GI QOD

• A previously healthy 4-year-old boy presents with a 1-week history of intermittent, crampy abdominal pain; watery diarrhea; and a 0.5-kg weight loss. His symptoms started after the family returned from a day of apple picking at a local farm-based orchard. He is receiving no medications.

Of the following, the MOST likely cause of his symptoms is

1. Blastocystis hominis

2. Clostridium difficile

3. enteropathogenic Escherichia coli

4. rotavirus

5. Yersinia enterocolitica

Answer C• Although rotavirus is the most common cause of diarrheal illness in infants and toddlers,

foodborne bacterial pathogens remain an important reservoir of infection. The 1 week of watery diarrhea that began after a visit to an apple orchard described for the boy in the vignette most likely is caused by enteropathogenic Escherichia coli (EPEC). This rod-shaped, gram-negative bacterium has been isolated from unfiltered, unpasteurized apple juice.

At least five E coli pathotypes have been associated with diarrheal illness in children. Each possesses a distinct set of somatic (O) and flagellar (H) antigens. Unfortunately, most laboratories are equipped to identify only E coli O157:H7 (STEC), a Shiga toxin-producing strain associated with hemolytic-uremic syndrome in all age groups and with postinfectious thrombotic thrombocytopenic purpura in adults.

Similar to most other gastrointestinal pathogens, many reservoirs of EPEC infection have been identified. These include animals, symptomatic or asymptomatic infants or children, and asymptomatic adult carriers. Transmission probably occurs via the fecal-oral route. Accordingly, close contact with animals or individuals harboring the organism, either as commensal flora or as a pathogen during diarrheal illness; sharing of food items; and food itself can be sources of infection. Because of its wide carriage in food items (one recent study identified 19 EPEC isolates out of 400 E coli isolates found in a variety of foods), proper hygiene in food handling and processing is essential to prevent infection. Although widespread diarrheal disease caused by EPEC is a problem confined largely to the developing world, outbreaks in nurseries resulting in severe chronic diarrhea have been reported in the United States.

• Symptomatic infection in the United States, in which EPEC has been identified as the offending organism, generally is confined to children younger than 5 years of age.

Blastocystis hominis is a commensal, protozoal organism commonly isolated from the stools of asymptomatic individuals. Its role in diarrheal illness is controversial. Symptomatic Clostridium difficile infection most frequently occurs in the setting of antibiotic-associated diarrhea and most often presents with hematochezia. This organism is not considered a foodborne pathogen. Rotavirus also is not transmitted predominantly via food items, and a 1-week duration of illness in a 4-year-old would be unusual. Yersinia enterocolitica is a known foodborne pathogen, especially associated with the consumption of chitterlings in the southern United States. However, the incidence of disease caused by this organism is very low in young children in the United States (estimated at 1.4 per 100,000). In older children, Y enterocolitica typically causes a pseudoappendicitis syndrome; younger children may present with fever and mucoid, bloody diarrhea.

American Board of Pediatrics Content Specification(s):Recognize the signs and symptoms of enteropathogenic Escherichia coli infection

• A 16-year-old previously healthy girl presents with a complaint of leg weakness. 2 weeks ago, she had a 5-day episode of watery diarrhea, abdominal pain, & fever. She had been gradually improving until this morning, when she fell while trying to get out of bed and could not stand or walk without support. She denies headaches, visual problems, vertigo, difficulty swallowing, or incontinence. She has been taking acetaminophen and ibuprofen for fever during her recent illness. Her immunizations are up to date. Exam demonstrates an alert but anxious girl who has normal vital signs. Other findings include:

Cardiac, respiratory, abdominal exam unremarkable Pupils equal & reactive to light, EOMI;No papilledemaNo facial weakness or asymmetryNormal cranial nervesUpper extremities: Strength 4/5, normal deep tendon reflexes and

sensationLower extremities: Strength 2/5, deep tendon reflexes absent,

sensation intact

Of the following, the MOST likely cause of this child's illness is

1. Acinetobacter baumannii

2. Campylobacter jejuni

3. enterotoxigenic Escherichia coli

4. Haemophilus influenza

5. Neisseria meningitidis

Answer B • Relatively mild infectious disorders may be associated with serious clinical sequelae.

