Chapters Transcript Video GI Manifestations of Cystic Fibrosis It's my pleasure to introduce our speaker for today, Doctor Jennifer Wong, a board certified pediatric gastroenterologist here at UCSF in Children's Oakland. She provides specialized GI care for children in both the outpatient and inpatient settings in Oakland, as well as working in both the aerodigestive clinic and the cystic fibrosis GI program. Uh, she completed her undergrad education at UC Berkeley, followed by her medical education at Washington University, and then she finally completed her pediatric residency and GI fellowship on the West Coast at Seattle Children's, where she was awarded multiple grants for cystic fibrosis research, including an award from the European Cystic Fibrosis Society. Um, please join me in welcoming Doctor Duang on today's talk on GI manifestations of cystic fibrosis. Thank you so much, Jay, for that lovely introduction. Um, again, my name is Doctor Jennifer Dung, and I'm an assistant professor within the Division of Pediatric Gastroenterology. And I'm excited to share with you all today the GI manifestations of cystic fibrosis. I have no disclosures related to this presentation. We have 4 objectives for today's discussion. First, we will be discussing the benefits and limitations of the tools used for cystic fibrosis screening and diagnosis. Secondly, we'll be discussing the most common GI, hepatobiliary, and pancreatic complications of CF, as well as the management of each. Thirdly, I will discuss the newest drugs that are currently used to treat CF, the CFTR modulators, and discuss how the modulators have really revolutionized the care for children with cystic fibrosis. Finally, I'll be highlighting the racial disparities that exist for patients with CF and again highlighting that more diagnostic tools and therapies are needed for individuals with less common CFTR mutations. So for some background, cystic fibrosis or CF is a multi-organ autosomal recessive disease that affects the gastrointestinal tract, lungs, and reproductive system. It affects 40,000 individuals in the United States and 100,000 individuals globally, and affects people of every racial and ethnic group. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane regulator gene, or CFTR, which encodes the CFTR protein. CFTR is an ion channel expressed by epithelial cells in the lung, intestine, pancreas, and bile ducts. Mutations in CFTR lead to abnormal ion composition and pH, thick mucus, and subsequent disease. Knowing a patient's CFTR mutation helps predict the severity of their disease and their response to CFTR modulator therapy. There are over 2000 mutations of CFTR described. And they're divided into 6 categories depending on how they impact CFTR function and stability. Class 1 to 3 mutations result in absent or non-functional CFTR. These patients have a more severe disease course. For instance, the most common mutation in the United States, Delta 508, is considered a class 2 mutation. Class 4 to 6 mutations result in residual function CFTR, and these patients have a milder disease course. With the introduction of CFTR modulator therapy, an expanded theme has been developed to include Class 7, which encompasses large deletions and frame shift mutations with limited therapeutic options. So why do we care about cystic fibrosis? We care because it involves multiple organ systems. Affects people of all ages and backgrounds. Leads to significantly decreased quality of life and shortened lifespan. And it's important for us as clinicians to recognize CF early, as early interventions have been associated with improved outcomes. Furthermore, it's important to recognize CF as these patients may be eligible for new therapies that can significantly improve their lives. So with that in mind, let's jump into our first objective, which is discussing the benefits and limitations of the tools used for CF screening and diagnosis. Found here are the consensus guidelines from the Cystic Fibrosis Foundation for diagnosing CF. Clinical suspicion for CF starts with either a positive newborn screen. Signs or symptoms suggestive of CA or a positive family history. It's important to note that each state has a different screening protocol for the newborn screen. In California, we use three-tier testing, with the first tier being immunoreactive tripsinogen, or IRT. IRT is elevated in the setting of pancreatic damage, so it's elevated for patients with cystic fibrosis. The second tier is a CFTR variant panel. And the third tier is CFTR sequencing if one variant is identified on the panel. If the newborn screen is positive, or if you have clinical suspicion, these patients go on to sweat chloride testing, which can be performed in infants older than 2 weeks of age and weight greater than 2 kg. It's recommended that sweat chloride testing be