Pediatric Annals

Special Issue Article 

Hereditary Pancreatitis

Edgardo D. Rivera Rivera, MD; Ankur Chugh, MD; Sona Young, MD; Jonathon Cordova, DO

Abstract

A 13-year-old boy with a strong family history of hereditary pancreatitis was found to have a PRSS1 mutation after being tested at age 5 years during his first documented incident of pancreatitis. Since then, a multidisciplinary team has been treating him for the diagnosis of hereditary pancreatitis. His pain episodes increased in severity over the past several months such that the pain began to severely interfere with his daily life. After extensive discussion, a total pancreatectomy with auto islet cell transplant was performed. He is now pain free and does not require any insulin. This leads us to the questions of what is hereditary pancreatitis and how is it diagnosed? What are the management and follow-up strategies needed for these patients? This article addresses these questions and informs the reader about this diagnosis and the importance of having a high index of clinical suspicion. [Pediatr Ann. 2016;45(2):e50–e53.]

Abstract

A 13-year-old boy with a strong family history of hereditary pancreatitis was found to have a PRSS1 mutation after being tested at age 5 years during his first documented incident of pancreatitis. Since then, a multidisciplinary team has been treating him for the diagnosis of hereditary pancreatitis. His pain episodes increased in severity over the past several months such that the pain began to severely interfere with his daily life. After extensive discussion, a total pancreatectomy with auto islet cell transplant was performed. He is now pain free and does not require any insulin. This leads us to the questions of what is hereditary pancreatitis and how is it diagnosed? What are the management and follow-up strategies needed for these patients? This article addresses these questions and informs the reader about this diagnosis and the importance of having a high index of clinical suspicion. [Pediatr Ann. 2016;45(2):e50–e53.]

Pancreatitis can be a challenging condition to identify and treat in the pediatric population. The overall low incidence as well as the wide range of different clinical presentations are some of the contributing factors for this difficulty. However, it is important to recognize the clinical manifestations, have a high index of suspicion, and consult a pediatric gastroenterologist in the setting of recurrent pancreatitis because appropriate investigations may unveil abnormalities or even genetic factors that could account for these episodes.

Illustrative Case

A13-year-old boy presented with recurrent abdominal pain that began at age 2 years. At approximately age 5 years, he was diagnosed with his first episode of documented acute pancreatitis. During this hospitalization, additional genetic testing was done and he was found to have a PRSS1 (R122H) mutation consistent with a diagnosis of hereditary pancreatitis.

Results of computed tomography scan of the abdomen at age 5 years and a magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) at age 6 years were entirely normal. Since then, the patient has had at least three hospital admissions per year for pain control. In addition, approximately every 3 months he has been treated at home with a diet of clear liquids and pain medications. The abdominal pain was epigastric and mostly triggered by food but occasionally was sudden in onset. On occasion, it would radiate to his back. When severe, the pain was 10 of 10 in intensity and without fever or chills. The patient took ondansetron as needed for intermittent nausea and occasional vomiting. The pain episodes would typically last 4 or 5 days, after which the patient would be completely pain-free. Bowel movements were well formed and without fat droplets.

Family History

The patient has one older sister without a history of pancreatitis but who is a carrier for the mutation. His father is healthy. His mother was diagnosed with acute pancreatitis at age 5 years and had recurrent bouts of acute pancreatitis; however, the episodes stopped after she gave birth to the patient. The mother is also positive for the PRSS1 mutation in the R122H location. The patient's maternal grandfather and maternal great-grandfather also have histories of hereditary pancreatitis. The patient's mother also has at least seven cousins with documented pancreatitis. His mother's sister does not have pancreatitis.

Disease Progression

At age 10 years, the pain episodes started to increase in frequency. An MRCP at that time revealed a normal biliary system with significant dilation of the main pancreatic duct and diffuse pitting and side branch dilation. An endoscopic retrograde cholangiopancreatogram (ECRP) was performed and showed stones in the pancreatic duct, consistent with calcified chronic pancreatitis. Pancreatic sphincterotomy was performed, followed by the removal of the majority of the pancreatic stones. A stent was placed in the main pancreatic duct. Three weeks later, the patient was readmitted with severe abdominal pain and recurrent pancreatitis. A repeat ERCP at that time resulted in replacement of the pancreatic duct stent and removal of additional stones. One month later, the patient was doing better clinically and an ERCP was performed to remove the pancreatic stent and sweep the main pancreatic duct, which still had some sludge and small stones.

