“Channelopathy of the Pancreas Causes Chronic Pancreatitis” and SARS-CoV-2 in Sewage

Interesting article: Full Text: SARS-CoV-2 RNA concentrations in primary municipal sewage sludge as a leading indicator of COVID-19 outbreak dynamics 


M Sahin-Toth. Gastroenterology 2020; 158: 1538-40. Full Text Link: Channelopathy of the Pancreas Causes Chronic Pancreatitis

Excerpt from editorial:

In this issue of Gastroenterology, Masamune et al report a landmark discovery, the genetic association of functionally defective TRPV6 channel variants and chronic pancreatitis. The authors investigated the TRPV6 gene in Japanese and European patients with nonalcoholic chronic pancreatitis using targeted sequencing followed by functional analysis of the identified variants. In the Japanese discovery cohort, they found functionally defective variants in 4.3% of the patients and in 0.1% of the controls (odds ratio 48). In the European replication cohort, 2% of the patients carried a defective variant and none was found in controls.

Original research study: A Masamune et al. Gastroenterology 2020; 158: 1626-41. Full text: Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis

An excerpt:

TRPV6 variants are globally associated with early-onset nonalcoholic CP. To our knowledge, TRPV6 is a novel pancreatitis-associated gene beyond the pancreatic digestive enzyme/enzyme inhibitor system, and it is the first gene that directly regulates Ca2+ homeostasis. Our findings open a completely new avenue by emphasizing the potential role of ductal cells and, especially, calcium channels in the pathophysiology of pancreatitis, which might lead to the development of personalized medicine targeting TRPV6 channel activity.

From editorial by Sahin-Toth

Visual abstract for research study by Masamne et al.


Diabetes Mellitus Associated with Acute Recurrent and Chronic Pancreatitis

Briefly noted: MD Bellin et al. JPGN 2019; 69: 599-606.

Using the INSPPIRE database with 397 children with either acute recurrent pancreatitis or chronic pancreatitis, the authors examined the frequency of diabetes mellitus (DM).

Key findings:

  •  6% (n=24) had a diagnosis of DM. This is 30-fold higher than the general pediatric population
  • The group with DM was more likely to have elevated triglycerides (OR 5.21) coexisting autoimmune disease (OR 3.94) or pancreatic atrophy (OR 3.64)
  • The group with DM tended to be older with a mean at first diagnosis of acute pancreatitis of 12.9 years compared to 8.7 years in those who did not develop DM

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Frontenac Hotel, Quebec City

Rapid Progression from Acute Recurrent Pancreatitis to Chronic Pancreatitis

Briefly noted: QY Lin et al. JPGN 2019; 69: 206-11.  In this INSPPIRE cohort of 442 children, 251 had acute recurrent pancreatitis and 191 had chronic pancreatitis.

Key finding:

  • “Within 6 years after the initial acute pancreatitis attack, cumulative proportion with exocrine pancreatic insufficiency was 18% …diabetes mellitus was 7.7%”

My take: Patients with ARP need routine followup.

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Bridge of the Gods, OR

Pediatric Pancreatitis -Working Group Nutritional Recommendations

Abstract Link: Nutritional Considerations in Pediatric Pancreatitis: A Position Paper from the NASPHAN Pancreas Committee and ESPHAN Cystic Fibrosis/Pancreas Working Group.

M Abu-El-Haija et al. JPGN 2018; 67: 131-43.  This working group made ~27 recommendations (summarized in Table 1) and indicated the quality of evidence supporting the recommendation as well as the agreement among team members –virtually all received at least 12 of 13 votes.

Here are the ones that grabbed my attention:

For Acute Pancreatitis (AP):

  • 1a & 1aa. Children with mild AP should be started on a regular diet –preferably via mouth as compared to nasogastric route
  • 1b. Enteral nutrition (EN) should be attempted in children with severe AP within 72 hours from presentation, once deemed hemodynamically stable.
  • 1.4 Even in severe AP, jejunal tube feeding should be reserved for those unable to tolerate oral or NG tube feeding

For Acute Recurrent Pancreatitis (ARP):

  • 2.1a & 2.1b. Children should receive a regular-fat diet in between bouts of ARP and a regular-fat diet can safely be started within 1 week after the onset of a bout of AP (except in those with very elevated triglycerids (>1000 mg/dL)
  • 2.2a & 2.3a. PERT is NOT recommended in children with ARP without eocrine pancreatic insufficiency (EPI). Antioxidants are NOT recommended (insufficient supporting evidence)

For Chronic Pancreatitis (CP):

  • 3.1b & 3.12a. Recommends routine followup every 3-6 months and a regular diet
  • 3.3a, 3.4a, & 3.5a Monitoring: recommends checking fat-soluble vitamin levels every 6 to 12 months, checking for EPI with elastase (or 72 hr fecal fat) every 6-12 months, and BMD (bone mineral density) if CP and malnutrition (especially if Vit D deficiency or hx/o fractures)

My take: This report provides a methodical approach for the care of children with these pancreatic disorders.

