KM Ellery et al. J Pediatr 2017; 191: 164-9. This prospective pediatric study examined 30 patients with mild acute pancreatitis in a “patient-directed nutrition” (PDN) pathway using a low fat diet and compared to a historical control of 92 patients in a “treatment team-directed nutrition” (TTDN) pathway. In the PDN group, patients were allowed a low-fat oral diet (<5 g fat per entrée, <1 g fat per snack, and only 1 entrée or snack at a time) at the time of admission.
- PDN group had median length of stay of 48.5 hours compared with 93 hours for the TTDN group
- PDN group was NPO for median of 14 hours compared to 34 hours for TTDN group
- No patients in the PDN group had complications within 30 days of discharge
Y Xiao et al. J Pediatr 2017; 191: 158-63. Among 55 pediatric patients with chronic pancreatitis and 14 with acute recurrent pancreatitis, there were 45 and 10 patients respectively who harbored 1 or more mutations in pancreatitis-associated genetic disorders: PRSS1, SPINK1, CFTR, CASR, CTSB, CTRC, KRT8
My take: These two studies indicate that oral feeding in mild acute pancreatitis leads to shorter hospital stays and that pediatric patients with chronic pancreatitis and acute recurrent pancreatitis frequently have predisposing genetic mutations.
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Near Bright Angel Trail, Grand Canyon
Two more studies have shown the effectiveness of CFTR modulators for subsets of patients with cystic fibrosis.
- JL Taylor-Cousar et al. NEJM 2017; 377: 2013-23
- SM Rowe et al. NEJM 2017; 377: 2024-35.
In the Taylor-Cousar study, the authors treated patients with homozygous Phe508del cystic fibrosis with either combination tezacaftor-ivacaftor or placebo for 24 weeks. Combination therapy resulted in FEV1 that was 4% higher along with a 35% lower rate of pulmonary exacerbations than placebo.
In the Rowe study which examined patients some retained CFTR function (which occurs ~5% of CF patients), a prospective trial of tezacaftor-ivacaftor had a greater effect on increasing FEV1 than ivacaftor alone. Ivacaftor monotherapy and tezacaftor-ivacaftor combination therapy were both more effective than placebo.
A related editorial (H Grasemann. pgs: 2085-8) helps provide context to help understand the importance of these studies. His key point:
“Although CFTR modulator therapies have measurable beneficial effects on some aspects of the disease, there is still an unmet need for truly effective new therapies to be developed for all persons with cystic fibrosis. The clinical efficacy of the current combination therapies for patients with cystic fibrosis who have the most common CFTR genotype (Phe508del/Phe508del) is suboptimal and falls within the range of established symptomatic therapies, such as nebulized inhaled hypertonic saline or recombinant human DNAse.”
This figure depicts the types of molecular defects: No functional CFTR with framshifts for deletions or insertions (class 1), CFTR trafficking defect due to misfolded protein (class II), defective channel regulation (class III), reduced cholirde conductance (class IV) , reduced synthessis (class V) or decreased CFTR stability (class VI)
While most clinicians are familiar with cystic fibrosis (CF), much fewer are familiar with a group of disorders related to the cystic fibrosis transmembrane conductance regulator (CFTR) that do not meet the criteria for cystic fibrosis. A summary of these disorders is provided in a recent editorial (Levy H, Farrell PM. J Pediatrics 2015; 166: 1337-40). In addition, the editorial provides insight into a related study: Groves T et al.. J Pediatrics 2015; 166: 1469-74.
The editorialists note that new disorders have been created due to newborn screening and due to the use of CF mutation analysis. New disorders:
- CRMS -CFTR-related metabolic syndrome. CRMS describes infants with elevated immunoreactive trypsinogen and inconclusive sweat testing and DNA results. Inconclusive sweat testing includes sweat tests 30-59 mmol/L if age <6 months or 40-59 mmol/L if >6 months on at least 2 occasions. DNA testing is inconclusive if there are fewer than 2 CF disease-related mutations identified. DNA testing is also considered inconclusive if there are 2 CFTR mutations but sweat testing is normal.
- CFTR-RD -CFTR related disease. CFTR-RD describes symptomatic individuals beyond infancy who have sweat testing <60 mmol/L and up to 2 CFTR mutations, at least one of which is not clearly categorized as a CF-causing mutation. Thus, these individuals do not fulfill criteria for CF but could have congenital bilateral absence of vas deferens, acute recurrent or chronic pancreatitis, or disseminated bronchiectasis.