The girl described in the vignette presents with an ascending neuropathic syndrome occurring approximately 2 weeks after the onset of a symptomatically resolved diarrheal illness. The physical findings suggest the onset of a symmetric polyneuropathy affecting the lower extremities. Based upon these data, the presumptive diagnosis is Guillain-Barré syndrome (GBS), now the most common cause of acute neuromuscular paralysis. Prior studies suggest that two thirds of patients who have GBS present following an undiagnosed and often mild respiratory or gastrointestinal illness. The organism that has been linked most closely with GBS is Campylobacter jejuni. Acinetobacter baumannii, enterotoxigenic Escherichia coli, Haemophilus influenzae, andNeisseria meningitidis have not been associated with this disorder. In addition, of these four organisms, only Shiga toxin-producing E coli is a significant gastrointestinal pathogen.

Campylobacter are motile, gram-negative bacilli that are the most common cause of acute bacterial gastroenteritis in the developed world, with the most prevalent pathotypes being C jejuni and C coli. These organisms are harbored in the gastrointestinal tracts of both wild and domestic birds and animals (isolates have been found in up to 100% of feces from chickens and turkeys), and outbreaks are common in children visiting dairy farms, particularly among those who drink unpasteurized milk. Following ingestion of Campylobacter and an incubation period of 1 to 7 days, an acute diarrheal syndrome may develop, often with visible or occult blood, accompanied by fever, malaise, and abdominal pain. Recovery usually occurs within 1 week of onset, although up to 20% of patients experience either a relapse or a prolonged illness.

• Severe infection with bleeding may mimic inflammatory bowel disease. Unlike the therapeutic approach to other foodborne pathogens, in which antibiotic therapy generally is not recommended, treatment of Campylobacter gastroenteritis with either erythromycin or azithromycin can eradicate the organism within 2 to 3 days, shorten the duration of illness, and prevent relapse when administered early in the course of infection.

With the virtual eradication of poliomyelitis in the developed world, GBS has become the most common cause of acute neuromuscular paralysis. It is an autoimmune disorder of the peripheral nervous system that is characterized by symmetric ascending weakness progressing over several days. Bacteriologic or serologic evidence of recent C jejuni infection has been found in 26% of those who have GBS compared with 1% of age-matched controls. Among patients who have clinical histories and serologic findings consistent with antecedentCampylobacter enteritis, the mean time between diarrheal illness and onset of neuropathic symptoms is 9 days. These patients appear to have a significantly worse outcome, with greater disability, than do patients who have GBS without evidence of a recent C jejuni infection. In addition to GBS, C jejuni also has been associated with other immunoreactive complications, including Miller-Fisher syndrome (ophthalmoplegia, areflexia, ataxia), Reiter syndrome (arthritis, urethritis, bilateral conjunctivitis), erythema nodosum, and reactive arthritis, all presenting during the convalescent phase of infection.

American Board of Pediatrics Content Specification(s):Recognize the signs and symptoms of Campylobacter diarrhea

• A previously healthy 7-year-old boy presents to your office following 5 days of crampy abdominal pain, tactile fevers, and watery diarrhea. For the past 2 days, the diarrhea has been bloody. Symptoms began shortly after his family visited a local petting zoo. He recently completed a 10-day course of amoxicillin for otitis media. Physical examination demonstrates a well-developed, well-nourished child who is in moderate distress because of diffuse, moderate, direct abdominal tenderness. Vital signs are normal, mucous membranes are dry, and capillary refill time is 2 seconds. Initial laboratory studies show:

Hemoglobin, 10.5 g/dL Platelet count, 70x103/mcL • PT: 12 seconds ,PTT: 23 seconds • Urinalysis positive for blood, protein, and ketones

Of the following, the MOST likely cause of this child's illness is

1. Campylobacter jejuni

2. Clostridium difficile

3. Escherichia coli O157:H7

4. Salmonella type D

5. Shigella dysenteriae

Answer C • The clinical history and available laboratory data described for the boy in the vignette indicate

development of anemia, thrombocytopenia, and urinary abnormalities in association with acute enteritis characterized by the development of hematochezia. These findings strongly suggest a diagnosis of hemolytic-uremic syndrome (HUS) as a consequence of infection with the Shiga toxin-producing bacterium Escherichia coli O157:H7 (STEC). Further studies likely will demonstrate evidence of both microangiopathic hemolytic anemia and renal dysfunction that, along with thrombocytopenia, define the HUS triad. In the United States, HUS occurs in approximately 8% of children who have E coli O157:H7 diarrhea, an incidence that is significantly greater than observed with other STEC serotypes.

