Pediatric Annals

Special Issue Article 

Pancreatic Malnutrition in Children

Inessa Normatov, MD; Timothy Sentongo, MD

Abstract

Exocrine pancreatic insufficiency in children can lead to lifelong complications related to malnutrition and poor growth. The clinical presentation can be subtle in the early stages of insufficiency as the large functional capacity of the pancreas is gradually lost. The pediatrician plays a crucial role in the early identification of these children to ensure a timely referral so that a diagnosis can be made and therapy initiated. Early nutritional therapy allows for prevention and correction of deficiencies, which leads to improved outcomes and survival. When insufficiency is suspected, the workup should start with an indirect test of exocrine pancreatic function, such as fecal elastase, to establish the diagnosis. Once a diagnosis is established, further testing to delineate the etiology should be pursued, with cystic fibrosis being high on the differential list and assessed for with a sweat test. Assessment of anthropometry at every visit is key, as is monitoring of laboratory parameters and physical examination findings that are suggestive of malabsorption and malnutrition. The mainstay of management is administration of exogenous pancreatic enzymes to facilitate digestion and absorption. [Pediatr Ann. 2019;48(11):e441–e447.]

Abstract

Exocrine pancreatic insufficiency in children can lead to lifelong complications related to malnutrition and poor growth. The clinical presentation can be subtle in the early stages of insufficiency as the large functional capacity of the pancreas is gradually lost. The pediatrician plays a crucial role in the early identification of these children to ensure a timely referral so that a diagnosis can be made and therapy initiated. Early nutritional therapy allows for prevention and correction of deficiencies, which leads to improved outcomes and survival. When insufficiency is suspected, the workup should start with an indirect test of exocrine pancreatic function, such as fecal elastase, to establish the diagnosis. Once a diagnosis is established, further testing to delineate the etiology should be pursued, with cystic fibrosis being high on the differential list and assessed for with a sweat test. Assessment of anthropometry at every visit is key, as is monitoring of laboratory parameters and physical examination findings that are suggestive of malabsorption and malnutrition. The mainstay of management is administration of exogenous pancreatic enzymes to facilitate digestion and absorption. [Pediatr Ann. 2019;48(11):e441–e447.]

Pancreatic malnutrition (exocrine pancreatic insufficiency [EPI]) is relatively uncommon in the pediatric population but can lead to malnutrition with serious implications. The gradual loss of function in most conditions leading to EPI can result in a delay in the diagnosis due to the subtle nature of the presenting symptoms. The pediatrician can play a crucial role in identifying children with EPI as early as possible. Early diagnosis and nutritional therapy improve nutritional status, quality of life, clinical outcomes, and survival. EPI should be considered in any child with failure to thrive, chronic diarrhea, steatorrhea, hypoalbuminemia, as well as trace vitamin and mineral deficiencies.

Pancreatic Physiology

The pancreas has a dual function (exocrine and endocrine) and has tremendous functional reserve. The endocrine portion is comprised of islets of Langerhans cells that are scattered throughout the pancreas. These secrete insulin and glucagon into the blood stream for blood sugar control. The exocrine portion of the pancreas, which accounts for most of the mass of the pancreas, responds to both hormonal (secretin and cholecystokinin) and vagal stimulation. It is made of clusters of acinar cells that produce enzymes necessary for the digestion of fats, starch, and protein (Table 1), as well as duct cells that are responsible for producing the alkaline fluid that carries these enzymes into the duodenum.1 This fluid is clear, colorless, isotonic, and alkaline, and it serves as the neutralizing agent for the chyme that is passing from the stomach so that the pancreatic enzymes can function in their optimal environment. Most of the enzymes are secreted as zymogens to prevent pancreatitis from autodigestion, with conversion into the active form in the duodenum.