done in the outpatient setting, as samples may be of insufficient quality in dehydrated, malnourished children admitted to the hospital. An abnormal sweat chloride is considered equal to or greater than 60 millimoles per liter. For those patients with an abnormal sweat test, we then proceed with genetic testing to confirm two disease-causing mutations in cystic fibrosis. In situations where the diagnosis is unclear, alternative CFTR function testing can be performed. These diagnostic tools have their limitations. First, the genetic screens utilized in the newborn screen typically includes 23 of the most common disease-causing variants in the United States, which typically reflects those of Northern European ancestry. Individuals of non-white backgrounds may have a different distribution of CFTR mutations, and therefore may be missed on newborn screening. Secondly, if a patient has minor or not present pancreatic damage, this may lead to a false negative IRT result on the newborn screen. Given these limitations, it is vital that we recognize the earliest manifestations of CF to optimize these patients' long-term nutritional and pulmonary outcomes. Moving on to our second objective, today, I'll be discussing the most common gastrointestinal, hepatobiliary, and pancreatic complications of CF, which is often some of the earliest manifestations of CF. GI manifestations lead to significant morbidity and mortality. There is growing attention to these GI issues, especially as pulmonary symptoms for these patients are improving and patients are living longer. These GI manifestations are divided into three categories, including pancreatic disease, The diseases of the gastrointestinal tract. And hepatobiliary disease. For today, we'll be focusing on a select number of GI manifestations, including exocrine pancreatic insufficiency. Meconium ileus. Dal intestinal obstruction syndrome. Constipation. And liver involvement. First, starting with the pancreas, Exocrine pancreatic insufficiency, or EPI is common. Up to 60% of infants present with EPI at the time of newborn screening, and 90% of infants by 1 year of age. Signs and symptoms of EPI are those of fat malabsorption, including bloating, abdominal pain, steatorrhea, poor growth, and fat-soluble vitamin deficiencies, specifically deficiencies in vitamins A, D, E, and K. EPI is more common in those with severe CFTR mutations, so the class 1 to 3 mutations. And diagnosis of EPI is usually made with fecal elastase, with an elastase of less than 100 being suggestive of EPI. To avoid the complications of fat malabsorption, it's important to treat patients with EPI with pancreatic enzyme replacement therapy or PERP. There are multiple formulations of PERT, dependent on whether a patient is taking by mouth or via a gastrostomy tube. For orally fed children, there is the enteric coated capsule, which contains beads with digestive enzymes, covered by a coating that dissolves in the small intestine. Examples of this include Creon, Zenpep, pancreas, and Pertsi. For children who are fed via a gastrostomy tube, there's the Relazorp cartridge, which is a digestive inline cartridge containing lipase. The lipase hydrolyzes fats as formula passes through the cartridge prior to entering the child. Another option for G tube fed children is the non-enteric coated tablet, which can be crushed and added to the feed prior to the infusion. Doing a pert is age dependent, but generally starts at 400 to 500 lipase units per kg per meal, to a maximum of 10,000 lipase units per kg per day. If PERD is maximized and malabsorption is still present, gastric acid suppression with a proton pump inhibitor can be considered, which functions to reduce the acidity of the duodenum and improves enzyme release and fat absorption. In addition, these patients need repletion of their fat-soluble vitamins. So vitamins A, D, E, and K. For those children who are unable to adequately take by mouth, G tube feedings may be needed in consultation with a CF dietitian and a gastroenterologist. Moving on to the GI tract, I would like first like to first discuss meconium ileus or MI. Which is a cause of neonatal small bowel obstruction. MI is divided into simple versus complex MI. In simple MI, meconium obstructs the terminal ileum, and the proximal small intestine becomes dilated. These patients usually manifest within the 1st 48 hours of life with bilious emesis, abdominal distention, and failure to pass meconium. Complex MI occurs when there are further complications from the dilated small bowel, including volvulus, ischemic necrosis, perforation, and meconium peritonitis. Diagnosis of MI is made based on clinical symptoms and imaging. On X-ray, you will see findings consistent with small bowel obstruction, including dilated bowel loops and air fluid levels. You may also see the soap bubble sign