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Hereditary pancreatitis (HP) is an
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
of the
pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an en ...
due to genetic causes. It was first described in 1952 by Comfort and Steinberg but it was not until 1996 that Whitcomb ''et al'' isolated the first responsible mutation in the
trypsinogen Trypsinogen () is the precursor form (or zymogen) of trypsin, a digestive enzyme. It is produced by the pancreas and found in pancreatic juice, along with amylase, lipase, and chymotrypsinogen. It is cleaved to its active form, trypsin, by ent ...
gene (''
PRSS1 Trypsin-1, also known as cationic trypsinogen, is a protein that in humans is encoded by the ''PRSS1'' gene. Trypsin-1 is the main isoform of trypsinogen secreted by pancreas, the others are trypsin-2 (anionic trypsinogen), and trypsin-3 (meso- ...
'') on the long arm of chromosome seven (''7q35''). The term "hereditary pancreatitis" is used when a genetic biomarker is identified, and "familial pancreatitis" otherwise.


Presentation

HP is characterised by attacks of
epigastric pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a more ...
, which are often associated with
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
and vomiting. Symptoms may start shortly after birth but onset varies periodically, with some patients not exhibiting symptoms until adulthood. There is usually progression to chronic pancreatitis with endocrine and
exocrine Exocrine glands are glands that secrete substances on to an epithelial surface by way of a duct. Examples of exocrine glands include sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, prostate and mucous. Exocrine glands are one of t ...
failure and a mortally increased risk of pancreatic cancer. Lifetime risk of cancer has been variously calculated as 35–54% to the age of 75 years and screening for early pancreatic cancer is being offered to HP sufferers on a scientific basis. Some patients may choose to have their pancreas surgically removed to prevent pancreatic cancer from developing in the future. The epidemiology of HP follows a similar pattern to alcohol-associated chronic pancreatitis, but there are important differences. For example, HP typically has an earlier age of pancreatitis onset; although malabsorption and
diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
occur at a later stage in the disease progression.


Genetics

The vast majority of the cases of HP are caused by substitutions, at base 365 (c.365G>A) and base 86 of the cDNA (c.86A>T) on the ''
PRSS1 Trypsin-1, also known as cationic trypsinogen, is a protein that in humans is encoded by the ''PRSS1'' gene. Trypsin-1 is the main isoform of trypsinogen secreted by pancreas, the others are trypsin-2 (anionic trypsinogen), and trypsin-3 (meso- ...
'' gene. The nucleotide substitutions were discovered in the late 1990s by classical linkage analysis and are now known as p.R122H and p.N29I respectively, according to the amino acid substitution and position in the protein sequence. These mutations are rarely identified in general screens of patients with
idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kin ...
disease and the phenotype of p.R122H and p.N29I is now well characterised with the p.A16V mutation recently characterised for the first time. There are many other rare mutations or polymorphisms of ''PRSS1'' which remain less well understood and not all HP families have had the responsible genetic mutation identified. The mechanism by which these genetic mutations cause pancreatitis is not yet known; but is likely to be the result of increased autoactivation or reduced deactivation of trypsinogen. However, a novel mechanism has recently been identified in a p.R116C kindred.


Diagnosis

Families are defined as having HP, if the
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...
is consistent with highly penetrant autosomal dominant inheritance. In simple terms, this would require two or more first degree relatives (or three or more second degree relatives) to have unexplained recurrent-acute or chronic pancreatitis in two or more generations. It is an autosomal dominant disease with penetrance that is generally accepted to be ≈80%.


Management

Treatment of HP resemble that of chronic pancreatitis of other causes. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications, such as pseudocysts, bile duct or duodenal obstruction.(PMC1774562)


Prognosis

A 2009 study which followed 189 patients found no excess mortality despite the increased risk of pancreatic cancer.


References


External links

{{Congenital malformations and deformations of digestive system Congenital disorders of digestive system Pancreas disorders Pancreatic cancer