Despite these improvements, the pain was not relieved and continued to increase in frequency. He eventually developed daily severe pain and was unable to attend school. Based on his clinical status and much discussion, 2 months after his last ERCP the patient underwent total pancreatectomy and islet cell transplantation. On follow-up 2 weeks after his procedure, the patient was pain free for the first time in years. In addition, he was on minimal insulin, which has been weaned off. He was placed on pancreatic enzyme supplementation for nutritional support. His fat-soluble vitamin levels and glycated hemoglobin (HbA1c) are currently normal.

Discussion

Pancreatitis is inflammation of the pancreas, which can progress from an acute presentation to a recurrent acute presentation (more than one episode of acute pancreatitis) or to chronic pancreatitis (inflammation lasting more than 6 months). Acute pancreatitis is characterized by the presence of two of the following three criteria: a sudden episode (usually severe) of epigastric pain, elevation of pancreatic enzymes (amylase and lipase) over three times the highest normal value, and radiographic evidence of inflammation in the pancreas.1,2 Chronic pancreatitis is an inflammatory condition of the pancreas characterized by morphologic changes, mostly irreversible, that cause pain and permanent loss of pancreatic function.3,4 Within the classification of chronic pancreatitis there are several subgroups, including familial pancreatitis, hereditary pancreatitis, and sporadic idiopathic pancreatitis.

Familial pancreatitis is characterized by the presence of pancreatitis caused by any etiologic origin affecting family members and whose incidence is higher than in the general population. The cause may be genetic or nongenetic and can be part of a syndrome that affects the pancreas.5 Unlike familial pancreatitis, hereditary pancreatitis is linked to a genetic disorder and is characterized by recurrent episodes of acute pancreatitis that becomes chronic pancreatitis and is associated with failure of both the exocrine and endocrine functions of the pancreas.6–9

The existence of hereditary pancreatitis as a disease entity was first described by Comfort and Steinberg in 1952.10 The authors reported the pedigree of a family through three generations in which four members presented with multiple episodes of pancreatitis. These patients presented between the ages of 5 and 23 years, typically with destruction of their pancreatic parenchyma. In 1996, Le Bodic et al.11 published a genealogy that described a family through eight generations and 249 affected members born between 1800 and 1993 with a hereditary pattern suggesting an autosomal dominant mode of transmission. However, it was not until later that year when Whitcomb et al.12 identified the first genetic defect associated with pancreatitis—the cationic trypsinogen gene (PRSS1). This significant discovery led to more research, and new mutations associated with hereditary pancreatitis have since been identified. In 2000, Witt et al.13 found a second gene, the inhibitor of the serine protease Kazal type 1 or SPINK1, that was also associated with hereditary pancreatitis. However, due to the complexity and depth of this disorder, progress in the knowledge and understanding of the role genes have in the development of hereditary pancreatitis has been slow.14

Genes Associated with Hereditary Pancreatitis

To date, dozens of genes that cause pancreatitis, including modifier genes as well as phenotypic and genotypic combinations associated with the development of hereditary pancreatitis and other chronic pancreatic disorders, are known.15 However, for the purpose of this article, we will discuss only those genes that appear to have the greatest impact on the development of hereditary pancreatitis.

PRSS1

The gene PRSS1 encodes for the protein trypsin 1, also called cationic trypsinogen, which is the predominant isoform of trypsinogen in human pancreatic juices and affects the activation of other digestive enzymes from the pancreas.16 In the PRSS1 mutation, trypsin is prematurely activated or it is resistant to degradation, causing its inappropriate activation into the pancreatic acini, triggering an uncontrolled inflammatory reaction that overwhelms the protective mechanisms of the pancreas and results in pancreatitis. The PRSS1 heterozygous variant has an autosomal dominant mode of transmission and is very prevalent in families with this disease.6,17

SPINK1

The inhibitor of the serine protease Kazal type 1 or SPINK1 is a powerful antiprotease and functions as an inhibitor of trypsin activation. Because this protease acts in a protective fashion, the mutation associated with the pathogenic mutation is where the inhibitory activity of the enzyme is decreased. Thus, there is an overall decrease in the body's ability to inhibit trypsin activation, resulting in increased trypsin activation and pancreatitis. This mutation likely acts as a disease modifier and lowers an individual's threshold for the development of pancreatitis in the setting of other genetic or environmental factors.5,13

