eMedicine Specialties > Pediatrics: Surgery > General Surgery

Surgical Aspects of Cystic Fibrosis and Meconium Ileus

Author: Michael S Irish, MD, Assistant Professor, Department of Surgery, The University of Iowa; Consulting Pediatric Surgeon, Department of Pediatric Surgery, Blank Children's Hospital and Children's Hospital Physicians Group
Coauthor(s): Philip M Bovet, DO, MPH, Resident, Department of Pediatric Surgery, Blank Children's Hospital
Contributor Information and Disclosures

Updated: Jul 31, 2006

Introduction

Meconium ileus (MI) is among the most common causes of intestinal obstruction in the newborn, accounting for 9-33% of neonatal intestinal obstructions. MI is the earliest clinical manifestation of cystic fibrosis (CF) and occurs as either simple or complicated in approximately 16-20% of patients who have CF, although MI also occurs in patients who do not have CF. Clinically, CF is characterized by the triad of (1) chronic obstruction and infection of the respiratory tract, (2) exocrine pancreatic insufficiency, and (3) elevated sweat chloride levels.

In 1905, Landsteiner described the association between inspissated meconium in a newborn and pathologic changes in the pancreas. He speculated that an enzyme deficiency causing pancreatic fibrosis also led to abnormally thick meconium. In 1936, Fanconi was first to use the term cystic fibrosis to describe the combination of pancreatic insufficiency and chronic pulmonary disease in childhood. Anderson associated MI with CF 2 years later, noting that the histologic lesions in the pancreas were identical in both conditions.

In 1946, Glanzman was first to suggest that abnormal intestinal mucus causes inspissation of meconium. In 1952, Buchanan chemically analyzed inspissated meconium from infants with MI. A year later, Bodian attributed the abnormally viscid nature of meconium in MI to abnormal mucus secreted by the intestines of patients with CF.

A possible MI diagnosis should raise the suspicion of CF in the fetus. Antenatal diagnosis of MI can be confirmed in 2 groups. In the low-risk group, the diagnosis is suspected when routine prenatal ultrasonography reveals the sonographic appearances of MI. The high-risk group consists of all pregnancies subsequent to the birth of a child with CF. Parents of a child with CF are obligate carriers of a CF mutation.

History of the Procedure

Before 1948, the prognosis for infants with MI was uniformly poor despite surgical treatment. In that year Hiatt and Wilson of Babies & Children's Hospital of New York reported the first successful surgical management of 5 infants with MI, using intraoperative disimpaction of meconium with saline instilled into the bowel via a tube enterostomy. In 1989, Fitzgerald proposed a similar technique in which an appendectomy is performed and a cecostomy catheter is placed through the appendiceal stump to insert irrigant and to evacuate impacted meconium.

Problem

In the simple form, thickened meconium begins to form in utero. It obstructs the mid ileum, causing proximal dilatation, bowel wall thickening, and congestion.

Frequency

  • MI is among of the most common causes of intestinal obstruction in newborns, accounting for 9-33% of neonatal intestinal obstructions.
  • MI is the earliest clinical manifestation of CF, occurring in approximately 16-20% of patients with the condition.
  • Of all operative cases of CF, 38% are due to MI.
  • CF is an autosomal recessive disease; its estimated heterozygote frequency in white people is up to 1 in 20. Each offspring of 2 heterozygote parents has a 25% chance of developing CF. A family history of CF has been noted in 10-40% of new patients with MI. Allan, in a 1981 review of 488 families with at least one child with CF, reported an MI recurrence rate of 39% in families with a previously affected sibling.

