ALTERATIONS OF DIGESTIVE FUNCTION IN CHILDREN

Cleft Lip and Cleft Palate

Cleft lip (harelip) and cleft palate are developmental anomalies of the first branchial arch (Figure 40-1). The incidence of cleft lip with or without cleft palate is estimated at 10.48 per 10,000 live births; the incidence of cleft palate only is 6.39 per 10,000 live births.¹ Incidence is lower in black populations and higher in Asian populations.² Cleft lip, with or without cleft palate, is more common in females. Both anomalies can be unilateral or bilateral, partial or complete and may also be associated with other malformations.³ Nonsyndromic cleft lip and/or palate is a malformation with an incomplete separation between nasal and oral cavities without any associated anomaly and is associated with a number of different genes.⁴

In most cases, cleft lip and cleft palate are caused by multiple gene-environmental interactions, including maternal deficiency of B vitamins (B₆, folic acid, and B₁₂), maternal tobacco⁵ and alcohol use, maternal diabetes mellitus, and genetic variations of several biomolecules including transforming growth factor, interferon regulatory factor-6, fibroblast growth factor, and other growth factors.^6–9 (This phenomenon, called multifactorial inheritance, is discussed in Chapter 4.) Maternal hyperhomocysteinemia also may be a factor associated with orofacial clefts.¹⁰ Together these factors reduce the amount of neural crest mesenchyme that migrates into the area that will develop into the face of the embryo. If the amount is sufficiently reduced, clefting occurs.

PATHOPHYSIOLOGY

Pyloric Stenosis

Pyloric stenosis is an obstruction of the pyloric sphincter caused by hypertrophy of the sphincter muscle. It is one of the most common disorders of early infancy and affects infants between the ages of either 1 and 2 weeks or 3 and 4 months.²⁶ The incidence of pyloric stenosis among males is approximately 5 in 1000, whereas among females it is only 1 in 1000. Whites are affected more often than blacks or Asians, and full-term infants are affected more often than premature infants.²⁷ The cause is unknown but increased gastrin secretion by the mother in the last trimester of pregnancy increases the likelihood of pyloric stenosis in the infant. The overproduction of gastric secretions in the infant may be caused by stress-related factors in the mother. Exogenous administration of prostaglandin E is associated with an increased incidence of pyloric stenosis. There is an increased incidence of pyloric stenosis in children with Down syndrome; 6.9% of children have a parent who had pyloric stenosis, and 4.9% have a close relative that is affected.^28,29 Pyloric stenosis occurs in approximately 20% of male and 10% of female descendants of mothers who had pyloric stenosis.³⁰

PATHOPHYSIOLOGY The circular muscle of the pylorus is grossly enlarged because of an increase in cell size (hypertrophy) and an increase in cell number (hyperplasia).³¹ Research has shown that transforming growth factor-alpha plays a role in stimulating this increase in muscle mass.³² The mucosal lining of the pyloric opening is folded and the lumen is narrowed by the encroaching muscle. Because of the extra peristaltic effort necessary to force the gastric contents through the narrow pylorus, the muscle layers of the stomach may become hypertrophied as well.

CLINICAL MANIFESTATIONS Between 2 and 3 weeks after birth, an infant who has fed well and gained weight begins to vomit without apparent reason. The vomiting gradually becomes more forceful. In some cases, stomach contents may shoot out 3 or 4 feet. Food is often regurgitated through the nose. The forceful, or projectile, vomiting usually occurs immediately after eating, and the vomitus consists of the bulk of the feeding plus some food retained from previous feedings but is almost always free of bile. Usually infants are hungry and want to eat again after vomiting.³³

Prolonged retention of food in the stomach is a characteristic feature of pyloric stenosis and food is present after 4 hours unless vomiting has occurred. Constipation is the rule because not much food reaches the intestine.

In severe untreated cases, increased gastric peristalsis and vomiting lead to severe fluid and electrolyte imbalances (hypochloremic metabolic alkalosis), chronic malnutrition, and weight loss that can be fatal within 4 to 6 weeks. Infants with pyloric stenosis are irritable because of hunger, and they may have esophageal discomfort caused by repeated vomiting and esophagitis. The vomitus may be blood streaked because of rupture of gastric and esophageal vessels.

EVALUATION AND TREATMENT Diagnosis is based on the history of clinical manifestations. Occasionally, gastric peristalsis is observable over the abdomen. A firm, small, movable mass, approximately the size of an olive, is felt in the right upper quadrant in 70% to 90% of infants with pyloric stenosis. A visible gastric peristaltic wave after eating is observed in some infants. Sonography is routinely done because this clearly shows the hypertrophied pyloric muscles and narrowed pyloric channel.³⁴

The standard treatment for hypertrophic pyloric stenosis is a pyloromyotomy, in which the muscles of the pylorus are split and separated. The procedure can be completed with an open technique or with laparoscopy.³⁵ The mortality rate associated with surgical correction is less than 0.5%.

Intestinal Malrotation

During the tenth week of embryonic development, the emerging ileum and cecum normally rotate, so that the cecum moves into the lower right quadrant of the abdomen and is fixed there by the mesentery. Intestinal malrotation is a condition in which rotation does not occur and the colon remains in the upper right quadrant, where an abnormal membrane may press on and obstruct the duodenum. The obstructing band over the duodenum, called a periduodenal band, is one of the most significant findings in malrotation. Associated abnormalities are seen in 30% to 62% of children in a reported series; 50% of children with duodenal atresia and 33% of those with jejunal atresia have associated malrotation.³⁶

PATHOPHYSIOLOGY The small intestine lacks a normal posterior fixation in malrotation because it has only a rudimentary attachment near the origin of the superior mesenteric artery. Therefore, the entire mass can twist when the mobile loops of intestine from the duodenojejunal junction to the middle of the transverse colon twist on themselves. The twisting is termed volvulus. Intestinal twisting around the rudimentary mesentery angulates and obstructs the intestinal lumen and partly or completely occludes the superior mesenteric artery, causing infarction and necrosis of the entire midgut.

CLINICAL MANIFESTATIONS Although most cases of malrotation-associated volvulus and infarction develop during the neonatal period (50%) or infancy (85% are younger than 1 year), some develop during childhood or even adulthood.³⁷ In infants the obstruction causes intermittent or persistent bile-stained vomiting after feedings. Abdominal distention is limited initially to the epigastrium because only the stomach and duodenum are dilated. The degree of distention depends on the pressure of swallowed air and the degree of obstruction caused by the volvulus. Dehydration and electrolyte imbalance may occur rapidly because large amounts of pancreatic juice, bile, and gastric secretions are lost through vomiting. Fever usually ensues. Pain, scanty stools, diarrhea, and bloody stools are associated with progressive volvulus, vascular compression, and infarction of the intestine in infants. Intermittent or partial volvulus may be seen in older children and adults. This may be asymptomatic (25% to 50% of the time) and discovered during unrelated abdominal surgery, or it may cause minor abdominal complaints, such as nausea after meals, recurrent episodes of vomiting, or abdominal pain.³⁸

EVALUATION AND TREATMENT Diagnosis of malrotation with volvulus and infarction is based on a review of the clinical manifestations. X-ray films of the abdomen show gas bubbles and distention proximal to the site of obstruction.