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Likelihood of Genetic Disease with Early-Onset Pancreatitis

Another study (MJ Giefer et al. J Pediatr 2017; 186: 95-100) from the INSPPIRE group provides data on early-onset pancreatitis.  Specifically, the group presents clinical information on 342 children with acute recurrent pancreatitis or chronic pancreatitis regarding disease burden and associations with genetic mutations.

Key findings:

Genetic disease is much more common in younger ages:

  • In subset younger than 6 years, 72 of 102 had genetic diseases identified:  PRSS1 in 42, CFTR in 27, SPINK1 in 12, and CTRC in 8.
  • In subset 6-11 years of age, 52 of 90 had genetic diseases identified: PRSS1 in 20, CFTR in 23, SPINK1 in 22, and CTRC in 1.
  • In subset greater than 12 years of age, 39 of 72 had genetic diseases identified: PRSS1 in 13, CFTR in 24, SPINK1 in 6, and CTRC in 1.
  • Testing for newer susceptibility genes were not evaluated as they had not become commercially available: carboxypeptidase 1, claudin 2, carboxylesterlipase, and carboxyesterlipase-hybrid
  • SPINK1 is noted to be present in 1-3% of general population; CTRC mutation occur in 0.7% of healthy controls.

Obstructive causes were common.  Pancreas divisum was identified in 38 patients but there was not a great deal of difference among the age groups; similarly, other obstructive causes were identified in about one-third of patients and included sphincter of Oddi dysfunction (n=9), gallstones (n=17), pancreaticobiliary malunion (n=12), biliary cyst (n=11), pancreatic stricture (n=2), annular pancreas (n=3), and duodenal diverticulum.

Disease burden:

  • Exocrine insufficiency noted in 52 (no strong age predilection)
  • Diabetes in 18 (11 of the cases occurred in those >12 years)
  • Constant moderate pain noted in 82 (25 in group <6, 27 in 6-12 group, and 30 in group >12 years)
  • Constant severe pain noted in 18  (4 in group <6, 5 in 6-12 group, and 9 in group >12 years)
  • Average number of hospitalizations in past year was 1 in those ≤12 and 2 in those older than 12.

My take: PRSS1 and CTRC mutations are associated with early onset pancreatitis.

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Pancreatitis Update (part 1)

Our group received a very helpful update on pancreatitis from Maisam Abu-El-Haija (GI) and Jaime Nathan (surgery). My notes may include some errors in transcription and errors of omission. Some pictures of the slides are included below as well.

Key points:

  • About 30% of acute pancreatitis patients have a 2nd bout of pancreatitis. Obesity is a risk factor for recurrence.
  • There has been a recent increase in incidence of acute pancreatitis.
  • Cincinnati has a gene panel to examine the four most common mutations which cause hereditary pancreatitis (PRSS1, SPINK1, CFTR, and CRTC) along with 6 other relevant genes. (28 day turnaround) In addition, there is a pancreatitis insufficiency panel.
  • Discussed screening for pancreatic insufficiency.  Directly measuring pancreatic enzymes are more sensitive for early insufficiency, but may be unnecessary if good growth and normal stool elastase.
  • There are NO proven medical/dietary therapies to prevent recurrent or chronic pancreatitis and eliminate pain symptoms.

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Consensus Pancreatitis Recommendations

The INSPPIRE Group (CE Gariepy et al. JPGN 2017; 64: 95-103) has published consensus recommendations for acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP).

While the authors acknowledge the need for high-level evidence/further research, they provide a large number of consensus recommendations.  These recommendations are succinctly summarized in Table 1 and Table 2.  From a reader’s perspective, my preference would have been to separate the recommendations for ARP and CP rather than to intermix them (though many of the recommendations are the same for both conditions).

