PANCREATITIS, CHRONIC PANCREATITIS, CHRONIC, SUSCEPTIBILITY TO, INCLUDED
PANCREATITIS, CALCIFIC, INCLUDED
PANCREATITIS, CHRONIC, PROTECTION AGAINST, INCLUDED
HPC
HP
PCTT
Gross et al. (1962) described a kindred with affected persons in 4 generations. Four other families had been reported from the Mayo Clinic, including the first reported example by Comfort and Steinberg (1952). A puzzling feature was the ... Gross et al. (1962) described a kindred with affected persons in 4 generations. Four other families had been reported from the Mayo Clinic, including the first reported example by Comfort and Steinberg (1952). A puzzling feature was the urinary excretion of lysine and cystine by about half the members of affected kindreds (with or without pancreatitis). Cystine urinary stones had not been observed. Singer and Cohen (1966) reported onset at about age 20 in a man whose younger sister and a cousin were similarly affected. The attacks were characterized by severe abdominal pains, fever, and marked elevation of serum amylase. Except for the last symptom, differentiation from familial Mediterranean fever (249100), also called 'familial paroxysmal peritonitis,' might be difficult. The aminoaciduria was almost certainly an incidental finding since family members without pancreatitis showed it and because other families with pancreatitis have not had this feature (Davidson et al., 1968). Robechek (1967) observed a family in which 5 individuals had hereditary chronic relapsing pancreatitis, 3 of whom obtained symptomatic relief after sphincterotomy or section of the hypertrophied sphincter of Oddi. Robechek (1967) suggested that hypertrophy of the sphincter of Oddi together with a common ampulla of the biliary and pancreatic ducts may be the inherited factor. Mann and Rubin (1969) described a 17-month-old boy with steatorrhea whose 26-year-old brother and mother had steatorrhea and pancreatic calcification. Hereditary pancreatitis occurs with hyperparathyroidism in the multiple endocrine adenomatosis syndrome (131100). McElroy and Christiansen (1972) described a family in which 10 persons had definite pancreatitis and 16 others may have been affected. They pointed out that thrombosis in the portal or splenic vein occurs with significant frequency. Sibert (1978) identified 72 patients in 7 families in England and Wales. Penetrance was about 80%. The mean age of onset was 13.6 years. There were 2 peaks, one at 5 years and one at 17 years. The second peak was thought to represent genetically susceptible persons with symptoms precipitated by alcohol, rather than genetic heterogeneity. In 5 of the families, members with both childhood and adult onset were identified. In most cases the attacks were of nuisance value only. Only 4 of the 72 patients had life-threatening disease. Pancreatic insufficiency (5.5%), diabetes mellitus (12.5%), pseudocysts (5.5%) and hemorrhagic pleural effusion were observed. Portal vein thrombosis occurred in 2 and was suspected in 3 others. Patients seemed to improve later in life. Attacks were precipitated by emotional upset, alcohol, or high fat intake. Sarles et al. (1982) pointed out that chronic calcifying pancreatitis is characterized by pancreatic stones in the ducts and acini. They had shown that 'stone protein' (see 167770) inhibits in vitro calcium carbonate nucleation and decreases the rate of crystal growth, suggesting that it acts as a physiologic inhibitor of spontaneous calcium carbonate formation in supersaturated pancreatic juice. (A similar function has been suggested for statherin in human saliva (Schlesinger and Hay, 1977).) Sarles et al. (1982) found absence of stone protein in the pancreatic stones in a case of calcific pancreatitis and interpreted this as indicating that the protein was not secreted into the pancreatic juice. Freud et al. (1992) described the cases of monozygotic twin girls of Ashkenazi origin who were admitted to hospital at the age of 9 years because of recurrent attacks of pancreatitis. Dalton-Clarke et al. (1985) found 10 definite and 4 suspected cases of pancreatitis in an English family. Lewis and Gazet (1993) reported pancreatitis in members of 4 successive generations of a second English family. A male in each of the first generations had a combination of calcific pancreatitis and pancreatic carcinoma. Rumenapf et al. (1994) stated that more than 50 families of hereditary pancreatitis had been reported since the first description by Comfort and Steinberg (1952). They reported on the case of a 26-year-old man from a family in which 6 of 34 members had confirmed pancreatitis and an additional 3 members had suspected pancreatitis. A great uncle had died of pancreatic cancer after suffering from pancreatitis for years. Numerous pancreatic calculi were removed surgically, and a side-to-side pancreaticojejunostomy with a Roux-Y loop was performed. Rumenapf et al. (1994) suggested that surgery may be superior to endoscopic drainage. Sarles et al. (1996) reported 11 families with hereditary pancreatitis characterized by the presence of calculi in pancreatic ducts. The disorder in 1 family with 5 cases was classified as calcic lithiasis because the calculi were composed of more than 95% calcium salts. Protein lithiasis was present in the other 10 families, the calculi being composed of degraded amorphous residues of lithostathine (167770), the pancreatic secretory protein that inhibits salt crystallization. Average age at clinical onset of symptoms was 15 years. Clinical progression seemed to be less severe than that in alcoholic chronic pancreatitis (alcoholic calcic lithiasis). Lowenfels et al. (1997) assembled records on 246 patients (125 males and 121 females) thought to have hereditary pancreatitis. In 218 patients the diagnosis appeared to be highly probable and in 28 patients it was thought to be less certain. The mean age of onset of symptoms of pancreatitis was 13.9 +/- 12.2 years. Compared with an expected number of 0.150, 8 pancreatic adenocarcinomas developed during 8,531 person-years of follow-up. The mean age at diagnosis of pancreatic cancer was 56.9 +/- 11.2 years. Frequency of other tumors was not increased. Eight of 20 reported deaths in the cohort were from pancreatic cancer. Thirty members of the cohort had been tested and all were found to have a mutated copy of the trypsinogen gene. The estimated cumulative risk of pancreatic cancer to age 70 years in patients with hereditary pancreatitis approached 40%. For patients with a paternal inheritance pattern, the cumulative risk of pancreatic cancer was approximately 75%.