- Delayed CF -Delayed CF describes patients eventually diagnosed with CF who had initially intermediate sweat chloride values. Over time, their condition evolves to fulfill the criteria for CF. In the retrospective study by Groves et al, 14 of 29 (48%) evolved to a diagnosis of CF. These patients with delayed CF had less pancreatic insufficiency (OR 0.06), milder obstructive lung disease, less colonization with Pseudomonas aeruginosa (OR 0.04), and overall disease severity as measured by Shwachman scores at 2 years.
- Nutritional outcomes were improved at 2 years in this Delayed CF cohort in comparison to 28 matched patients diagnosed with CF in the newborn period, but did not persist to later ages.
The editorial notes that nearly 20% of patients with CF are being enrolled in the CF foundation patient registry without sweat chloride testing results. They do not favor this approach because the diagnosis of CF requires proof of CFTR dysfunction, not simply CF DNA mutations.
Take-home message: Patients who do not meet the criteria for CF but who have intermediate sweat testing or abnormal CF DNA mutations need to be followed. Some will fulfill the criteria with time and others may develop other clinical problems even without having CF.
“Genius is one percent inspiration and ninety-nine percent perspiration.” – Thomas A. Edison
I thought about this saying as I was reading an editorial titled: “Understanding Pediatric Chronic Pancreatitis: Inspiration and Hard Work Required” (Pant C, Sferra TJ. J Pediatr 2015; 166: 798-800). The editorial was reviewing the article “Pediatric Chronic Pancreatitis Is Associated with Genetic Risk Factors and Substantial Disease Burden” (Schwarzenberg SJ et al. J Pediatr 2015; 166: 890-6).
The study comes from the International Study Group of Pediatric Pancreatitis: In Search of a Cure (INSPPIRE) consortium. None of the findings in the study are particularly surprising; nevertheless, a descriptive study of the patients in the registry who had strictly defined chronic pancreatitis (n=76) is still an important early step in improving our understanding of this dreaded problem.
Chronic pancreatitis required either:
- Abdominal pain consistent with pancreatic pain with imaging findings suggestive of chronic pancreatic damage
- Evidence of exocrine or endocrine pancreatic insufficiency and imaging findings suggestive of chronic pancreatic damage
- Histology (surgical biopsy) findings suggestive of chronic pancreatitis
- Two-thirds of patients with genetic testing had identified genetic mutations: PRSS1 (n=33), SPINK1 (n=14), CFTR (n=11), chymotrypsin C (CTRC) (n=2). Mutations in more than 1 gene were noted in 9 patients, including 6 of the 11 with CFTR mutations. Several newer mutations, like calcium-sensing receptor and carboxypeptidase A1, were not evaluated in any of the patients.
- Pancreas divisum was present in 15 patients; however, 8 of 15 of these patients had an identified genetic mutation as well.
- Radiographic findings of chronic pancreatitis were most commonly ductal abnormalities and pancreatic atrophy. This is in contrast to adults in which pancreatic calcifications are common.
- The researchers also document severe disease burden with patients reporting a median of 3 emergency dept visits and 2 hospitalizations in the previous year. In addition, 70% (n=47) had missed 1 day of school in the past month and 34% had missed 3 or more days.
- Medical treatment (eg. pancreatic enzymes) was ineffective in the majority of patients.
- 43% had undergone ERCP and two-thirds noted improvement from this intervention
- Surgical procedures were performed in 39% and were helpful in the majority. Total pancreatectomy with islet autotransplantation was the most common surgery in this cohort and was helpful in 20 of 21 patients.
- The authors recommend avoidance of CT scans due to concerns of accumulating excess ionizing radiation exposure.
Take home message: For me, this study helps define the problem. As a practical matter, it would be helpful to have a genetic panel to check for the lesser frequent mutations if PRSS1, SPINK1, and CFTR are normal.
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While the absolute number of patients with genetic causes of pancreatitis is small, due to frequent hospitalizations, this remains a significant problem. This month additional information on genetic predisposition for pancreatitis is available (JPGN 2012; 54: 645-50).
Sultan et al (Milwaukee, WI) reviewed the charts of children <18 years with recurrent acute pancreatitis (RAP) and patients with chronic pancreatitis (CP) from 2000-2009. RAP was considered if patient had a minimum of two distinct episodes of acute pancreatitis. Acute pancreatitis was considered the diagnosis if patient had typical symptoms associated with 3-fold elevation of amylase or lipase or imaging changes consistent with acute pancreatitis. CP was defined as a minimum of 2 episodes of acute pancreatitis associated with pancreatic duct abnormalities or pancreatic insufficiency.
