Hereditary Pancreatic Dysfunction

Pancreatic dysfunction due to an isolated embryogenetic defect is rare. More often dysfunction is part of an inherited abnormality manifesting at multiple sites. Cystic fibrosis is an example of the latter. It is the most common
cause of hereditary pancreatic dysfunction.
Cystic Fibrosis In this autosomal-recessive disorder obstruction of small and large pancreatic ducts by thick, viscid secretions and surrounding inflammation induces fibrosis and an eventual atrophic pancreas. As a result, most patients develop exocrine pancreatic insufficiency. Acute pancreatitis is not common in cystic fibrosis patients, with some authors postulating that their pancreatic atrophy prevents a major inflammatory response. Pathologically, parenchymal atrophy, fibrosis, and fatty infiltration are evident. In some patients fatty infiltration predominates and the pancreas appears enlarged; in others, atrophy predominates with varying degrees of fatty infiltration.
Calcifications are not common in chronic pancreatitis secondary to cystic fibrosis. When present, calcifications are scattered and not as prominent as in hereditary pancreatitis. Cysts, fatty replacement, and atrophy are detected with imaging. Once small, the pancreas may have a CT density approaching that of fat, similar to severe lipomatosis. Cysts are interspersed with segments of dilated pancreatic ducts or
they may essentially replace the pancreatic parenchyma. Computed tomography in adolescents and adults with cystic fibrosis revealed less pancreatic tissue and more fat than in controls; no relationship was found between the degree of pancreatic fat and pancreatic endocrine dysfunction, but a relationship existed between the degree of fatty replacement and exocrine dysfunction.
The varied composition is reflected in the US appearance, which can range from normal to a hyperechoic pattern caused by fibrosis and fatty infiltration. In some, the pancreas blends into surrounding extraperitoneal fat and is difficult to define.Likewise, smaller cysts are not identified. Magnetic resonance signal intensity varies depending on the degree of fatty infiltration and fibrosis present. Pancreatic T1-weighted MR in patients with cystic fibrosis reveals hyperintense signals ranging from homogeneous to a lobular outline, focal sparing, and even a normal appearance.Magnetic resonance cholangiopancreatography is useful in evaluating pancreatic duct dilation and cyst formation.
Hereditary Pancreatitis The rare hereditary (familial) pancreatitis eventually leads to pancreatic exocrine dysfunction. It has an autosomal-dominant mode of inheritance with variable penetrance, but tends to affect only a few members of each family. This genetic defect is believed to be due to mutations in the trypsinogen gene leading to failure in inactivating prematurely activated cationic trypsin within acinar cells; two types are described: type I involves mutations in trypsinogen R117H and type II in trypsinogen N211. Accumulation of active trypsin mutants are believed to activate a digestive enzyme cascade process in pancreatic acinar cells, leading to autodigestion, inflammation, and acute pancreatitis. An enzymatic mutation detection method is accurate in screening individuals for known trypsinogen gene mutations.
Two types of pancreatic stones develop in this condition. Calculi in members of 10 families were composed of degraded residues of lithostathine, a pancreatic secretory protein inhibiting calcium salt crystallization; in one family with five affected individuals calculi were composed of >95% calcium salts. This condition typically develops in childhood or early adolescence as acute episodes of pancreatitis, evolves into chronic pancreatitis, and gradually progresses with episodes of pancreatitis, including pseudocyst formation, to pancreatic insufficiency. An early diagnosis prior to onset of chronic pancreatitis is often not considered. Compared to patients with chronic alcoholic pancreatitis, patients with chronic hereditary pancreatitis have an earlier onset of symptoms, a delay in diagnosis, and a higher prevalence of pseudocysts, but otherwise the natural history is similar for both conditions. These patients are at increased risk for developing a pancreatic duct adenocarcinoma, the risk being approximately 50 to 60 times greater than expected; smoking increases this risk and lowers the age of onset by approximately 20 years.
Prominent calcifications in the pancreatic ducts are a common feature and appear similar to those seen with chronic alcoholic pancreatitis, except that this finding is almost pathognomonic of chronic hereditary pancreatitis in a
young patient. A dilated pancreatic duct is also often detected. Hereditary pancreatitis has a different clinical presentation and imaging findings, and
usually is not in the differential diagnosis with cystic fibrosis.
Less Common Syndromes The syndromes listed below are rare and have little radiologic relevance, but are occasionally raised in a differential diagnosis. Shwachman-Diamond syndrome is a rare congenital disorder consisting of pancreatic insufficiency, growth retardation, and other abnormalities. These patients have steatorrhea, a normal sweat test, and normal intestinal mucosa. Some eventually improve their enzyme secretions and have pancreatic sufficiency.
Imaging shows extensive replacement of pancreatic tissue by fat.
Pearson marrow-pancreas syndrome manifests during early infancy with failure to thrive and involves the hematopoietic system, exocrine pancreas dysfunction, and others. A primary defect involves deletions in mitochondrial
DNA.
Johanson-Blizzard syndrome is an autosomal recessive syndrome consisting of ectodermal dysplasia. Among other abnormalities, these infants develop both exocrine and endocrine pancreatic insufficiency. The primary
defect is in acinar cells; at autopsy some of these infants have total absence of acini and the pancreas is replace by fat.
Histopathologically, patients with the Johanson-Blizzard syndrome and Schwachman- Diamond syndrome have preserved ductular output of fluid and electrolytes; this distinguishes them from patients with cystic fibrosis, who have a primary ductular defect.
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