Several genes previously mapped to 7q were considered candidates for HPC because they were known to be expressed in the exocrine pancreas and to encode enzymes that could potentially activate digestive enzymes within the pancreas. The hypothesis that ... Several genes previously mapped to 7q were considered candidates for HPC because they were known to be expressed in the exocrine pancreas and to encode enzymes that could potentially activate digestive enzymes within the pancreas. The hypothesis that pancreatitis results from inappropriate activation of pancreatic proenzymes was first promulgated by Chiara (1896) and subsequently demonstrated to be an experimental model for pancreatitis (Steer and Meldolesi, 1987). However, at least 8 trypsinogen genes are located on 7q35 between markers D7S495 and D7S498 and within the V and D-C segments of the complex T-cell receptor beta chain gene (see 186930). Trypsinogen is an inactive proenzyme for trypsin, which becomes active when an 8-amino acid N-terminal peptide is removed. Of the 8 trypsinogen-like genes sequenced and identified within the TCRB locus by Rowen et al. (1996), 3 were determined by sequence analysis to be pseudogenes. Another group of 5 trypsinogen genes, including the cationic and anionic pancreatic trypsinogen genes, were found to be in a cluster located between 2 elements near the 3-prime end of the TCRB locus. Tzetis et al. (2007) genotyped the CFTR, SPINK1, and PRSS1 genes in 25 Greek patients with chronic pancreatitis and found that 20 (80%) of 25 had a molecular defect in 1 or both of the CFTR and SPINK1 alleles, whereas no mutations were detected in PRSS11. The authors suggested that mutations or variants in CFTR plus or minus mutations in SPINK1, but not PRSS1, may confer high risk for recurrent pancreatitis. - Mutations in the PRSS1 Gene Whitcomb et al. (1996) noted that the 5 trypsinogen genes are highly homologous, each residing within a tandemly duplicated 10-kb segment and each composed of 5 exons. Mutational screening analyses for each of the exons from the cationic and anionic trypsinogen genes in multiple affected and unaffected family members allowed Whitcomb et al. (1996) to identify a missense mutation in the cationic trypsinogen (PRSS1; 267000) in all affected members and obligate carriers in 1 family (276000.0001). The same R122H mutation (previously designated R117H by the chymotrypsin numbering system) was identified in 5 separate kindreds, raising the possibility that these families might be distantly related and the mutation centuries old. Although no genealogic link could be found through 8 generations, subsequent haplotyping revealed that all 4 of the American families had the same high-risk haplotype over a 4-cM region encompassing 7 STR markers, confirming the likelihood that these kindreds share a common ancestor. A fifth family from Naples, Italy, displayed a unique haplotype indicating that the same mutation had occurred on at least 2 occasions. The R122H mutation created a novel restriction enzyme recognition site for AflIII that permitted facile screening for the mutation in the general population. The mutation was not found in any of 140 unrelated control individuals. X-ray crystal structure analysis, molecular modeling, and protein digest data indicated that the arg122 residue is a trypsin-sensitive site. Whitcomb et al. (1996) provided a diagram of a model of the trypsin self-destruct mechanism designed to prevent pancreatic autodigestion. Active trypsin is inhibited normally by a limited supply of trypsin inhibitor (e.g., SPINK1; 167790). If trypsin activity exceeds the inhibitory capacity of PSTI, then proenzymes, including mesotrypsin (PRSS3; 613578) and enzyme Y, are activated. The activation of these enzymes is postulated to be part of a feedback mechanism for inactivating wildtype trypsinogen, trypsin, and other zymogens. When the arg122 cleavage site for mesotrypsin, enzyme Y, and trypsin is replaced by histidine, trypsin continues to activate trypsinogen and other zymogens unabated, leading to autodigestion of the pancreas and pancreatitis. In affected members and obligate carriers of a large family originally reported by Robechek (1967) with hereditary pancreatitis believed to be due to hypertrophy of the sphincter of Oddi, Gorry et al. (1997) identified heterozygosity for a missense mutation in the PRSS1 gene (N21I; 276000.0002). The pancreatitis in this family appeared to be a milder form of the disease, with a later onset of symptoms and fewer hospitalizations than that seen in the so-called 'S-family' in which Whitcomb et al. (1996) identified the R122H mutation. Noting that prematurely activated trypsin must pass through the sphincter of Oddi and may produce chronic inflammation, scarring, and stenosis, Gorry et al. (1997) suggested that high sphincter pressures may be an independent complication of hereditary pancreatitis rather than the cause. The authors stated that 4 of the 5 patients reporting symptomatic improvement after surgical sphincterotomy had progressed to chronic pancreatitis with insulin-dependent diabetes mellitus, supporting the hypothesis that the underlying pathophysiologic mechanism persists. Affected members of a second, unrelated family with hereditary pancreatitis were also found to have the N21I mutation, which was not found in 188 control chromosomes. Dasouki et al. (1998) reported on the results