Among this cohort of 29 children, 23 (79%) had mutations which have been associated with genetic pancreatitis (GP). Family history was positive in only five patients.
- CFTR mutation in 14 (48%): two had homozygous mutations, six heterozygous, and four had 5 T variants. The importance of a single CFTR mutation in contributing towards pancreatitis is unclear. However, the Wisconsin population has a carrier frequency of 1:32; the striking difference in frequency indicates that even a single mutation may be important in the pathogenesis of RAP.
- SPINK1 (serine protease inhibitor Kazal type 1) in 8 (27%). SPINK1 mutations occur in 1-3% of the general population. It is often a modifying factor rather than an isolated causal factor in the development of RAP. Four of the patients with SPINK1 mutations also had a CFTR mutation.
- PRSS1 (cationic trypsinogen gene) in 7 (24%). Individuals with these mutations are considered to have hereditary pancreatitis, an autosomal disease with incomplete penetrance.
- Only one patient was tested for chymotrypsin C gene (CTRC) –tested negative.
Seven patients with RAP did not undergo genetic testing & were excluded from the study. These patients had other known causes of RAP: 3 had gallstones, 2 had pancreas divisum, 1 had a metabolic disorder, and 1 had a medication-induced pancreatitis. The authors note, however, that patients with pancreas divisum have had genetic mutations identified in other studies.
- www.uni-leipzig.de/pancreasmutation. This link will take you to the hereditary pancreatitis database where you can search for the specific mutation you identified and find articles dealing with a variety of aspects of that particular mutation.
- 2011 Naspghan Postgraduate Course:
-1st bout, check U/S, trig
-if 2nd bout, suggested to check MRI, genetics (SPINK1, PRSS1, CFTR), sweat test, fecal elastase, possibly IgG4/ANA
- -Gastroenterology 2006; 131: 1844. Mouse model w R122H Trypsiongen expression.
- -Whitcomb DC. Gut 2004; 53: 1710-17. test for PRSS1 (cationic trypsinogen), SPINK1 (Serine protease inhibitor, Kazal Type 1), and CFTR gene.
- -JPGN 2002; 34: 1A pg 444. n=108 with hereditary or idiopathic pancreatitis. (28% had + fhx) 12 c PRSS1 mutation, 24 c SPINK1 (21 s fhx); 22 had + CFTR mutation.
-Pancreatology 2001; 1: 405-415. Consensus guidelines for testing for H. Pancreatitis. PRSS1 gene -cationic trypsinogen
- David Whitcomb’s laboratory at the University of Pittsburgh. The test is commercially available there. Their web site for the forms is:
- -JPGN 2011; 52: 262. Review.
- -J Pediatrics 2011; 158: 612. Acute pancreatitis can result in diabetes.
- -Clin Gastro & Hep 2010; 8: 410-416, 417. REVIEW of acute pancreatitis. Rec NJ generally over TPN.
- -Clin Gastro Hep 2010; 8: xxii. Anomalous pancreatobiliary jxn as a cause.
- -JPGN 2009; 49: 137. Pancreatitis assoc w celiac
- -Clin Gastro & Hep 2009; 7: 702. Harmless Acute pancreatitis score. Nonsevere when NL hgb, NL creatitine, and no rebound tenderness/guarding
- -Alim Pharm Ther 2008; 28: 777-781. Use of a low fat diet helped shorten hospital stay among adult pts with acute pancreatitis.
- -Clin Gastro & Hep 2008; 6: 1070, 1077. Fluids and imaging in acute pancreatitis. With imaging, CT probably best.
- – J Pediatrics 2008; 152: 106. Acute pancreatitis in young children
Related blog entry:
Indomethacin to prevent post-ERCP pancreatitis
Recent FDA approval of Ivacaftor (Kalydeco) is a promising step for a subset of patients with cystic fibrosis who have the G551D mutation. This drug enhances the cystic fibrosis transmembrane regulator (CFTR) gene in these patients; only ~4% of CF patients or about 1200 patients in the US have this genetic defect.
-NEJM 2011; 365: 1663. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 167 pts. (Ivacaftor).
-NEJM 2010; 363: 1991. Effect of VX-770 -a CFTR potentiator -mild improvement in study of 39 adults.