Pathologic E coli species are transmitted most commonly via contaminated food products. Particular reservoirs of STEC include raw or undercooked ground beef, unpasteurized milk, and any food or beverage (eg, unpasteurized apple cider) that may be contaminated with bovine feces. Because all STEC are excreted in the feces of cattle, sheep, deer, and other ruminants, direct contact with these animals is another significant source of contamination. Several human outbreaks of E coli O157:H7 enteritis have been linked to animals in petting zoos.

STEC is an important cause of acute renal injury and accounts for 70% to 90% of all HUS cases in countries where these bacteria are endemic. HUS typically develops 5 to 9 days (mean, 7 days) after the onset of gastrointestinal symptoms and 2 to 6 days (mean, 4 days) after the appearance of bloody stools. Accordingly, when acute enteritis is associated with the passage of blood, clinical assessment must include both a hematologic profile (including examination of a blood smear for fragmented cells) and an evaluation of renal function.

• The previous treatment with amoxicillin for otitis media reported for the boy in the vignette raises the question of a possible role for antibiotics in the development of HUS. Although earlier studies suggested that antibiotic usage in hemorrhagic colitis increased the risk of developing HUS, a meta-analysis failed to confirm these findings. Nevertheless, available evidence clearly indicates that antimicrobial agents do not alter the duration or outcome of illness, and the use of antibiotics for E coli O157:H7 infection is not recommended. Furthermore, because most clinical microbiology laboratories can culture and identify this organism, as well as the other common bacterial pathogens that cause acute enterocolitis (Salmonella, Shigella dysenteriae, Campylobacter jejuni, Clostridium difficile), decisions about specific therapy generally should await bacteriologic identification.

Although Campylobacter, Salmonella type D, and C difficile may cause acute gastroenteritis with hematochezia, they are not associated with HUS. Campylobacter are the most common cause of acute bacterial gastroenteritis in the developed world, and nearly 50% of all Salmonella infections in the United States are caused by Salmonellaserotypes B, D, and Newport. C difficile is a common cause of antibiotic-associated enterocolitis, and the organism has been linked to exacerbations of inflammatory bowel disease. Although S dysenteriae (type 1) has been associated with HUS, the incidence of this disorder is far greater following infection with either E coli O157:H7 or another STEC species.

American Board of Pediatrics Content Specification(s):Recognize the clinical signs and laboratory findings associated with Escherichia coli O157:H7 infection

• You are asked to see a 14 month-old boy who has rectal bleeding. The child was seen at another practice 6 months ago because of a history of intermittent constipation, and a barium enema examination was performed. For the past week, he has experienced several loose-to-watery and occasionally explosive bowel movements per day, which now contain streaks of blood. Over the past 24 hours, he has developed a low-grade fever. Physical examination demonstrates a well-developed, thin child whose height is 77 cm, weight is 9.2 kg, temperature is 38.1°C, heart rate is 110 beats/min, and blood pressure is 90/60 mm Hg. His abdomen is moderately distended and diffusely tender, with bowel sounds present. Initial laboratory data demonstrate:WBC: 16 Hemoglobin, 10.4

• Na 136 mEq/L K 4.8 mEq/L CO2 16 mEq/L ESR 32

Of the following, the child's symptoms are MOST likely caused by

1. Clostridium difficile infection

2. cow milk protein allergy

3. Escherichia coli O157:H7 infection

4. Hirschsprung disease

5. inflammatory bowel disease

Answer D • Rectal bleeding in infants and young children can be alarming for both parents and physicians.

The symptoms described for the 14-month-old child in the vignette appear to be consistent with an acute bacterial colitis, and the child's clinical history indicates a problem with constipation. The lateral projection of the previously performed barium enema demonstrates a relatively narrow diameter rectosigmoid colonic segment compared with the more proximal colon, a common radiographic finding in Hirschsprung disease (HD), also known as colonic aganglionosis. The present illness is consistent with Hirschsprung enterocolitis, a serious complication that, in this case, likely developed because of the delay in diagnosing HD.