of linkage and direct mutation analysis for the common R122H mutation (276000.0001) in the PRSS1 gene in 8 unrelated families with hereditary pancreatitis. By 2-point linkage analysis with the 7q35 marker D7S676, done initially in 4 families, positive lod scores were found in 2, a negative lod score in 1, and a weakly positive lod score in 1. Direct mutational analysis of exon 3 of the cationic trypsinogen gene in 6 families showed that all symptomatic individuals tested were heterozygous for the R122H mutation. Also, several asymptomatic but at-risk relatives were found to be heterozygous for this mutation. Affected individuals in the remaining 2 families did not have the mutation. Radiation hybrid mapping assigned the gene to 7q35 between 2 specific markers. The negative linkage and absence of the trypsinogen mutation in 2 of 8 families suggested locus heterogeneity in hereditary pancreatitis. Ferec et al. (1999) studied 14 families with hereditary pancreatitis and found mutations in the PRSS1 gene in 8 families. In 4 of these families, the mutation (R122H; 276000.0001) had been described by Whitcomb et al. (1996). Three novel mutations were described in 4 other families (276000.0003, 276000.0004, 276000.0005). - Mutations in the CFTR Gene Sharer et al. (1998) and Cohn et al. (1998) demonstrated that mutations in the cystic fibrosis gene (CFTR; 602421) can cause idiopathic pancreatitis when present in heterozygous state in association with the variable number of thymidines in intron 8 of the CFTR gene, specifically the 5T allele (602421.0086). Chang et al. (2007) identified mutations in the CFTR gene in 14.1% of total alleles and 24.4% of 78 Chinese/Taiwanese patients with idiopathic chronic pancreatitis compared to 4.8% of total alleles and 9.5% of 200 matched controls. The findings indicated that heterozygous carriers of CFTR mutations have an increased risk of developing ICP. The mutations identified were different from those usually observed in Western countries. The T5 allele with 12 or 13 TG repeats was significantly associated with earlier age at onset in patients with ICP, although the frequency of this allele did not differ between patients and controls. - Mutations in the SPINK1 Gene Witt et al. (2000) demonstrated mutations in the SPINK1 protease inhibitor gene (N34S, 167790.0001; L14P, 167790.0005) in children and adolescents with chronic pancreatitis. The N34S mutation was found in 18 of 96 patients. Chen et al. (2000) reported mutation analysis in the PSTI (SPINK1) gene in 14 families with hereditary pancreatitis and in 30 individuals with sporadic chronic pancreatitis. A total of 7 polymorphisms, but no pathogenic mutations, were detected. Audrezet et al. (2002) analyzed systematically the entire coding sequence and exon/intron junctions of the PRSS1 (276000), SPINK1 (167790), and CFTR genes in 39 white French patients with idiopathic chronic pancreatitis. One patient had a missense mutation (R122H; 276000.0001) in the PRSS1 gene; 4 patients had the same missense mutation in the SPINK1 gene, 3 in heterozygosity and 1 in homozygosity (N34S; 167790.0001); and 8 patients carried 1 of the most common mutations of the CFTR gene. A trans-heterozygous state with sequence variations in the SPINK1/CFTR genes was found in 3 patients. The results demonstrated that about one-third of the patients labeled as having idiopathic chronic pancreatitis had, in fact, a genetic defect. Audrezet et al. (2002) noted that long-term follow-up of these patients, including heterozygotes, homozygotes, compound heterozygotes, and trans-heterozygotes, would improve the understanding of the complex nature of idiopathic chronic pancreatitis. In affected members of 2 unrelated families with autosomal dominant chronic pancreatitis, Kiraly et al. (2007) identified a heterozygous mutation in the SPINK1 gene (L14R; 167790.0006). The proband of the Bulgarian family was diagnosed at age 10 years. His father had died of acute pancreatitis, and his paternal grandmother developing pancreatitis at age 59 years. The second family was German and had 3 affected members. Kiraly et al. (2007) noted that the N34S mutation had not to date been demonstrated to result in a functional defect. By expression studies, they demonstrated that the L14P and L14R mutations markedly reduce SPINK1 expression and result in loss of function. - Variation in the CTRC Gene Rosendahl et al. (2008) found that 2 alterations in the CTRC gene, R254W (601405.0001) and K247_R254del (601405.0002), were significantly overrepresented among German patients with idiopathic or hereditary chronic pancreatitis. A replication study identified overrepresentation of these variants among German patients with alcoholic chronic pancreatitis versus control subjects with alcoholic liver disease without pancreatitis. Functional analysis of these and other associated CTRC variants showed impaired chymotrypsin C activity and or reduced secretion. Rosendahl et al. (2008) concluded that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. Masson et al. (2008) sequenced the CTRC gene in 287 white French patients with idiopathic chronic pancreatitis and 350 controls and identified 2 common variants and 19 rare variants. The combined frequency of the rare variants in patients with sporadic chronic pancreatitis was significantly higher than that of controls (12% versus 1.1%; OR, 11.8; p less than 10(-6)).