Treatment consists of opening the abdomen and reducing the volvulus manually. Necrotic bowel is resected and a primary anastomosis performed. An enterostomy may be created. In cases of malrotation without duodenal obstruction, the operative survival rate is 80%. The operative survival rate is 40% to 50% in cases of malrotation complicated by obstruction caused by periduodenal bands or other intra-abdominal anomalies. Resection of large segments of the small intestine results in short-bowel syndrome and its long-term sequelae.

Meconium Ileus

Meconium is a substance that fills the entire intestine before birth. It consists of intestinal gland secretions and some amniotic fluid. Normally, meconium is passed from the rectum during the first 12 to 72 hours after birth.

Meconium ileus is intestinal obstruction caused by meconium formed in utero that is abnormally sticky and adheres firmly to the mucosa of the small intestine, resisting passage beyond the terminal ileum. The cause is usually a lack of digestive enzymes during fetal life. This meconium is also found to contain albumin, which is not normally found in meconium. The detection of albumin in meconium has been used as a screening test for cystic fibrosis.³⁹ Neonatal meconium ileus occurs in 15% of newborns with cystic fibrosis.⁴⁰ Partial aplasia of the pancreas is an associated factor, however, and one fifth of infants with meconium ileus are premature or have a history of maternal hydramnios (excessive amniotic fluid). After intestinal atresia and malrotation with volvulus, meconium ileus is the most common cause of small intestinal obstruction in newborns.

PATHOPHYSIOLOGY The terminal ileum is plugged with thick, viscous meconium resulting from the formation of an insoluble, calcium-glycoprotein compound in abnormal mucus. The segment of the ileum proximal to the obstruction is distended with liquid contents, and its walls may be hypertrophied. The segment distal to the obstruction is collapsed and filled with small pellets of pale-colored stool. Meconium in the obstructed segment has the consistency of thick syrup or glue. Peristalsis fails to propel this viscous material through the ileum, so it becomes impacted. Volvulus, atresia, or perforation of the bowel sometimes accompanies meconium ileus.

CLINICAL MANIFESTATIONS Abdominal distention usually develops during the first few days after birth. The infant does not pass meconium and begins to vomit within hours or days of birth. Infants with cystic fibrosis may have signs of pulmonary involvement, such as tachypnea, intercostal retractions, and grunting respirations. The distended abdomen shows patterns of dilated intestinal loops that feel doughlike when palpated. Some of the loops contain scattered, firm, movable masses. Despite hyperactive peristalsis, the rectal ampulla is empty.

EVALUATION AND TREATMENT Radiologic examination is used to confirm the presence of meconium ileus.⁴¹ The sweat test, which is accurate in 90% of infants, is performed to detect or rule out cystic fibrosis. The treatment of choice for cases not complicated by volvulus or perforation is a hyperosmolar enema done using fluoroscopy to evacuate the meconium. Although the success of this technique has not correlated with osmolality of the enema, the overall success rate is higher when metglutamine diatrizoate (Gastrografin) is used or when additives, such as polysorbate 80 (Tween 80) and acetylcysteine (Mucomyst), are used.⁴² Enterotomy and irrigation are reserved for complicated cases and enema failures.

Survival of infants with meconium ileus is improving, with a 97% to 98% survival rate at 1 year.⁴³ The mortality rate increases to 70% if obstruction is complicated by peritonitis. After recovery from neonatal meconium ileus, the long-term outlook depends on the severity and progression of pulmonary disease. Recent research demonstrates a clear association of meconium ileus with poor long-term nutritional outcomes in children with cystic fibrosis related to surgical treatment for the ileus and poor essential fatty acid status.⁴⁴

Distal Intestinal Obstruction Syndrome

Distal intestinal obstruction syndrome (DIOS), formerly called meconium ileus equivalent, affects approximately 15% of children and adults with cystic fibrosis.⁴⁵ Intestinal contents may become abnormally thick and impact the intestinal lumen, particularly after episodes of dehydration or lack of pancreatic enzymes. Use of high-strength pancreatic enzymes has been implicated in formation of strictures of the ascending colon in children with cystic fibrosis and resultant chronic DIOS.⁴⁶ The child displays signs and symptoms of intestinal obstruction. In most cases the obstruction is relieved by hypertonic enemas. Meconium ileus and DIOS have been shown to be risk factors for the development of liver disease and other abdominal manifestations in those with cystic fibrosis.⁴⁷

Obstructions of the Duodenum, Jejunum, and Ileum

Congenital obstruction of the duodenum can be caused by intrinsic malformations or external pressure. Intrinsic obstruction is caused by failure of the duodenum to become patent. The obstruction may be partial or complete and usually is located at or near the major duodenal papilla. Extrinsic obstructions can be caused by peritoneal bands that constrict the duodenum. The duodenum can be obstructed by an annular pancreas—a defect in which the head of the pancreas surrounds part of the duodenum. Congenital obstructions of the jejunum and ileum can be attributable to atresia, stenosis, meconium ileus, megacolon (Hirschsprung disease), intussusception, Meckel diverticulum, intestinal duplication, or strangulated hernia.

In ileal atresia or jejunal atresia, the intestine ends blindly proximal and distal to an interruption in its continuity, with or without a gap in the mesentery. Stenosis (narrowing of the lumen) causes dilation proximal to the obstruction and luminal collapse distal to it.

Congenital Aganglionic Megacolon

Congenital aganglionic megacolon (Hirschsprung disease) is a functional obstruction of the colon caused by the absence of the enteric ganglia along a variable length of the colon with inadequate motility. The incidence is 1 in 5000 live births with an increased incidence in males, siblings of children with Hirschsprung disease, and children with Down syndrome.⁴⁸ The exact cause is unknown but multiple interacting factors and a complex inheritance pattern that involves the RET proto-oncogene have been found.⁴⁹

PATHOPHYSIOLOGY Congenital aganglionic megacolon is caused by a malformation of the parasympathetic nervous system. It is characterized by abnormalities of the basement membrane and extracellular matrix and absence of the intramural ganglion cells in the enteric nerve plexuses (Meissner and Auerbach plexuses) along variable lengths of the colon.⁵⁰ Lacking neural stimulation, the muscle layers of the colon wall fail to propel feces through the colon, leading to functional obstruction. In 80% of cases the aganglionic segment is limited to the rectal end of the sigmoid colon; in 3% the entire colon lacks ganglion cells. The abnormally innervated colon impairs fecal movements, causing the proximal colon to become distended, hence the term megacolon (Figure 40-3).

The ganglia normally develop from an advancing neural crest between the muscle layers (tunica muscularis) in the submucosal area (muscularis mucosae) of the intestinal wall. In cases of congenital megacolon, neurologic development is blocked and large, nonmyelinated fibers develop in place of these ganglion cells.⁵⁰ The segment of colon that lacks ganglion cells has a relatively normal lumen caliber and wall thickness. In the segment of the colon proximal to it, the lumen is dilated and the muscle hypertrophied. Therefore, the abnormal portion of the colon appears to be normal and the normal portion appears to be diseased.

CLINICAL MANIFESTATIONS The extent of the aganglionic portion of the colon determines the severity of the symptoms of congenital aganglionic megacolon. The most distal part of the rectum is always involved. This is the extent of the aganglionic portion in some children, and the child is said to have “ultrashort-segment” Hirschsprung disease and generally has only mild constipation as a symptom. These individuals may not be diagnosed until adulthood.⁵¹ Symptoms of constipation, poor feeding, poor weight gain, and progressive abdominal distention increase in severity as the aganglionic portion extends proximally. Diarrhea may be the first sign, however, because only water can travel around the impacted feces.