ARP specific recommendations:

  • “Initial evaluation should include AST,ALT, GGT, Total bilirubin (fractionate if elevated), fasting lipids, and total serum calcium.”
  • Evaluate for fat-soluble vitamin deficiency, and pancreatic exocrine insufficiency at least annually

ARP and CP recommendations:

  • Consider ammonia and urine organic acids if there is a concern for undiagnosed metabolic disease.
  • Check for celiac disease.
  • Check for O&P if immunosuppressed, travel to endemic areas of Ascaris, or if peripheral eosinophilia.
  • Evaluation of genetic causes: should include sweat chloride test and PRSS1 gene testing. Consider SPINK1, CFTR, and CTRC evaluation.
  • Evaluate with MRCP (not ultrasound) acutely if GGT >2 x ULN or if direct bilirubin is elevated.
  • Non-acutely, MRCP recommended to evaluate pancreatic ductal abnormalities.  “When available, secretin-enhanced MRCP …should be obtained.” sMRCP can provide dynamic images of the pancreatic duct allowing differentiation of fixed from nonfixed lesions; this technique has not been widely adopted by pediatric radiologists compared with adult radiologists.

CP specific recommendations:

  • Evaluate for fat-soluble vitamin deficiency, pancreatic exocrine insufficiency, and pancreatic endocrine insufficiency at least annually

The authors did not recommend checking serum IgG4 in the absence of associated systemic disease or suggestive imaging for autoimmune pancreatitis.

Briefly noted: J-H Choi et al. Clin Gastroenterol Hepatol; 2017: 15: 86-92.  This study indicated that vigorous hydration with lactated ringer’s (LR) reduces risk of pancreatitis after ERCP.  A potential inference would be that LR would be an optimal fluid for pancreatitis more broadly. (Related: Why an ERCP Study Matters to Pediatric Care | gutsandgrowth)

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Dragon Point, Labadee

Total Pancreatectomy with Islet Autotransplantation for Refractory Recurrent Pancreatitis

A recent study (MD Bellin et al. Clin Gastroenterol Hepatol 2016; 14: 1317-23) describes the use of Total Pancreatectomy with Islet Autotransplantation (TPIAT) in 49 patients (mean age 32.8 years).  This study included 6 children.

All of these patients met strict criteria for recurrent acute pancreatitis and lacked imaging or functional evidence for chronic pancreatitis.  All 49 required narcotics for pain management prior to TPIAT.

The surgical technique for TPIAT is well-described in the report.  Patients underwent total pancreatectomy, splenectomy, cholecystectomy and partial duodenectomy with continuity restored via doudenoduodenostomy or Roux-en-Y duodenojejunostomy.  The islets were isolated and then infused intraportally.

Key findings:

  • At 1 year following TPIAT, 22 (46%) reported no use of narcotic pain medications.
  • Health-related quality of life scores improved (see Figure 3)
  • Diabetes is a common post-op concern.  Approximately half were insulin-independent at 1 and 2 years out from surgery, with one-third remaining so at 5 years.
  • Histopathology was consistent with chronic pancreatitis in 37 (76%) indicating that current imaging/functional features do not reliably identify chronic pancreatitis with adequate sensitivity.

In the discussion, the authors note the selected patients, due to having normal caliber pancreatitis ducts, were not candidates for surgical drainage procedures like the Puestow procedure.  They also note that the Puestow procedure can compromise later islet cell isolation.

My take: TPIAT is an important option in those with severe recurrent or persistent pancreatitis disease.

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Quiet spot on Univ Virginia Grounds

Chronic Pancreatitis in Pediatrics -Descriptive Study

“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

Key points:

  • 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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Postgraduate Course Notes -Pancreatitis Module

When and how to assess pancreatic function: an update for clinicians –Sohail Z. Husain, MD (page 31)

Reviewed methods of detecting pancreatic insufficiency

Indirect (non-stimulatory) Methods


  • Fecal Fat Analysis: Coefficient of fat absorption (CFA): (fat intake – fat in stool / fat intake) * 100
  • Normal > 93% (> 85% in less than 6 mo.
  • old)
  • 72 hr collection gold standard

ELASTASE-1: Stable, specific for human pancreas

  • Normal > 200 μg elastase/g stool
  • Particularly good for monitoring the development of PI in patients with CF
  • Low levels (false-positive) with diarrhea
  • Only detects severe PI

Other tests

  • Chymotrypsin: less sensitive; requires discontinuation of enzymes
  • Steatocrit: cheap; has low sensitivity
  • Serum
  • Breath
  • Direct (stimulatory)
  • Dreiling tube
  • Endoscopic pancreatic function testing (ePFT)
  • Secretin-enhanced MRCP (sMRCP)

Causes of Pancreatic Insufficiency

-85% of patients with Cystic Fibrosis have pancreatic insufficiency

Shwachman-Diamond Syndrome

  • Mutation in SBDS, found in ~90% of SDS patients
  • PI affects almost all SDS pts

