Idiopathic chronic pancreatitis treated with ivacaftor in a CFTR carrier with methylmalonic acidemia

Design

Case presentation

A 28-year-old female with non-vitamin B12 responsive methylmalonic acidemia (MMA) and recurrent admissions for acute pancreatitis was diagnosed with chronic pancreatitis, specifically the paraduodenal subtype, based on MRI findings. Despite normal stool fats and random triglycerides, a genetic examination revealed a heterozygous R668C variant of unknown significance in the CFTR gene, which was predicted to impair protein function. In vitro studies corroborated these findings, showing reduced chloride transport, aligning with characteristics of a Class III CFTR mutation.

The patient was not a candidate for surgical intervention but responded significantly to ivacaftor, a medication used compassionately, which led to notable improvements in clinical symptoms, serological lipase levels, and radiographic inflammation. Her fentanyl requirement was reduced by 75% due to decreased chronic pain. After starting ivacaftor, her average lipase levels decreased dramatically, stabilizing within the normal range, and no further episodes of pancreatitis were observed. This marked improvement in her condition also improved her quality of life, allowing her to remain medically stable at home.

Unfortunately, the patient passed away 109 days after starting ivacaftor due to sepsis related to a pre-existing central line, unrelated to her pancreatitis or MMA management. Upon starting ivacaftor until her death, the patient never showed symptomatic evidence of pancreatitis.

Study Author Conclusions

This case study presents the first documented instance of a carrier of the CFTR R668C mutation manifesting CFTR-related pancreatitis, which was successfully treated with the CFTR modulator ivacaftor. The patient's positive response to ivacaftor suggests that dysfunction from the CFTR mutation contributed significantly to her chronic pancreatitis. Although methylmalonic acidemia (MMA) is also linked to pancreatitis, ivacaftor does not target MMA-related pathways, indicating that the CFTR mutation played a pivotal role. This reinforces the idea that a "second hit," such as MMA or other factors like alcohol or hypertriglyceridemia, can precipitate disease in CFTR mutation carriers.

The patient declined further confirmatory tests for CFTR dysfunction due to discomfort concerns, leaving some questions on pathogenicity unanswered. However, the patient's clinical improvement post-ivacaftor supports the potential role of CFTR-modulating therapies in managing similar cases. The case advocates for future clinical trials to assess ivacaftor and newer drug combinations like Elexacaftor–Tezacaftor–Ivacaftor, which could benefit a broader population of patients with CFTR mutations.

The effect of CFTR modulators on a cystic fibrosis patient presenting with recurrent pancreatitis in the absence of respiratory symptoms: a case report

Design

Case presentation

A 24-year-old white male with a significant medical history of recurrent acute pancreatitis, gastroesophageal reflux disease, and obesity was evaluated following a referral after a prolonged hospital stay for refractory acute pancreatitis. Initially experiencing gastrointestinal issues in his teenage years, his condition progressed to severe abdominal pain, resulting in over 20 hospitalizations over the past decade. The frequency of pancreatitis episodes increased over the years, occurring approximately every three months. Notably, while alcohol use initially exacerbated symptoms, two years of abstinence did not decrease recurrence likelihood. Both ultrasound and CT imaging ruled out gallstones or anatomical causes. The patient was on proton-pump inhibitors and avoided triggers like spicy food and alcohol, with minimal symptom relief.

On presentation, he had intermittent right upper quadrant pain, nausea, and variable bowel habits but no evidence of fat malabsorption. Despite normal liver function tests, he had mildly elevated lipase levels, severely diminished fecal elastase, and reduced Vitamin D, suggesting potential pancreatic insufficiency. Imaging showed acute interstitial edematous pancreatitis without necrosis and hepatic steatosis with potential fibrosis. Pulmonary testing indicated modest air trapping and early bronchial wall thickening, but negative sputum cultures for cystic fibrosis pathogens.

Sweat chloride testing revealed CFTR dysfunction, and genetic testing confirmed CFTR mutations (R1117H/7T/F508del). Initially treated with pantoprazole and pancrelipase, he reported worsened symptoms. After discontinuation of pancrelipase and initiation of ivacaftor, his symptoms improved significantly, and he experienced no pancreatitis episodes for 19 months until stopping ivacaftor, which led to the recurrence of symptoms and pancreatitis episodes. After being instructed to resume ivacaftor, he was lost to follow-up.

Study Author Conclusions

Mild class IV (e.g., R117H) and class V (e.g., 3849 + 10kbC) CFTR mutations result in decreased channel conductance and reduced synthesis, leading to preserved pancreatic function compared to class I, II, or III mutations. Despite initial pancreatic sufficiency, these mutations have a high propensity for causing pancreatitis due to ductal blockage and inflammation. Over time, recurrent episodes can lead to defective pancreatic secretion and exocrine insufficiency, with about 20% becoming pancreatic insufficient.

The R117H mutation is particularly complex, as it affects exon 9 splicing and is influenced by the status of the intron 8 Poly-T tract, with the 5 T variant linked to male infertility (CBAVD), bronchiectasis, and chronic idiopathic pancreatitis. The 7 T variant is also significant, often presenting with CBAVD and late-onset respiratory disease.