Digestive Enzymes Secreted by the Pancreas

Table 1:

Digestive Enzymes Secreted by the Pancreas

Pancreatic Stimulation

The exocrine pancreatic cells respond to both hormonal and neuronal stimuli. The hormones that stimulate the pancreas get produced in response to the chyme, consisting of gastric juices, bile, and partly digested food in the proximal small bowel. The neuronal stimulation starts even before any food is ingested, in what is referred to as the cephalic phase of digestion. This is the sensory portion of the meal and triggers are sight, smell, and taste of food. Once food is ingested and the gastric phase of digestion occurs, the distension of the gastric fundus and antrum further stimulate the vagus nerve (Table 2).

Hormonal and Neuronal Pancreatic Stimulation

Table 2:

Hormonal and Neuronal Pancreatic Stimulation

Clinical Presentation

The general clinical picture in a patient with EPI will show clues for fat and/or protein malabsorption; however, the severity of symptoms depends on the degree of insufficiency. In adults, the most common cause of EPI is chronic pancreatitis (CP) from alcohol abuse, whereas in children the most common cause is cystic fibrosis (CF). CF leads to a gradual loss of pancreatic exocrine function, so some children may be asymptomatic from a gastrointestinal and nutritional standpoint in the early stages. Nevertheless, the resultant malnutrition can have long-term health implications and, therefore, it is crucial to identify these children early. A diligent assessment of the growth parameters at every well-care visit with the pediatrician is necessary for early diagnosis. Some children may have mild and nonspecific symptoms such as abdominal discomfort and bloating, with normal-appearing bowel movements. As the disease progresses and the EPI worsens (thus worsening malabsorption), they may present with weight loss, steatorrhea, bloating, cramping, increased flatulence, and, in severe cases, clinical symptoms of vitamin deficiencies such as impaired night vision and metabolic bone disease.

Steatorrhea implies the presence of excessive amounts of fat in the stool, and these stools typically are loose, greasy, foul smelling, and sometimes are reported as difficult to flush. It is important to be aware that overt steatorrhea does not occur until approximately 90% of the glandular function of the pancreas has been lost,2 which is often not the case in children. Another stool finding that may be reported is the appearance of meat fibers in the stool, which could be from protein maldigestion or constipation, as undigested fat makes the stool “sticky” and can lead to distal small bowel obstruction. Carbohydrate digestion is typically not affected because of salivary amylase and brush border enzymes.

Diagnostic Approach

Laboratory abnormalities that are nonspecific but suggestive of fat malabsorption are elevated levels of fecal fat and low levels of the fat-soluble vitamins (vitamins A, D, E, and K). When evaluating the serum levels for vitamins A, D, E, and K, tests should be done for retinol, 25-hydroxy vitamin D, alpha-tocopherol, and prothrombin time, respectively. Vitamin B12 deficiency may also occur but is rare. The mechanism of this deficiency is interference of transfer of vitamin B12 from R protein to intrinsic factor from acidic intestinal pH.

There are several pancreatic function tests available (Table 3), and these are divided into two broad categories: indirect (or nonstimulatory) and direct (stimulatory). For the initial screening of a child with suspected EPI, the workup starts with an indirect test of exocrine pancreatic function such as fecal elastase. If these tests are inconclusive, but a high clinical suspicion of EPI remains, then direct pancreas function testing with an endoscopic secretin test may be appropriate. The direct pancreatic function tests are the current gold standard for diagnosis of EPI. The general idea is that the pancreas gets stimulated through intravenous administration of hormonal secretagogues (secretin, cholecystokinin, or both), so the test collects duodenal fluid that gets analyzed for pancreatic secretory content (enzymes and bicarbonate). These tests are time consuming and invasive, and care needs to be taken to avoid contamination with gastric juices.

