An 11-year-old Boy with Stunting, Wasting and Diarrhea
- Name at least three major causes of pediatric short gut syndrome
- Differentiate between anatomic and functional short gut syndrome
- Identify at least one typical nutritional/non-caloric deficit in short gut syndrome
- Differentiate between short gut syndrome and intestinal failure
James is an 11-year-old boy with a remote history of necrotizing enterocolitis (NEC) that has just moved to your area and presents for a well child check. He is short and very thin. His family is concerned about encopresis. Upon further questioning he has three to four loose stools per day and when he leaks at night it is always liquid stool. His history is significant for a recent fracture of his humerus from a fall on pavement from a standing position. His review of systems is also significant for long term general fatigue compared to his peers.
During your exam he complains to his mother that he is hungry, to which his mother remarks, he is always hungry. On exam, he is short and very thin with minimal body fat. He has a transverse scar on his abdomen above the umbilicus and another small scar in the right lower quadrant.
Pediatric Short Gut Syndrome
Short gut syndrome is a disease that results from permanent incapacitation of a large portion of the gastrointestinal tract. The GI tract in this disease is defined as the absorptive regions of the intestine running from the duodenum to the right colon. Shortgut can be segregated into two categories: anatomical disease and functional disease.
In patients with anatomical disease, symptoms arise due to loss of intestinal length and absorptive capacity. In pediatric patients, loss of intestinal length results from congenital defects such as intestinal atresia (Figure 1A), gastroschisis (Figure 1B), and malrotation/volvulus or acquired conditions such as necrotizing enterocolitis (Figure 2) or less frequently Crohn’s disease, traumatic injury to the mesenteric vessels and adhesive bowel obstruction.
A patient with intestinal atresia. Black arrow indicates distal extend of small intestine. White arrow indicates proximal end of distal intestine.
Newborn with gastroschisis. The majority of the intestine (white arrow) protrudes through a defect at the right of the umbilical cord at the junction with the abdominal wall.
An abdominal film of a premature infant with necrotizing enterocolitis. White arrows indicated pneumatosis
Symptoms in these patients include: diarrhea, fluid and electrolyte abnormalities, malabsorption, and malnutrition. Severity of anatomical disease can vary based on the length of intestine that is lost as well as the specific regions that are absent. Accordingly, the intensity of symptoms corresponds to the severity of disease. Thus manifestations of anatomical shortgut can range from a child that is hungry all the time and is not growing to a patient that has minimal intestinal length, high GI fluid losses, and is dependent on total parenteral nutrition (TPN).
In functional short gut, the entire intestinal length is present; however, patients are unable to either absorb or tolerate enteral feeds. In children, etiologies include microvillus inclusion disease and the poorly understood entities of pseudo-obstruction and visceral neuropathies. Presenting symptoms in patients with pseudo-obstruction include pain with enteral feeds, nausea, and vomiting whereas patients with microvillus inclusion disease present as newborns with intractable diarrhea. Functional short gut typically does not present with a range of severity. In almost all patients, the disease is severe and incapacitating requiring full nutritional support with TPN.
Long term, patients with functional or moderate to more severe forms of anatomical shortgut syndrome are at risk for nutritional deficits even when their caloric needs are being met. These deficits include iron, fat soluble vitamins (D, E, A and K) as well as trace elements and nutrients (copper and zinc). The most common deficits encountered are typically iron deficiency with associated anemia and vitamin D deficiency. In children, vitamin D deficiency can result in osteomalacia (Figure 3A) with associated severe joint pain and Rickets (Figure 3B). Vitamin D deficiency is extremely difficult to treat because currently in the United States there is not an available isolated intravenous form of this nutrient.
Manifestations of vitamin D deficiency in short gut syndrome. A. Osteo-malacia of the humeral head (white arrows).
Manifestations of vitamin D deficiency in short gut syndrome. B. Rickets (Varus/Valgus) in a 2 year old.
Children with functional disease and severe anatomical disease are TPN dependent, a condition termed intestinal failure. Long term TPN exposure is associated with liver fibrosis (Figure 4A) and can lead to cirrhosis. These patients have sustained and worsening elevations in direct serum bilirubin and transaminases.
Figure 4A. H&E stain of a patient with TPN induced hepatic fibrosis. Green arrow heads indicate proliferating bile ducts. Blue arrowheads indicate edge of fibrotic tract.
The root cause of this is not entirely clear although phytosterols and Omega-6 fatty acids in the lipid fraction of TPN have been implicated. Liver fibrosis, once initiated, is typically thought to be irreversible although the progression can be stopped. Options for treating this include: 1) limiting intralipid infusions, 2) cycling TPN (the effect of serum bilirubin which can be seen in Figure 4B), and 3) introducing enteral feeds.