Hereditary pancreatitis (HP) is defined as either two or more individuals with pancreatitis in two or more generations of a family (i.e., an autosomal dominant pattern of inheritance) or pancreatitis associated with a known disease-causing germline mutation [Whitcomb & Lowe 2010]. The diagnosis of PRSS1-related hereditary pancreatitis requires the identification of a disease-causing PRSS1 mutation. ...
DiagnosisClinical DiagnosisHereditary pancreatitis (HP) is defined as either two or more individuals with pancreatitis in two or more generations of a family (i.e., an autosomal dominant pattern of inheritance) or pancreatitis associated with a known disease-causing germline mutation [Whitcomb & Lowe 2010]. The diagnosis of PRSS1-related hereditary pancreatitis requires the identification of a disease-causing PRSS1 mutation. Hereditary pancreatitis usually has an acute phase and a chronic phase. Acute pancreatitis is defined as the presence of two of the following three findings [Banks & Freeman 2006]: Sudden onset of typical epigastric abdominal pain Elevation of serum amylase or lipase more than three times the upper limits of normal [Neoptolemos et al 2000]Characteristic findings of acute pancreatitis on abdominal imaging [O’Connor et al 2011]Chronic pancreatitis is a syndrome of pancreatic inflammation lasting more than six months with irreversible pancreatic changes documented by one of the following:Histology (atrophy; fibrosis and/or sclerosis)Abdominal imaging (inflammatory masses; pancreatic parenchyma and ductal calcifications; pseudocysts)Functional studies (pancreatic exocrine insufficiency with maldigestion of food; pancreatic endocrine insufficiency with diabetes mellitus)Molecular Genetic Testing Gene. PRSS1, encoding cationic trypsinogen, is the only gene in which mutations are known to cause PRSS1-related hereditary pancreatitis. Clinical testingSequence analysis/mutation scanning. Sequence analysis identifies PRSS1 mutations in 60%-100% of families with hereditary pancreatitis [LaRusch & Whitcomb 2011]. Deletion/duplication analysis. Copy number variation (CNV) may play a role in the etiology of PRSS1-related hereditary pancreatitis. A study from France identified CNV in up to 6% of persons with idiopathic chronic pancreatitis and no PRSS1 mutation identified by sequence analysis [Masson et al 2008a].Families with hereditary pancreatitis have been found to have affected individuals with copy number variants caused by duplication of a 605-kb segment containing PRSS1 and PRSS2; the same duplication was detected in persons with idiopathic chronic pancreatitis in France [Masson et al 2008b]. Additional families have been identified; details have not been published [LaRusch & Whitcomb 2011].Targeted mutation analysis. Two common PRSS1 mutations, p.Arg122His in exon 3 and p.Asn29Ile in exon 2, account for approximately 90% of mutations observed in PRSS1-related hereditary pancreatitis [Rebours et al 2009]. Specific population testing for these two mutations is limited: the majority of individuals with PRSS1-related hereditary pancreatitis are of northern European ancestry; however, these mutations were also identified in families and persons from Japan [Otsuki et al 2004, Kaneko et al 2001], Korea [Lee et al 2011], China [Liu et al 2009], aboriginal Australia [McGaughran et al 2004], and India [Midha et al 2010].Table 1. Summary of Molecular Genetic Testing Used in PRSS1-Related Hereditary PancreatitisView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityPRSS1Sequence analysis 2 / mutation scanning 3Sequence variants 460%-100%ClinicalDeletion / duplication analysis 5Exonic or whole-gene deletions≤6%Targeted mutation analysisMutation panels vary by laboratorySee footnote 61. The ability of the test method used to detect a mutation that is present in the indicated gene2. Some laboratories offer sequence analysis of select exons (e.g., exons 2 and 3) because of the high prevalence of mutations in these exons, namely p.Asn29Ile in exon 2 and p.Arg122His in exon 3.3. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. 6. 90% of PRSS1 mutations include p.Asn29Ile and p.Arg122His. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband. Molecular genetic testing of PRSS1 is indicated in persons with the following:An unexplained documented episode of acute pancreatitis in childhood Recurrent acute attacks of pancreatitis of unknown causeChronic pancreatitis of unknown cause, particularly with onset before age 25 yearsA family history of recurrent acute pancreatitis, chronic pancreatitis of unknown cause, and/or childhood pancreatitis of unknown cause consistent with autosomal dominant inheritanceApproach to molecular genetic testing: 1.Targeted mutation analysis (of exons 2 and 3, in which 90% of mutations have been identified to date) or sequence analysis of the complete coding region of PRSS12.If no mutation is identified, consideration of deletion/duplication analysisFor guidelines related to testing strategy, see:Ellis et al [2001] (click Guidelines for full text)Fink et al [2007] (click Guidelines for full text; registration or institutional access required)Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in PRSS1.
