Cystic Fibrosis-Navigating Gastrointestinal Complications

4/8/2021

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Participating in the Webinar

All attendees will be muted and will remain in Listen Only Mode.

Type your questions here so that the moderator can see them. Not all questions will be answered but we will get to as many as possible.

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American College of Gastroenterology

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How to Receive CME and MOC Points

LIVE VIRTUAL GRAND ROUNDS WEBINAR

ACG will send a link to a CME & MOC evaluation to all attendees on the live webinar.

ABIM Board Certified physicians need to complete their MOC activities by December 31, 2021 in order for the MOC points to count toward any MOC requirements that are due by the end of the year. No MOC credit may be awarded after March 1, 2022 for this activity.

MOC QUESTION

If you plan to claim MOC Points for this activity, you will be asked to: Please list specific changes you will make in your

practice as a result of the information you received from this activity.

Include specific strategies or changes that you plan to implement.THESE ANSWERS WILL BE REVIEWED.

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ACG Virtual Grand RoundsJoin us for upcoming Virtual Grand Rounds!

Visit gi.org/ACGVGR to Register

Week 16, 2021Opioid Induced Esophageal Dysfunction: What to Know and How to Manage ItMarcelo F. Vela, MD, MSCR, FACGApril 22, 2021 at Noon Eastern

Week 15, 2021Exocrine Pancreatic InsufficiencyJodie A. Barkin, MDApril 15, 2021 at Noon Eastern

Disclosures:

Speaker: Christine Y. Hachem, MD, FACGDIGEST grant awardee from Cystic fibrosis foundation

Moderator: James M. Abraham, MDDr. Abraham, faculty for this educational event, has no relevant financial relationship(s) with ineligible companies to disclose.

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Cystic Fibrosis‐Navigating Gastrointestinal ComplicationsChristine Y. Hachem, MD, FACG

Objectives

• Recognize GI dysfunction in Cystic Fibrosis

• Identify risk factors for GI complications in Cystic Fibrosis

• Discuss management of GI issues in Cystic Fibrosis

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Genetics of Cystic Fibrosis

https://www.cff.org/What‐is‐CF/Genetics/Types‐of‐CFTR‐Mutations

• Autosomal recessive• 10 million people in US

are CF carriers• More than 1700

mutations of the CFTR gene identified

• CFTR mutations found throughout the body

• Therapies are directed at mutation class

Advent of personalized medicine‐CFTR modulator therapies• Correct the malfunctioning protein made by the CFTR gene

• Different mutations cause different defects in the protein

• Medications are effective only in people with specific mutations

• Four CFTR modulators for people with certain CFTR mutations: • Kalydeco® (ivacaftor)

• Orkambi® (lumacaftor/ivacaftor)

• Symdeko® (tezacaftor/ivacaftor)

• Trikafta® (elexacaftor/tezacaftor/ivacaftor)

Types of CFTR Mutations CF FoundationCystic Fibrosis Foundation Patient Registry 2019 Annual Data Report Bethesda, Maryland ©2020 Cystic Fibrosis Foundation

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Survival in Cystic Fibrosis Improving

Cystic Fibrosis Foundation Patient Registry 2019 Annual Data Report Bethesda, Maryland ©2020 Cystic Fibrosis Foundation

Improved survivalAdult population increasingMedian survival age ~50 years

Beyond pulmonary disease…

Rey Annu Rev Med 2019

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FINDING THE INTESTINAL

FEV1

EQUIVALENT:THE GALAXY

STUDY

402 children and adults (ages 2‐61) enrolled at 26 CF Centers

Feasibility of out of clinic community‐endorsed ePROM questionnaires

Define prevalence and variability of GI symptoms

Identify GI outcome measures for clinical trials

ResultsFirst study through the TDN to use ePROMs

77.6% of subjects completed all PROMS

Study completed in 4 months

Courtesy of Steve Freedman, MD

GALAXY DATA: MOST PREVALENT GI SYMPTOMS

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Bloating Distention Postprandial Fullness

% Prevalence Dysmotility

Dysbiosis


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MODERATE TO VERY SEVERE GI SYMPTOMS AS A FUNCTION OF AGE

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Incomplete BM Straining Fullness Bloating Distention

