This newborn female was admitted to the neonatal intensive care unit at an outside hospital because a prenatal ultrasound demonstrated intestinal obstruction. She was the 2,660 gram product of a full-term gestation to a 19-year-old GlPl female. The pregnancy was complicated by the findings on a "routine" ultrasound at 31 weeks gestation of dilated loops of intestine with peristalsis. It was a spontaneous vaginal delivery. Apgar scores were 9 at 1 minute and 9 at 5 minutes. The family history was unremarkable.
On physical examination at birth, she was an alert, nondysmorphicappearing girl with a distended abdomen. Vital signs were unremarkable. Her weight, length, and head circumference were all in the 10th percentile. HEENT exam was unremarkable. Lungs were clear. Sl and S2 were normal without murmurs. Her abdomen was distended without tenderness, masses, or organomegaly. She had normal female genitalia. The anus was normally positioned and patent. Her back was straight. Neurologic examination was unremarkable in detail.
An initial x-ray of the abdomen revealed dilated loops of small bowel with no gas at the level of the colon. There was no free air. No other radiographie studies were performed at this time. A sweat test and thyroid testing were normal. An exploratory laparotomy was performed on the second day of life, and a loop ileostomy was created. Inspissated meconium was evacuated from the intestines. A serum immunoreactive trypsinogen was negative. A colonie biopsy was normal; ganglion cells were present. A diagnosis of intestinal pseudo-obstruction syndrome ultimately was made.
Robert Listernick, MD, moderator: Comments?
Marieta Reynolds, MD, pediatrie surgeon: I'm not at all happy with the preoperative evaluation. Unless the child was in extremus with an acute abdomen, several x-ray studies should have been performed. An infant who has multiple dilated loops of small intestines does not have an upper obstruction. The first test she needed was an enema with water-soluble contrast looking for evidence of Hirschsprung disease, a distal small intestinal or colonie atresia, small left colon syndrome, or meconium ileus. We would avoid the use of barium at first, in case the child had meconium ileus; if this were the case, the contrast would pull water into the lumen of the colon and aid in the dissolution of the thick meconium. If the abdomen were scaphoid, we would have performed a barium examination of the upper gastrointestinal tract looking for a malrotation with volvulus.
Dr. Listernick: Before we even get there, how would you have counseled this family at the time of the prenatal ultrasound?
Robin Steinhorn, MD, neonatologist: These findings can be seen as early as the second trimester. However, on occasion, the baby will be born and be fine, without any signs of obstruction. In this case, the family would have met with both the neonatologist and the surgeon. We would have talked to them about the causes of both anatomic obstruction, as Dr. Reynolds delineated, and nonanatomic obstruction such as cystic fibrosis. A detailed family history would have been obtained, looking for other cases of familial diseases associated with neonatal small bowel obstruction, such as cystic fibrosis or Hirschsprung disease.
Dr. Listemick: You mentioned cystic fibrosis. Can accurate sweat tests be performed during the first few days of life?
Adrien ne Prestridge, MD, pediatrie pulmonologist: Yes. The most important factor is the amount of sweat collected. If the infant doesn't sweat enough, an accurate test can't be performed. More important, the physicians should not have relied solely on an immunoreactive trypsinogen in the presence of what sounds like meconium ileus. DNA testing for the cystic fibrosis gene should have been performed.
Dr. Listemick: What is intestinal pseudo-obstruction syndrome?
Miguel Saps, MD, pediatric gastroenterologist: Intestinal pseudo-obstruction is a rare disorder characterized by either continuous or repeated episodes of intestinal obstruction without any physical obstruction within the lumen of the bowel. Chronic intestinal pseudoobstruction (CIP) can be diagnosed if the symptoms are congenital and persist for more than 2 months, or if the symptoms start later in life and persist for more than 6 months. CIP may be a primary disorder, usually of either neurologic or myopathie origin. Alternately, it may develop secondarily to any one of a number of disorders such as connective tissue diseases (eg, lupus, scleroderma), diabetes, electrolyte disorders (eg, hypokalemia, hypomagnesemia), or celiac disease.