The most serious complication in the neonatal period is enterocolitis related to fecal impaction. Bowel dilation stretches and partly occludes the encircling blood and lymphatic vessels, causing edema, ischemia, infarction of the mucosa, and significant outflow of fluid into the bowel lumen. Copious, liquid stools result. Infarction and destruction of the mucosa enable enteric microorganisms to penetrate the bowel wall. Frequently, gram-negative sepsis occurs, accompanied by fever and vomiting. Severe and rapid electrolyte changes may take place, causing collapse and rapid death.

EVALUATION AND TREATMENT Anorectal manometry and rectal suction biopsy are the most reliable screening tools for the diagnosis of Hirschsprung disease. Serial manometry measurements may be required in neonates.⁵² This test has uncovered ultrashort-segment Hirschsprung disease in older children with a history of constipation.⁵³ The definitive diagnosis is made by rectal suction biopsy showing an absence of ganglion cells in the submucosa of the colon.⁵⁴ X-ray films show dilated loops of colon, and contrast films show aganglionic areas. The infant usually cannot expel the barium.

The involved segment is resected within the first few months of life. For children with short-segment Hirschsprung disease, enemas are given to relieve impaction, and laxatives with a dietary and bowel training program are used in preference to surgical intervention.⁵³ The child is not treated for diarrhea.

After surgery, enterocolitis sometimes recurs. If the postoperative enterocolitis is allowed to persist, pseudopolyps may appear. Because these are essentially identical to the lesions of ulcerative colitis, they have malignant potential. Therefore, a colectomy is indicated if pseudopolyps develop.

In general, the prognosis of congenital megacolon is satisfactory for children who undergo surgical treatment. Bowel training may be prolonged, but most children achieve bowel continence before puberty.⁵⁵

Anorectal Malformations

Several congenital malformations of anorectal structures can obstruct the passage of feces. The incidence of minor abnormalities is approximately 1 in 500 and that of major anomalies is approximately 1 in 5000.

Congenital anorectal malformations range from mild anal stenosis, which is corrected by simple dilation, to complex deformities, such as anal or rectal agenesis, atresia, and rectourethral fistula (Figure 40-4). Deformities that cause complete obstruction are known collectively as imperforate anus.

Approximately 40% of infants with anorectal malformations have other developmental anomalies as well. The most commonly associated major anomalies are Down syndrome, congenital heart disease, renal and urologic abnormalities, cryptorchidism, esophageal atresia, and malformations of the spine.⁵⁶

Imperforate anus may not be obvious. It can be detected by gentle insertion of a rectal tube. X-ray films show dilations throughout the intestinal tract. Anal stenosis can be treated by dilations, but all other anorectal malformations require surgical correction. The overall mortality rate is approximately 10%. More than 90% of children with a low (anal) anomaly and intact sacrum achieve bowel continence; however, less than 30% of those with very high anomalies or anomalies associated with genitourinary fistulae achieve continence.⁵⁷

Intussusception

The most common cause of acquired intestinal obstruction in infants is intussusception. Intussusception is the telescoping or invagination of one portion of the intestine into another. Usually, the ileum invaginates the cecum and part of the ascending colon by collapsing through the ileocecal valve. Intussusception involving the ileum and colon (ileocolic intussusception) accounts for 80% to 90% of intestinal obstructions in infants and is two to three times more common in males than in females.⁵⁸ Most intussusceptions occur before 1 year of age, most commonly between 4 and 7 months. Intussusception is rare in infants younger than 3 months and is infrequent after 36 months. Intussusception has occurred in children of all ages recovering from abdominal surgery; intussusception has been found in children with cystic fibrosis and symptoms of bowel obstruction that were initially misdiagnosed as having distal intestinal obstruction syndrome (meconium ileus equivalent).^59,60

PATHOPHYSIOLOGY Most commonly, the proximal portion of the intestine, the intussusceptum, collapses into the distal portion, the intussuscipiens, in the direction of peristaltic flow (Figure 40-5). As it does so, the intussusceptum drags its mesentery into the enveloping lumen. Initially, the mesentery is constricted, obstructing venous return. Compression of the mesenteric vessels between the two layers of intestinal wall and at the U-shaped angle at either end of the intussusceptum leads within hours to venous stasis, engorgement, edema, exudation, and further vascular compression. Unless the intussusception is treated, bleeding and gangrene ensue. The tension of the mesentery on the intussusceptum tends to arch the bowel in a curve with its center at the mesenteric root. Edema and compression obstruct the flow of chyme through the intestine.

CLINICAL MANIFESTATIONS The affected infant suddenly develops abdominal pain, becomes irritable (colicky), and draws up the knees. Vomiting occurs soon afterward. A single normal stool may be passed, evacuating the colon distal to the apex of the intussusception. After that, 60% of infants pass “currant jelly” stools, which appear dark and gelatinous because of their blood and mucus content. In one study, less than one third of children had this clinical triad of vomiting, colicky abdominal pain, and bloody stools.⁶¹ Most infants have a tender, sausage-shaped abdominal mass. Abdominal tenderness and distention develop as intestinal obstruction becomes more acute.⁶²

EVALUATION AND TREATMENT Diagnosis is based on clinical manifestations and onset of symptoms. Ultrasound of the abdomen, computed tomography (CT) and magnetic resonance imaging (MRI) are commonly completed for diagnosis.⁶³ More than 82% of children have positive ultrasound results in ileocolic and jejunointestinal intussusception. Reduction is an emergency procedure involving hydrostatic pressure generated by an air or a barium enema given using fluoroscopic guidance.⁶⁴ This technique is successful 45% to 90% of the time. A potential complication of enema reduction is bowel perforation, and for this reason the use of air rather than barium is favored.⁶⁵ Surgical reduction is done on children who fail or are not candidates for hydrostatic reduction. Untreated intussusception in infants is nearly always fatal. Most infants recover if the intussusception is reduced within 24 hours.⁶⁶ Spontaneous reduction of intussusception may occur in symptomatic or asymptomatic children and occurs more commonly than previously reported. These intussusceptions are usually short-segment, small-bowel intussusceptions with no recognizable lead point.⁶⁷ Recurrent intussusception is more common after nonsurgical reduction than after surgical reduction. Risk of recurrence cannot be predicted by initial features or symptoms, and children with recurrent intussusception may exhibit fewer symptoms with a shorter interval to bowel necrosis and perforation.⁶⁸

Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is common in children and involves dilation of the esophagus and intrusion of acid contents into it; GERD is believed to be related to relaxation or incompetence of the lower esophageal sphincter (see Chapter 39). In newborns, reflux is normal because neuromuscular control of the gastroesophageal sphincter is not fully developed. The frequency of reflux is highest in premature infants and decreases during the first 6 to 12 months of life.

