Intestinal Enterokinase Deficiency 

Only 13 confirmed cases of primary enterokinase deficiency have been reported since the condition was first described in 1969.[1] Secondary enterokinase deficiency has been reported in patients with partial or total villous atrophy; however, enterokinase activity is usually not significantly affected in these conditions. A previously described patient developed celiac disease at age 25 years, but enterokinase levels remained low after normalization of intestinal mucosa with gluten-free diet.[2] Enterokinase, also known as enteropeptidase, is a key enzyme for intestinal digestion of proteins. Therefore, enterokinase deficiency causes severe protein malabsorption with poor growth and development.

Enterokinase is synthesized by the enterocytes of the proximal small intestine and can be found in the brush border membrane and as a soluble form in intestinal fluid. Human enterokinase appears to be a disulfide-linked heterodimer, composed of a 784 amino acid heavy chain and a 235 amino acid light chain, derived by processing of the single-chain precursor. According to the deduced amino acid sequence, enteropeptidase is a serine protease. The active 2-chain enteropeptidase is derived from the single-chain precursor proenteropeptidase. It is activated by duodenase, a serine protease expressed in the duodenum.[3]

Duodenopancreatic reflux of the duodenal contents could result in trypsinogen activation by enteropeptidase within the pancreas, followed by acute pancreatitis.[4] Beta-site APP-cleaving enzyme1 (BACE1), a protease that has been closely linked to the pathogenesis of Alzheimer disease but highly expressed in pancreatic acinar cells, could possibly protect the pancreas from premature trypsinogen activation.[5]

Enterokinase is secreted by the mucosa of the small intestine. It is absent in crypts but significant in villous enterocytes and maximal in the upper half of the villi, especially on the brush border. The enzyme catalyzes the conversion of trypsinogen to its active product, trypsin. In turn, trypsin activates the other pancreatic proteolytic zymogens (chymotrypsinogen, procarboxypeptidase, proelastase) to chymotrypsin, carboxypeptidase, and elastase.

Enterokinase deficiency seriously impairs protein absorption. Proteinase-activated receptor 2 is present at the apical and basolateral membrane of enterocytes; activation of this receptor by trypsin stimulates enterocytes to secrete eicosanoids, which act locally in the intestinal wall to regulate epithelial growth. Therefore, in addition to its purely digestive role, enterokinase localization on the luminal surface of the duodenal villi possibly contributes to enterocyte growth by generating active trypsin on the cell surface.

The human genetic locus appears to be close to the gene for beta-amyloid precursor protein at band 21q.21.2. The human proenteropeptidase gene consists of 25 exons (24 introns) and spans around 88 kb of genomic DNA sequence.[6] Duodenase mutations that result in defective activation of proenteropeptidase may possibly lead to disease, similar to enterokinase deficiency.

Position of mutations (red arrows), in relation to proenteropeptidase exon organization, domains, and amino acid residues forming the active site of the serine protease domain (H825, D876, and S971 [blue arrows]). All 4 mutations identified are null mutations that predict the absence of a correctly formed active site. The previously described modular structure of proenteropeptidease domains, based on primary-structure comparison, correlates with exon boundaries. SA = signal/anchor sequence; LDLR = LDL receptorlike domain; Muc = Mucin-domain; Meprin = Meprinlike domain; C1r/s = Complement component C1rlike domain; MSCR = Macrophage scavenger receptorlike domain. Adapted from American Journal of Human Genetics.

Frequency

International

Only 13 cases of primary enterokinase deficiency have been reported. Three additional patients were reported with a similar clinical picture but with unmeasured intestinal enterokinase activity.

Mortality/Morbidity

Prognosis is good with adequate treatment.

Sex

No sex predilection is evident among the few reported cases.

Age

With one reported exception, affected patients present at birth with diarrhea and failure to thrive.[7] That exception was the sister of an affected boy; she was aged 5 months at onset and was diagnosed at age 8 years.

Because protein digestion is expected to be largely dependent on enteropeptidase activity, enterokinase deficiency causes protein malabsorption during early infancy. However, for unknown reasons, protein digestion improves with time and can be adequate in the adult. In adulthood, patients have normal body weight and no GI symptoms, even in the absence of pancreatic enzyme supplements.

Almost all patients present at birth with diarrhea and failure to thrive.

All patients exhibit hypoproteinemia.

Vomiting has been reported in approximately 50% of patients.

Affected children present with a malabsorption syndrome characterized by muscle wasting, failure to thrive, and hypoproteinemia (eg, kwashiorkor). This malabsorption syndrome is generalized during the disease's early phase and includes steatorrhea, but these changes are probably secondary to protein malnutrition.

Generalized edema occurs in one half of affected patients.

Severe anemia, which is common, is presumably secondary to protein malabsorption and vitamin E deficiency.

Identification of enterokinase deficiency in 2 pairs of siblings has suggested that the condition is inherited. In these families, Holzinger et al identified mutations in the serine protease-7 gene (PRSS7 gene), which encodes proenterokinase. Therefore, enterokinase deficiency can be considered to be caused by a mutation in the PRSS7 gene.[6]

Determine proteolytic activity in patients with intestinal enterokinase deficiency before and after activation with exogenous enterokinase in a duodenal juice sample collected during a pancreozymin-secretin test.

Perform column chromatography of duodenal juice before and after activation with exogenous enterokinase.

Trypsin activity in duodenal fluid is low or absent; activity returns after the addition of enterokinase. Lipase and amylase activity levels are within reference ranges.

Assay enterokinase activity in duodenal juice and intestinal mucosa.

Enterokinase activity in duodenal fluid and mucosal homogenate is less than 10% of age-matched control values.

The human proenteropeptidase complementary DNA (cDNA) has been cloned, and the gene has been mapped.[8]

Pancreatic enzyme replacement is indicated in patients with intestinal enterokinase deficiency.

In exocrine pancreatic deficiency, the efficacy of enzyme substitution therapy appears to be higher when enzymes are administered either portioned along with meals or just after meals. Administration of enzymes in the form of enteric-coated minimicrospheres avoids acid-mediated lipase inactivation and ensures gastric emptying of enzymes in parallel with nutrients.[9, 10]

Treatment of enterokinase deficiency involves no dietetic restrictions or recommendations after starting proper pancreatic enzyme replacement therapy.

Class Summary

These agents aid digestion when the pancreas is malfunctioning. The products contain various ratios of lipase, amylase, and protease. Most of the preparations are available in multiple strengths to ease administration. A particular dose is prescribed based on clinical symptoms and age and weight and then modified according to the clinical response.

Pancrelipase (Creon, Pancrease, Ultrase, Viokase)

Assists in digestion of protein, starch, and fat.

Patients with intestinal enterokinase deficiency who are adequately treated have an excellent prognosis.

Children with enterokinase deficiency tend to improve spontaneously after age 6-12 months.

Pancreatic replacement therapy can usually be discontinued in later life.