Dr. Listemick: In looking at the records at the outside hospital, this child also had several episodes of urinary tract obstruction for unclear reasons. One diagnosis that was considered was a form of visceral myopathy-megacystis, microcolon, intestinal hypoperistalsis syndrome (hollow visceral myopathy). Ultimately, this was not felt to be the cause of the symptoms.
Dr. Reynolds: Let's be clear on one extremely important fact. CIP in this age group is essentially a diagnosis of exclusion. Any baby born with dilated loops of bowel and abdominal distention needs a sweat test, thyroid function tests, and a suction rectal biopsy looking for the absence of ganglion cells as seen in Hirschsprung disease.
Dr. Steinhorn: Even if the sweat test were negative, it would be important to perform genetic testing in this situation, given what should have been a high index of suspicion.
Dr. Listemick: How do you make the diagnosis of CIP?
Dr. Saps: The first step is to document that there is no obstructing lesion such as an intrinsic bowel mass or Hirschsprung disease. Next, all the medical causes of bowel obstruction should be ruled out, as discussed above. A number of diagnostic modalities, such as measurement of gastric emptying and intestinal transit time with radioactive isotopes, can document the magnitude of the pseudo-obstruction. Antroduodenal manometry can be used to distinguish between the various neuropathic and myopathie causes. Much of this testing is impossible to perform in a neonate or infant.
Dr. Listemick: Is histology of an intestinal biopsy useful in establishing the diagnosis of CIP?
Hector Melin-Aldana, MD, pediatrìe pathologist: The pathologic diagnosis of CIP is a huge quagmire. One example of this confusion is the disorder known as "intestinal neuronal dysplasia." Children with this condition present in the neonatal period with signs and symptoms suggestive of Hirschsprung disease. Initial reports demonstrated hyperplastic submucosal ganglia on intestinal biopsy and increased acetylcholinester-ase-positive fibers in the adventitia around blood vessels. However, even the world's experts can't agree on the histologie criteria for this diagnosis or even whether the disease truly exists. This is just one example of the confusion surrounding the diagnosis of CIP. I would be extremely cautious making the diagnosis of CIP on pathologic grounds alone.
Dr. Listemick: What's the treatment for CIP?
Dr. Saps: The mainstay of treatment is nutritional supplementation with total parenteral nutrition (TPN). Ultimately, intestinal transplantation is the only definitive therapy for most of these conditions. However, in unusual cases, if the problem is limited to the colon, the performance of an ileostomy may be curative.
Dr. Listernick: Moving on, this child was maintained nutritionally with TPN exclusively. Her predominant symptoms were repeated episodes of small bowel obstruction and dysfunction. During her course, she developed signs of cholestasis, including hepatomegaly. A diagnosis of biliary atresia was entertained but eliminated by liver biopsy, which demonstrated severe hepatocellular and canalicular cholestasis with mild portal fibrosis and nonspecific inflammation. She had multiple central line infections. Finally, she was transferred here for revision of her ileostomy, which repeatedly prolapsed.
Let's talk about TPN cholestasis. Have the pundits decided on the cause - protein or sugar?
Timothy Sentongo, MD, pediatrie gastroenterologist: TPN-related cholestasis has a multifactorial origin, with many factors having been incriminated. Potential culprits that have been examined have included excess carbohydrate, protein, lipid (phytosterols), or copper, as well as specific nutrient deficiencies (eg, choline). Other potential factors include recurrent sepsis and bacterial overgrowth.
Dr. Listernick: Does it ever cause irreversible hepatic dysfunction?
Dr. Sentongo: Yes, with chronic prolonged exposure.
Dr. Saps: The cause of death in patients with CIP generally was infection or malnutrition and nutritional deficiencies. Now, if they have small bowel transplant, they die of small bowel transplant.
Dr. Listernick: That reminds me of an old Abbott and Costello joke: "There are some doctors that you go to because of kidney disease, you die of liver disease. You come to me for kidney disease, you die of kidney disease."