CFTR

The cystic fibrosis transmembrane conductance regulator (CFTR) is a protein that regulates the transport of chloride and bicarbonate ions in the pancreas and regulates the movement of these ions through the membrane into the pancreatic duct lumen. CFTR is the most important molecule in the regulation of the secretion of fluid into the cells of the pancreatic duct and its main function is to secrete fluid high in bicarbonate, which removes digestive zymogens outside of the pancreatic duct into the duodenum. However, when there is a dysfunction of this membrane protein, such as in the case of a CFTR mutation, removal of the zymogens does not occur. This results in activation of the zymogen into the pancreatic duct, causing adjacent tissue damage and pancreatitis.18

Genetic Studies

Genetics has emerged as a decisive factor in the evaluation and management of hereditary pancreatitis.16 It is important to note that there has been a clear correlation between the type of mutation and the severity of the presentation in cases of hereditary pancreatitis.19 It is also important to consider that the result of a genetic test (whether positive or negative) should be interpreted in the full context of the patient and that environmental, metabolic, and epigenetic factors can affect the way in which the clinician should intervene.20

Criteria have been developed to determine which patients should undergo genetic tests for pancreatitis. Table 1 lists the criteria that must be present before a patient should have genetic testing.

Criteria Necessary for Genetic Testing for Pancreatitis

Table 1.

Criteria Necessary for Genetic Testing for Pancreatitis

Genetic Counseling

Genetic counseling before and after testing, as well as a detailed discussion of the results and medical consequences, should be included as an essential part of the visit of the patient and family. Identification of those patients who should undergo genetic testing for hereditary pancreatitis is certainly imperative in managing this condition.21

Total Pancreatectomy with Auto Islet Cell Transplant

Total pancreatectomy with auto islet cell transplant (TPAIT) was first described in the medical literature by Najarian et al.22 in 1970, when they reported that they had successfully transplanted islet cells to prevent postoperative diabetes in a total pancreatectomy patient. Currently, more than 20 centers around the world perform this procedure.

The main objective of the TPAIT is to relieve pain caused by chronic pancreatitis as well as reduce the severity of pancreatectomy-induced diabetes. Recent reviews have concluded that TPAIT is successful in terms of reducing pain in patients with chronic pancreatitis and results in reduced demand for daily insulin compared with those patients who had a total pancreatectomy and no TPAIT.23–26

The monitoring of these patients is life-long, and follow-up and testing should be done in order to monitor for the emergence of diabetes mellitus. Some of the required testing in these patients are glucose level testing (done by the patient), fasting glucose, HbA1c, and C-peptide level. Also, pancreatic enzyme replacement is mandatory for the duration of their lifetime.27

Conclusion

It is important to recognize hereditary pancreatitis as a clinical entity. Moreover, screening for symptoms such as recurrent abdominal pain, multiple episodes of pancreatitis, or even family history of pancreatitis should be done when clinically suspected by the general practitioner. Referral to a specialist should not be delayed if considered appropriate or indicated. However, the management of hereditary pancreatitis can be complex and challenging for patients and physicians, so a multidisciplinary approach that includes genetic counseling and testing as well as potential therapeutic options such TPAIT should be considered.

References

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Criteria Necessary for Genetic Testing for Pancreatitis

Episodes of pancreatitis unexplained in childhood

Family history of idiopathic chronic pancreatitis, recurrent acute pancreatitis, or pancreatitis in pediatric patients without a definite cause

Recurrent episodes of acute pancreatitis that have no explanation or apparent cause

Patients with a known family history of mutations associated with hereditary pancreatitis

Idiopathic chronic pancreatitis manifested in patients younger than age 25 years

Authors

Edgardo D. Rivera Rivera, MD, is an Assistant Professor of Clinical Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Miami Miller School of Medicine. Ankur Chugh, MD, is a Pediatric Gastroenterology, Hepatology and Nutrition Fellow, University of Chicago, Comer Children's Hospital. Jonathon Cordova, DO, is a Pediatric Gastroenterology, Hepatology and Nutrition Fellow, University of Chicago, Comer Children's Hospital. Sona Young, MD, is a Clinical Assistant Professor of Pediatrics, University of Chicago, Pritzker School of Medicine; and a Pediatric Gastroenterology, Hepatology and Nutrition - Attending, NorthShore University HealthSystem.

Address correspondence to Edgardo D. Rivera Rivera, MD, Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Miami Miller School of Medicine, 1601 NW 12th Avenue, Suite 3005A, Miami, FL 33136; email: eriverarivera@med.miami.edu.

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

10.3928/00904481-20160115-01

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