that occurs due to meconium mixing with air in the small bowel, which is shown in the image to the right. Contrast enema is also helpful to distinguish MI from other causes of neonatal small bowel obstruction, such as Hirsprung's disease and intestinal atresias. Typical findings include microcolon due to colon disuse, as well as meconium pellets in the terminal ilium, which is shown in the white arrow in the image to the right. Management of MI depends on a patient's hemodynamic stability. If a patient is stable with simple MI, management is usually with bowel rest and gastric decompression. Antibiotics, and water-soluble gastrographin hyper osmolaren. If a patient is unstable or with complex MI, surgical intervention may be warranted. Hang on to children and adults, you may encounter distal intestinal obstruction syndrome, or DOS. This is complete or incomplete obstruction of the distal small bowel by incipiated fecal material. It occurs more commonly in adults compared to children, but can really occur at any age. It occurs due to fat malabsorption, and the reason for this is high fecal fat increases the viscosity of the stool and slows intestinal transit, which leads to the incipiation of fecal material in the small bowel. For that reason, risk factors for Dios include anything that is associated with fat malabsorption, including severe CFTR mutations, exocrine pancreatic insufficiency, a prior Dio's history, as well as dehydration. Symptoms of Dios are consistent with small bowel obstruction, including colicy right lower quadrant, abdominal pain, abdominal distention, and bilious vomiting. On imaging with X-ray or CT, you may see small bowel dilation and fecal material in the terminal ileum, as indicated in the arrow to the right. Management of DIDOs is um primarily supportive with rehydration, correction of electrolyte arrangements, as well as osmotic laxatives. For patients who have complete obstruction, hyper osmolarenommas may also be needed. And for refractory or complicated cases, surgery may be needed. It's important to prevent future cases of DOS by ensuring a patient is on the adequate dose and is compliant with their perks. That they remain on osmotic laxatives, even if they don't endorse symptoms of constipation, and that they stay adequately hydrated. Our final GI tract manifestation is constipation, which is very common in the CF population, with a prevalence of greater than 40%. In contrast to Dios, in which stool is present in the distal small intestine, in constipation, stool is distributed throughout the colon. This may increase a patient's risk for developing rectal prolapse. And treatment again, is with osmotic and stimulant laxatives and ensuring the patient is on the appropriate dose and is compliant with their pancreatic enzyme replacement therapy. Moving on to the liver, this is again a very common manifestation in CF patients, with about 40% of patients having some form of liver involvement. That being said, only 5 to 10% have the most significant form of liver disease, which is cirrhosis with or without portal hypertension, usually presenting in the first decade of life. CF liver disease is a significant cause of morbidity and mortality, and is the 4th most common cause of mortality in this population. And it's challenging to treat and diagnose as there is currently no treatment, and it's challenging to diagnose these patients early, as they are often asymptomatic and have a wide range of manifestations. Down here are some of the liver manifestations in CF patients. These manifestations range from asymptomatic liver enzyme elevation and hepatic steatosis, to again, more clinically significant disease, including multilobular cirrhosis with or without portal hypertension, and non-cirrhotic portal hypertension. Part of the challenge is that our current diagnostic tools and symptoms do not predict disease severity well. At our disposal, we have physical exam, labs, and imaging. These patients require at least annual physical exam to assess for complications of portal hypertension, such as hepatosplenomegaly. Labs are done at least annually and include LFTs, GGT, fractionate bilirubin, and platelets, which are used to calculate liver fibrosis indices scores, including the AST to platelet index, fibrosis 4 score, and GDT to platelet ratio. Imaging includes abdominal ultrasound, which is used to assess for signs of portal hypertension, such as splenomegaly and and liver elastography, which is used to measure liver stiffness. In some situations, liver biopsy can also be helpful. As there is currently no cure, management of these patients is primarily supportive, including Nutritional optimization. Risk reduction by avoiding hepatotoxic medications and alcohol. Psodiol, while typically had been used in the past, is not currently recommended for the prevention or