GERD is thought to be a factor in the stimulation of reactive airway disease and otitis media with effusion in some children.^69,70 Reflux also is thought to be a contributing cause in apparent life-threatening events and a significant problem for children with cerebral palsy and cystic fibrosis.^71–74 The relationship between apnea of prematurity and GERD is controversial.^75,76

PATHOPHYSIOLOGY Delayed maturation of the lower esophageal sphincter or impaired hormonal or neurotransmitter response mechanisms (i.e., vasoactive intestinal peptide and nitric oxide) are possible causes of inappropriate sphincter relaxation. Factors that maintain lower esophageal sphincter integrity in children include location of the gastroesophageal junction in a high-pressure zone within the abdomen, mucosal gathering within the sphincter, and the angle at which the esophagus is inserted into the stomach. Reflux persists if any of these pressure-maintaining factors is altered. Irritation of the mucosa by acidic gastric contents results in deterioration of the esophageal epithelium and stimulation of the vomiting reflex.^77,78

Eosinophilic esophagitis also occurs in children (see Chapter 39). It is thought to be an atopic disease involving immediate as well as delayed hypersensitivity reactions to food ingestion. An eosinophilic infiltrate is associated with inflammation of the entire esophagus that is nonresponsive to acid-suppression therapy.⁷⁹ Dysphagia, food impaction, and vomiting are common symptoms and other atopic diseases, such as asthma and eczema, may be present. Treatment includes elimination diets and corticosteroids.⁸⁰ The eosinophilic inflammation may lead to progressive subepithelial fibrosis with esophageal strictures, narrowing, and dysphagia.⁸¹

CLINICAL MANIFESTATIONS The signs and symptoms of GERD are caused by exposure of the esophageal epithelium to refluxed gastric contents. Eighty-five percent of affected infants vomit excessively during the first week of life and usually have other symptoms by 6 weeks.

Vomiting may be forceful and must be differentiated from pyloric stenosis. Aspiration pneumonia develops in one third of infants with gastroesophageal reflux (GER). In cases that persist into childhood, chronic cough, wheezing, and recurrent pneumonia are common.^82,83 Repeated vomiting leads to inadequate retention of nutrients, adversely affecting growth and weight gain. Esophagitis from exposure of the esophageal mucosa to acidic gastric contents is manifested by pain, bleeding, and eventually stricture formation and abnormal motility. Approximately 10% to 25% of children with GERD also have iron deficiency anemia caused by frank or occult blood loss.

EVALUATION AND TREATMENT The clinical manifestations are often adequate to confirm a diagnosis of GERD. Esophageal pH monitoring with a probe for 24 hours and endoscopy are routinely used for diagnosis.⁸⁴

Mild GER resolves without treatment. Maintaining infants in a flat prone or a left lateral position, particularly during and for the first hour after a feeding, results in fewer or shorter episodes of GER.⁸⁵ Infants with GER are excepted from the Academy of Pediatrics recommended sleep position for healthy infants to decrease the risk of sudden infant death syndrome (SIDS).⁸⁶ Older infants and children achieve better results in an upright (sitting or standing) position while awake, with prone positioning used for sleeping.⁸⁷ Thickened feedings may help some infants⁸⁸; however, this has not been shown to be consistently helpful. For some infants, thickened feedings may actually worsen reflux by causing a delay in gastric emptying time. Small, frequent feedings and frequent burping are generally universally accepted strategies for managing reflux.²⁹ Medications to increase motility, increase lower esophageal sphincter pressure, or decrease gastric acid production have been used to treat GERD. If no improvement is seen with medical management or the child has life-threatening events with reflux, an antireflux surgical procedure, including gastropexy and fundoplication, is performed. A fundoplication re-creates a valve by wrapping the fundus of the stomach around the lower esophagus.⁸⁹

Cystic Fibrosis

Cystic fibrosis (CF) of the pancreas, which is also called mucoviscidosis or fibrocystic disease of the pancreas, is a genetically transmitted disease (mutation of the long arm of chromosome 7) that involves many organs and systems and usually causes death in childhood or young adulthood. It is the most common cause of chronic suppurative lung disease in children and is the most common life-threatening inherited disease in the white population. This section focuses on the deficiency of pancreatic enzymes. (Chapter 34 discusses the pulmonary consequences of cystic fibrosis.)

PATHOPHYSIOLOGY The pathophysiologic triad that is the hallmark of CF includes (1) pancreatic enzyme deficiency, which causes maldigestion; (2) overproduction of mucus in the respiratory tract and inability to clear secretions, which cause progressive chronic obstructive pulmonary disease; and (3) abnormally elevated sodium and chloride concentrations in sweat. Exocrine secretions tend to be abnormally thick and precipitate in the glandular ducts, obstructing flow. Almost all clinical manifestations of CF are a result of overproduction of extremely viscous mucus and pancreatic enzyme deficiency. The full spectrum of involvement is summarized in Table 40-1.

Pancreatic function may range from normal to completely ablated. Approximately 85% of patients have pancreatic insufficiency. Obstruction of the pancreatic ducts with thick mucus blocks the flow of pancreatic enzymes and causes degenerative and fibrotic changes in the pancreas. Pancreatic damage eventually can affect the beta cells, resulting in diabetes mellitus in some children. The incidence of diabetes mellitus and cirrhosis in this population has increased as larger numbers of people with cystic fibrosis have moved into young and middle adulthood. Severe problems with maldigestion of proteins, carbohydrates, and fats occur because of insufficient secretion of pancreatic enzymes.⁹⁰

CLINICAL MANIFESTATIONS Clinical manifestations are presented in Table 40-1.

EVALUATION AND TREATMENT To determine the extent of pancreatic function 72-hour stool fat measurements are used. Stools also may be examined for absence of pancreatic enzymes, particularly fecal elastase, trypsin, and chymotrypsin. To optimize treatment, the carbon-13 (¹³C) mixed triglyceride breath test offers a simple, noninvasive way of assessing the need for pancreatic enzyme supplementation in children with cystic fibrosis.⁹¹ Pancreatic replacement enzymes are administered before or with meals and high-calorie, high-protein diets with frequent snacks and vitamin supplements are used to treat the malnutrition. However, anorexia is not uncommon in this group secondary to pulmonary disease and frequently large sputum output. To combat the worsening problem of growth failure in children with cystic fibrosis, nasogastric or gastrostomy tube feedings are used to supplement oral intake and promote weight gain. Monitoring of growth and body mass index is critical to treatment evaluation.^92,93

Gluten-Sensitive Enteropathy

Gluten-sensitive enteropathy, formerly called celiac sprue or celiac disease, is an autoimmune disease that damages the small intestinal villous epithelium when there is ingestion of gluten (gliadin), the protein component of cereal grains. The gluten in wheat, rye, barley, and oats is toxic to the intestinal epithelial cells of genetically susceptible individuals.⁹⁴ The disease occurs largely in whites and has been documented in Asians from India and Pakistan, but it is almost nonexistent in native Africans, Japanese, and Chinese. Prevalence rates in Europe range from 1 in 1000 to 1 in 3000. Recent data suggest that gluten-sensitive enteropathy, traditionally considered rare in the United States, occurs in about 1% of the population or 1 in 100 children.⁹⁵ Other autoimmune diseases have been associated with gluten-sensitive enteropathy including type 1 diabetes mellitus and autoimmune thyroiditis.⁹⁶

The pathogenesis appears to require interaction between a number of intrinsic factors (genetic susceptibility, activation of the immune system) and extrinsic factors (gluten and possibly other environmental factors). Cellular immunity as well as humoral immunity are implicated. There are increases in the percentages of T cells, immunoglobulin, and complement in the mucosa of active celiac disease. Immunoglobulin A (IgA) and immunoglobulin M (IgM) antigliadin antibodies have been found in jejunal fluid of persons with untreated disease.⁹⁷ Autoantibody reactivity to transglutaminase-2 (TG-2) has been shown to closely correlate with the acute phase of the disease.⁹⁸ Although gluten-sensitive enteropathy is widely perceived as a malabsorption syndrome of childhood, the diagnosis is increasingly being made for the first time in adult life.⁹⁹

PATHOPHYSIOLOGY The major pathophysiologic characteristics of the disease are atrophy and flattening of villi in the upper small intestine and malabsorption of most nutrients in the presence of cereal gluten (Figures 40-6 and 40-7). The atrophy is caused by accelerated shedding of epithelial cells from the villi. To compensate for this loss, epithelial cell production increases, causing hypertrophy of the crypts of Lieberkühn.¹⁰⁰ Increased cell production is not sufficient to keep pace with cell loss, however. Inflammation and edema develop around the enlarged cysts. The villi shorten and atrophy, and their surface cells are not mature enough to sustain absorptive functions. The microvilli and brush border disappear, leaving patches of bald mucosa. The loss of mucosal surface area and brush-border enzymes leads to severe malabsorption. The pathologic process is most pronounced in the duodenum and jejunum. The ileum may be spared. The severity of disease correlates with the length of the small intestinal mucosa involved.