Etiology

Genetic causes of cystic fibrosis

  • In 1989, the CF locus was localized through linkage analysis to the long arm of human chromosome 7, band q31. The disease is caused by mutations in the gene that codes for the cell membrane protein CF transmembrane (conductance) regulator (CFTR). This protein is an adenosine 3',5'-cyclic adenosine monophosphate (cAMP)–induced chloride channel, which also regulates the flow of other ions across the apical surface of epithelial cells. The alteration in CFTR causes abnormal electrolyte content in the environment external to the apical surface of epithelial membranes. This leads to desiccation and reduced secretion clearance from tubular structures lined by affected epithelia.
  • The most common mutation of the CFTR gene is a 3 base pair deletion that removes a phenylalanine residue at amino acid position 508 of CFTR. This is called the DF508 mutation. More than 1437 CFTR mutations have been reported to the CF Genetic Consortium, as of November 2005. About 41% (595) of these mutations are missense, and approximately 50% of individuals with CF are homozygous for DF508; another 25-30% have one copy of DF508 plus another mutation.
  • Certain alleles cluster with increased frequency in specific populations. For example, W1282X is common in Ashkenazi Jewish people, and A455E is common both in Dutch people and in individuals from northern Quebec. D1152H is the third most prevalent in Ashkenazi and other ethnic Jewish groups. Past tests were only for F508del, G542X, N1303K, and 3849+10KbC>T. The prevalence of D1152 mutation in Jewish population comprises 5.2% of all CFTR mutations.
  • Genotype-phenotype correlation demonstrates that DF508 homozygosity nearly always confers a pancreatic exocrine insufficiency. Individuals with 1 or 2 copies of missense mutations (eg, R117H) tend to be pancreatic sufficient and have milder disease. The incidence of MI is higher in patients who are homozygous for DF508 or who have DF508 plus G542X. Conversely, not all patients with these genotypes have MI, so other non -CFTR factors, either genetic and/or environmental, must be involved in MI pathogenesis.
  • Regarding MI, no specific haplotype variant is available to determine its presence; however, 79% of the patients who have DF508 mutations presented initially with abdominal pain instead of lung problems.
  • Due to the significant variability in disease presentation, evidence supports the role of modifier genes. Studies in CF model mice have shown an increase in mast cells and neutrophils as part of the immune response.
  • For example, the Kitl gene plays a vital role in the differentiation of mast cells, as demonstrated by a decreased expression of Mcpt2. Another focus would be the proteins selectin and ICAM-1, which facilitate neutrophil extravasation. Neutrophils and mast cells release proteases, prostaglandins, and histamine that influence mucus production.
  • The 129/Sv allelic contribution in mice yields a milder inflammatory response and was potentially linked to chromosomes 1, 9, and 10.
  • The regulation of these genes and processes may help explain the range of variability in similar genetic mutations.

Pathophysiology

  • Meconium in patients with MI has higher protein and lower carbohydrate concentration than that in control populations. In 1958, Green, Clarke, and Schwachman found that albumin was the major protein present in the meconium of infants with MI. The concentration of albumin is 5-10 times higher, along with a significant increase in the liver's production of intraluminal glutamyltranspeptidase (GGTP) and 5'-nucleotidase in the meconium that causes MI. Addition of albumin to normal meconium makes it viscid; addition of pancreatic protease liquefies the viscid mass. This led to the belief that pancreatic insufficiency played a central role in MI pathogenesis, although pancreatic insufficiency is not the sole cause of abnormal meconium in MI. In 1988, Lands et al reported 2 infants with CF and MI, aged 9 and 11 months, who displayed no clinical evidence of pancreatic insufficiency.
  • Abnormal intestinal motility may also contribute to MI development. Some patients with CF have prolonged small intestinal transit times. Non-CF diseases associated with abnormal gut motility (eg, Hirschsprung disease, chronic intestinal pseudo-obstruction) have been associated with MI-like disease, suggesting that decreased peristalsis may allow increased resorption of water, thus favoring MI development.
  • In the murine model of CF, developed in 1992, newborn mice had severe intestinal obstruction at birth with minimal pulmonary or pancreatic involvement. These animal studies support the concept that MI may occur in patients with sufficient pancreatic activity. The lack of concordance between MI and severity of pancreatic disease suggests that intraluminal intestinal factors contribute to MI development.
  • Postnatally, intestinal disease is characterized by a glandular abnormality that produces hyperviscous mucus. How mutations of the CF gene generate abnormal mucins is not fully described, nor is the developmental sequence of mucin secretion in the fetal intestine, although the CFTR ion channel defect possibly leads to dehydration of intraluminal contents. The meconium of fetuses with CF and MI has increased viscosity and decreased water content compared to healthy controls.

Presentation

  • Patients with simple MI usually present with abdominal distension at birth, eventually progressing to failure to pass meconium, bilious vomiting, and progressive abdominal distension. Often, examination reveals dilated loops of bowel with a doughy character that indent on palpation. The rectum and anus usually are narrow, a finding possibly misinterpreted as anal stenosis.
  • Patients with complicated MI present more dramatically at birth with severe abdominal distension, sometimes accompanied by abdominal wall erythema and edema. Abdominal distension may be severe enough to cause respiratory distress. Signs of peritonitis include tenderness, abdominal wall edema, distension, and clinical evidence of sepsis. A palpable mass may indicate pseudocyst formation. Often, the neonate is in extremis and needs urgent resuscitation and surgical exploration.
  • CF is characterized clinically by the following triad:
    • Chronic obstruction and infection of the respiratory tract
    • Exocrine pancreatic insufficiency
    • Elevated sweat chloride levels
  • Approximately 10% of patients with CF remain pancreatic sufficient and tend to have a milder course.
  • Other clinical variants have been described recently, such as adult males with bilateral absence of the vas deferens who have little other clinical involvement. Absence of the vas deferens is considered an atypical presentation of CF, and 80% of men with this presentation have at least one CFTR gene mutation. In 1995, Zielenski reported the most common of these mutations is the IVS8/5T mutation.