CFTR modulators like ivacaftor have shown improvements in FEV1, reduced pulmonary exacerbations, and decreased hospitalization rates in patients with certain mutations, including R117H, regardless of Poly-T status. While the effects on the gastrointestinal tract are less understood, ivacaftor appears to enhance gastrointestinal physiology, potentially improving pancreatic exocrine function through increased bicarbonate secretion and weight gain. Evidence from recent studies, including in young children with G551D mutations treated with ivacaftor, points to partial rescue of pancreatic function.

Tezacaftor combined with ivacaftor has been effective in improving exocrine function in patients with the F508del mutation and residual function mutations. Ivacaftor treatment has been associated with the resolution of recurrent pancreatitis in CF patients, as noted in case studies where recurrence was prevented during treatment but returned upon discontinuation. Despite being generally well-tolerated, ivacaftor requires careful monitoring for potential side effects, such as elevated liver enzymes, and dose adjustments when used with CYP3A4 modulators. The case supports the utility of CFTR modulators like ivacaftor in managing recurrent pancreatitis in CF patients with responsive CFTR mutations, even without respiratory symptoms.

Ivacaftor CFTR Potentiator Therapy is Efficient for Pancreatic Manifestations in Cystic Fibrosis

Design

Case presentation

A 48-year-old male presented with recurrent pancreatitis in 2010, following a medical history of cholecystectomy in 2000 and non-severe recurrent pulmonary infections. In 2007, he experienced non-severe acute pancreatitis, with no alcohol or tobacco use reported. Extensive diagnostic work revealed no residual gallstones, hypercalcemia, hypertriglyceridemia, pancreatic tumors, or autoimmune pancreatitis. From 2007 to 2010, he had monthly episodes of pancreatic pain relieved by fasting. In 2010, he was diagnosed with exocrine pancreatic insufficiency (steatorrhea, fecal elastase-1: 143 µg/g of stool) and vas deferens agenesis, treated with pancreatic enzyme supplementation and a compound heterozygous CFTR mutation (G551D:R347H) identified, with no SPINK1, CTRC, or PRSS1 mutations.

In 2011, due to repeated respiratory infections (FEV1: 86%, SO2: 94%), his hospitalization in a pulmonology unit was necessary. Between 2010 and 2012, the frequency and severity of pancreatic symptoms increased to two bouts of abdominal pain per month, and fecal elastase-1 levels dropped to 66 µg/g. In 2012, Ivacaftor treatment (300 mg/day) was initiated, resulting in significant improvements: by 2016, lung performance enhanced (FEV1: 105%, SpO2: 98%), pancreatic episodes ceased, and fecal elastase-1 normalized to 236 µg/g, reducing the required pancreatic enzyme dosage to 36,000 UI/day.

Study Author Conclusions

This particular case involved a patient with a class III (G551D) mutation, who exhibited pancreatic exacerbations prompting ivacaftor treatment. Following treatment, the patient experienced improved lung function, and notably, all pancreatic manifestations disappeared. This included the normalization of stool characteristics and faecal elastase levels, alongside complete cessation of pancreatic attacks. This case suggests that ivacaftor might address pancreatic manifestations in cystic fibrosis, offering additional therapeutic benefits beyond its established role in lung function improvement.

Ivacaftor, a CFTR channel potentiator, has shown significant benefits in improving lung function in patients with class III CFTR mutations. In randomized trials, ivacaftor treatment led to a roughly 10% improvement in FEV1, a measure of lung function, compared to placebo. It also reduced sweat chloride concentration by about 60 mmol/L, enhanced quality of life, and decreased the frequency of pulmonary exacerbations. Furthermore, a pilot study indicated potential benefits in endocrine pancreatic function, with improved insulin secretion in patients with the G551D mutation. Despite this, no studies had focused on ivacaftor’s effects on exocrine pancreatic manifestations until a report documented the evolution of faecal elastase-1 levels and pancreatic bouts before and after the initiation of ivacaftor therapy.

Pancreatitis in A Patient with Cystic Fibrosis Taking Ivacaftor

Design

Case presentation

A 14-year-old girl with cystic fibrosis (CF) and a genotype of F508del/G551D was admitted to the hospital with progressively worsening epigastric pain and nausea. Despite a mild cough from a recent respiratory infection, her condition was improving, and she had been taking ivacaftor 150 mg BID for four years. She had significantly reduced her pancreatic enzyme replacement therapy (PERT), using it only with very fatty meals, as her pancreatic insufficiency symptoms had diminished, and her body mass index had increased from 21 to 27 kg/m². Her diet was high in fat, including fast food and fried items.

On examination, she was afebrile, with few lung crackles and diffuse abdominal tenderness, but no hepatosplenomegaly. Significantly elevated levels of amylase (197 U/L) and lipase (647 U/L) suggested pancreatitis, aligning with the epigastric pain and abdominal tenderness. The patient was treated with intravenous fluids and discharged in good condition after four days. Over two years later, no pancreatitis recurrence was noted, and ivacaftor was well tolerated after being restarted post-discharge.