Damage to the mucosa of the duodenum and jejunum has secondary effects that exacerbate malabsorption. The secretion of intestinal hormones, such as secretin and cholecystokinin, may be diminished. Because these chemical messengers are scarce, secretion of pancreatic enzymes and expulsion of bile from the gallbladder decrease.

Destruction of mucosal cells causes inflammation, and water and electrolytes are secreted, leading to watery diarrhea. In addition, absorption that normally occurs by sodium-dependent active transport or facilitated diffusion is impaired. Carbohydrates, amino acids, dipeptides, water-soluble vitamins, bile salts, and cations are not absorbed from the intestinal lumen. Potassium loss, which is more severe than sodium loss, leads to muscle weakness. Magnesium and calcium malabsorption can cause seizures or tetany. Unabsorbed fatty acids combine with calcium, and secondary hyperparathyroidism increases phosphorus excretion, resulting in bone reabsorption. Calcium is no longer available to bind oxalate in the intestine and is absorbed, which causes hyperoxaluria. Gallbladder function may be abnormal, and bile salt conjugation may be decreased.

Fat malabsorption in the jejunum is the major cause of steatorrhea (fatty stools). Malabsorption may be mild early in the disease. Fecal nitrogen is elevated because peptidase deficiencies impair protein absorption. Pancreatic function is decreased, not only because of decreased hormonal levels but also because of malnutrition.

Deficiencies of fat-soluble vitamins are common in children with gluten-sensitive enteropathy. Vitamin K malabsorption leads to hypoprothrombinemia. In one third of cases, iron and folic acid malabsorption is manifested as cheilosis; anemia; and a smooth, red tongue. Vitamin B₁₂ absorption is impaired in those with extensive ileal disease. Because the absorption of folate and iron is greatest in the proximal small intestine, deficiencies of these substances are common.

CLINICAL MANIFESTATIONS The onset of clinical manifestations of gluten-sensitive enteropathy depends on the age of the infant when gluten-containing substances are added to the diet. In 50% of affected children, onset occurs by 18 months of age, with latent intervals varying from months to years. Severity of symptoms can vary tremendously, and many children older than 3 years of age present with non-gastrointestinal symptoms.¹⁰¹

Diarrhea is an early sign in most infants accompanied by failure to thrive and anemia. The stools are pale, bulky, greasy, and foul smelling, and may contain oil droplets. Three to five such movements occur daily. As early as 3 or 4 months of age, growth failure, anorexia, and constipation can begin. In older children constipation is occasionally seen despite steatorrhea. Vomiting and abdominal pain are prominent in infants but unusual in older children. Anorexia is prevalent. The classic physical manifestations of organic failure to thrive, such as abdominal protuberance, wasted buttocks and limbs, and hypotonia, occur in less than 50% of infants with gluten-sensitive enteropathy. Growth is usually diminished.¹⁰²

Manifestations of malabsorption, such as rickets, tetany, frank or occult bleeding, or anemia, may be obvious. Some children urinate more at night. The tongue is smooth and red, and the child may bruise and bleed easily. Hypomagnesemia and hypocalcemia cause irritability, tremor, convulsions, tetany, bone pain, osteomalacia, and dental abnormalities. If vitamin D deficiency is prolonged, rickets and clubbing of the terminal phalanges are likely. Eighty-six percent of older children have fingerprint changes (ridge atrophy). In older children, delayed puberty and infertility may be a manifestation of otherwise subtle gluten-sensitive enteropathy.¹⁰³ Osteomalacia may be severe.¹⁰⁴ Small intestinal lymphoma is also associated with gluten-sensitive enteropathy.¹⁰⁵

A rare complication of gluten-sensitive enteropathy in infancy is celiac crisis. Celiac crisis is characterized by severe diarrhea, dehydration, and hypoproteinemia as a result of malabsorption and protein loss and requires aggressive treatment.

EVALUATION AND TREATMENT Diagnosis includes confirmation with serologic antiendomysial or antitransglutaminase IgA antibodies as well as an intestinal biopsy to detect the classic mucosal changes caused by gluten-sensitive enteropathy.¹⁰⁶ The initial biopsy may be followed by a second intestinal biopsy to demonstrate regeneration of intestinal villi after treatment with a gluten-free diet. Most children with celiac disease remain undiagnosed.

Treatment consists of the immediate and permanent institution of a diet free of cereal grains (wheat, rye, barley, oats, malt). Lactose intolerance is presumed because of damage to the villi; therefore, lactose (milk sugar) is excluded from the diet. Tolerance to lactose improves with removal of gluten and healing of the mucosa and may be reintroduced at a later point.¹⁰⁷ Infants are routinely given vitamin D, iron, and folic acid supplements to treat deficiencies. Breast-feeding at the time of gluten introduction in the diet delays the appearance of celiac disease.¹⁰⁸

Approximately 25% of children experience recurrent relapses that interfere with growth. For most children, however, the long-term prognosis is excellent. There is an increased incidence of malignant disease, particularly T-cell lymphoma, in individuals who fail to respond to gluten-free diets.¹⁰⁹

Protein Energy Malnutrition

Kwashiorkor and marasmus are the two most common types of malnutrition in children. These disorders are known collectively as protein energy malnutrition (PEM). Both are states of long-term starvation (see Chapter 39). Kwashiorkor is a severe protein deficiency, and marasmus is a severe deficiency of all nutrients. Kwashiorkor is a widespread nutritional problem among children in developing countries and economically destitute populations particularly when associated with human immunodeficiency virus (HIV) infection.¹¹⁰ The disease usually occurs in infants or children from 1 to 4 years of age who have been weaned from breast milk to a high-starch, protein-deficient diet.

Marasmus can occur at any age, but it is common in children younger than 1 year. In marasmus, starvation is attributable to lack of protein and carbohydrates. One third of the world’s children suffer from PEM, with the highest concentrations in, Asia, Africa, Latin America, and the Carribbean.^111,112 The mortality risk for children in developing countries has been found to be inversely related to anthropometric indicators (height, weight, head circumference, skinfold thickness, midarm muscle circumference). There is elevated risk even in the mild to moderate range of malnutrition.¹¹³ Poor sanitation, early weaning of breast-fed infants, use of overdiluted commercial formulas, and infection (measles, malaria, pneumonia, HIV, and diarrheal disease) are major risk factors for PEM.