Pancreatitis refers to inflammation of the pancreas that can be acute (sudden onset; duration <6 months), recurrent acute (>1 episode of acute pancreatitis), or chronic (duration >6 months). ...
Natural History Pancreatitis refers to inflammation of the pancreas that can be acute (sudden onset; duration <6 months), recurrent acute (>1 episode of acute pancreatitis), or chronic (duration >6 months). The range of symptoms and disease course vary in persons with hereditary pancreatitis. On average, onset of the disease (as acute pancreatitis) occurs by age ten years, chronic pancreatitis develops by age 20 years, and the incidence of pancreatic cancer dramatically rises at age 50 years. Acute pancreatitis. Findings can range from vague abdominal pain lasting for one to three days to episodes of severe acute pancreatitis requiring hospitalization that may last for days to weeks. Recurrent acute pancreatitis (RAP). Signs and symptoms of RAP secondary to hereditary pancreatitis are identical to those of pancreatitis of any other cause except they usually occur earlier in life and in the absence of an identifiable precipitating event. Persons with a PRSS1 mutation may also have other risk factors for pancreatitis, such as gallstones, alcohol consumption, and/or smoking, especially when the onset is later in life. Of note, persons with hereditary pancreatitis report that even small amounts of alcohol may sometimes trigger episodes of pain or acute pancreatitis. In hereditary pancreatitis, RAP can lead to chronic pancreatitis [Yadav & Whitcomb 2010] and is thus regarded as a transition state to chronic pancreatitis. Chronic pancreatitis. Long-standing inflammation results in complications that can include the following [Etemad & Whitcomb 2001]:Episodic or continuous mild to severe abdominal pain. Pain is usually sharp and stabbing in initial attacks, becoming deep and burning as the syndrome progresses. The most psychologically distressing pain is chronic pain, regardless of intensity. Exocrine pancreatic insufficiency leading to maldigestion with symptoms of gas and bloating and the appearance of diarrhea, oil in the stool (steatorrhea) and/or floating stools. Other signs of maldigestion include weight loss and protein-vitamin deficiency detected on blood testing. Pancreatic endocrine insufficiency manifesting initially as inappropriately elevated levels of blood glucose (glucose intolerance). Up to 48% of persons with HP develop diabetes mellitus type I [Howes et al 2004, Rebours et al 2009].High risk for pancreatic cancer in some families and not in others [Rebours et al 2012]
Genotype-phenotype correlations found in persons with a p.Arg122His mutation included earlier age of onset and a more severe phenotype [Creighton et al 2000, Howes et al 2004]....
Genotype-Phenotype Correlations Genotype-phenotype correlations found in persons with a p.Arg122His mutation included earlier age of onset and a more severe phenotype [Creighton et al 2000, Howes et al 2004].
The morphologic features and laboratory findings of hereditary pancreatitis are the same as those of other etiologies including alcohol-related chronic pancreatitis, tropical pancreatitis, and idiopathic chronic pancreatitis [Shrikhande et al 2003]. Of note, alcoholic pancreatitis refers to pancreatitis resulting from increased alcohol exposure. A minimum of five drinks (>60 oz of ethanol) per day is usually required for alcohol to be a risk factor [Yadav et al 2009]. The effect of alcohol is potentiated by cigarette smoking [Yadav et al 2009]....
Differential DiagnosisThe morphologic features and laboratory findings of hereditary pancreatitis are the same as those of other etiologies including alcohol-related chronic pancreatitis, tropical pancreatitis, and idiopathic chronic pancreatitis [Shrikhande et al 2003]. Of note, alcoholic pancreatitis refers to pancreatitis resulting from increased alcohol exposure. A minimum of five drinks (>60 oz of ethanol) per day is usually required for alcohol to be a risk factor [Yadav et al 2009]. The effect of alcohol is potentiated by cigarette smoking [Yadav et al 2009].Smoking is a dose-dependent, independent risk factor for development of chronic pancreatitis [Yadav et al 2009, Andriulli et al 2010].The differential diagnosis of PRSS1-related hereditary pancreatitis includes familial pancreatitis, idiopathic chronic pancreatitis, CFTR-related hereditary pancreatitis, CTRC-related hereditary pancreatitis, and SPINK1-related hereditary pancreatitis. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with PRSS1-related hereditary pancreatitis, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with PRSS1-related hereditary pancreatitis, the following evaluations are recommended:Evaluation of pancreatic exocrine function (see Treatment of Manifestations, Maldigestion) Evaluation of pancreatic endocrine function (i.e., assessment of glucose tolerance) Consideration of pancreatic cancer surveillance in persons with chronic pancreatitis.Treatment of ManifestationsMedical treatment and management for PRSS1-related hereditary pancreatitis are similar to those for non-hereditary pancreatitis. Treatment of acute pancreatitis usually focuses on pain management and discontinuation of smoking and alcohol use to slow the rate of progression and to decrease the likelihood of complications, including pancreatic cancer. Pancreatic pain can result from pancreatic duct obstruction, parenchyma hypertension, pancreatic ischemia, inflammation, neuropathy, and central pain [Fasanella et al 2007, Mullady et al 2011]. Genetic factors, many of which remain unknown or not convincingly