Exocrine Pancreatic Insufficiency in Children – Challenges in Management

Figures & data

Table 1 Causes of Exocrine Pancreatic Insufficiency in Children

Primary Pancreatic Disorders

Genetic syndromes

Cystic fibrosis*

Shwachman Diamond syndrome*

Johanson-Blizzard syndrome

Pearson marrow-pancreas syndrome

Jeune syndrome

Pancreatic aplasia/hypoplasia

Deficiency of isolated pancreatic enzymes

Chronic pancreatitis*

Hereditary pancreatitis (mutations in PRSS1, CFTR, SPINK1, CTRC)

Obstructive causes such as pancreas divisum, sphincter of Oddi dysfunction, gallstones

Drug-induced pancreatitis

Toxic/metabolic causes

Autoimmune pancreatitis

Surgical resection

For pancreatic tumors or chronic pancreatitis

Secondary Pancreatic Disorders

Duodenal inflammatory conditions resulting in reduced cholecystokinin or secretin

Inflammatory bowel disease

Celiac disease

Postcibal asynchrony between pancreatic enzyme delivery and intestinal chyme

Upper gastrointestinal surgeries

Excessive gastric acidity inactivating pancreatic lipase

Zollinger-Ellison syndrome

Transient pancreatic insufficiency

Malnutrition, after a viral illness, abdominal trauma, maturation delay in infants

Note: * relatively common causes of primary exocrine pancreatic insufficiency in children.

Table 2 Inherited Syndromes Which Causes Exocrine Pancreatic Insufficiency During Infancy:^15,21

