You are in: eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology Intestinal Enterokinase DeficiencyArticle Last Updated: Nov 5, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: Agostino Nocerino, MD, PhD, Chief of Pediatric Oncology, Department of Pediatrics, University of Udine, Italy Agostino Nocerino is a member of the following medical societies: American Society of Pediatric Hematology/Oncology Coauthor(s): Stefano Guandalini, MD, Director, University of Chicago Celiac Disease Program, Section Chief of Gastroenterology, Hepatology and Nutrition; Professor, Department of Pediatrics, University of Chicago Comer Children's Hospital Editors: Hisham Nazer, MB, BCh, FRCP, DCh, DTM&H, Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, Bushnaq Medical Centre, University of Jordan; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine; Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine; Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, State University of New York, Downstate Medical Center College of Medicine; Distinguished Lecturer, New York Medical College, School of Public Health; Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine Author and Editor Disclosure Synonyms and related keywords: intestinal enterokinase deficiency, enteropeptidase deficiency, primary enterokinase deficiency, secondary enterokinase deficiency, villous atrophy, malabsorption, diarrhea, failure to thrive, vomiting, hypoproteinemia, malabsorption syndrome, steatorrhea, anemia, vitamin E deficiency INTRODUCTIONSection 2 of 10
  BackgroundOnly 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. 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. PathophysiologyEnterokinase 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 an 80784 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. 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.2 Duodenase mutations that result in defective activation of proenteropeptidase may possibly lead to disease, similar to enterokinase deficiency (see Media file 1). FrequencyInternationalOnly 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/MorbidityPrognosis is good with adequate treatment. SexNo sex predilection is evident among the few reported cases. AgeWith one reported exception, affected patients present at birth with diarrhea and failure to thrive.3 That exception was the sister of an affected boy; she was aged 5 months at onset and was diagnosed at age 8 years. CLINICALSection 3 of 10
HistoryBecause 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.
Physical
Causes
DIFFERENTIALSSection 4 of 10
Cystic Fibrosis Protein-Losing Enteropathy Sprue
| ||||||||||||||||||||||||||||||
| Drug Name | Pancrelipase (Creon, Pancrease, Ultrase, Viokase) |
|---|---|
| Description | Assists in digestion of protein, starch, and fat. |
| Adult Dose | 1-3 cap or tab PO with meals; titrate dose to desired clinical effect |
| Pediatric Dose | 6-12 months: 2000 IU PO lipase with feedings 1-6 years: 4000-8000 IU PO lipase with meals 7-12 years: 8,000-12,000 IU PO lipase with meals Adjust dose according to stool fat and nitrogen content |
| Contraindications | Documented hypersensitivity; history of pork protein allergy |
| Interactions | Drugs that increase gastric pH (eg, H2 antagonists) may increase effects of pancreatic enzymes by inhibiting destruction of ingested enzymes |
| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus |
| Precautions | Doses >6000 U/kg per meal may be associated with fibrosing colonopathy, which has been evident in patients with cystic fibrosis who developed strictures of the ascending colon; high degree of variability between enzyme products (do not interchange once stabilized); monitor weight gain or loss, abdominal cramps, frequency and nature of stools, and bloating; patient can take more enzymes with large fatty meals; products are enteric coated and should be swallowed whole or sprinkled on food immediately prior to ingestion; do not chew, crush, or take with hot liquids (destroys enteric coating) |
| Media file 1: 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. | |
 | View Full Size Image | Media type: Graph |
Intestinal Enterokinase Deficiency excerpt
Article Last Updated: Nov 5, 2008
