Hereditary pancreatitis chronic (Hereditary pancreatitis) - Genes PRSS1, SPINK1, CTRC and CFTR.
Hereditary chronic pancreatitis is a disease characterized by a permanent inflammation of the pancreas leading to its destruction and prevents its main functions resulting in malabsorption of food and increase in blood glucose concentrations. Symptoms include recurrent epigastric pain associated with nausea, vomiting and flatulence and bloating. Many individuals with hereditary pancreatitis develop pancreatic calcifications also adulthood. With the passage of time, inflammation damages the pancreas, causing fibrosis in pancreatic tissue. Pancreatic fibrosis causes loss of pancreatic function in many affected individuals, which may endanger the production of digestive enzymes and disrupt normal digestion, resulting in steatorrhea, weight loss, and deficiency of protein and vitamins. Due to a decrease in insulin production by loss of pancreatic function, a quarter of people with hereditary pancreatitis develop type 1 diabetes mellitus in mid-adulthood, risk increases with age.
And chronic damage to the pancreas pancreatic inflammation increase the risk of developing pancreatic cancer. The risk is particularly high in people with hereditary pancreatitis who also smoke, drink alcohol, have type 1 diabetes mellitus or a family history of cancer. In affected individuals who develop pancreatic cancer, it is usually diagnosed in mid-adulthood. Complications of pancreatic cancer and diabetes mellitus type 1 are the most frequent causes of death in people with hereditary pancreatitis, although it is thought that people with this disease have a normal life expectancy.
Hereditary chronic pancreatitis is due to mutations in genes PRSS1, SPINK1, CTRC and CFTR.
Mutations in the gene PRSS1, located on the long arm of chromosome 7 (7q34), are responsible for most cases of hereditary chronic pancreatitis. The PRSS1 trypsinogen gene encodes the enzyme cationic. This enzyme is synthesized in the pancreas and helps the digestion of food. When the enzyme is required, it is secreted by the pancreas and is transported to the small intestine where splits into its active form, trypsin. When digestion is complete and no longer needed trypsin, the enzyme decomposes. They have identified more than 40 mutations in the gene responsible for hereditary PRSS1 chronic pancreatitis. Some gene mutations cause hereditary pancreatitis PRSS1 that result in coding an enzyme cationic trypsinogen is transformed early in trypsin while it is still in the pancreas. Other mutations prevent trypsin haywire. In any case, the most frequent alteration in cases of HCP is R122H. Normally, self - activates trypsinogen slowly and pancreatitis given the presence of protective occurs. Inhibitors pancreatic secretory trypsin can inhibit the activity of the pancreas within acinar cells and pancreatic duct. Once activated, the trypsin may be inactivated by cleavage at point 122 where the R122H mutation interferes, preventing the inactivation of trypsin and activated. Thus, trypsin remains active inside the pancreas to reach concentrations that exceed inhibitors secretory trypsin, being resistant to inactivation by other mechanisms and activating possibly other proenzymes and resulting pancreatitis. Other mutations associated with less frequent HCP are N29I and A16V, which cause the trypsin resistant to inactivation. Others, like K23R and D22G affect trypsinogen activation peptide, the promoter PRSS1 (-delTCC) or cationic trypsinogen (L104P, R116C, C139F). These changes result in high concentrations of trypsin in the pancreas. The trypsin activity in the pancreas can damage the pancreatic tissue and may also trigger an immune response, causing inflammation of the pancreas. It is estimated that 65% to 80% of people with chronic pancreatitis have inherited mutations in the gene PRSS1.
SPINK1 gene, located on the long arm of chromosome 5 (5q32), encoding a protein inhibitor of trypsin, which is secreted from pancreatic acinar cells in the pancreatic fluid. It is believed to act in preventing premature activation of zymogens catalyzed by trypsin in the pancreas and pancreatic duct.
The CTRC gene, located on the short arm of chromosome 1 (1p36.21), encodes a member of the S1 peptidase family. The encoded protein is a factor of lowering serum calcium having activity of chymotrypsin - like protease. They have been observed alternative spliced transcript variants, but their long - term nature has not been determined. The loss of function of the CTRC variants predispose to pancreatitis by decreasing the activity of trypsin degrading protection.
The CFTR gene, located on the long arm of chromosome 7 (7q31.2), encodes a protein called transmembrane conductance regulator in cystic fibrosis. This protein acts as a channel through the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. The channel carries chloride ions into and out of cells. Transport of chloride ions helps control the movement of water in the tissues. CFTR also regulates the function of other channels, such as those transporting sodium ions across cell membranes. These channels are required for normal function of organs such as the lungs and pancreas. Mutations in the CFTR gene altered production, structure, or stability of the chloride channel. All these changes inhibit the proper functioning of the channel, disrupting transport of chloride ions and water movement in and out of cells. As a result, the cells that line the ducts of the pancreas and other organs produce mucus that is abnormally thick and sticky.
When hereditary pancreatitis is due to mutations in the PRSS1 gene is inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient to express the disease. In some cases, an affected person inherits the gene mutation from an affected parent PRSS1. Other cases are due to new mutations in the gene and occur in people with no history of disease in your family. It is estimated that 20% of people with the altered gene PRSS1 not have an episode of pancreatitis, a condition known as reduced penetrance. It is not clear why some people with a mutated gene never develop signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI perform detection of mutations associated with hereditary chronic pancreatitis, by complete PCR amplification of the exons of the genes PRSS1, SPINK1, CTRC and CFTR, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).