Types of Pancreatic Function Tests

Table 3:

Types of Pancreatic Function Tests

Indirect Tests of Exocrine Pancreatic Function

Fecal elastase. The elastase enzyme is produced by acinar cells in the pancreas. This is the most sensitive and specific indirect test of pancreatic function, with good correlation between pancreatic elastase concentrations in pancreatic fluid and stool thanks to the fact that it remains relatively stable during transport through the gastrointestinal tract. A fecal elastase level <200 mcg/g is considered abnormal and a level of 200 to 250 mcg/g is borderline, so retesting should be considered. The sensitivity of the test depends on the severity of EPI. In EPI due to CP, the sensitivity is 63% in mild EPI and 100% in moderate to severe EPI. The specificity of the test is approximately 93%.3 It is important to be aware that false-positive results from dilution related to watery diarrhea from nonpancreatic diseases can occur.

Fecal chymotrypsin. Chymotrypsin is another digestive enzyme produced by the pancreas, but it is variably affected during intestinal transport and, therefore, has lower sensitivity than elastase: 49% in mild to moderate EPI and 85% in advanced EPI.4 It too may be diluted in the presence of concomitant diarrhea, leading to false-positive results. Also, because chymotrypsin is present in commercially available enzymes, patients must stop exogenous enzymes for 2 days prior to testing. However, one can use this limitation to assess compliance to pancreatic enzyme replacement therapy (PERT).

Stool smear for fecal fat and 72-hour fecal fat. A fecal fat smear is a simple, although inaccurate, method for assessment of steatorrhea. In this technique, a sample of stool is stained with Sudan red stain and reviewed under a microscope to look for presence of fat droplets. Petroleum jelly lubricants, suppositories, and mineral oil can cause false-positive results and should be avoided prior to collection of the specimen.

A quantitative fecal fat test is usually done over a period of 3 days, during which time the patient collects all of his or her feces into a container. During the collection period, the stool needs to be refrigerated to prevent bacteria from breaking down the fat. Steatorrhea is defined as excretion of more than 7 g of fat after consuming 100 g of fat in a 24-hour period or more than 7% of the measured fat intake over a 3-day period.

Serum immunoreactive trypsinogen. Serum immunoreactive trypsinogen (IRT) is an inexpensive and widely available test that reflects pancreatic acinar cell mass. Elevated IRT in dried blood spot samples is the basis of CF newborn screen.5 It has high sensitivity for advanced EPI when trypsinogen levels are <20 ng/mL but lower sensitivity in mild and moderate EPI. Patients with CF have trypsinogen levels well below normal by age 7 years, so this test can validate this disease. It is important to note that levels rise with acute pancreatitis and abdominal pain of nonpancreatic origin, thus possibly leading to falsely elevated results.

Imaging Findings in EPI

Abdominal imaging with ultrasound, computed tomography, or magnetic resonance imaging may show findings consistent with pancreatic inflammation such as calcifications, ductal dilatation, enlargement of the pancreas, and peripancreatic fluid collections. In conditions in which significant pancreatic mass is lost, such as with advanced CP, CF, Shwachman-Diamond syndrome, and advanced hemochromatosis, pancreatic atrophy can be seen on imaging.

Etiology and Pathogenesis

Table 4 lists the causes of EPI in children and adults.

Causes of Exocrine Pancreatic Insufficiency in Children and Adults

Table 4:

Causes of Exocrine Pancreatic Insufficiency in Children and Adults

Chronic Pancreatitis

CP is a disorder in which there is a progressive inflammatory process in the pancreas that leads to irreversible changes. There are multiple etiologies that can lead to CP. Some common ones are genetic mutations leading to the premature activation of pancreatic zymogens within the pancreas (eg, PRSS1, SPINK1, CTRC, and CPA1 mutations), alpha-1-antitrypsin deficiency, CF, infections, and structural anomalies leading to impaired drainage of the pancreatic fluid. These include pancreatic divisum, pancreaticobiliary maljunction, biliary cysts, annular pancreas, and intestinal duplications.

