Indian Pediatrics Case Reports

: 2021  |  Volume : 1  |  Issue : 3  |  Page : 214--216

Hereditary pancreatitis: A tale of 50 years

Anu Maheshwari 
 Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children Hospital, New Delhi, India

Correspondence Address:
Dr. Anu Maheshwari
Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children Hospital, New Delhi - 110 001

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Maheshwari A. Hereditary pancreatitis: A tale of 50 years.Indian Pediatr Case Rep 2021;1:214-216

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Maheshwari A. Hereditary pancreatitis: A tale of 50 years. Indian Pediatr Case Rep [serial online] 2021 [cited 2021 Oct 25 ];1:214-216
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Acute pancreatitis is a common cause of abdominal pain in children. Hereditary pancreatitis (HP) refers to an autosomal dominant condition (with high penetrance) in which acute and chronic pancreatitis occurs in both children and adults. The most common genetic cause is variants in the PRSS1 gene (serine protease 1). Other causes include variants of serine protease inhibitor Kazal type 1 (SPINK1), some other genes, and often multiple genetic factors. This is a brief review of the history and evolution of genetic diagnostic tests for HP since the publication of the case report on Familial Pancreatitis by Choudhry et al. way back in 1996.

 Clinical Case Description

The authors reported a 7-year-old child with a history of recurrent severe abdominal pain for 4 years prior to presentation. The pain was localized to the epigastric and umbilical region and had increased progressively from episodes that occurred every 4–5 months, to almost weekly. Each episode lasted for 3–4 days. There was no history of jaundice, loose stools, or any other significant abdominal complaints. The child had been assessed in many hospitals, but a diagnosis had not been established.

The patient was a moderately nourished child with a weight of 17 kg and height of 98 cm. No abnormalities were identified on examination, besides mild pallor. Salient investigations revealed anemia (hemoglobin 9 g/dL) with neutrophilic leukocytosis (total leukocyte count 17,700/mm3 with 65% neutrophils and 35% lymphocytes). The amylase levels were raised, varying between 290 and 400 Somogyi units, with the higher values observed during the episodes of acute abdominal pain. An abdominal X-ray revealed pancreatic calcifications. A barium meal and cholecystogram were normal. When a urinary aminoacidogram was undertaken, generalized aminoaciduria was identified. Familial pancreatitis was suspected and a family survey of history and relevant investigations was undertaken.

Salient history of recurrent abdominal pain was found in the father that had started at the age of 24 years and often required hospitalization. He had also been diagnosed with diabetes mellitus that was controlled with insulin and tolbutamide and was also undergoing treatment for pulmonary tuberculosis. The mother, two brothers, and one sister were asymptomatic. Only the father was detected to have pancreatic calcifications, whereas serum amylase was raised in one of his sisters. All of them had generalized aminoaciduria. The family survey suggested some underlying genetic defects responsible for the spectrum of abnormalities in the family. At that point of time, the condition was referred to as familial pancreatitis. At the time of this case report, a diagnosis of familial/HP was made based only on a history of familial involvement and clustering. The genetic basis of pancreatitis was not established till 1996.

 Review of Hereditary Pancreatitis through 50 Years

In 1952, Comfort and Steinberg,[1] reported chronic pancreatitis in six members of a single family over three generations. This was called hereditary chronic relapsing pancreatitis and assumed to be due to an autosomal dominant inheritance. Later in 1962, Gross et al. evaluated this condition in 38 patients from five families.[2] It was proposed that HP be defined by the following clinical and epidemiological characteristics: (1) three or more patients with pancreatitis within the same family; (2) onset at a young age; and (3) pancreatitis unrelated to excessive alcohol ingestion, gallstones, or trauma.

A relationship between a mutation in the PRSS1 gene and HP was identified as late as 1996, almost two decades after the said case report.[3] The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene, a causative gene of CF, was also reported to be associated with acute relapsing pancreatitis and chronic pancreatitis. A mutation in the serine protease inhibitor gene (Kazal type 1: SPINK1) was reported to be related to chronic idiopathic pancreatitis of unknown cause.[4] Multiple genetic causes of pancreatitis have been identified in the past 25 years. They include calcium-sensing receptor in 2003, chymotrypsin C in 2008 (CTRC), claudin-2 in 2012, carboxypeptidase A1 in 2013, carboxyl ester lipase in 2015, chymotrypsin B1 and B2 in 2017, pancreatic lipase in 2019, and transient receptor cation channel subfamily V member 6 gene in 2020.