PEM is a complication of some diseases, such as chronic fever, tuberculosis, malignancy, digestive and malabsorptive disorders, and psychogenic illness. Radiation therapy and chemotherapy also can contribute to PEM. Acute and chronic malnutrition is common in hospitalized children in the United States and Europe. ¹¹⁴

PATHOPHYSIOLOGY In kwashiorkor, the deficit of dietary amino acids reduces protein synthesis in all tissues. Physical growth and mental growth are stunted, and maintenance of minimal life processes is in jeopardy. The lack of sufficient plasma proteins, particularly albumin, causes systemic pressure changes that result in generalized edema. The volume of total body water and extracellular fluid increases, causing a substantial loss of potassium. The liver swells with stored fat because no hepatic proteins are synthesized to form and release lipoproteins. Pancreatic atrophy and fibrosis may be present. Kwashiorkor also causes malabsorption, reduced bone density, and impaired renal function. If the condition is not reversed, the prognosis is very poor.

Because the intake of all dietary nutrients is reduced to a minimum in marasmus, metabolic processes, including liver function, are preserved but growth is severely retarded. Caloric intake is too low to support protein synthesis for growth or the storage of fat. If more protein is needed than is ingested, muscle wasting occurs. Fat wasting and anemia are common and can be severe. The volume of total body water is high. Serum triglyceride and phospholipid levels increase with increasing severity of malnutrition, but other serum values, such as cholesterol, are normal or slightly reduced. High fasting phospholipid and triglyceride concentrations are predictive of a poor prognosis for these children.¹¹⁵ Severe vitamin A deficiency contributes to blindness.¹¹⁶

CLINICAL MANIFESTATIONS Retarded physical, mental, and psychologic development; muscle wasting; diarrhea; dermatosis; low hemoglobin; and infection characterize marasmus. The presence of subcutaneous fat, hepatomegaly, and fatty liver distinguishes kwashiorkor from marasmus. These manifestations are missing in marasmus because caloric intake is not sufficient to support fat synthesis and storage.¹¹⁷

EVALUATION AND TREATMENT Evaluation of PEM is based on nutritional history and clinical manifestations. Providing deficient nutrients resolves clinical symptoms in 4 to 6 weeks. Physical and mental retardation may not be reversible, however. Nutritional rehabilitation with appropriate environmental stimulation for infants and young children resolves or improve cerebral shrinkage, physical growth, and psychomotor development.^118,119 Advances are being made in the local preparation of ready-to-use therapeutic food for both home- and community-based malnutrition management.¹²⁰

Failure to Thrive

Failure to thrive (FTT) is the inadequate physical development of an infant or a child. It is manifested as a deceleration in weight gain, a low weight/height ratio, or a low weight/height/head circumference ratio. FTT is a common problem and can present at any time in childhood.

PATHOPHYSIOLOGY Organic FTT has a pathophysiologic cause, such as GERD, pyloric stenosis, gastroenteritis, malabsorption syndromes, infection by intestinal parasites, congenital anomalies, very low birth weight, or chronic diseases of major body systems. All these factors either reduce the availability of nutrients for maintenance and growth or increase nutrient requirements, particularly when there is chronic infection. A chronic disease or congenital anomaly that causes weakness or reduced stature can create developmental, psychosocial, and emotional problems for the child.¹²¹

Nonorganic FTT occurs in the absence of any gastrointestinal, endocrine, or other chronic diseases. It is usually associated with psychosocial deprivation, although behavior problems may contribute to its occurrence in the absence of maternal pathologic findings. Behavioral and psychosocial problems may be compounded by inadequate economic resources and lack of knowledge. Generally the problem in nonorganic FTT is ineffective nurturing by parents and primary caregivers. A variety of parental stressors may be involved and include the following:

The first few postnatal months appear to be a sensitive period in the relationship between growth and mental development, suggesting a critical need for early diagnosis and aggressive interventions.^122,123

CLINICAL MANIFESTATIONS Clinical manifestations of organic FTT are restricted growth accompanied by manifestations of the underlying disease. Manifestations of nonorganic FTT are restricted growth plus reduced energy level, reduced responsiveness and interaction with the environment, social isolation, spasticity or rigidity when held or touched, inability to make eye contact or smile, refusal to eat, and rejection of foods. Weight loss and decelerated growth are accompanied by restricted development in many areas. Nonorganic FTT is a complex syndrome involving psychosocial, emotional, and parent-child problems that compound the pathophysiologic abnormalities.^124,125 Children with primarily organic FTT have been found to have lower developmental skills, and their parents have been found to have higher emotional distress. Infant stress, vomiting, feeding disorders, and psychosocial factors have been noted in children with organic and inorganic FTT making the distinction between the two complex.¹²⁶

EVALUATION AND TREATMENT Failure to thrive is suggested if a child falls below the third percentile on the growth curve or is falling off a previously established growth curve. Organic FTT is manifested in infancy by weight, height, and head circumference growth that may be parallel to but below the normal ranges. If no genetic, endocrine, or other systemic disorder is identified and if the physical and laboratory examinations show no abnormalities other than delayed growth, an environmental cause is indicated.

Hospital admission is recommended if the diagnosis is unclear or the child is in nutritional or emotional jeopardy. Eating patterns, food preferences, caloric intake, and family interactions can be assessed during the hospital stay. If the cause is environmental, the hospitalized child with FTT usually begins to gain weight.

If an organic problem has been identified, management of FTT consists of treating the cause. Management of nonorganic FTT involves the immediate total care of the child and measures to address (1) the psychosocial and emotional problems of the caregivers and (2) parent-child interactions. Counseling, parental modeling, and long-term family support are sometimes required.^127,128 Clinical manifestations of organic FTT have inorganic components in the majority of children. The most successful interventions not only treat the underlying organic cause but also address assisting parents with feeding practices and management of psychosocial symptoms.^129,130

Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is an ischemic, inflammatory condition of the bowel that causes necrosis, perforation, and death if untreated. It is the most common gastrointestinal emergency in the newborn. The overall mortality rate is between 12% and 30% and is higher for infants requiring surgery.¹³¹ The incidence of NEC is increasing, causing 1500 to 2000 infant deaths every year in the United States.¹³² Premature very-low-birth-weight infants are the most likely victims; it rarely occurs in full-term infants, but when it does it usually is a result of other complications.¹³³ The risk of NEC decreases as the gastrointestinal tract matures.

PATHOPHYSIOLOGY The exact etiology of NEC is unclear. Multiple factors probably contribute to the development of NEC including premature birth, immature immunity, immature intestinal motility and barrier function, abnormal bacterial colonization, infections, maternal age greater than 35 years, perinatal stress, effects of medications, feeding practices, and genetic predisposition.^131,134 The intestinal mucosal barrier in premature infants is scanty, which delays digestion. Motility is slower, allowing for the accumulation of noxious substances that damage the intestine and increase the risk for infection. Immaturity of the intestinal mechanical and biochemical barrier contributes to increased permeability resulting in translocation of bacteria and other substances, causing injury, inflammation, and development of systemic inflammatory disease.¹³⁵ Preterm infants also may have immature intestinal innate immunity and an unfavorable balance between commensal and pathogenic bacteria, promoting intestinal inflammation and release of proinflammatory mediators.¹³⁶

Reduced mucosal blood flow leading to hypoxic injury to intestinal mucosa is thought to be a cause. Normally there is a balance between vasodilator and vasoconstrictor inputs with a tendency toward vasodilation because of the copious production of endothelium-derived nitric oxide. With endothelial injury the balance is shifted toward endothelin-1–mediated vasoconstriction leading to ischemia, injury, and inflammation.¹³⁷ This injury allows bacterial invasion of the bowel wall and release of inflammatory mediators. Accumulation of gas in the mucosa and submucosa also can lead to ischemic inflammation and necrosis of intestinal segments. The terminal ileum and proximal colon are most often involved.¹³⁸

CLINICAL MANIFESTATIONS Manifestations of NEC usually appear within 2 weeks of birth, with earlier symptoms in full-term infants (5.3 days compared with 15.3 days in premature infants).¹³⁹ They range from mild abdominal distention to bowel perforation, sepsis, and death. Abdominal pain, unstable temperature, bradycardia, and apnea are nonspecific signs. Affected infants have abdominal distention, occult or grossly bloody stools, retained gastric contents, and septicemia with elevated white blood cell and falling platelet counts. The more premature the infant, the greater the incidence of NEC and related diseases of prematurity, such as respiratory distress syndrome and immunocompromise.

