Probiotics treatment for the prevention of cystic fibrosis-related liver disease

 

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  1. Definitie casus, probleemstelling en wetenschappelijke vraag (MAXIMAAL 250 WOORDEN)
    Kies als groep één patiëntcasus met een vraag of onduidelijkheid betreffende het wetenschappelijke draagvlak voor de gehanteerde strategie (diagnostiek en/of interventie). Omschrijf kort de casus met de gevolgde strategie en de probleemstelling. Definieer een wetenschappelijk correct geformuleerde vraag, met de mogelijkheid tot uitwerking van de onderstaande onderdelen.

Case

Mr. Dijkstra, 23 years old, is affected by cystic fibrosis (CF). Besides frequent pulmonary exacerbations, Mr. Dijkstra also has exocrine pancreatic insufficiency, frequent abdominal pain and nasal polyps. Mr. Dijkstra is followed at the CF policlinic for adults at the UMCG, where he receives a checkup every 3 months. For the last 6 years, Mr. Dijkstra has had elevated liver enzymes and increased echogenicity on liver echography. He was told that he may have a mild degree of cystic-fibrosis liver disease (CFLD) and he was given ursodeoxycholic acid (UDCA) 20 mg/kg/day. He was told that this treatment could perhaps prevent further progression of his liver disease. However, this year, his yearly liver echography brought bad news: Mr. Dijkstra had developed liver cirrhosis.

Problem

Mr. Dijkstra developed progression of CFLD despite treatment with UDCA. Mr. Dijkstra was handled according to the UMCG CF guidelines. These guidelines do not report any other prophylactic or curative treatment for CFLD than UDCA, and further specify that treatment with UDCA is controversial.

Research question

We reviewed the literature concerning the management of CFLD and hypothesized that a possible preventative treatment for CFLD could be probiotics. Our research question is: “Can treatment with probiotics delay the development of CFLD?”

 

 

 

 

 

 

 

 

  1. Wetenschappelijke analyse van zelfgezochte literatuur (MAXIMAAL 500 WOORDEN)
    Zoek literatuur over de gevolgde strategie bij de patiënt (diagnostiek en/of interventie) en over alternatieve strategieën voor het probleem in de casus. Analyseer de essentie(s) van de artikelen en de voor- en nadelen van onderzochte strategieën. Vat dit samen om zo tot een beargumenteerde keuze te komen welke strategie in de patiëntcasus wetenschappelijk gezien de beste is. Er dienen tenminste 6 artikelen te worden behandeld uit tijdschriften die een peer-review systeem hanteren. Bij voorkeur gaan minimaal 2 artikelen over een alternatieve strategie voor het probleem in de casus.

 

Cystic fibrosis (CF) is an autosomal recessive disease in which reduced cystic fibrosis transmembrane conductance regulator (CFTR) function in the epithelia leads to accumulation of viscous mucus, which promotes obstruction and bacterial infection (1). The main cause of death in CF patients is obstructive lung disease (2). In addition, one third of patients develop liver disease, which represents the third leading cause of death in CF (3). CF-related liver disease (CFLD) encompasses numerous hepatobiliary pathologies, ranging from abnormal liver biochemistry and mild steatosis, (neonatal) cholestasis, biliary tract disease, and even cirrhosis with portal hypertension (4).

 

The study of CFLD treatments is hindered by the lack of knowledge concerning its pathophysiology. In the liver, CFTR is solely expressed in cholangiocytes (5). The most widely accepted hypothesis for CFLD development proposes the increased bile viscosity due to CFTR dysfunction would lead to reduced bile flow, resulting in accumulation of toxic bile acids in biliary ductules. Inflammation resulting from toxicity would then lead to fibrosis (6). However, this hypothesis is not supported by histological findings in CF patients, in whom bile inspissation was infrequently found and did not correlate with liver fibrosis (7). Regardless, to date, the most widely used treatment for CFLD, the hydrophilic bile acid ursodeoxycholic acid (UDCA), relies on this hypothesis and aims to avoid bile duct blockage by inducing a bicarbonate-rich bile that flows more easily (8). A Cochrane review revealed that there is insufficient evidence to support the use of UDCA in CF (9). In fact, although its use was associated with slight improvements in liver enzymes in the short term in some studies (10–13), long-term randomized-controlled trials showing effectiveness in preventing cirrhosis, liver transplantation or death are lacking. Moreover, recently, concerns have been raised concerning the safety of UDCA, as use in high doses was associated with increased risk of malignancy in primary sclerosing cholangitis (14,15). Unfortunately, the effects on CFLD of the recently developed CFTR modulators (Ivacaftor, Lumacaftor) that target the basic cellular defect have not been studied yet. Besides UDCA and CFTR modulators, a number of experimental treatments are being studied. Other bile acid-derivatives, such as obeticholic acid and nor-UDCA, have shown positive outcomes in nonalcoholic steatohepatitis and primary sclerosing cholangitis (16,17) and are theoretically thought to have potentials in CFLD. Of these, however, nor-UDCA did not prevent or decrease biliary injury in a CF mouse model (18). Other treatments that aim to prevent hepatic inflammation or fibrosis are agonists for farnesoid X receptor/G protein-coupled bile acid receptor 1(TGR5), fibroblast growth factor 1 and vitamin D receptor agonists, which showed benefits in mouse models of non-CF liver diseases (19–21). Moreover, supplementation of docosahexaenoic acid, stimulation of peroxisome proliferator-activated receptor, as well as Src inhibition have been used with success in a mouse model of CF, where they reduced bile duct injury (22–24). However, all these treatments are in a very early experimental stage and, besides effectiveness, their safety is to be explored. Once cirrhosis and portal hypertension have ensued, supportive therapy is the mainstay and liver transplantation can take place in selected cases (25).