Age <18 Age ≥18

% Prevalence


HIGH DEGREE OF DISSATISFACTION WITH CURRENT GI TREATMENTS

We now have the tools to address this:• DIGEST to expand the multidisciplinary

workforce• Best practice guidelines• Research tools• New therapies ‐ HEMs


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GERD in Cystic Fibrosis


Incidence of GERD in CF


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Factors for Increased GERD in CF

Sathe Pediatr Clin N Am 63 (2016)

Transient LES Relaxation in CF

90% of reflux episodes in adult patients with CF occur during transient LES relaxations

Pauwells 2012 AJG:107:1346

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Use of Acid Suppression in CF


Exponential Rise in Use of PPI in CF registry

Robinson Ann Am Thorac Soc 2014

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Indication for PPI Use in Patients with CF

McCrory Pharmcotherapy 2018;38(7):725‐29

Consequences of GERD in CF

•Aspiration events due to proximal reflux

• Lung decline•Chronic rejection•Barrett’s esophagus, GE junction adenocarcinoma

•3‐fold increased odds of BE or related neoplasia in patients with CF

•Average age is 36

Knotts Journal of Cystic Fibrosis 18 (2019) 425–429

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GI complications in CF


Intestinal Dysmotility and CF

• Delayed gastric emptying in 1/3 adults

• Delayed small bowel transit

• Constipation

• Distal Intestinal Obstructive Syndrome• Partial or complete intestinal obstruction in terminal ileum/cecum

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DIOS and CF


Unique to CFOccurs at all ages

Symptoms and Diagnosis of DIOS/Constipation

• Symptoms•Acute or subacute abdominal pain•Abdominal distention•Palpable mass in the right lower quadrant

•Diagnosis•KUB•CT

J.M. Abraham, C.J. Taylor / Journal of Cystic Fibrosis 16 (2017) S40–S49

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Pathophysiology of DIOS

• Intestinal dysmotility

• Intestinal inflammation

• Fat malabsorption (activation of ileal break)

• Defective ion and water secretion into the gut lumen

Abraham J Cyst Fibrosis 2017

Risk Factors for DIOS/Constipation in CF

• Adults

• Dehydration

• Genotype

• Pancreatic insufficiency – 90%

• History of meconium ileus‐ 50%

• Lung transplant history‐10‐20% in post operative period

• Prior DIOS

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Management of Constipation/DIOS

•Constipation; a spectrum to “DIOS”• Keep at risk patients on Polyethylene glycol (PEG)

• Teach to recognize early symptoms, start oral polyethylene glycol at high dose at home

• Slow NG PEG +/‐ lytes (“Golytely”). “colonoscopy clean out”

• Minimize pain meds

• Hyperosmolar contrast enema/Gastrograffin enemas

• Mucomyst

• Anecdotal experience with other bowel agents (lubiprostone, linaclotide, etc)

• Adherence to PERT

• Surgical consultation

Surgery

Endoscopy/Imaging Therapies

Aggressive Medical therapy

GI Management

A child with constipation and abdominal pain

Courtesy of Jeff Teckman, MD

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GI Management

Hyperosmolar contrast enema refluxing terminal ileumCourtesy of Jeff Teckman, MD

Post evacuation film

GI Dysfunction in CF‐Pancreas

•90% have pancreatic insufficiency

•CFTR mutations predictive • Class I‐III‐> pancreatic insufficient • Class IV‐V‐> pancreatic sufficient

•Diagnosis: fat malabsorption, fecal elastase, secretin stimulation testing

•Usually develops early in life, but can appear later

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IS PANCREATIC DAMAGE REVERSIBLE?Most damage occurs in utero/1st year of life

Thought irreversible but some restoration possibleARRIVAL: 19 children with CF, ages 1‐2 yrs, Ivacaftor for 24 wks

KLIMB: 28 children with CF, ages 2‐5 yrs, Ivacaftor for 84 wks

Is there a point of no return?May improve ductal bicarbonate secretion (any age)

But recover acinar cell function only in young children

Opportunity to prevent treatment of non‐pancreatic GI symptoms with higher‐than‐needed

PERT doses

Rosenfeld et al. Lancet Respir Med. 2018 July ; 6: 545–553Rosenfeld et al. Journal of Cystic Fibrosis. 2019; 18: 838–843McNamara et al. Respir Med. 2019; 7: 325–335PANCREAS

Slide courtesy of Steven Freedman, MD

CF Management of Pancreatic Insufficiency

• PERT with fat soluble vitamin supplementation

• Acid suppressing medications to increase pH of gastric fluid delivered to duodenum

