Chronic Pancreatitis and Familial Pancreatitis

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Familial pancreatitis is a broader term to describe families in which the incidence of pancreatitis is higher than expected according to the frequency of pancreatitis in the general population. Since pancreatitis, especially chronic pancreatitis, is rare, two first- or second-degree relatives with pancreatitis are sufficient for classification as a familial pancreatitis kindred. However, other causes of pancreatitis, including gallstones and trauma, must be excluded.

Furthermore, episodic abdominal pain from AP may not be diagnosed in stoic patients, and older members of the family with diabetes mellitus or PDAC may represent late stages of undiagnosed CP. Thus, collecting an accurate family history and identifying familial pancreatitis may be challenging. The contribution of genetics to familial pancreatitis is often broad and complex. Known genetic contributors to familial pancreatitis include recessive inheritance of mild variable or borderline CFTR mutations, pathogenic variants in SPINK1 , and variants in other genes with small but interacting or additive effects.

Whitcomb et al. In this HP kindred, two key affected family members were found to have completely different complex combinations of genetic and environmental risk factors The classification of hereditary pancreatitis and familial pancreatitis and examples of genotype-phenotype correlations are given in Table 1. However, penetrance may vary by the presence of modifying risk factors and type of mutation.

For example, one study reported a PRSS1 RH kindred in Venezuela with low penetrance, as demonstrated by the presence of only 2 affected individuals in a large family The complications of HP are similar to those of chronic pancreatitis. Early on it was recognized that some patients had severe acute pancreatitis with portal vein thrombosis 41 , but this does not appear to be the most common characteristic. The primary distinguishing features of HP from other forms of pancreatitis are an early age of onset and a family history in the absence of environmental risk factors e.

Furthermore, HP patients who progress to CP have higher cumulative risks for diabetes mellitus and exocrine insufficiency, and a higher overall risk for PDAC. This may be attributed to an early age of onset, resulting in longer lifetime exposure of the pancreas to injury and inflammation. As compared to the general population, lifespan is not reduced in HP patients who do not develop pancreatic cancer Hereditary pancreatitis typically presents in childhood at a median age of years Figure 1 26, Severity, length, and frequency of attacks can also vary substantially between families.

The same study found no significance difference in the number of attacks by type of mutation, suggesting that the RH mutation may be associated with more severe attacks but no greater susceptibility Figure 1. Historic data on the time from birth to detection of first symptoms e. PEI , Diabetes mellitus e. T3cDM and pancreatic cancer i. Figure based on models by Howes The degree of fibrosis is influenced by the number of attacks and other modifying factors.

Eventually, progressive inflammation and fibrosis lead to pancreatic exocrine insufficiency in a significant amount of patients. The cumulative risk for exocrine failure at 50 years has been estimated at Diabetes arising from destruction of the islets of Langerhans by exocrine pancreatic disease is classified as T3cDM. Destruction of insulin-secreting beta cells also leads to glucose intolerance, followed by pancreatic endocrine insufficiency.

The cumulative risk for endocrine failure is Risk is further increased in the presence of smoking and diabetes mellitus 37, The increased risks for pancreatic cancer appear to result from prolonged pancreatic exposure to chronic inflammation 25, 74, 75, 82 , particularly in HP patients who develop pancreatitis in adolescence. However, the risk of PDAC does not tightly correlate with the severity of pancreatic inflammation and fibrosis 49, Hereditary pancreatitis is rare and primarily a disease of Caucasians.

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The majority of identified families originate from the United States and European countries, including Italy 58, 77 , England and Wales 59 , Germany 70 , France 35, 48 , Turkey 69 , Denmark 29 , Spain 17 and others Reports of HP from Asia are rare, though a few kindreds have been reported from Japan and China 36, 44, 45, No reports of HP families or individuals of African ancestry have been published to date.

L12F variant has been observed in some African patients with pancreatitis, but functional analyses showed no detrimental effects from this common polymorphism The frequency of hereditary pancreatitis seen in clinical practices varies widely by geographic region. The elevated concentration of HP kindreds in these regions is believed to originate from early founders of the disease within large families who tended to remain within the previously described geographic regions.

Early estimates of the prevalence of HP in the United States was about cases 39 , although the actual numbers are not known. The population prevalence in France is estimated to be at least 0. Pathogenesis and Pathology. The pathogenesis of hereditary pancreatitis was discovered by Whitcomb et al. Trypsinogen is the zymogen precursor to trypsin, a serine protease that hydrolyzes peptide bonds following an arginine or lysine, preferably in the small intestine.