treatment of CF liver disease. I'll go into this into greater detail during our next section, but the long-term effect of CFTR modulators on the liver isn't currently known. Finally, it's important to manage the complications, including ascites and GI bleeding. And in certain situations, liver transplant may be warranted, especially in situations of refractory ascites, bleeding, jaundice, and progressive hepatic dysfunction. This may be combined with or without a lung trans. This is a very brief discussion on CF liver disease, which in itself a whole grand rounds talk could be devoted to. If you're interested in learning more, I would recommend the CF consensus guidelines for the screening, evaluation and management of hepatobiliary disease, which is published in hepatology. This was a brief discussion of some of the CFGI manifestations, and there are many more manifestations including pancreatitis, CF related diabetes. In susception, small intestinal bacterial overgrowth, dysbiosis and malignancy. And gallbladder involvement. Moving on to our third objective, I'd like to highlight that CF care in childhood is rapidly changing in the setting of highly effective CFTR modulator therapies. CFTR targeted therapies are drugs that have the potential to reverse or halt disease. They've been shown to increase FEV1. Decrease pulmonary exacerbation and sweat chloride, and increase body mass index. These drugs include potentiators, which improves CFTR channel opening. And correctors which improve protein folding and trafficking to the epithelial cell surface. Here are the FDA therapies that are currently approved in children. As you can see, eligibility depends on a patient's CFTR mutation and their age. Children with a CFTR gamutation, and as young as one month of age may be eligible for IVIA. The newest CFTR therapies are the triple combination therapies, Triafta and Elitric, which are the two shown at the very bottom of the screen. They can be used starting at 2 and 6 years of age, and specifically, a lifttrek is a once daily medication which may improve patient compliance. Modulators have really revolutionized the care of patients with CF. Comparing the last 20 years, so comparing 2003, compared to 2023, there has been an increase in median predicted FEV1 from 80 to 94%. A decreased percentage of both children and adults on inhaled antibiotics. The annual mortality rate has been halved from 16 to 7%. And median predicted survival has nearly doubled. In the past, patients typically lived into their 30s, but nowadays, a patient with CF can potentially survive into their 60s, which is a really revolutionary and life-changing thing. So the question then becomes, what are the implications of these modulators on the GI tract? Well, so far, we've seen an improvement in pancreatic function. And with that decrease in fat val absorption, there have been rising rates of overweight and obesity. We've seen an increase in liver enzyme abnormalities. And finally, as patients are living longer, we've seen increased lifespan and the risk for developing GI malignancies. Starting first with the pancreas, studies have suggested an improvement in pancreatic function with CFTR modulators. Shown here is the arrival study in which children aged 12 to 24 months were given IVAC after. Comparing 24 weeks of therapy to baseline, investigators saw an increase in fecal elastase. And a decrease in IRT, which again is a marker of pancreatic damage. Similar findings were seen in children 4 to 12 months of age. These results suggest that modulators, if given early, may have the potential to reverse pancreatic dysfunction and cystic fibrosis. With that improvement in pancreatic function, we have started seeing some nutritional trends, including rising rates of obesity and overweight status after modulators. Shown here is the 2023 patient registry report. This is a bar plot that demonstrates the last 10 years on the Y axis, so 2013 to 2023. percent on the X axis and categorizes age and sex-reed BMI. Obese is shown by the lime green and overweight by the light blue. As you can see, over the last 10 years, obese and overweight status has been steadily increasing for patients with CF ages 2 to 19 years of age. Why is obesity and overweight status increasing in CA? The causes are likely multifactorial. In addition to improvement in gut fat absorption, there may be a reduction in cellular inflammation, as well as a decrease in resting energy expenditure, especially due to improvement in patients' pulmonary symptoms and fewer pulmonary exacerbations. This is likely compounded by the traditional CF diet, which emphasizes high fat and high calories. This has significant consequences for the CF population, including complications of metabolic syndrome, such as CF related diabetes, cardiovascular disease, hepatic steatosis and