• Dosages titrated for weight and symptoms of malabsorption

• Adults: 500‐2500 lipase units/kg/meal, ½ for snack or 500‐4000 lipase units/g fat eaten

• Fecal elastase annually if Pancreatic Sufficient

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Use of PERT in Cystic Fibrosis


Use of PPI in Pancreatic Insufficiency

• If persistent fecal fat malabsorption despite hypercaloric diets and maximized enteric coated pancreatic enzymes

• Enteric coated enzymes need to be exposed to pH>5.8 for enzyme release

• Has been shown to improve acid steatocrit, anthropometric parameters

• H2RA not as good at acid suppression‐> variable results

• Low dose PPI good enough to show a change

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Pancreatitis in Cystic Fibrosis

• Milder class mutations Class IV and V

• Pancreatic sufficient

• Good correlation between genotype and PI/PS but not pancreatitis

• Risk factors for pancreatitis: pulmonary exacerbations, viral infections, post surgical

• Can be initial presentation

• Recurrent in 2‐13%

• Can lead to CF related diabetes

Liver Disease in Cystic Fibrosis


Presence of liver cirrhosis and portal hypertension or Liver involvement (liver enzyme elevations, steatosis, fibrosis,

cholangiopathy, and/or ultrasound abnormalities)

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CF liver disease

•About 1/3 have evidence of some liver dysfunction by young adulthood. Risk may increase over time.

•Hepatic steatosis is most common finding (10‐70%)

• Transient elevation in liver enzymes seen frequently

• 8‐10% severe CFLD (cirrhosis or transplant) by age 25‐30 (class I‐III mutation with PI and male gender)

•Image: DOI:10.1007/s00428-007-0434-3

Pathophysiology may be twofold: 1. Early Childhood (median age 10)

Biliary cirrhosis and portal hypertension

Due to bile duct plugging

2. Late Childhood/AdultsNodular regenerative hyperplasia without cirrhosis

Due to obliterative venopathy

Distal spleno‐renal shunt for symptomatic portal htn

Modifier genes‐1 Antitrypsin: 7‐fold increased risk for advanced CFLDPresent only in 9% of individuals with advanced CFLD

Sokol et al. JPGN. 1999; 28 Suppl 1:S1‐S13Ling et al. JPGN. 2019;69: 351–357Wu et al. Clin Gastro Hepatol. 2019;17:2134–2136Siegel et al. J Pediatr. 2020;219:62‐69Lemoine C et al. J Ped Surg. 2019; 54:1076‐1082

CFLD: UNDERSTANDING THE CAUSE

LIVERCourtesy of Steve Freedman, MD

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CF Severe Liver Disease Risk Factors

•Male sex•Δ F508 homozygote•Worse lung function•Worse nutritional status•History of meconium ileus

CFLD: DEFINING BIOMARKERS

PUSH trialDefining biomarkers predictive of progression to CFLD

Liver US patterns (heterogeneous or nodular) correlated with biomarkers of liver disease severity

4‐year planned interim analysisHeterogeneous liver ultrasound pattern using research criteria

9.1‐fold increased incidence of nodular pattern, surrogate for advanced CFLD

Reflects clinically relevant, progressive liver disease

Opens the possibility of preventive interventions

Sokol et al. JPGN. 1999; 28 Suppl 1:S1‐S13Ling et al. JPGN. 2019;69: 351–357Wu et al. Clin Gastro Hepatol. 2019;17:2134–2136Siegel et al. J Pediatr. 2020;219:62‐69

LIVER


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Causes of Death


CF complications of Cirrhosis


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GI bleeding in CFLD

• Variceal bleeding rates 40‐50% historically

• Recent registry data not common <10% (6.6% at 10 years)

• Bleeding occurs in adolescence

• Increased mortality among CF cirrhosis patients

• Cirrhosis with VH‐> 5x more likely to be transplanted

Ye J pediatr Gastroenterol Nutr 2018

Suggested algorithm for liver disease in CF

Sathe Pediatr Clin N Am 2016

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Use of ursodiol in CF

Cystic Fibrosis Foundation Patient Registry 2019 Annual Data Report Bethesda, Maryland ©2020 Cystic Fibrosis FoundationCheng, K Cochrane Database Syst Rev 2017