Indications

Surgical exploration is indicated for patients with progressive distension, signs of peritonitis, or clinical deterioration.

Surgery is always indicated for complicated MI. Complicated MI requires resection more often than simple MI and always requires temporary stomas.

The following complications require surgical management:

  • Persistent or worsening abdominal distension
  • Persistent bowel obstruction
  • Enlarging abdominal mass
  • Intestinal atresia
  • Volvulus
  • Perforation
  • Meconium cyst formation with peritonitis
  • Bowel necrosis

Relevant Anatomy

Fetuses with CF have abnormal development of the pancreas and intestinal tract. CFTR expression can be detected in the pancreatic ductules at 18 weeks' gestation. In patients with CF, abnormal pancreatic secretions obstruct the duct system, leading to autodigestion of the acinar cells, fatty replacement, and ultimately, fibrosis. Beginning in utero, this progressive process occurs variably over time. Approximately two thirds of infants later diagnosed with CF by neonatal screening have pancreatic insufficiency at birth. Approximately 10% of patients with CF remain pancreatic sufficient and tend to have a milder course.

Contraindications

See Treatment.

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References
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Further Reading

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Keywords

cystic fibrosis, CF, meconium ileus, MI, simple meconium ileus, complicated meconium ileus

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Contributor Information and Disclosures

Author

Michael S Irish, MD, Assistant Professor, Department of Surgery, The University of Iowa; Consulting Pediatric Surgeon, Department of Pediatric Surgery, Blank Children's Hospital and Children's Hospital Physicians Group
Michael S Irish, MD is a member of the following medical societies: International Pediatric Endosurgery Group and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Philip M Bovet, DO, MPH, Resident, Department of Pediatric Surgery, Blank Children's Hospital
Philip M Bovet, DO, MPH is a member of the following medical societies: American Academy of Osteopathy and American College of Osteopathic Pediatricians
Disclosure: Nothing to disclose.

Medical Editor

Denis Bensard, MD, Director, Pediatric Trauma, Division of Pediatric Surgery, Children's Hospital of Denver; Associate Professor, University of Colorado Health Sciences Center
Denis Bensard, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Surgeons, American Pediatric Surgical Association, Association for Academic Surgery, and Society of University Surgeons
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Gail E Besner, MD, Professor of Surgery and Pediatrics, Department of Surgery, Ohio State University College of Medicine and Public Health; Director, Pediatric Surgical Research, Department of Surgery, Children's Hospital
Gail E Besner, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Burn Association, American College of Surgeons, American Gastroenterological Association, American Medical Association, American Medical Women's Association, American Pediatric Surgical Association, Association for Academic Surgery, Federation of American Societies for Experimental Biology, Society of Critical Care Medicine, Society of Surgical Oncology, and Society of University Surgeons
Disclosure: Nothing to disclose.

CME Editor

H Biemann Othersen Jr, MD, Professor of Surgery and Pediatrics, Emeritus Head, Division of Pediatric Surgery, Medical University of South Carolina
H Biemann Othersen Jr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association for the Surgery of Trauma, American Burn Association, American Cancer Society, American College of Surgeons, American Medical Association, American Pediatric Surgical Association, American Society for Parenteral and Enteral Nutrition, American Surgical Association, American Thoracic Society, British Association of Paediatric Surgeons, Pediatric Oncology Group, Society for Surgery of the Alimentary Tract, Society of Critical Care Medicine, South Carolina Medical Association, Southeastern Surgical Congress, Southern Medical Association, Southern Society for Pediatric Research, and Southern Thoracic Surgical Association
Disclosure: Nothing to disclose.

Chief Editor

Marleta Reynolds, MD, Professor of Surgery, Feinberg School of Medicine, Northwestern University; Interim Head, Division of Pediatric Surgery, Department of Surgery, Children's Memorial Hospital of Chicago
Marleta Reynolds, MD is a member of the following medical societies: American Pediatric Surgical Association
Disclosure: Nothing to disclose.

 
 
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