Johanson-Blizzard syndrome (JBS): Key findings

  • PI
  • Severe developmental delay
  • Hypoplasia or aplasia of the nasal wings

Pearson marrow pancreas syndrome Key findings: Severe hypoplastic,macrocytic anemia,  Pancreatic insufficiency (due to pancreatic fibrosis)

Diagnosis: Clinical picture, High serum lactate/pyruvate,  Southern blot for mtDNA rearrangements

Other causes of pancreatic insufficiency

  • Chronic pancreatitis
  • Pancreatic obliteration after severe, acute pancreatitis
  • Pancreatic tumors
  • Celiac disease
  • Diabetes
  • IBD

Managing nutrition in cystic fibrosis: the role of the pediatric gastroenterologist  Sarah Jane Schwarzenberg, M.D. (page 41)

Good nutrition status correlates with better heights, better lung function, and better survival.  (Presentation did not delve into the issue of potential reverse causation.)

  • Patients with a Weight-for-Age percentile >50% at age 4 years reached a much higher height-for-age early in life and maintained this advantage into adulthood
  • Pulmonary function (FEV1%predicted) was much lower in CF patients with WAP<10% at age 4 years. This finding tracked through age 18 years.
  • Small bowel overgrowth is common in CF
  • Small bowel bacterial overgrowth contributes to poor nutritional intake and increased nutrient losses

Options to improve nutrition in CF

  • Review and optimize enzyme dose and adherence
  • Review patient’s diet with an experienced CF dietician
  • Consider adding a PPI to improve intestinal pH
  • Consider confounding disease
  • Evaluate for signs and symptoms of small bowel overgrowth and consider trial of metronidazole or rifaximin
  • Ask patient about abdominal pain
  • Evaluate for gastroparesis
  • Evaluate for DIOS
  • Consider non-CF gastrointestinal disease
  • Consider oral glucose tolerance test

Therapy to improve nutrition

  • Time-limited interventions
  • Behavior therapy to improve intake
  • Offer oral supplements
  • Consider cyproheptadine as an appetite stimulant
  • Consider a G-tube for nocturnal feeds
  • Consider Endocrinology consult

Beyond the Basics in the Management of Pancreatitis  –Aliye Uc, M.D. (page 51)

INSPPIRE To Study Acute Recurrent and Chronic Pancreatitis in Children-180 children from 14 centers enrolled to study the etiologies, epidemiology, natural history and outcome.

Pediatric Acute Recurrent and Chronic Pancreatitis-etiologies

  • Genetic (49%) (61 of 91 tested)
  • PRSS1-30%, CFTR-22%, SPINK1-14%, CTRC-3%
  • Obstructive (34%)
  • Idiopathic (20%)
  • Toxic-Metabolic (17%)
  • Autoimmune (3%)

Genetics of Pancreatitis:

1. PRSS1 (cationic trypsinogen): Autosomal dominant, 80% penetrance, Mutations are due to increased activation or decreased inactivation of trypsin (i.e. R122H, N29I).

2. SPINK1 (trypsin inhibitor): Autosomal recessive/complex inheritance, 2% have mutation, <1% have pancreatitis (i.e. N34S), Pancreatitis is dose-related (homozygous>>>het), Associated with other mutations (CFTR)

3. CFTR (>1700 mutations):

  • 2 Severe mutations = Cystic Fibrosis
  • 1 severe, 1 mild mutation = mild or atypical CF, ARP, CP
  • CF carriers = 3-4 fold increase risk in pancreatitis.
  • 1 any +SPINK1 = CFTR-associated pancreatitis
  • 1 any +divisum = CFTR-associated pancreatitis

4.New Modifier Genes in ARP and CP

  • CTRC (trypsin degrading enzyme)
  • CASR (a calcium-sensing receptor)
  • CLDN2 (tight junction protein on X chromosome)
  • CPA1 (Carboxypeptidase 1)  increased riskf for CP in younger patients


  • Unclear if antioxidants helpful for pain.
  • The role of pancreatic enzymes in CP is equivocal.


  • When to start feeds? depends on the severity of AP, OK to start early; correlate with clinical readiness, abd pain
  • What mode of nutrition? prefer enteral over TPN, NG vs. NJ
  • What to feed?  recent studies in adults with mild AP support full diet

(Moraes JM et al. J Clin Gastroenterol 2010 44:517)

No evidence that low-fat diet is helpful

IV Fluids: With acute presentation, Lactated Ringer’s preferred over Normal saline.

NG Suction

  • Not shown to decrease symptoms,mortality or hospital stay.
  • May be useful if: severe gastric distention, refractory nausea and vomiting, or obstruction seen on abdominal x-ray