dysfunction, and sleep disordered breathing. Furthermore, this may also affect their CF transplant candidacy. For that reason, individualized care regarding diet and exercise is really needed in this post-modulator era. Moving on to the liver, So far with modulators, we've seen some short-term and long-term consequences. In the short term, liver enzyme abnormalities are common, usually 3 to 8 times the upper limit of normal. These abnormalities generally resolve with decreasing modulator dose or with temporary cessation of the treatment. Generally though, patients don't require permanent discontinuation of therapy. Additionally, there have been some rare reports of acute severe hepatitis related to ETI presumed from drug-induced liver injury. Given this, with modulators, it is recommended to check labs frequently, usually monthly LFTs in the 1st 6 months of initiation of therapy. In the long term, we really don't know what effect modulators have. So long-term studies are needed to see if they have the potential to reverse or delay progression of liver disease. Finally, in the GI tract, we have noticed that with increasing life expectancy, so does the risk of GI malignancy. Risk factors for malignancy include a history of lung transplantation, previous episodes of Dios, male gender, and homozygosity for Delta 508. These patients tend to present at a younger age compared to those patients without CF. Presenting in their 30s compared to 50s for patients without CF. The most common GI malignancy is colon carcinoma. Which is why the CF Foundation recommends screening with colonoscopy, which is done every 2 years, post-s solid organ transplant for patients older than 30. And every 5 years for all of their patients greater than 40. What about other GI symptoms? In the United States, the POMIS study includes 56 CF centers, and what investigators found is that after 6 months of Alexxoa tea, Icater or ETI they have seen a decrease in fecal inflammation as measured by calprotectin, and a decrease in some GI symptoms, including bloating and rectal symptoms. In the UK and Ireland, The recover study has shown that after 6 months, there's a decrease infla inflammation, as again measured by calprotectin and M2 pyruva kinase. And a significant decrease in pain, reflux, disorders of appetite, and impaired quality of life scores after 12 months of therapy. Thus, there could be a potential reduction in GI symptoms with modulators. Further improvement of these GI symptoms may be seen with earlier initiation of therapy, and so ongoing studies are being done in children ages 6 to 11, so the promised pediatric study, and children under 5 years of age, which is the Begin study. Our last objective is to discuss the racial disparities that exist for patients with CF and to highlight that more diagnostic tools and therapies are needed for uncommon CFTR mutations. As I've mentioned previously, CF may be missed in certain racial and ethnic groups. Most of the genetic screens in the newborn screen, as well as the carrier screen, includes 23 of the most common disease-causing mutations, which typically reflects those of Northern European ancestry. There are different CFTR variants in those categorized as black and African American. Native Indian and Native Alaskan, Asian and Hispanic. Shown here is the detection rate for the 23 mutation panel for carrier screen. As you can see, Ashkenazi Jewish has the highest detection rate of 94%, but African American and Asian Americans have the lowest rates of detection. This can result in a delayed diagnosis and intervention, and creates racial disparities. For those individuals, CFTR gene sequencing may be necessary. In addition to this, these same groups are less likely to be eligible for modulators based on their CFTR genotype. Shown below is the eligibility for any modulator based on racial and ethnic groups. As you can see, black, African American, and Asian have the lowest eligibility rates. For that reason, more therapies are needed for those with uncommon CFTR mutations. It's also important to remember that CF is a global disease and is not limited to the Western world. Here is a map showing parts of the world where newborn screening is performed. As you can see, newborn screening isn't widely performed in many parts of the Middle East, Africa, Latin America, and Eastern Europe. These are the parts of the world where childhood mortality is high from malnutrition and infectious disease, and in many cases, the diagnosis of CF isn't even considered. This map shows countries with a cystic fibrosis registry, shaded according to the size of the registry. Registries are really helpful tools because they help us understand population dynamics, progression of disease, and the effectiveness of our treatments. The number of people affected by CF worldwide is likely underestimated due to