GI Cancers and Cystic Fibrosis

• Increased risk of GI tract cancers:• GE junction, biliary tract, small bowel, colon

•CF Lung transplant recipients have higher risk of cancer than non‐CF lung transplant recipients•Esophageal, CRC, PTLD

• NEJM 1995; 332: 494

• J Natl Cancer Inst 2013; 105: 122

• J Cyst Fibros 2016; 16: 91

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Colon Cancer Risk in Cystic Fibrosisrosis

• CFTR: tumor suppressor gene in GI tract of mice• Loss of CFTR results in GI tumor formation• Dysregulation of immune response, intestinal stem cells and growth signaling regulators

• Stagnant mucous‐> bacterial overgrowth‐> dysregulation in gene expression and epithelial homeostasis, inflammation

• Nearly all CRC in CF patients diagnosed before age 50• Screening colonoscopy at age 50 not appropriate in CF patients

• Majority of CRC appear to be right sided• Science 2009; 323: 1747

• Oncogene 2016; 35: 4179

Risk Factors for Cystic Fibrosis related CRC

•Male sex

• Severe functional CF genotype• F508del homozygosity

•Age >30 years • Lung transplantation

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Colonoscopy in Cystic Fibrosis

• Prospective study University of Minnesota 2008‐2015

• Screening colonoscopy at age 40 in CF

• Adenomatous polyps detected on initial screening colon in 49%

• 25% had 1 or more advanced adenomas (5 x higher than general population)

• Majority had > 3 adenomatous polyps

• Negative initial screening‐> follow up within 49 months‐47% adenomas (half of these with advanced adenomas)

Observed and expected post transplant cancers and SIR among CF patients after transplantation

• CFF patient registry from 1999‐2009

• 250 CF care center programs

• 41,188 CF patients• 8235 person years transplanted CF

• Increased risk of digestive tract cancer in CF patients following transplantation

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Risk of Cancer

• SIR for CF CRC in CF greater than other known risk factors

• Increased risk of digestive tract cancers

• CF patients develop GI malignancies at earlier mean 32.2 years

Alexander CL J Cyst Fibros 2008;7:1‐6Neglia JP NEJM 1995;332 (8):494‐9

What causes colorectal cancer?

• We do not know the exact cause

• Some changes in the genetic material (DNA) in our cells

• Related to lifestyle

• Many risk factors

Risk Factors for Colon Cancer

Cystic Fibrosis and CF post Transplant

Patients

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CF Consensus Recommendation Statement1. Shared decision between patient and provider

2. Jointly managed by CF health care professionals and an endoscopist

3. Colonoscopy only *****

4. Insufficient evidence for the use of CT colonography, FIT/FOBT, or flex‐sig in CRC for CF

1. * Stool based FIT testing may be cost effective and attractive option but FIT characteristics in CF population are lacking

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Cost effectiveness analysis

• Microsimulation screening analysis‐colon model for CRC

• Optimal interval for Colonoscopy rescreening for transplanted individuals with CF with negative prior colon exams was 3 years between age 35‐55

• Prevented 82% of CRC mortality (ICER of $71,000)

• Shorter than the current consensus recommendations

Gini, A Gastro 2018, 154:556

CF Colon Preparation

‐Intensive bowel prep recommended

‐Bowel prep three to four washes (minimum of 1‐liter purgative per wash) with the last wash occurring within 4−6 hours before the examination

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Gastro 2018;154:746

CRC incidence without screening

Gini, A Gastro 2018, 154:556

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Take home points• CF is a multisystem disease that involves the GI tract

• CFTR mutations play a role in GI presentations

• Risk of CRC with CF may be greater than that in Lynch syndrome

• All patients with CF should be screened for CRC with colonoscopy and need extended preps

• Stool based testing may be an option in future

• Multiple opportunities for research in CF GI related diseases

Research and Clinical Grants through Cystic Fibrosis Foundation• Developing Innovative Gastroenterology Specialty Training (DIGEST) Program

• The Cystic Fibrosis Foundation recognizes the growing demand for physicians who are trained to address the unique gastroenterological needs of people with cystic fibrosis and the need for a greater focus on gastrointestinal (GI) issues in the clinical research enterprise.

cff.org

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Questions?

Speaker: Christine Y. Hachem, MD, FACG

Moderator: James M. Abraham, MD

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Documents

Cystic Fibrosis-Navigating Gastrointestinal Complications