Two gain-of-function mutations were identified, the first being RH and the second, N29I initially designated RH and N21I using the chymotrypsin numbering system Figure 2 is an x-ray crystallography figure of cationic trypsinogen illustrating 2 calcium-binding sites and 2 sites of trypsin-catalyzed hydrolysis.

The trypsinogen activation peptide TAP on the N-terminus maintains the zymogen in an inactive form. First, trypsin can activate other trypsinogen molecules by cleaving the TAP [at residue K12] in the process of autoactivation This process is facilitated by calcium binding to the first calcium binding pocket, which stabilizes the TAP. Once trypsinogen is activated, other trypsin molecules can induce autolysis by hydrolyzing arginine on a flexible side chain or autolysis loop that links the 2 globular domains of trypsin 54, The site is flexible, but protected from trypsin by calcium-binding to a second, adjacent pocket.

Figure 2. The flexible side chain connecting the two globular domains illustrates the location of R as an autolysis site, which is the amino acid substituted in the RH gain-of-function variant. The two calcium binding sites are illustrated by the arrows from calcium, with the activation site of calcium binding being lost by activation and release of trypsinogen activation peptide TAP. Conversion Mutations between trypsinogen genes and pseudogenes. Additional inhibitors of trypsin activity include CTRC, which cleaves the calcium binding loop, and SPINK1, which binds to the trypsin active site as a suicide inhibitor.

From a functional standpoint, the trypsinogen or trypsin molecule is susceptible to hydrolysis in low calcium concentrations, as seen inside the pancreatic acinar cell after synthesis or in the distal intestine, but is resistant to hydrolysis when the calcium levels are high, as seen in the pancreatic duct duodenum and jejunum Thus, in high calcium concentrations, trypsin is more easily activated whereas in lower trypsin concentrations, activation is minimized. The degradation of trypsin is a complex and well-orchestrated process involving both an additional trypsin molecule and CTRC.

The interaction of these molecules under various conditions has been defined see 7 T6, Table 2. Pseudogenes are noncoding relatives of functional genes that have typically acquired mutations rendering them non-functional. Generally, pseudogenes are harmless, except in cases where sequence homology with its functional paralog leads to recombination and acquisition of a pathogenic variant in the expressed gene.

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In one HP family, a novel 9 nucleotide intragenic duplication c. In addition to gain-of function-mutations, trypsin activity can be markedly increased by copy number variations CNVs. A variety of CNVs have been identified in HP families, and additional copies of PRSS1 act as gain-of-function mutations by increasing trypsin expression, which predisposes to recurrent pancreatitis and hereditary pancreatitis 12, Additional mutations have been identified in the trypsin molecule that are associated with chronic pancreatitis, but do not appear to be inherited as highly penetrant autosomal dominant variants.

The most common one is the PRSS1 A16V variant, which appears to act as a secondary or modifier variant to increase risk of pancreatitis Furthermore, not all trypsinogen mutations found in pancreatitis patients are gain-of-function variants. At least a dozen PRSS1 variants that are rare and scattered throughout the molecule have been identified in case reports, and functional studies suggest that these variants are associated with misfolding of the mutant trypsinogen protein, triggering acinar cell stress through the unfolded protein response 32 , Further genotype-phenotype and therapeutic response studies need to be conducted to fully understand the implications of these findings for affected patients.

Additional genes have been associated with recurrent acute and chronic pancreatitis, a number of which regulate trypsin activity. Next generation sequencing suggests that more complex combinations of genes also play a significant role in the development and progression of CP Inspection of pancreatic tissue revealed progressive lipomatous atrophy and fat replacement, with thin and loosely packed fibrosis in comparison to alcoholic and obstructive CP Genetic Testing and Counseling.

The goals of genetic testing differ depending on the circumstances surrounding the patient.

Chronic Pancreatitis

In general, asymptomatic subjects are not tested, especially if they are not in an HP family. In patients with recurrent acute pancreatitis or early signs of chronic pancreatitis, genetic testing is medically indicated to make a diagnosis, and to develop a management plan. In established CP, genetic testing may be useful for anticipating and managing complications of CP.