Almost two years after the episode, stool elastase measurements indicated moderate pancreatic insufficiency (159 µgE/g, with normal being >200 µgE/g and moderate insufficiency 100–200 µgE/g). This measurement had not been taken previously during diagnosis or before starting ivacaftor. As of now, the patient reports no symptoms of pancreatic insufficiency and continues to use PERT selectively with very fatty meals.

Study Author Conclusions

This case emphasizes the importance of measuring stool elastase in patients taking ivacaftor to evaluate the recovery of pancreatic function, aligning with the recommendations by Megalaa et al. (Table 5) Despite moderate pancreatic insufficiency, the patient in question experienced an acute pancreatitis episode requiring hospitalization, suggesting that ivacaftor may improve CFTR function and potentially reduce pancreatitis frequency and recurrence.

The potential of CFTR modulators like ivacaftor to restore pancreatic function raises the possibility of discontinuing pancreatic enzyme replacement therapy (PERT), thereby reducing treatment burdens. This observation is particularly noteworthy because pancreatitis is uncommon in patients with pancreatic insufficiency. The occurrence of pancreatitis in such patients on ivacaftor might indicate partial restoration of pancreatic function. Consequently, clinicians and patients should remain vigilant for pancreatitis symptoms when treated with ivacaftor. Proactive education for patients and parents during clinical visits is advised to prevent delays in treatment.

Time for a gut check: Pancreatic sufficiency resulting from CFTR modulator use

Design

Case presentation

A 6-year-old male patient with cystic fibrosis and pancreatic exocrine insufficiency underwent a notable clinical transition following the initiation of ivacaftor therapy in 2014. Initially, the patient exhibited classic symptoms of cystic fibrosis, including greasy stools, poor weight gain, and flatulence, which were effectively managed with pancreatic enzyme replacement therapy (PERT) initiated during infancy. Despite a stable course with normal liver function tests, the patient presented at age 10 to the emergency department with epigastric, intermittent, stabbing abdominal pain radiating to the back, without systemic symptoms like fever or vomiting. Laboratory analysis revealed markedly elevated serum lipase and amylase levels, leading to a diagnosis of acute pancreatitis. An ultrasound supported this by showing mild prominence of the pancreatic duct without gallstones or other common complications.

The unusual occurrence of pancreatitis in a patient previously characterized as pancreatic insufficient prompted further investigation. Fecal elastase testing showed levels greater than 500 mcg/g, suggesting an unexpected improvement in pancreatic function, corroborated by repeat testing. An MRI and MRCP confirmed pancreatic atrophy and identified small pancreatic cysts, but did not find significant peripancreatic edema or pseudocysts. Given these findings, PERT was gradually reduced and eventually discontinued, without recurrence of symptoms. Six weeks post-discontinuation, the patient showed a slight weight gain and reported no typical symptoms of pancreatic insufficiency.

This case highlights the potential reversible nature of pancreatic exocrine insufficiency in cystic fibrosis patients undergoing CFTR modulator therapy. The improvement of pancreatic function challenges the traditional view of irreversible pancreatic damage in cystic fibrosis and suggests ivacaftor might facilitate pancreatic recovery. The case emphasizes the need for close monitoring of pancreatic function and dietary management in patients on CFTR modulators, as well as the need for further research on the long-term effects of these treatments on pancreatic health.

Study Author Conclusions

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a critical epithelial anion channel responsible for pancreatic ductal fluid and bicarbonate secretion. Mutations affecting CFTR can lead to reduced ion transport and retained pancreatic function, but a complete absence of effective CFTR results in pancreatic exocrine insufficiency, necessitating lifelong Pancreatic Enzyme Replacement Therapy (PERT).

This case study details a patient with two pancreatic insufficient mutations who exhibited symptoms of insufficiency during early life, requiring PERT. After commencing ivacaftor therapy, there was a marked improvement in CFTR expression, enhancing ductal ion conductance and the resumption of partial pancreatic acinar cell function. The case presents the first documented instance of full pancreatic function recovery with a CFTR modulator. The risk of pancreatitis appears linked to the balance of acinar cell preservation and ductal obstruction, with pancreatitis occurring at a threshold balance.

Additional studies and case reports have suggested decreased need for PERT and improved pancreatic function following ivacaftor initiation, further supported by a mouse model demonstrating reduced inflammation and acinar cell damage when treated with CFTR correctors/potentiators. A retrospective series highlighted reduced pancreatitis episodes and severity post-CFTR modulator therapy, potentially through enhanced bicarbonate and fluid transport. The young age at ivacaftor initiation likely aided pancreatic function restoration, with speculation that earlier treatment could reverse exocrine insufficiency in more patients. The ARRIVAL study further supports this by showing improved markers of pancreatic function in young children. The 10-year-old male in this case achieved pancreatic recovery after four years of ivacaftor, with pancreatitis being the catalyst for screening pancreatic function recovery. Clinicians should consider evaluating pancreatic function in stable ivacaftor-treated patients to assess the ongoing necessity of PERT.