Cystic Fibrosis

CF affects 1 out of 2,000 white children and is the most common cause of EPI in children. It is an autosomal recessive disease caused by mutations in the gene that encodes the CFTR (cystic fibrosis transmembrane conductance regulator) protein, located on chromosome 7. There are nearly 2,000 identified mutations, with the most common one being the loss of phenylalanine at position 508 (F508Del). In CF, the decreased chloride transport causes thickened mucosal secretions and decreased bicarbonate flow in the pancreas, liver, and intestinal tract. Approximately 80% of patients develop progressive pancreatic fibrosis and destruction of acinar cells from inspissated pancreatic secretions that block the ductules, and 65% of children with CF already have evidence of EPI at birth.6

Shwachman-Diamond Syndrome

Shwachman-Diamond syndrome is an inherited syndrome that affects multiple body systems, particularly the bone marrow, pancreas, and skeletal system. The estimated incidence of clinically affected people is 1 in 77,000 to 168,000,7,8 and it follows an autosomal recessive pattern of inheritance. Most cases result from mutations in the SBDS gene, which encodes a ribosomal protein.9 Clinically, it presents with malabsorption from EPI, anemia, and neutropenia with recurrent infections from bone marrow abnormalities, hypotonia, metaphysial dystosis (abnormal development of the long bones), and growth retardation. Other physical abnormalities may also be present.10

Johanson-Blizzard Syndrome

Johanson-Blizzard syndrome is an extremely rare autosomal recessive disorder, affecting about 1 in 250,000 people and being caused by mutations in the UBR1 gene.11 This gene encodes a protein necessary for proper acinar cell function, and in affected people there is progressive destruction of the pancreas leading to replacement of the tissue by abnormal accumulations of fat. The spectrum of findings is wide and can differ dramatically between affected people. Common features are malabsorption from pancreatic insufficiency, failure to thrive, short stature, abnormal permanent teeth (most will be missing), a small “beak-shaped” nose (hypoplasia of nasal alae), other craniofacial abnormalities, and varying degrees of intellectual disability.11

Pearson's Bone Marrow Syndrome

Pearson's bone marrow syndrome is caused by large deletions of mitochondrial DNA. This leads to impaired oxidative phosphorylation and lack of cell energy. The clinical features are EPI, bone marrow failure, and sideroblastic anemia. Prognosis is poor, with mortality in infancy or early childhood due to severe lactic acidosis or liver failure.

Establishing the Etiology of EPI

In children in whom the diagnostic workup is consistent with EPI, CF should be high on the differential and assessed for with a sweat test. A negative newborn screen does not rule out the disease because routine screening programs will miss 2% to 7% of cases.12,13 Children with CF will have a normal amount of sweat but with high sodium chloride content. A sweat test may show false-positive results for other conditions such as glycogen storage disease type I, familial cholestasis, hypothyroidism, and eczema. False-negative results can also occur such as if the patient is edematous, if an inadequate amount of sweat is collected, or due to testing error. It can be a difficult test to perform in infants due to inadequate hidrosis. Alternatives in such cases are genetic analysis for CFTR gene mutations and measurement of nasal potential differences (which is performed in specialized centers).

Nutritional Considerations in EPI

Therapy for all children with EPI generally follows the guidelines that exist for CF patients. Poor growth is an early manifestation of CF and the etiology is often multifactorial, including poor intake, malabsorption, increased metabolic needs, and in some patients, liver dysfunction and respiratory insufficiency. Some of the most convincing literature supporting the importance of early screening and intervention in CF comes from the field of growth and nutrition.14–18

Nutritional Assessment

Nutritional assessment and growth monitoring using anthropometry and growth charts from the Centers for Disease Control and Prevention should be performed regularly in all children, and particularly so in children who are at high risk for the development of malnutrition. Children with CP, with or without EPI, should be screened for impaired growth and/or malnutrition every 3 to 6 months. Children with CP who develop EPI and/or pancreatogenic diabetes require more frequent follow-up. The aspects of nutritional assessment include obtaining a dietary history, anthropometry, physical examination with specific assessment of clinical signs of fat malabsorption (Table 5), and biochemical testing.