the lack of registries in many parts of the world, including Africa, Asia, the Middle East, and South America. For that reason, it's important to recognize that disparities exist in access to diagnosis, diagnostic tools, clinical care, and therapeutic options. And this is especially important for us, given our very diverse patient population in the Bay Area. So in summary, I hope we've learned um from this talk. How to recognize the benefits and limitations of the tools used for CF screening and diagnosis. Learned how to identify and treat the most common GI hepatobiliary, and pancreatic complications of CF. Again, highlighting that CF care in childhood may change in the setting of highly effective CFTR modulator therapies. And we discussed the racial disparities that exist for patients, and that more tools and therapies are needed for less common mutations. Here are our take-home points. CF is a progressive disorder that affects multiple organ systems caused by mutations in CFTR. CF is often diagnosed in infancy with the newborn screen, but diagnosis can be missed, so a high index of suspicion is key. GI manifestations are a significant source of morbidity and mortality, and includes exocrine pancreatic insufficiency, meconium ileus, distal intestinal obstruction syndrome, and hepatobiliary involvement. Current FDA approved therapies include potentiators and correctors, with many more therapies being developed. GI manifestations, which are growing in attention, are evolving in the setting of CFTR modulator therapy, and long-term studies in younger children are needed to see if these modulators can potentially reverse or delay progression of disease. And finally, health care disparities exist for patients with less common mutations, and in countries without a newborn screening protocol and a registry. Finally, here are some helpful resources. Um, I really recommend the Cystic Fibrosis Foundation for both um clinician geared as well as um patient-friendly information. If you're interested in learning more about this uh CFGI manifestations, the North American Society of Pediatric Gastroenterology has a podcast series called Bowel Sounds, and there is one specifically on CFGI manifestations. And then if you have any other questions, um feel free to ask the pulmonology and GI team at the Cystic Fibrosis Center at UCSF. Thank you. Hey Doctor. Uh, that was perfect. Um, I feel like there was so much information that we have to, uh, really learn from that. Um, I think, um, we'll take some questions right now, but to start off with, uh, so we had a A question asking if we could just review the diagnosis slide, um, as well, just to go over the finer points of it. Let me Go to that slide. Sorry, we'll do it this way. I'll just show it here. Uh, was there a specific question about the slide, or was it just going through the slide in greater detail? I think just trying to go through the slide in greater detail again. Yeah, of course. Um, so we, we talked about first having clinical suspicion for CF. So the positive newborn screen, um, the reason I wrote IRT DNA or IRTIRT is that most states use a two-tier testing system that relies on IRT, which is the immunoreactive tripsinogen, that's the marker of pancreatic dysfunction. And then um a CFTR variant panel. Um, what's unique about California again is the three-tier panel, which first is a blood test for IRT and that IRT um in patients with CF would be elevated. Um, then it would be a 23 um genetic panel reflecting the most common mutations. And then, um, if there's one variant that is identified in California, the additional staff is doing um CFTR uh gene sequencing. Um, the next step is sweat chloride testing, which I said can be done as early as 2 weeks of age, and patients who are weighing greater than 2 kg. Um, the important thing to know about sweat chloride testing is that we really recommend performing it in the outpatient setting. Um, and the reason for this is that patients need to be adequately hydrated in order to sweat. And so what we found um when we do this inpatient is that a lot of infants that have failure to thrive and dehydration um in the inpatient setting don't have enough um sweat or don't have a sufficient sample. And so, um, if you have any further questions about sweat testing or if you're interested in this or concern for a patient, then I recommend referring to pulmonary or GI um to discuss sweat testing, uh, sweat testing. Um, next is, um, sequencing analysis for CFTR. And so having two disease-causing mutations in CFTR cinches that diagnosis. Um, but in certain situations where you're not sure, um, you can do additional CFTR function testing. And so that includes, um, organoid swelling assays, um, nasal potential differences. Um, intestinal current, um, measurements, um, which again should be done in consultation