Genetic Conditions with OMIM	Gene/Locus	Inheritance	Approximate Incidence	Salient Features	References
Cystic fibrosis 219,700	CFTR in chromosome 7q	Autosomal recessive	1 in 3000–4000 live births in Caucasians	CF was first described by Dorothy Andersen in 1938. It is the most common lethal genetic condition in Caucasians with approximately 30,000 patients live in the US. In developed countries, more than 90% of CF are diagnosed by newborn screening. Most countries utilize serum immunoreactive trypsinogen (IRT) and/or genetic analysis for CF newborn screening. Confirmation of diagnosis is by sweat testing and can be done after 6 weeks of age. Approximately 2000 mutations have been identified, and about 85% of patients have at least one copy of F508del. CFTR gene encodes the Cystic Fibrosis Transmembrane Regulator Protein (CFTR). CFTR is expressed in various epithelial cells such as respiratory cells, pancreatic ducts, intestinal cells, biliary tract, sweat duct, and vas deferens which results in multisystem involvement in CF. Before the advent of newborn screening, most patients with CF were diagnosed based on clinical presentations such as meconium ileus, poor growth, rectal prolapse, steatorrhea, and recurrent pulmonary infections. Meconium ileus occurs in approximately 15% of newborns with CF. Fecal elastase-1 is used to confirm EPI in infants newly diagnosed infants with CF, monitor pancreatic sufficient CF patients (during annual evaluation or if they develop manifestations of EPI), and evaluate older CF patients at the time of diagnosis.	[13,18–31]
Shwachman-Diamond syndrome 260,400	SBDS in chromosome 7q11	Autosomal recessive	1 in 76, 000	SDS was first described by Shwachman et al in 1964. SDS is the second most common inherited syndrome causing EPI after CF. SDS is characterized by multisystem involvement including the bone marrow failure, predisposition to infections, and hematologic malignancies, pancreatic lipomatosis, skeletal anomalies, and failure to thrive. About 90% of patients with a classic presentation of SDS have mutations in the Shwachman-Bodian-Diamond (SBDS) gene which codes for the SBDS protein. This protein is postulated to play a vital role in ribosomal maturation (60S subunits) and proliferation of cells. The most likely underlying biochemical mechanism is a complex IV defect leading to defective oxidative phosphorylation and endoplasmic reticulum stress.	[32–43]
Johanson-Blizzard syndrome 243,800	UBR1 in chromosome 15q15.2	Autosomal recessive	1 in 250,000	JBS was first described by Johanson and Blizzard in 1971. The UBR1 (ubiquitin protein ligase E3 component N-^81recognin 1) gene encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system whose substrates include proteins with destabilizing N-terminal residues 20. UBR1 is involved in controlling cellular proliferation and leucine-m-TOR signaling pathway and this resulting genetic imbalance is associated with dysregulated apoptosis resulting in a variety of development anomalies including pancreatic lipomatosis. Alae nasi hypoplasia or aplasia, scalp defects (cutis aplasia), hearing impairment, dental anomalies, microcephaly, cardiac anomalies, hypothyroidism, imperforate anus, and urogenital defects along with EPI (pancreatic lipomatosis) are noted in JBS. Severe growth and developmental delay are often noted.	[44–52]
Pearson’s marrow-pancreas syndrome 557,000	Mitochondrial DNA	Mitochondrial inheritance	Unknown (About 100 cases have been reported)	Pearson-marrow pancreas syndrome or Pearson-marrow syndrome was originally described in 1979 by Pearson. This syndrome is due to deletions of mitochondrial DNA resulting in defective oxidative phosphorylation. The most characteristic features include depressed hematopoietic cell lines (either singly or in combination). Sideroblasts are noted in ~50% of cases with ringed sideroblasts and cell vacuolization in the bone marrow. Characteristic features include depressed hematopoietic cell lines (either singly or in combination). Sideroblasts are noted in ~50% of cases with ringed sideroblasts and cell vacuolization in the bone marrow. EPI is noted in half the patients and the pancreas is usually fibrotic. Majority of deaths were attributed to multi-organ failure, metabolic acidosis, and severe infections.	[53–58]
Jeune asphyxiating thoracic dystrophy 208,500	Multiple genes implicated in chromosome 15q13	Autosomal-recessive	1:100,000–1:130,000 live births	Jeune syndrome or asphyxiating thoracic dystrophy was first described in 1955. The phenotype of Jeune syndrome is variable. It is characterized by musculoskeletal abnormalities including a small, narrow chest leading to respiratory distress and, short-limbed dwarfism. EPI is due to pancreatic fibrosis. Renal abnormalities (cystic dysplasia/nephronophthisis), hepatic and pancreatic fibrosis, and ocular complications may occur later in life. Multiple musculoskeletal manifestations of varying severity such as abnormalities of the thorax, short-limbed dwarfism, and cystic dysplasia/ nephronophthisis of the kidneys are also noted.	[16,59–62]
Pancreatic agenesis 260,370	PDX1 gene (codes for insulin promoter factor‐1 IPF1) in chromosome 13q12.2	Autosomal recessive	Unknown	Diabetes and EPI have been noted with onset in neonates with variable severity.	[51,63–67]
Pancreatic and cerebellar agenesis 609,069	PTF1A gene in chromosome 10p12	Autosomal recessive	Unknown	Pancreatic and cerebellar agenesis, diabetes mellitus	[68–70]
Pancreatic agenesis and congenital heart defects 600,001	Heterozygous mutations in GATA6 gene in chromosome 18q11.2	Autosomal dominant	Unknown	EPI, congenital heart defects, and diabetes mellitus	[71–73]
Syndrome of EPI, dyserythropoietic anemia, calvarial hyperostosis 612,714	COX4I2 in chromosome 20q11.21	Autosomal recessive	Unknown	EPI, dyserythropoietic anemia, and calvarial hyperostosis	[74]
Congenital pancreatic lipase 614,338	PNLIP in chromosome 10q25.3	Autosomal recessive	Unknown	Chronic diarrhea and steatorrhea and malnutrition	[75–81]
Congenital pancreatic colipase 120,105	CLPS in chromosome 6p21.21*	Unknown	Unknown	Chronic diarrhea and steatorrhea	[16,78,80,82,83]
Congenital trypsinogen deficiency 614,044	PRSS1 in chromosome 7q35*	Unknown	Unknown (few cases reported)	Failure to thrive, diarrhea, hypoproteinemia, and peripheral edema	[84–86]
Congenital enteropeptidase 226,200	TMPRSS15/PRSS7 in chromosome 21.q21.1	Autosomal recessive	Unknown (few cases reported)	Even though in a strict sense, this condition is not an EPI, this brush border enzyme activates pancreas-derived zymogens in the small bowel. This disorder is characterized by severe protein malabsorption in early infancy, with growth faltering, chronic diarrhea (no steatorrhea), and anasarca. Adults may have mild symptoms, even after stopping pancreatic enzyme supplementation.	[87–89,148]

Note: *Not documented in clinical cases.