Clinical Signs of Fat Malabsorption

Table 5:

Clinical Signs of Fat Malabsorption

Nutritional Management

Growth and diet. Children with CP may have up to 50% higher resting energy expenditure than healthy children. The goal with nutritional management is ensuring normal growth and normal body composition and preventing micronutrient deficiencies. The ideal dietary macronutrient composition has not been studied in children with CP, and current recommendations support following a regular diet.19 Children who develop pancreatogenic diabetes require specialized nutritional evaluation.

The mainstay of management is administration of PERT to prevent malabsorption. The dose of the enzymes should be adjusted according to the foods consumed, weight gain, and steatorrhea (via repeated tests of fat maldigestion/malabsorption as necessary). Typical dosing is outlined in Table 6. It is important to keep in mind that supratherapeutic dosing of PERT can lead to a condition called fibrosing colonopathy, in which colonic wall thickening and narrowing occurs.

Dosing of Pancreatic Enzyme Replacement Therapy

Table 6:

Dosing of Pancreatic Enzyme Replacement Therapy

Micronutrients. Prevention and monitoring of fat-soluble vitamin deficiencies is prudent, and fat-soluble vitamin supplementation is recommended for all patients with CP, with or without EPI. Fat-soluble vitamin levels should be assessed every 6 to 12 months. If supplementation is required, levels should be rechecked 3 months after dose adjustment. There is no evidence to recommend routine monitoring of other vitamins, minerals, or trace elements unless clinical suspicion is present.19

Other dietary considerations. Bone mineral density (BMD) screening is recommended for children with CF and should also be implemented in children with pancreatic insufficiency from other etiologies. Therefore, it is recommended to check BMD in children with CP and malnutrition, persistently low vitamin D, or history of fractures (specifically vertebrae, hip, or wrist).19

Medications to suppress gastric acid production (eg, proton pump inhibitor or H2 blocker) are often used in children with CP to help neutralize the gastric chyme because the EPI leads to inadequate pancreatic bicarbonate production. This allows the pancreatic enzymes to work in a more optimal environment.

Conclusion

Absorption and digestion are contingent on adequate exocrine pancreatic function. When EPI develops in children, the earliest signs can be nonspecific gastrointestinal symptoms and slowing growth. When suspected, fecal elastase should be checked and if concentration is consistent with EPI, the etiology should be sought. In children, the most common cause is CF and the mainstay of management is administration of PERT.

References

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Digestive Enzymes Secreted by the Pancreas

Enzyme Target
Amylolytic enzymes
Amylase alpha-1,4-glycosidic bonds in starch
Lipolytic enzymes
Lipase Triglyceride, producing fatty acids and 2-monoglycerides
Phospholipase A2 Phosphotidylcholine, producing a free fatty acid and lysophosphotidylcholine
Carboxylesterase Cholesterol esters, lipid-soluble vitamin esters, and glycerides (tri-, di-, or monoglycerides)
Proteolytic enzymes
Trypsin Interior peptide bonds involving basic amino acids
Chymotrypsin Interior peptide bonds involving aromatic amino acids
Carboxypeptidase A and B External peptide bonds involving aromatic and neutral aliphatic amino acids (A) and basic amino acids (B) at the carboxy-terminal end
Elastase Interior peptide bonds involving neutral aliphatic amino acids
Nucleases
Deoxyribonuclease (DNAse) Endonuclease that splits phosphodiester linkages adjacent to pyrimidine nucleotide
Ribonuclease (RNAse) Catalyzes the breakdown of RNA