In end-stage disease, genetic testing is most useful for establishing risk to family members and for research purposes. Hereditary pancreatitis should be suspected in cases of idiopathic pancreatitis, early onset pancreatitis, and in families with multiple affected individuals. At least a three-generation pedigree should be ascertained and evaluated for pancreatitis, pancreatic cancer, diabetes mellitus, pancreatic exocrine insufficiency, cystic fibrosis, and exposures to smoking and alcohol to establish a HP kindred Risk calculation should always be taken in the context of the family history, particularly genotype if known , inheritance pattern, environmental exposures, penetrance, ages of onset, and severity.

The patient should be provided with both pre- and post-test counseling to ensure that they understand the benefits, implications, and limitations of testing 5, Insurance discrimination is a major concern for genetic testing in HP patients. L, — , which protects against genetic discrimination in health insurance and employment, but affords no protection for life, disability, or long-term care insurance. As noted above, the trypsinogen gene family is complex and both genes and pseudogenes are highly homologous.

Pancreatitis

Therefore, specially designed genetic tests are required — and next generation sequencing approaches such as whole exome sequencing or whole genome sequencing should not be used for PRSS1 testing because of challenges in sequence alignment. Notably, these calculations should always be provided in the context of family history, as many HP families demonstrate significant differences in penetrance and severity. When genetic testing is indicated in a family, testing should always begin in a symptomatic individual. Test results may identify a genetic etiology in a family, thereby accelerating the diagnosis of other affected family members.

Results may also have implications for risk to develop other complications, risk to other family members, and family planning. Not all families meeting clinical criteria for hereditary pancreatitis have an identifiable PRSS1 mutation. Therefore, negative genetic test results in the affected proband of a family does not preclude the diagnosis of hereditary pancreatitis.

In families where a deleterious variant has been identified, predictive genetic testing may be considered in close family members.

Pathophysiology

Single-site testing for this mutation can provide information on risk and risk to descendants. Generally, risk to develop pancreatitis in an asymptomatic, mutation-positive adult decreases with age. A family member who tests negative for the familial mutation has a significantly reduced, but not absent, risk for hereditary pancreatitis. Family members may have other unknown risk factors and are still at risk for pancreatitis of non-genetic etiology.

Genetic testing of asymptomatic family members in a family without an identifiable mutation is uninformative. As always, genetic counseling for risk should be provided in the context of family history. Genetic testing may be indicated in a child with diagnosed or suspected pancreatitis. Parents or legal guardians are responsible for the decision to pursue genetic testing. However, children 7 years and older should provide assent for the testing. Predictive genetic testing for asymptomatic patients less than 16 years of age is not recommended and does not have clear benefits The lifestyle practices that may be relevant to at risk carriers, such as a healthy low-fat diet and avoidance of alcohol, tobacco, and stress, are recommended for all children Management and Treatment.

HP represents a complex syndrome, and studies on management are limited. Acute pancreatitis episodes are managed identically to AP from other etiologies — with attention to intravascular fluid status, oxygenations and pain control Once the diagnosis is established, the focus is on minimizing recurrence and complications.


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Alcohol lowers the threshold for attacks of acute pancreatitis and contributes to progression to chronic pancreatitis. Smoking further increases the risk for pancreatic cancer by two-fold A low fat diet in the form of multiple small meals a day and good hydration is often recommended but remains unproven. Stress reduction with activities such as running has been reported to be of major benefit in some patients unpublished communications. Pancreatic pain is complex and multifactorial 3.

Analgesics are commonly required to help control pain, ranging from acetaminophen and NSAIDs to narcotics. In some patients, antioxidants may also reduce pain by reducing oxidative stress in acinar cells 11, As with other forms of pancreatitis, endoscopic or surgical interventions may also be indicated to alleviate pain.

Recurring Acute Pancreatitis and Chronic Pancreatitis | Children's Hospital of Philadelphia

There is growing use of total pancreatectomy with islet autotransplantation TP-IAT in the United States, and this appears to be an effective and radical treatment in some patients 8, 14 see below. Pancreatic Exocrine Insufficiency. About a third to a half of the patients with HP will develop pancreatic exocrine insufficiency PEI in their lifetime 27, PEI is a complex condition of insufficient pancreatic enzymes for digestion and absorption of nutrients. The threshold between sufficiency and insufficiency is vague because it depends on the meal, the diet and the capacity of the intestines in addition to the capacity of the pancreas to deliver enzymes Pancreatic Endocrine Insufficiency.

Patients with chronic pancreatitis should be monitored for development of T3cDM Diminished insulin secretion resulting from loss of beta islet cells may be further reduced by declines in proximal gut digestion and incretin secretion.


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