with, um, the pulmonary and GI team as these are more complex procedures. And then similarly along that vein, if there is concern for a cystic fibrosis-like uh disease rather than cystic fibrosis itself, then it sounds like uh GI um and probably genetics gets involved to try to help with the diagnosis altogether, um, and sort of takes it off the hands of the PCP at that point. Correct. So there is an entity called CRMS which is um cystic fibrosis-related metabolic um syndrome. And so these are patients who may have one disease-causing mutation in CF um so they have the potential to develop cystic fibrosis, so they're evolve very closely um in pulmonary, um, to see if they develop any potential complications. Great, yeah, I think it's just a lot of information to sort of digest, uh, in this slide, but I think this breaks it down very well, uh, be able to see it and visualize it. Um, I had another question regarding, uh, kids who are too young for the CFTR modulator therapies. Um, are we still using the older approved therapies for those kids, or are we using the newer therapies just they're just not FDA approved? What's sort of the, the strategy up there? Let me pull up that slide, so. And I know that slide also has a lot of information. Yeah, so, um, for children who aren't eligible, um, based on age or mutation, um, then typically it's the traditional therapies to manage their pulmonary symptoms, um, as well as like pancreatic enzyme replacement therapy if, if they have um exocrine pancreatic, uh, insufficiency. That being said, um, as I was mentioning, a lot of modulators are being Like FTAs, you know, tested on younger and younger children, um, especially the newest variety, tricata and liftre. And so I anticipate, um, very soon that these will be approved for younger and younger age children. And then in that same vein, um, could you discuss what that modulator therapy looks like on the, the patient level? Are they taking it every day? Is it a weekly treatment? What does that, and then what's the follow up and lab testing and all that sort of stuff look like? Yeah, so, um, most of these modulators, with the exception of a liftrek are taken twice daily. So, um, patients have a morning pill um and an evening pill. And so the morning pill, um, typically is the Ircafter component. Um, again, the only distinction with that is that a liftrek, um, is, depending on the age, 2 or 3 pills taken once daily, usually in the morning. Um, as far as follow-up for these patients, um, these patients usually need to be seen, um, in pulmonary clinic at least quarterly, so every 3 months. Um, if not more frequently depending on the severity of their symptoms, um, especially with the newer modulators, so tricata and lyric, because there is a risk of, um, liver enzyme abnormalities and, as I mentioned, the rare reports of drug-induced liver injury, it is recommended that these patients have um monthly LFTs, uh, done with uh in the 1st 6 months of therapy and then usually every 3 months thereafter, uh, for the first year. Gotcha. OK. Great. Um, I think there's also a few questions regarding, uh, with patients who do not present with primary pulmonary symptoms or more indolent forces of, um, GI symptoms, things like, um, In the primary care world, I think we see a lot of babies that are constipated, quote unquote, from the family since birth, but they have regular poops and stools, but they just appear uncomfortable or don't poop at the frequency that families would necessarily like them to, or maybe they do have some element of constipation. Are, are these kids that we should be suspicious for, um, like an indolent course of CF that was missed on initial screening. Um, and then how often is a two-pared question, and then how often do you sort of see these patients really? Yeah, so, um, you know, as far as infants with constipation, I, I would still, I would keep CF on the differential, but I would still, you know, remember the other Diagnosis that we typically think of for, for patients with constipation. So checking thyroid, celiac, um, consideration of Hirschrung's disease with a contrast enema, surgical consult, um, MRI to look for tethered cord or spinal cord abnormalities, um. You know, in some cases, if there's constipation with a concern for poor growth, the first screening test that you could obtain would be a fecal elastase. Um, the caveat with using fecal elastase is that you have to remember that um it can, it, it can, it's an indirect um test of pancreatic function. Um, it also can be diluted in the setting of large stool volume, so you want to make sure that um the patient gives you a form specimen. For the fecal elastase, um, and then the second thing is that fecal elastase suggests EPI, but exocrine pancreatic insufficiency. But exocrine pancreatic insufficiency in itself is a clinical