi: 10.1016/j.bpg.2022.101788. Epub 2022 Feb 24.[Pubmed]

Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disease in Caucasians, affecting the respiratory tract, but also the pancreas, gut, and hepatobiliary tract. CF is caused by variants in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Prognosis of CF has markedly improved over the last 20 years because of the management in CF centers and recent introduction of CFTR modulators, aimed at correcting the defective CFTR protein. There are nowadays more CF adults than children, with a predicted median survival age of around 50 years in high-income countries. Around 85% of CF patients have pancreatic insufficiency present at birth. Gastroesophageal reflux disease (GERD) is more frequent in CF patients, but its role on decline in lung health is controversial. Distal small bowel obstruction syndrome (DIOS) caused by meconium-like stool plugs occurs at any age after the neonatal period, affecting up to 15-20% of CF patients. Because of increased life expectancy, most CF patients are expected to live to their fifties or beyond, when cancer is more frequent. In addition, CF is associated with a higher risk for GI malignancy as compared with the general population. Colorectal cancer represents the most significant risk, and colonoscopy-based screening is recommended from 40 years of age onwards. Other digestive outcomes in CF reviewed in this paper include meconium ileus, Clostridium difficile infection, intussusception, acute appendicitis, small intestinal bacterial overgrowth, appendiceal mucocele and rectal prolapse. Every CF Center should comprise a gastroenterologist with expertise in the care of CF patients.

Delphine Ley  is at the Univ. Lille, Inserm, CHU Lille, U1286 – INFINITE – Institute for Translational Research in Inflammation, F-59000, Lille, France; Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Jeanne de Flandre Children’s Hospital, CHU Lille, F-59000, Lille, France

Meghana Sathe  , Baha Moshiree , Enid Aliaj  , MinJae Lee  , Jessica Hudson   , Alex Gifford  , Susan Attel  , Breck Gamel Med , Steven D Freedman , Sarah Jane Schwarzenberg  , A Jay Freeman.    Need to study simplification of gastrointestinal medication regimen in cystic fibrosis in the era of highly effective modulators.Pediatr Pulmonol. 2022 Nov 30.  doi: 10.1002/ppul.26257.  Online ahead of print.  pubmed.ncbi.nlm.nih.gov/36448312/

Introduction: The success of highly effective modulator therapy (HEMT) has led to consideration of simpler regimens for people with CF (PwCF) with opportunities to modify burdensome regimens. Despite the intuitive appeal of discontinuing chronic therapies no longer necessary, this process should be pursued systematically to ensure safety, adherence, and validate patient-centered preferences. We designed a questionnaire to determine the state of use of acid suppressive medications (ASM) and pancreatic enzyme therapy (PERT), current self-withdrawal and provider-directed withdrawal practices, and interest in a standardized withdrawal study.
Methods: In collaboration with CF Foundation (CFF), a questionnaire was developed and distributed to members of Community Voice (CV, comprised of PwCF and their loved ones), and CF providers regarding the need to study simplifying the gastrointestinal (GI) regimen for PwCF on HEMT.
Results: Approximately 20-40% of CV or CF providers have decreased or stopped ASM for those on HEMT. For PERT, CV and CF providers have decreased dose (34-48% and approximately 25%, respectively) more often than having stopped it altogether (13-24% and 3-12%, respectively). Cumulatively, there is interest in pursuing research in this area (86% CV, 89% CF providers) and willingness to enroll in such a study (80% CV and 89% CF providers).

Conclusion: Systematically studying withdrawal of common GI medications, ASM and PERT, is important to CV and CF providers. Decreases in dosing and withdrawal are already taking place without evidence to support this practice. This questionnaire is the first step in designing a GI medication simplification study in PwCF on HEMT. This article is protected by copyright. All rights reserved.

Dr Meghana Sathe is a paedaitric gastroenterologist and professor at Pediatric Gastroenterology, Hepatology and Nutrition, University of Texas Southwestern/Children’s Health, Dallas, TX.