accountable, are thought to play a role in pain perception, tolerance, and response to medication. Analgesics are offered when pancreatic enzyme replacement therapy is not sufficient to control pain. Antioxidants have been reported to improve pain control in a few individuals with hereditary pancreatitis [Perrault 1994, Uomo et al 2001] and non-alcoholic chronic pancreatitis [Bhardwaj et al 2009, Burton et al 2011]. Endoscopic and surgical interventions are reserved for complications such as pseudocysts, bile-duct or duodenal obstruction, infected pancreatic necrosis, and malignancy.Obstructions or calcifications in the pancreatic ducts may be relieved by procedures such as endoscopic retrograde cholangiopancreatography (ERCP), in which endoscopic cannulation of the common bile duct and pancreatic duct is followed by injection of radiographic dye. Decompressing/clearing of blockage decreases pain as well as the number of hospitalizations and recurrent attacks in many persons with HP [Dever et al 2010]. Note: Because of the risk of acute pancreatitis following ERCP, it is only recommended for obtaining brushings (for evaluation of strictures) and for therapeutic intervention, not diagnosis. Although a variety of surgical approaches are used for non-cancerous pancreatic disorders that cause pain or obstruction from multiple strictures, pancreatic surgery in those with hereditary pancreatitis is unlikely to stop the underlying inflammatory process. Furthermore, pancreatic surgery often reduces the number of islet cells which are essential in pancreatic endocrine function [Sutton et al 2010, Kobayashi et al 2011]. Because total pancreatectomy with islet cell auto-transplantation may be a future option for persons with HP, retaining as many islet cells as possible is an important consideration before proceeding with any pancreatic surgery [Sutton et al 2010, Bellin et al 2011].Although controversial, pancreatectomy has been performed as a last resort to improve the quality of life in those with uncontrolled pain, particularly young adults and children [Sutton et al 2010]. It is recommended that persons in whom pancreatectomy is being considered be referred to expert centers. In persons with adequate endocrine pancreatic function, islet cell isolation and autotransplantation may be considered at the time of total pancreatectomy [Bellin et al 2008]. Note: Islet autotransplantation should not be offered to older adults with long-standing chronic pancreatitis and diabetes mellitus because the implanted cells may be malignant. Pain is a variable complication of recurrent and chronic inflammation and ranges from minimal to severe and disabling. Pain can result from inflammation, ischemia, obstructed ducts, pseudocysts, and/or maldigestion [Fasanella et al 2007]. One small study from Italy suggested that vitamins and antioxidants reduced pain in hereditary pancreatitis [Uomo et al 2001]; two larger studies found that antioxidants helped relieve pain in idiopathic pancreatitis [Bhardwaj et al 2009, Burton et al 2011]. Pain from maldigestion is improved with pancreatic digestive enzymes [Whitcomb et al 2010, Burton et al 2011]. If the main pancreatic duct is obstructed, a trial of endoscopic treatment is often used for diagnostic, therapeutic, and prognostic reasons in determining longer-term therapy. Surgery has been reported to be helpful by many patients; however, surgical approaches should be postponed if islet autotransplantation is being considered. Several expert groups (e.g., University of Minnesota, University of Pittsburgh) are offering pancreatic islet autotransplantation in an effort to both control severe pain and delay the development of diabetes mellitus [Sutton et al 2010, Kobayashi et al 2011]. It is recommended that physicians and patients work closely with expert centers since the process is irreversible. Treatment of chronic pancreatitis focuses on improving quality of life by managing pancreatic pain, maldigestion, and diabetes mellitus. Maldigestion results from pancreatic exocrine insufficiency, which is the failure of the pancreas to produce enough digestive enzymes to digest a meal. Clinical measures of pancreatic exocrine insufficiency include observation of steatorrhea (fat and oil in the stool), symptoms of maldigestion (bloating, gas, cramps, and diarrhea) and nutritional deficiencies (e.g., fat soluble vitamins, and protein malnutrition with low albumin, prealbumin, or retinal binding protein). Pancreatic enzyme deficiency can be identified using invasive or noninvasive testing (see review by Lieb & Draganov 2008): Fecal elastase-1 analysis (ScheBo® Biotech AG; Giessen, Germany). This simple and relatively inexpensive test evaluates the amount of human elastase-1 present in the stool. It can be falsely positive with diarrhea, but can be used while an individual is taking pancreatic enzyme replacement therapy. The test is insensitive for mild pancreatic exocrine insufficiency [Amann et al 1996]. Secretin-stimulated pancreatic bicarbonate secretion testing (ChiRhoStim®, ChiRhoClin, Inc; Burtonsville, MD). This test requires intubation of the duodenum and careful measure of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive, but only assesses duct function. Cholecystokinin (CCK) and its analogues (e.g., CCK-8) or receptor agonists (e.g., cerulean) have also been used to assess acinar cell function. 