Figure 4B. Effects of TPN cycling (initiated at red arrowhead) on total (purple line) and direct bilirubin (blue line).
It is critical when implementing lipid limiting strategies in children to closely monitor essential fatty acid levels as fatty acid deficiencies can impair neurodevelopment. A handful of centers around the country are giving these patients intravenous Omega-3 fatty acids (Omegaven®) with limited success. Currently Omegaven® is not FDA approved in the United States and obtaining insurance approval for use is very difficult. Thus, other centers are administering enteral Omega-3 Fatty acids in the form of fish-oil supplements. Data supporting the use of these agents is limited and currently under investigation.
Perhaps one of the hardest concepts to understand about shortgut syndrome is that the severity of disease and the potential for rehabilitation are not just a function of loss of length. Potential for rehabilitation is dependent of retaining parts of a key region of intestine (terminal ileum, ileocecal valve, cecum and proximal right colon). This region generates glucagon like peptide-2 (GLP-2). GLP-2 is secreted into the blood stream by the enterocyte cell population enterochromaffin cells in response to feeding (Figure 5).
Figure 5. Schematic of GLP-2 production and distribution. The peptide (blue dots) is generated in the terminal ileum, cecum and ascending colon and secreted into the blood stream and acts upstream on receptors in the proximal small bowel to enhance mucosal growth and adaptation.
GLP-2 acts upstream within the intestine to drive the growth of the crypts and villi, which increases the absorptive capacity of the intestine. TPN dependent anatomical short gut patients that retain all or part of this region typically can be slowly transitioned to enteral feeds and partially or fully weaned off of TPN, a process termed intestinal rehabilitation. Some patients achieve complete, enteral caloric independence although the risks for non-caloric nutritional deficits (as described in paragraph 4) remain.
One of the key strategies in rehabilitation is achieving durable enteral access with a surgically placed gastrostomy tube. This enables the metered administration of bolus feeds, which helps to avoid overfeeding and osmotic diarrhea. It also allows for the implementation of an additional strategy: nighttime drip feedings. Nighttime drip feedings promote adaptation and improve absorptive capacity.
Often success in treating one problem begets another. With successful intestinal rehabilitation, the diameter of the intestine increases dramatically (Figure 6A and B). This alters the normal surface area to volume ratio of the intestine and predisposes these patients to bacterial overgrowth. Patients with bacterial overgrowth are typically managed by cycling on and off oral antibiotics for a week at time. However when diametric growth reaches a point where overgrowth cannot be controlled with antibiotics and patients are coming in monthly with infections, surgical intervention is required. The intestine can then be surgically reconfigured to restore the normal surface area to volume ratio (Figure 6F) through a serial transverse enteroplasty or STEP procedure (Figure 6C-E).
Figure 6. Management of a patient with bacterial overgrowth and massive diametric intestinal growth as a result of successful adaptation.
C. Beginning of STEP procedure. The enteroplasty is performed transversely with a surgical stapler.
D. Corners of the staple line are over sewn.
E. Completed enteroplasty.
In addition to reducing bacterial overgrowth, this operation also has the added benefit of increasing secretion of GLP-2 levels and improving intestinal absorption.
The current state of management of shortgut and intestinal failure patients has improved dramatically over the last 20 years in large part due to the creation of multidisciplinary programs at large academic institutions around the country. Many challenges remain as we have yet to develop a technology to replace the intestine. For example, outcomes with intestinal transplant have not achieved the success rate of other organ transplants such as liver, kidney, or heart and availability of suitable organs is severely limited. Furthermore, the pharmacologic armamentarium for treatment of this disease and its sequelae is very limited as well. We still struggle to keep children out of liver failure; we do not have an intravenous form of vitamin D. For patients with motility disorders and pseudo-obstruction we have only two medications: erythromycin and metoclopramide. The future for further drug development does not appear bright due to a very limited understanding of enteric nervous system function. One bright spot on the horizon is the coming release of a synthetic GLP-2 analog called Teduglutide®. Teduglutide® has a much longer half-life than GLP-2 due to the alteration of one amino acid in the peptide. However it will need to be administered intravenously on a daily basis. This drug is entering the market for the treatment of shortgut syndrome in adults and phase three testing in children is set to begin in the next year. Although it may help a sub-segment of the anatomical intestinal failure population achieve enteral caloric independence, nutritional deficits will remain in this population. Nevertheless, a small victory in this disease is still a victory.
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