Hormonal and Neuronal Pancreatic Stimulation

Stimulant Secreted By Secretion in Response To Pancreatic Response
Hormonal
Secretin Duodenal S cells Gastric acid in the duodenum Augmented by the presence of bile and products of fat and protein digestion Acts through the bloodstream on the pancreatic duct cells to release bicarbonate and water for neutralization of acid
Cholecystokinin Gut endocrine cells (I cells) Fatty acids, amino acids, small peptides in the duodenum and proximal jejunum Acts directly and through vagal mechanisms to stimulate the release of enzymes from pancreatic acinar cells
Neuronal
Vagus nerve Sympathetic and parasympathetic nervous systems via the celiac plexus, superior mesenteric and hepatic plexuses Sight, smell, and taste of food Stretching of the gastric fundus and antrum Cholecystokinin Parasympathetic stimulation of the acini, ducts, and islets; sympathetic innervation of blood vessels; leads to production and release of digestive proenzymes, bicarbonate and water

Types of Pancreatic Function Tests

Indirect (Nonstimulatory)   Stool     Elastase-1     Chymotrypsin     Smear for fat     72-hour fecal fat   Serum     Immunoreactive trypsinogen   Breath      13C-mixed triglyceride breath test   Urine     Pancreolauryl test Direct (Stimulatory)   Dreiling tube test   Endoscopic stimulation test

Causes of Exocrine Pancreatic Insufficiency in Children and Adults

Children   Cystic fibrosis   Shwachman-Diamond syndrome   Chronic pancreatitis (anatomical obstruction, hereditary pancreatitis, alpha-1 antitrypsin deficiency)   Johanson-Blizzard syndrome   Pearson's bone marrow syndrome   Congenital rubella syndrome   Pancreatic isolated enzyme defects   Pancreas agenesis/hypoplasia Adults   Chronic pancreatitis   Cystic fibrosis   Gastric, pancreatic, or small bowel resection   Chronic pancreatic duct obstruction (eg, pancreatic/ampullary tumor)     Other       Hereditary hemochromatosis       Gastrinoma (Zollinger-Ellison syndrome)       Small bowel mucosal disease (eg, celiac disease and inflammatory bowel disease)

Clinical Signs of Fat Malabsorption

Deficient Nutrient Sign
Vitamin A Night blindness, Bitot's spots (small, triangular, foamy white patcheson the sclera), xerophthalmia (excessive dryness) Less common findings: xerosis (corneal drying), keratomalacia (softening of the cornea), hyperkeratosis20
Vitamin D Bowed lower limbs, rachitic rosary, persistently open anterior fontanelle, tetany, enamel hypoplasia hypotonia21,22
Vitamin E Peripheral neuropathy with altered reflexes, strabismus, muscle weakness, visual field defects to complete blindness, cardiac arrhythmias20,22
Vitamin K Easy bruising, epistaxis, bleeding with brushing of teeth, heavy menstrual periods22
Signs of essential fatty acid deficiency Scaly dermatitis,23 alopecia, hair depigmentation, thrombocytopenia, and poor wound healing24,25 Can affect growth, and cognitive and visual function in infants26–28

Dosing of Pancreatic Enzyme Replacement Therapy

Infants   2,000–4,000 U lipase for every 120 mL of formula Age >1 year   Meal: 500–2,500 U lipase/kg/meal   Snack: 250–1,000 U lipase/kg/meal
Authors

Inessa Normatov, MD, is an Assistant Professor of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital at Montefiore, Albert Einstein College of Medicine. Timothy Sentongo, MD, is an Associate Professor of Pediatric Gastroenterology; the Director, Pediatric Nutrition Support; and the Director, Pediatric Gastrointestinal Endoscopy, Section of Gastroenterology, Hepatology and Nutrition, The University of Chicago Medical Center.

Address correspondence to Inessa Normatov, MD, Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital at Montefiore, Albert Einstein College of Medicine, 3411 Wayne Avenue, Bronx, NY 10467; email: inormatov@montefiore.org.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20191018-01

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