13C-mixed triglyceride breath test. Of limited availability in the US, this test measures the ability of pancreatic lipase to digest a special substrate in the intestine after a test meal [Domínguez-Muñoz et al 2007].72-hour fecal fat. This test is used to demonstrate that pancreatic digestive enzyme supplements are effective in digesting fat in the intestine of persons with severe pancreatic exocrine insufficiency. It is usually performed in a clinical research unit over four to five days during which time the patient eats a special high-fat meal (>100 grams of fat per day) and all stool samples are collected and analyzed. It is not used for diagnosis because of the complexity and inconvenience of the test. Sudan stain. This test, which identifies fat in the stool, is not sensitive or specific for pancreatic insufficiency since undigested oils or fats can be present as a result of: Their nature (e.g., mineral oil, olestra);Blocking of pancreatic lipase (e.g., orlistat); or Diseases of the intestinal mucosa. Diffusion-weighted MRI. Various “functional” tests have been advocated using abdominal imaging techniques, including secretin-stimulated MRI. Although diffusion-weighted MRI is probably better at detecting the structural changes of chronic pancreatitis than standard MRI [Akisik et al 2009], it does not measure function, and fluid volume cannot measure bicarbonate output.Pancreatic enzyme replacement therapy improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea (fat in the stool), and/or diarrhea [Perrault 1994, Whitcomb et al 2010, Burton et al 2011]. Pancreatic enzymes most effectively relieve symptoms in persons with steatorrhea and in a subset of persons without steatorrhea [Bhardwaj et al 2009, Burton et al 2011].The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU, and 1 IU = 3 USP units) [Pongprasobchai & DiMagno 2005]. Since a minimum of 10% of normal pancreatic enzyme output is needed to digest a meal, about 70,000-80,000 USP units of lipase are required for an average-sized adult (70 kg) with total pancreatic insufficiency. The amount can be reduced for smaller persons and those with residual pancreatic exocrine function – while monitoring symptoms and nutritional parameters. Diabetes mellitus. Diabetes mellitus is a common disorder and both type 1 and type 2 can overlap with HP. Type 3c diabetes mellitus is caused by loss of pancreatic tissue as a result of surgery, chronic pancreatitis, or other rare pancreatic diseases [Rossi et al 2004, Cui & Andersen 2011]. Type 3c is important because loss of both the insulin-producing beta cells and the glucagon-producing alpha cells results in loss of counter-regulatory hormones and risk of hypoglycemia. Chronic pancreatitis is associated with a gradual loss of function. The following may be of benefit [Cui & Andersen 2011]:Monitoring for glucose intoleranceOptimizing pancreatic insulin secretion with pancreatic enzyme replacement therapy via amino acid and fatty acid-stimulated release of endogenous incretins from the foregut, with the addition of antidiabetic agents as neededSynchronizing the entry of nutrients into the circulation with exogenous insulin therapy delivery through diet and promoting predictable early nutrient digestion and absorption with pancreatic enzyme replacement therapyUse of metformin as an oral antidiabetic agent [Decensi et al 2010]Prevention of Primary ManifestationsPrevention of primary manifestations in hereditary pancreatitis is limited. The following recommendations are for individuals with (or at risk for) hereditary pancreatitis; beginning in early childhood can help prevent attacks of acute pancreatitis: Low-fat diet. No formal guidelines for amount of dietary fat exist; however, some physicians recommend a low-fat diet to minimize pancreatic stimulation. Multiple small meals. No evidence-based guidelines exist; however, small meals are recommended to minimize pancreatic exocrine stimulation. Good hydration. Poor hydration (for example during exercise) can lead to episodes of pancreatitis [Authors, unpublished]. Antioxidants. One small study suggested that antioxidants may be useful in reducing the likelihood of acute pancreatitis in persons at risk for hereditary pancreatitis [Uomo et al 2001]. SurveillanceLong-standing chronic inflammation of the pancreas is associated with an increased risk for pancreatic cancer. Persons with hereditary pancreatitis are at high risk because their onset of chronic pancreatitis is 20-30 years earlier than in sporadic forms of chronic pancreatitis. Because surveillance for early evidence of colon cancer is effective, it is hypothesized that such surveillance may benefit individuals with hereditary pancreatitis age 40 years and older who have long-standing chronic pancreatitis and a strong family history of pancreatic cancer. Because long-standing chronic pancreatitis results in pancreatic scarring and fibrosis that make assessment of abnormalities difficult [Brand et al 2007, Ulrich 2001], it is recommended that concerned individuals be referred to a surveillance program that includes biomarker research and other new techniques.Agents/Circumstances to AvoidAlcohol and tobacco use exacerbate all pancreatitis regardless of cause [Lowenfels et al 1997]. In combination, smoking and alcohol use increases the risk of developing pancreatitis eightfold [Yadav et al 2009]. Smoking doubles the risk for all forms of pancreatitis, including hereditary pancreatitis [Maisonneuve et al 2005, Yadav et al 2009]. Tobacco use is also linked with early onset of pancreatic cancer [Lowenfels et al 2001].Dehydration worsens episodes of acute pancreatitis. Maintaining good hydration may be helpful in minimizing attacks, especially since nausea, vomiting, and loss of appetite limit oral intake during an attack. Physical and emotional stresses aggravate pancreatitis [Applebaum et al 2000]. Avoiding