In conclusion, there is currently no concrete alternative to UDCA. 522 words

 

 

  1. Onderzoeksplan om het probleem beter in kaart te brengen en nieuwe kennis te genereren (wetenschappelijk redeneren) (MAXIMAAL 500 WOORDEN)
    Maak een onderzoeksplan voor wetenschappelijk onderzoek om de uit de literatuur voortkomende controverses of hiaten beter in kaart te brengen en meer duidelijkheid hierover te krijgen (en zo mogelijk op te lossen). Beschrijf kort de aanleiding voor het onderzoek (de controverses uit de gekozen artikelen of hiaten in de bestaande evidentie met betrekking tot de probleemstelling van de casus) en geef de probleemstelling en het plan van aanpak. Zorg dat in het onderzoeksplan in ieder geval een beschrijving van de steekproefomvang met powerberekening staat en een beslissingsdiagram waaruit naar voren komt wat de betekenis is van een positief danwel negatief resultaat van de te onderzoeken hypotheses. Uit het beslissingsdiagram komt naar voren welke (deel)onderzoeken volgen als geformuleerde hypothesen verworpen of bevestigd worden.

UDCA treatment, although not proven to be effective, is thus the only treatment option for CFLD and is based on the most widely accepted CFLD pathophysiological hypothesis.

An alternative hypothesis for CFLD pathophysiology is that the dysbiosis, small-intestinal bacterial overgrowth and increased permeability observed in the CF gut (26–31) could allow excessive translocation of bacterial products from enteric microflora (endotoxins, pathogen-associated molecular patterns) from the gut to the liver (32). Whereas, normally, cholangiocytes do not react to these bacterial stimuli, it was found that CF cholangiocytes respond with excessive pro-inflammatory cytokine secretion, which can stimulate inflammation and fibrosis in the liver (18). According to this hypothesis, a therapeutic option for CFLD could be targeting hepatic inflammation, as discussed above. Instead, to prevent CFLD development, the translocation of bacterial products from the gut to the liver could be reduced by targeting dysbiosis, SIBO and abnormal intestinal permeability in CF. It was already shown that the insurgence of biliary damage, as induced by provoking colitis in CF mice, was reduced by bowel decontamination through antibiotic treatment (18), although it is unclear whether this antibiotic allowed for similar extent of colitis in the groups compared. Such intensive antibiotic treatment, however, is undesirable in patients, whereas milder antibiotic treatments already used in CF further exacerbate dysbiosis by killing beneficial bacteria. A safe, potential way to reduce dysbiosis in CF patients is through the use of probiotics. Probiotics could improve the inflammatory status of the CF gut and reduce its permeability (10), as well as decrease the number of pathogenic bacteria able to elicit inflammatory responses in the liver. Therefore, we want to investigate the effects of probiotics treatment on the development of CFLD.

Here follows: description of trial (rationale human subjects, subjects, intervention, schedule, outcomes), power analysis and beslissingsdiagram.

Rationale human subjects: mouse model of colitis is difficult to use, already far enough in mouse models to proceed in humans, robiotics are safe.

Idea 1: give probiotics to a random group of CF patients at diagnosis, then follow them up once a year and (years later) compare the outcomes (liver enzymes, echo) of the group taking probiotics vs the group not taking probiotics. Pro: answers research question ‘do probiotics prevent/delay CFLD development’

Idea 2: run a short-term study on children and adult with CF (confirmed by genetic analysis) with raised liver enzymes and/or increased liver echogenicity but without liver cirrhosis, and who do not currently use URSO. The intervention would be probiotics vs UDCA for 6 months, either as parallel trial with patients matched based on starting liver enzymes and fibroscan (one group takes probiotics and one UDCA), or as crossover (patients take first one treatment and then the other). Outcomes are the (delta) change of liver enzymes and of liver echogenicity (Fibroscan). Cons: does not answer research question (this is more about treating CFLD) and is a short-term study, which does not add much to what we know about UDCA, and does not say much about the long-term efficacy of probiotics.

  1. Relevance, impact and ethical consequences (max 250 words)
    Describe briefly the most important ethical consequences that follow from the research proposal as described in the previous section. These are ethical consequences that follow from the OWN research proposal and not ethical problems in scientific research in general. Think of the significance of this research for the patient. But also the impact of the research on the patient in relation to the social importance and / or the socio-economic impact of the research

Make sure to answer these questions in this section:

  • Probiotics treatment for the prevention of cystic fibrosis-related liver disease…
  • (begin treatment at 6 year old patients until they become 18 years old to properly study the effect of probiotics on development of cystic fibrosis liver cirrhosis).

Is it ethical to give this treatment for this long ? Because only 10% of children patients will develop chirrosis, so is it ethical to give unnecessary treatment (probiotics and UDCA) to the other 90% who will either way not develop cirrhosis ?

Why did we chose to study probiotics effect in humans directly? Because we do not have animal models suitable for the study of the progression of cirrhosis in CF patients and the effect of probiotics on it.

Is it ethical to do Probiotics treatment for the prevention of cystic fibrosis-related liver disease research in children
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