diagnosis. So even if a patient has a fecal elastase, uh, greater than 200, if you're concerned for CF um based on symptoms, poor growth, um, Then using the elastase alone, um, wouldn't be sufficient. And so in that situation, I would recommend referring to to GI and home. And along that spectrum of workup for constipation, where would you put like a spike chloride test? Would that be on par with the fecal elastase, or would that be something the fecal elastase you start off with? Um, I would start off with the fecal elastase, um, and then if there are more questions based on the result of fecal elastase or if there are ongoing concerns, then I would recommend consulting with our CF team, um. To, to do this white chloride because it is, um, you know, a very specific protocol. Um, and so, you know, I would wanna make sure that the patient is, is seen in our clinics, um, so that we can do that, um, for them. Perfect, thank you. Um, let's see, we have a lot of questions coming in, so, um, Let's see. Can you discuss whether carriers of CFTR genes uh manifest any GI symptoms, not the homozygous disease, but just the carrier form. Is there any sort of uh moderate elevation of LFTs or hostasis or EPI? Yeah, um, you know, in carriers, what I've seen most commonly reported is, you know, um, findings like prenatally, like hypoecogenic bowel and that type of thing. Not to my knowledge of carriers having elevations, but that's definitely something I, I need to look into myself. Then, um, a follow-up question for the fecal lasses, um, because we don't do that testing quite as often, what does that look like? Can we pick it up at lab for or Quest, um, or do you send them home with a, a sample cup and they just bring it back and we just send it to Archo Lab? Yeah, so, uh, fecalastase can be done at really any lab. Um, usually what I recommend to patients is to pick up the specimen cup themselves, um, as each lab has a different protocol for stool testing, and then they can just drop it off, uh, like they would do with any other stool testing. But again, the key is just making sure that they submit a form specimen as a uh a high volume loose specimen is gonna dilute your sample and so you're gonna have a false positive fecal elastase if they're having diarrhea. Got you. Um, and then how sensitive is the California newborn screen for cystic fibrosis? If the newborn screen is negative, um, how sure can we be of that result? Yeah, um, unfortunately, I don't, I don't have the exact numbers. I wonder if one of our pulmonary colleagues is here to tell me the exact numbers. I know that the California screen, um, that extra third tier, um, the DNA. Sequencing um does capture some cases because again, that 23 variant panel is not going to capture everyone. So having that additional sequencing um does increase the sensitivity of our of our screening compared to other states um screening protocols. Gotcha, gotcha. Uh, and then for recent, uh, immigrants or newcomers to the country, uh, from countries where they don't get regular newborn screening for CF, um, when they're coming into the US, is there any sort of recommendations for a routine screening for everyone like this, or, um, a more symptomatic testing? They were symptomatic testing at that point. Sounds good. So like fecal elastase concerns for, you know, malnutrition, pulmonary or GI symptoms refer to us. We will help with the sweat chloride and then the genetic analysis. Gotcha. That sounds great. And then last question that we have, we got through a lot of them very quickly. Um, silly question, what would sciata look like in an infant? Uh, diaper, and how would family possibly describe it? Um, in an infant and in an older child, cause the way that families describe poop can be very, uh, ranged, um, is the way I would say. Yeah, so, I mean, older children, it's a little bit easier to assess for steatorrhea, um, because typically you'll see fatty or floating stools in the toilet bowl. Um, for infants, it's really more like loose, um, greasy looking stools in the diaper, sometimes can look even a little mucousy. Um, I think that's all the questions. We cleared out a whole bunch of them real quick. I think, um, the folks who joined us for the lecture would really appreciate, uh, looking back and reviewing the recording too, as well as the PDF just cause there's so much uh information packed into these slides. So thank you so much, Doctor Dung for sharing with us, um, on this Tuesday morning. Um, we don't, I hope it was helpful. No, it was very helpful. It was very nice, um, to Hear about new therapies and just review cystic fibrosis and how to get to the diagnosis too. We really appreciate it. I think we'll finish early, if that's OK with everyone. Um, thank you for joining us. Right, thank you, everybody. Alright. Have a good day. Bye, bye-bye. Created by