Abbreviations: CF, cystic fibrosis; EPI, exocrine pancreatic insufficiency; JBS, Johanson-Blizzard syndrome; OMIM, Online Mendelian Inheritance in Man; SDS, Shwachman Diamond syndrome.

Table 3 Pancreatic Function Tests

Name of the Test	Comments Regarding Their Utility in Children
Indirect tests - Noninvasive tests, simple to administer
Fecal elastase-1 (monoclonal)	Qualitative and easy to obtain. Lower sensitivity in early EPI and false-positive result if the stool is watery loose. This test should be repeated with formed stools.
Fecal chymotrypsin	Less sensitive than fecal elastase-1. PERT should be discontinued prior to testing. On the contrary, this test can be utilized to check PERT compliance.
72-hour fecal fat estimation (co-efficient of fat absorption)	Gold standard test fat malabsorption. But nonspecific for EPI. Provides quantitative assessment of fecal fat absorption; can assess the adequacy of pancreatic enzyme replacement therapy. The 72-hour collection of stools is cumbersome and unpleasant. Requires detailed diet records to assess fat intake.
^13C-mixed triglyceride breath test	Not widely available in all countries and limited data in children. May pose challenges to administer in infants and young children.
IRT	Plasma IRT is elevated in CF infants and this is utilized in CF newborn screening test. Upon developing pancreatic insufficiency, IRT levels fall below normal around 6–7 years of age. Beyond CF newborn screening, serum IRT or trypsin is not useful for evaluating pancreatic status due to lack of specificity for EPI.
Direct tests (Based on stimulation of pancreatic secretions)
Dreiling tube test	Old fashion test - performance is cumbersome in children and outdated in current practice.
Endoscopic pancreatic function tests	Performed in lieu of the Dreiling tube test. The need for anesthesia and endoscopy limits its widespread availability to tertiary pediatric centers.
Secretin-enhanced magnetic resonance cholangiopancreatography	Need for anesthesia in young children. Limited availability in tertiary pediatric centers. Also needs radiologists with pediatric pancreatology expertise. Limited data in the pediatric population.

Abbreviations: CF, cystic fibrosis; EPI, exocrine pancreatic insufficiency; IRT, Immunoreactive trypsinogen; PERT, pancreatic enzyme replacement therapy.

Figure 1 (A) Computed tomography (axial view) of a 8-year-old patient with cystic fibrosis showing pancreatic atrophy and pancreatic calcifications (white arrow). (B) Magnetic resonance cholangiopancreatography (axial view) of an infant with exocrine pancreatic insufficiency from Pearson syndrome showing pancreatic atrophy with fatty replacement (white arrow). (C) Computed tomography (axial view) of a 5-year-old patient with exocrine pancreatic insufficiency from tropical calcific pancreatitis showing extensive pancreatic calcifications (white arrow). (D) Magnetic resonance enterography (coronal view) of a 4-year-old patient with exocrine pancreatic insufficiency showing annular pancreas (white arrow) and pancreatic hypoplasia with small body and tail of the pancreas (black arrow).

Table 4 Factors to Consider for Poor Response to PERT and Persistence of EPI Symptoms

Ensure correct dosage is used (in relation to the fat content of the food or body weight) or consider increasing the PERT dose in smaller increments (daily dose not exceeding 10,000 lipase units/kg/day)

Evaluate efficacy of PERT (appropriate storage and checking expiry date)

Ensure administration just before the meal/snack and fat containing beverages

Evaluate for adherence to PERT

Evaluate for “graze” pattern throughout the day without taking PERT

Consider a trial of acid suppression if the symptoms do not improve with optimizing dose changes

Consider other causes of malabsorption such as celiac disease, small intestinal bacterial overgrowth, inflammatory bowel disease

Abbreviations: EPI, exocrine pancreatic insufficiency; PERT, pancreatic enzyme replacement therapy.

Figure 2 Median predicted survival age of patients with cystic fibrosis from the year 1990 to 2021 in five-year increments (reproduced with permission from the Cystic Fibrosis Foundation).

Notes: Cystic fibrosis patients under care at CF Foundation-accredited care centers in the United States, who consented to have their data entered. Cystic Fibrosis Foundation Patient Registry, 2021 Annual Data Report, Bethesda, Maryland, ©2022 Cystic Fibrosis Foundation.

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