these stressors in families with HP may prevent or delay worsening of symptoms and progression of disease. Yoga and other relaxation techniques may increase quality of life in persons with pancreatitis [Sareen et al 2007]. Some patients report that regular exercise, such as running, helps reduce the frequency of episodes of pancreatitis [Authors, unpublished]Evaluation of Relatives at RiskIt is recommended that relatives at risk for PRSS1-related hereditary pancreatitis be offered molecular genetic testing for the family-specific germline PRSS1 mutation to allow early diagnosis and prevention and/or management of symptoms [Applebaum et al 2000, Ellis et al 2001, Fink et al 2007]. Testing of children is appropriate in families with early onset symptoms. Presymptomatic testing is best performed in the context of genetic counseling [Fink et al 2007].See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationCurrently, chemopreventive agents such as calcium-channel blockers are being investigated for treatment of manifestations of hereditary pancreatitis [Morinville et al 2007].A pilot study evaluated the use of the calcium channel blocker amlodipine [Morinville et al 2007]; however, this treatment cannot yet be recommended.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. PRSS1-Related Hereditary Pancreatitis: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDPRSS17q34Trypsin-1Database of PRSS1 variants in patients with chronic pancreatitis PRSS1 homepage - Mendelian genesPRSS1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for PRSS1-Related Hereditary Pancreatitis (View All in OMIM) View in own window 167800PANCREATITIS, HEREDITARY; PCTT 276000PROTEASE, SERINE, 1; PRSS1Molecular Genetic Pathogenesis Autosomal dominant hereditary pancreatitis has been conclusively linked with gain-of-function mutations in PRSS1, the gene encoding cationic trypsinogen. Gain-of-function mutations increase conversion of trypsinogen to active trypsin, or reduce the degradation of active trypsin; thus, the amount of active, intrapancreatic trypsin is increased. Active intrapancreatic trypsin may activate other zymogens (preactivated digestive enzymes), cross-activate the immune system, and/or cause direct injury [Whitcomb 2004]. The effect of premature trypsin activation may be accentuated by loss of function in modifier genes including the genes encoding the following proteins [Chen & Ferec 2009, Whitcomb 2010]: Pancreatic secretory trypsin inhibitor (encoded by SPINK1)Chymotrypsin C (CTRC)Calcium sensing receptor (CASR)Cystic fibrosis transmembrane conductance regulator (CFTR)This suggestion is based on the observation that the non-PRSS1 mutations are seen as part of a complex genotype more often than would be expected by chance alone. Normal allelic variants. PRSS1 comprises five exons.Pathologic allelic variants. The mutations p.Arg122His and p.Asn29Ile are found in approximately 90% of mutation-positive individuals [Rebours et al 2009].Affected individuals in families with hereditary pancreatitis have been found to have copy number variants in segments containing PRSS1 and PRSS2; the same finding was reported in individuals with idiopathic chronic pancreatitis in France [Masson et al 2008a]. To date, approximately 40 additional rare or private PRSS1 variants have been identified in individuals with hereditary chronic pancreatitis or simplex (i.e., a single occurrence in a family) idiopathic chronic pancreatitis of previously unknown cause. Many of these variations have not been observed in more than one affected individual. Their clinical significance is uncertain. Copy number variants of PRSS1 should also be assessed. Table 2. Selected PRSS1 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.47C>Tp.Ala16ValNM_002769.4 NP_002760.1c.63_71dupp.K23I_I24insIDKc.65A>Gp.Asp22Glyc.68A>Gp.Lys23Argc.86A>Tp.Asn29Ilec.86A>Cp.Asn29Thrc.116T>Cp.Val39Alac.346C>Tp.Arg116Cysc.364C>Tp.Arg122Cysc.365G>Ap.Arg122Hisc.415T>Ap.Cys139SerSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). Normal gene product. PRSS1 encodes the cationic trypsinogen, one of three trypsinogens synthesized by the pancreas as digestive enzymes. Cationic trypsinogen (or trypsinogen-1) makes up about two thirds of the trypsinogens; anionic trypsinogen or trypsinogen-2 (PRSS2) makes up one third; and mesotrypsinogen makes up less than 5% [Whitcomb & Lowe 2007]. Cationic trypsin is expressed as a pre-propeptide of 247 amino acid residues that is processed to trypsinogen by cleavage of a 15-residue signal peptide. Trypsinogen is activated to trypsin by cleavage of an eight-amino-acid trypsinogen activation peptide (TAP), which is typically initiated in the intestine by the action of enterokinase. The TAP can also be cleaved by trypsin in the presence of calcium and association with a binding site formed in the activation region. Trypsinogen has a second calcium-binding site that persists in trypsin which when occupied by calcium prevents trypsin degradation by the action of trypsin on the autolysis site (Arg-122), and by chymotrypsin C (CTRC) at Leu-81 within the calcium binding site [Szmola & Sahin-Toth 2007]. The mature trypsin molecule is an endopeptidase that cleaves peptide chains following an Arg or Lys amino acid residue. It also serves as the master activator of pancreatic zymogens by cleaving the activation peptide of most of the other major digestive enzymes made by the pancreas.Abnormal gene product. PRSS1 mutations associated with disease are gain of function mutations. Gain of function variants have altered regulation leading to enhanced activation or delayed or impaired inactivation.