Dr. Reynolds: There's also a definite increased risk of hepatocellular carcinoma in neonates treated for a prolonged period with TPN.
Dr. Listernick: Is there any treatment for TPN-associated cholestasis?
Dr.Reynolds:Itry to avoidthe development of TPN-associated cholestasis by cycling the TPN at regular intervals. I use ursodeoxycholic acid to stimulate bile flow and, at times, I add phenobarbitol to "rev up" the glucuronyl transferase in the liver to promote conjugation of bilirubin. The only way to alleviate the cholestasis is through the introduction of enterai feeds.
Dr. Saps: Some physicians even use rotating antibiotic cocktails to prevent intestinal bacterial overgrowth.
Dr. Listernick: After this child was transferred, Dr. Sentongo was asked to see her. Can you tell me your thoughts at the time?
Dr. Sentongo: There were some aspects of her history that went unrecognized during the previous evaluation. These included the history of persistently "pasty" acholic stools in the absence of identifiable biliary obstruction or gallstones and the history of "pneumonia." Furthermore, the small bowel biopsy obtained earlier in the assessment for CIP showed inspissated intestinal secretions in the duodenal mucosa. Together, these findings raised the suspicion of cystic fibrosis.
Dr. Melin-Aldana: First, there were ganglion cells present in normal numbers, and I could find no evidence of intestinal neuronal dysplasia or any other cause of primary CIP. Next, there was a moderate degree of inflammation in the lamina propria. The intestinal crypts were mildly dilated and filled with thick secretions. These findings also raise the possibility of cystic fibrosis.
Dr. Listerai ck: A sweat test performed here was positive; the chloride concentrations were 83 mEq/L and 79 mEq/L, respectively.
So, this child has cystic fibrosis. How was the diagnosis missed?
Adrien ne L. Prestridge, MD, pediatrie pulmonologist: First, the gold standard method for performing a sweat test is pilocarpine iontophoresis. However, if the clinical suspicion remains high, genetic DNA analysis should be performed. This method was not performed at the outside hospital. Even if pilocarpine iontophoresis had been performed, it's clear that sweat tests performed at accredited cystic fibrosis centers, where many more tests are performed yearly, are decidedly more accurate than tests performed infrequently at smaller hospitals.
Dr. Listemick: What are the causes of false negative sweat tests?
Dr. Prestridge: Most commonly, false negative tests are due to poorly performed tests, inadequate sweat collection (usually in the first few weeks of life), and the presence of edema. False positive sweat tests may be due to malnutrition, ectodermal dysplasia, hypothyroidism, hypoparathyroidism, panhypopituitarism, nephrogenic diabetes insipidus, pseudohypoaldosteronism, fucosidosis, and some of the mucopolysaccharidoses.
Dr. Sen tongo: Another simple test that could have been performed is a fecal elastase assay. Elastase is a pancreatic enzyme that is measurable in stool. Unlike chymotrypsin, elastase is resistant to bacterial degradation; thus, fecal levels reflect pancreatic output. The levels of fecal elastase in individuals with normal pancreatic function are greater than 200 mcg/g of stool. Levels below this value, in the absence of diarrhea, suggest pancreatic insufficiency.
Dr. Listeraick: How is the child doing now?
Dr. Prestridge: She has pseudomonas pneumonia, another clear indication that she has cystic fibrosis. She hasn't had any food by mouth for months, so she has severe oral aversion and is receiving all her enterai feeds through the gastrostomy. We are slowly weaning her from TPN. She gained 400 grams the first week after pancreatic enzymes were started. Eventually, the ileostomy will have to be taken down and reattached.
Dr. Listemick: What did the liver biopsy show?
Dr. Melin-Aldana: The liver biopsy shows moderate cirrhosis.
Dr. Listeraick: What is the prognosis for return of hepatic function?
Dr. Melin-Aldana: TPN-associated fibrosis has been known to regress. However, once cirrhosis develops, particularly in the setting of underling cystic fibrosis which itself may cause biliary cirrhosis, I suspect that the prognosis is fairly poor.
Dr. Listeraick: Thank you, everybody.