EVALUATION AND TREATMENT Diagnosis is based on clinical manifestations, laboratory results, and plain films of the abdomen that show gas accumulation in the intestine. Preventive strategies include breast milk feeding, judicious fluid management to prevent patent ductus arteriosus, administration of arginine and glutamine supplements and epidermal growth facor to support intestinal epithelial cell growth, and enteral probiotics to support commensal gut bacteria.^140,141 Treatments include cessation of feeding, gastric suction to decompress the intestines, fluid and electrolyte maintenance, and administration of antibiotics to control sepsis.¹⁴² Surgical resection is the treatment of choice for intestinal perforation, and the mortality rate is high. For very ill infants weighing less than 1000 g, peritoneal drainage may used as an adjunct to laparotomy.¹⁴³ Following treatment of NEC, infants treated by medical and surgical management are at risk for intestinal obstruction related to the development of strictures.¹⁴⁴ Infants who have extensive resection of necrotic bowel may develop short-bowel syndrome, requiring chronic total parenteral nutrition. Intestinal lengthening procedures and intestinal transplantation are available as a lifesaving option for these children.¹⁴⁵

Acute Diarrhea in Children

Infectious diarrhea in newborns is usually associated with nursery epidemics involving such pathogens as Escherichia coli, Klebsiella, staphylococci, Salmonella, and Shigella. Diarrhea caused by these agents has a rapid onset, and acidosis and shock can occur quickly. Clostridium difficile, often associated with previous antibiotic therapy, can cause acute, profuse, watery diarrhea and symptoms of colitis.¹⁴⁶ Viral causes of diarrhea include rotaviruses, noroviruses, astroviruses, and certain types of adenoviruses. Causes of diarrhea in young children are unknown in about 40% of cases.¹⁴⁷ True milk-protein allergy, which is uncommon, causes bloody, explosive stools after the introduction of milk into the diet.

Acute diarrhea in children is almost synonymous with acute viral or bacterial gastroenteritis. Viral gastroenteritis tends to be self-limiting. Bacterial gastroenteritis is treated with antibiotics if the causal pathogen can be identified. Other causes of acute diarrhea in the older child include antibiotic therapy, appendicitis, chemotherapy, inflammatory bowel disease, parasitic infestation, and ingestion of toxic substances.

Rotavirus, the leading cause of severe diarrhea in infants and young children, invades enterocytes of the intestinal mucosa and releases an enterotoxin that damages these cells. Damage decreases viable absorptive surface causing an imbalance of secretion and absorption and increases motility resulting in diarrhea and dehydration. Recovery from mucosal damage may take several weeks. Rotavirus is transmitted by the fecal-oral route among humans.¹⁴⁸ Two new live, oral, attenuated rotavirus vaccines were licensed in 2006 and appear safe to use for prevention of rotavirus infection without any increased risk of intussusception as occurred with the first rotavirus vaccine.¹⁴⁹ By 5 years of age most children have developed resistance to rotavirus infection.

Chronic Diarrhea in Children

Children with acute gastroenteritis often remain mildly symptomatic for up to 4 weeks; therefore, diarrhea that persists longer than 4 weeks is considered to be chronic. Children with chronic diarrhea can be divided into two groups: (1) otherwise well children whose growth is normal and (2) ill children whose growth is restricted. Causes of chronic diarrhea in the first group include abnormal colonic motility, lactose intolerance, encopresis, parasitic infestation, and antibiotic use.^150,151 Chronic diarrhea in the second group is usually caused by a disease that impairs absorption.

Neonatal Jaundice

Physiologic jaundice of the newborn is usually a transient, benign icterus that occurs during the first week of life in otherwise healthy full-term infants. Physiologic jaundice is caused by mild unconjugated (indirect-reacting) hyperbilirubinemia. Total serum bilirubin greater than 20 mg/dl or an indirect bilirubin greater than 15 mg/dl is considered pathologic jaundice. Risk factors include fetal-maternal blood type incompatibility (ABO and Rh incompatibility), prematurity, exclusive breast-feeding, maternal age greater than or equal to 25 years, male sex, delayed meconium passage, and excessive birth trauma such as bruising or cephalhematomas.¹⁵⁴ Hyperbilirubinemia is a risk with early hospital discharge (within 48 hours) because hyperbilirubinemia may not be evident prior to this time.¹⁵⁵

PATHOPHYSIOLOGY Physiologic jaundice results from the complex interaction of factors that cause (1) increased bilirubin production (e.g., hemolysis), (2) impaired hepatic uptake or excretion of unconjugated bilirubin, and (3) delayed maturation of liver conjugating mechanisms.¹⁵⁵ Unconjugated bilirubin is lipid soluble, bound to albumin in the blood, and in the free form readily crosses the blood-brain barrier in infants. Chronic bilirubin encephalopathy (kernicterus) is caused by the deposition of toxic, unconjugated bilirubin in brain cells and usually does not occur in healthy full-term infants. Elevated conjugated bilirubin in a sign of underlying disease. A late rising indirect bilirubin level also may be a manifestation of glucose-6-phosphate dehydrogenase deficiency, a hereditary X-linked genetic defect.^156,157 Elevated unconjugated bilirubin levels also can cause hemolysis, further increasing neonatal jaundice.¹⁵⁸

CLINICAL MANIFESTATIONS Physiologic jaundice develops during the second or third day after birth and usually subsides in 1 to 2 weeks in full-term infants and 2 to 4 weeks in premature infants. After this, increasing bilirubin values and persistent jaundice indicate pathologic hyperbilirubinemia. Manifestations include yellowing skin, dark urine, light-colored stools, and weight loss. Premature infants with respiratory distress, acidosis, or sepsis are at greater risk for encephalopathy. The resulting disabilities include athetoid cerebral palsy and speech and hearing impairment.^159,160

EVALUATION AND TREATMENT Total and direct (conjugated) bilirubin levels are monitored and the bilirubin/albumin ratio is being evaluated.^{161, 161a} Pathologic jaundice should be suspected with serum bilirubin values that increase greater than 5 mg/dl per day, persistent jaundice (greater than 7 to 10 days in the full-term infant), or conjugated bilirubin greater than 2 mg/dl. Other causes of jaundice must be eliminated to confirm physiologic jaundice. Treatment depends on the degree of hyperbilirubinemia. Physiologic jaundice is usually treated by phototherapy (ultraviolet light) with good eye protection.¹⁶² Pathologic jaundice requires an exchange transfusion and treatment of the underlying cause.