When acute recurrent or chronic pancreatitis occurs due to a single-gene disorder, and Mendelian inheritance is likely, it is termed as HP. Familial pancreatitis refers to pancreatitis that occurs in a family, with an incidence that is greater than that would be expected by chance alone, given the size of the family and the standardized incidence of pancreatitis within a defined population. There are at least three different inheritance patterns for hereditary/familial pancreatitis. Autosomal dominant or “hereditary” pancreatitis is most often associated with mutations in the PRSS1 gene on chromosome 7q35, which encodes trypsin-1 (cationic trypsinogen). Autosomal recessive or “familial” pancreatitis is usually associated with CF or mutations in the SPINK1 gene. A complex genetic pattern has been described that is associated with a combination of genetic and environmental factors, for example, heterozygous SPINK1 mutations, in which the mutation probably acts as a disease modifier factor.

Patients with HP have recurrent acute pancreatitis in childhood or early adolescence, chronic pancreatitis in late adolescence or early adulthood, and an increased risk for pancreatic cancer beginning in the fifth decade of life. The primary manifestations are abdominal pain and malabsorption due to pancreatic exocrine dysfunction, and diabetes mellitus due to islet cell damage. This is known as diabetes of exocrine pancreas which is usually treated with metformin and insulin therapy. This form of diabetes mellitus is different from typical type 1 diabetes in that the pancreatic alpha cells, which produce glucagon, are also affected (type 3c diabetes mellitus). This leads to a very high risk of hypoglycemia.

Major advancements have occurred in the field of diagnostics in the past 50 years. Genetic testing (PRSS1, CFTR, and SPINK1, plus CTRC) is now easily available and plays an important role in diagnosis, management, and prognostication. It is indicated in idiopathic acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis after common causes (i.e., gallstone disease, heavy alcohol use, duct obstruction, and specific medications) have been excluded and one or more of the following criteria are satisfied: (1) an unexplained documented episode of pancreatitis as a child; (2) idiopathic chronic pancreatitis (particularly when the onset is <25 years); (3) family history of recurrent acute pancreatitis; (4) idiopathic chronic pancreatitis, or childhood pancreatitis without a known cause; and (5) relatives known to carry mutations associated with HP (i.e., PRSS1 mutations).[5.6] These tests must be coupled with pre- and posttesting counseling. Predictive testing (that of asymptomatic individuals) can be considered in the presence of a first-degree relative with a known PRSS1 mutation, but it must be accompanied by expert genetic counseling, and should not be done not in adolescents <16 years of age.[6] If a family carries a known mutation, a negative test eliminates the risk of HP in that individual, whereas a positive test result confers an 80% risk of developing pancreatitis. In contrast, predictive testing of SPINK1 or CFTR mutations in presymptomatic individuals is of minimal value because these mutations are common and most positive patients do not develop the disease.

 Future Directions

Three genes, with Mendelian genetic biology (PRSS1, CFTR, and SPINK1), have been recognized for over a decade to cause chronic pancreatitis, but little progress has been made since then. The availability and application of high-throughput genetic techniques, including genome-wide association studies and next-generation sequencing, will provide a large volume of new genetic variants that are associated with HP. However, the major challenge will be deciding causation in these complex genetic disorders.To understand these genetic variants and translate them into clinically useful information requires a new framework based on modeling and simulation of physiological processes. This framework involves genetic, metabolic and environmental variables at the cellular and organ levels, along with the integration of the immune system, nervous system, tissue injury and nucleic acid repair systems. This will help to identify pancreatic dysfunction in the early stages before irreversible damage occurs.

In future, genetics will be the mainstay of clinical management of many diseases including HP. The development of HP is associated with a limited number of etiologies, and there may be several years gap between the first symptoms and organ destruction. The need of the hour is to develop early and effective interventions that are based on the etiology rather than symptoms and complications. If the target of the etiology of pancreatic dysfunction can be recognized in the early stages of the disease, theoretically intervention can be developed to prevent the development of irreversible damage. Hope springs eternal!

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Conflicts of interest

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