Biliary Atresia

Biliary atresia is a rare congenital malformation characterized by the absence or obstruction of intrahepatic or extrahepatic bile ducts. Extrahepatic ducts may end in a blind pouch. The cause of the intrauterine injury to the ducts is not clear, but is thought to be related to a chromosomal abnormality or active agents, such as infection or drugs or an autoimmune response.¹⁶³ The disease expression is a continuum in which the principal process is one of bile duct destruction. The points of destruction are influenced by the stage of intrauterine development in which injury occurs.¹⁶¹

The atresia or obstruction of the bile ducts leads to plugging, inflammation, and fibrosis of the bile canaliculi and extrahepatic biliary tree. Progressive obstruction may lead to biliary cirrhosis (see Chapter 39), portal hypertension, or liver failure.¹⁶⁴

Jaundice is the primary clinical manifestation of biliary atresia. Other signs are hepatomegaly and acholic (clay-colored) stools. Fat absorption is impaired for lack of bile salts, and the infant may fail to gain weight. Cirrhosis and liver failure lead to death within 2 years if untreated.

Early diagnosis of biliary atresia is mandatory and is based on clinical manifestations and liver biopsy. Liver function test results are abnormal. Serum transaminase and alkaline phosphatase values are elevated, and conjugated (direct) serum bilirubin levels rise progressively.

Extrahepatic atresia can be relieved by surgical drainage and correction in approximately 10% of cases. Some infants benefit from the Kasai procedure, in which a hepatic duct remnant is anastomosed to the jejunum or a jejunal segment is anastomosed to the porta hepatis if the patent hepatic duct remnant is not available (Figure 40-8). Even with initial restoration of bile flow, however, fibrosis and obliteration of intrahepatic bile ducts continue and cirrhosis results. Liver transplantation is the long-term therapy for biliary atresia. Approximately 40% of children with biliary atresia are immediate candidates for transplantation. Approximately 90% of children transplanted for biliary atresia become long-term survivors with good physical and mental development.¹⁶⁵ The use of reduced and split livers from living, related donors has increased the number of children who survive after transplantation.¹⁶⁶

Hepatitis

The pathophysiology of viral and fulminant hepatitis is described in Chapter 39.

Cirrhosis

Cirrhosis is the excessive formation of fibrous tissue in response to inflammation and tissue damage (see Chapter 39). Most forms of chronic liver diseases in children can progress to cirrhosis, but they seldom do. Nonalcoholic fatty liver disease (steatohepatitis) is increasing in children in correlation with an increase in childhood obesity and it can progress to cirrhosis and liver cancer¹⁷⁶ (see What’s New? Childhood Obesity and Nonalcoholic Fatty Liver Disease).

The complications of cirrhosis in children are the same as those in adults: portal hypertension, the opening of collateral vessels between the portal and systemic veins, and varices. In addition, children with cirrhosis experience growth failure caused by nutritional deficits and developmental delay, particularly in gross motor function because of ascites and weakness. The cause of cirrhosis may influence its severity and course. Some types of cirrhosis can be stabilized if the cause is identified and treated early.

Types

Wilson Disease

Wilson disease (hepatolenticular degeneration) is an autosomal recessive defect of copper metabolism that causes toxic amounts of copper to accumulate in the liver, brain, kidneys, and corneas. The gene ATP7B is localized on chromosome 13 and encodes copper-transporting P-type adenosine triphosphatase (ATPase) membrane-spanning protein. It is highly expressed in the liver, kidney, and placenta and is expressed in lower levels in the brain, heart, muscle, and pancreas.¹⁸¹ This defect in the uptake and excretion of copper by hepatocytes is an important cause of progressive liver disease in children and young adults. Wilson disease is very rare, with an incidence of 1 in 30,000 live births worldwide.¹⁸² Between 1 in 200 and 1 in 500 persons are carriers.¹⁶¹

PATHOPHYSIOLOGY Two major abnormalities in copper metabolism have been identified: (1) diminished biliary excretion of copper and (2) failure to insert copper into ceruloplasmin (a glycoprotein that transports copper in the blood). A positive copper balance is present from birth in children with Wilson disease, despite increased excretion of copper in the urine. Copper toxicity with accumulation in the liver and brain is the major abnormality. Excesses of copper generate free radicals that disrupt cellular organelles, deoxyribonucleic acid (DNA), microtubules, enzymes, and proteins. Copper overload is related to impaired biliary excretion of copper and may be related to failure of hepatocyte lysosomes to eliminate copper by exocytosis.¹⁸³

Early in the disease, intestinal absorption of copper is normal, as is hepatic clearance of albumin-bound absorbed copper. As copper-binding proteins in the liver become saturated, hepatic uptake of copper diminishes, with elevated serum copper levels and biochemical and clinical evidence of liver damage caused by copper accumulation. In later stages of the disease copper accumulates in extrahepatic tissues, including the eyes, brain, and kidneys.

When cerebral copper-binding proteins become saturated, a characteristic pattern of brain damage develops, particularly in the basal ganglia. Neural effects include intention tremor, unsteady gait, dystonia, and behavioral changes. Manifestations of renal tubular injury usually appear simultaneously. The uptake of copper by red blood cells is thought to cause hemolytic anemia, a condition sometimes seen early in the clinical course of Wilson disease.

CLINICAL MANIFESTATIONS The clinical manifestations of Wilson disease may begin as young as 4 years of age, when control mechanisms responsible for copper homeostasis and biliary excretion should have matured. The mean age at diagnosis in one large study was 15.5 years.¹⁸⁴

The classic clinical presentation of Wilson disease is a triad of neuromuscular abnormalities, intention tremors, dysarthria (indistinct speech), and dystonia (disordered muscular tonicity): (1) Kayser-Fleischer rings (accumulation of copper in the limbus of the cornea, causing a greenish-yellow ring), (2) cirrhosis associated with elevated serum copper, and (3) low ceruloplasmin levels.¹⁸⁵ Initial symptoms vary from malaise and abdominal pain to jaundice. Changes in mental and motor performance may develop at age 6 years or into adult life. The earliest signs of liver involvement include enlargement of the liver and spleen, jaundice, and anorexia. Edema and ascites may develop suddenly, or gastrointestinal hemorrhage may be the initial sign of the disease. Occasionally Wilson disease begins with a hemolytic crisis caused by the toxic effects of copper on the red blood cells. Cirrhosis develops in all untreated cases. Copper deposition in the kidneys causes a proximal renal tubular defect that results in losses of glucose, amino acids, phosphate, and uric acid in the urine and renal tubular acidosis. All untreated individuals will develop behavioral or psychiatric disorders.

EVALUATION AND TREATMENT Because Wilson disease is rare, it may not be diagnosed until clinical manifestations develop in older childhood or adulthood. Laboratory tests detect a serum ceruloplasmin concentration less than 30 mg/dl. Serum copper values may be normal or high, and urine copper values are elevated. Liver biopsy is used to assess structural changes and measure copper concentrations. The goal of therapy is to decrease copper accumulation by decreasing intestinal absorption and increasing renal excretion. Medical treatments include D-penicillamine, trientine, zinc, and ammonium tetrathiomolybdate.¹⁸⁶ Copper intake is reduced by eliminating organ meats, nuts, legumes, shellfish, and chocolate from the diet. Physiotherapy may accelerate the recovery of gait and muscular coordination. Liver transplantation is the sole resolutive therapy for Wilson disease and is the treatment of choice for persons who develop fulminant hepatic failure or end-stage cirrhosis.¹⁸⁷ Children with untreated Wilson disease die of neural, hepatic, renal, or hematologic complications.