Although laboratory evaluation for potential infectious causes of enterocolitis, including Clostridium difficile andEscherichia coli O157:H7, must be performed, this child's clinical history and presentation make a primary infectious process unlikely. The enterocolitis of cow milk protein allergy rarely, if ever, presents after the first few postnatal months. Inflammatory bowel disease, particularly ulcerative colitis, has been described in infants and toddlers, but the history and radiographic findings for this boy clearly suggest an alternate diagnosis.

HD is the most common cause of lower intestinal obstruction in infants, with an incidence of approximately 1 per 5,000 live births. Trisomy 21 is the most frequently associated anomaly. HD also may present as intractable constipation in toddlers and school-age children. The disorder is characterized by the absence of ganglion cells in the myenteric and submucous colonic plexuses. The abnormality in colonic innervation results in sustained contraction of the aganglionic segment.

• More than 90% of healthy newborns and fewer than 10% of infants who have HD pass meconium during the first 24 hours after birth. One exception to this characteristic clinical history is the child who has short-segment HD, in which only the most distal rectal segment is aganglionic. Short-segment HD may present early in the newborn period with signs of low intestinal obstruction or the condition may not be diagnosed until childhood, when children are evaluated because of intractable constipation that often is marked by the passage of ribbonlike stools, abdominal distension, and failure to thrive. Overall, 8% to 20% of patients who have HD are not diagnosed until they are 3 years of age or older.

A digital rectal examination in an infant or child who has a history of constipation typically demonstrates increased anal sphincter tone and an empty rectal vault for the patient who has HD. When HD is suspected, and before diagnostic studies are undertaken, patients should be referred to a center where further evaluation may be conducted by a pediatric gastroenterologist and pediatric surgeon. Any delay in diagnosis increases the risk of developing enterocolitis.

A barium enema (BE) frequently is the first diagnostic test obtained. In infants who have HD, the typical BE finding is a relatively narrow-diameter rectosigmoid colonic segment. A clear transition zone, demarcating the junction between a contracted rectosigmoid and a dilated proximal colon, is more commonly found in toddlers and older children who have HD. A BE should not be performed following the recent use of enemas because rectal manipulation may dilate the distal colonic segment mechanically and obscure the findings consistent with HD. Although a BE usually is not required to diagnose HD beyond infancy, it may be useful in determining the length of the aganglionic colonic region prior to surgery.

•Rectal biopsy and anorectal manometry are the only studies that may establish or rule out HD reliably. Histopathologic examination of suction rectal biopsy specimens, usually obtained approximately 2 and 5 cm from the anal verge, demonstrates absence of ganglion cells in the submucosal plexus. This finding is diagnostic, and the presence of ganglion cells rules out HD. In some cases of inconclusive suction biopsy results, a surgically obtained full-thickness biopsy may be required. In the cooperative child and in equivocal situations, particularly when short-segment HD is suspected, anorectal manometry may be recommended. This test examines the response to balloon inflation in the region of the internal and external anal sphincters. In HD, absence of normal internal sphincter relaxation following balloon inflation is noted. Properly conducted, anorectal manometry is both sensitive and specific for HD.

Enterocolitis is the most serious complication related to HD. It usually presents with watery, explosive stools, with or without gross bleeding, and may be the initial presentation of HD. Hirschsprung enterocolitis most commonly occurs at 2 to 3 months of age in previously undiagnosed patients and is associated with a 20% mortality rate. However, it may occur at any age prior to a diagnosis of HD. Enterocolitis also has been reported to occur up to 2 years following an endorectal pull-through surgical correction.

American Board of Pediatrics Content Specification(s):Know the complications of Hirschsprung disease

• Know the clinical manifestations of Hirschsprung disease• Recognize the role of rectal biopsy in an infant with suspected Hirschsprung disease

• You are evaluating a 7-week-old infant for persistent jaundice. She was born at term, following an uncomplicated pregnancy and delivery, weighed 3.2 kg at birth, and has been exclusively breastfed. She was first evaluated for jaundice at 3 weeks of age. The total bilirubin concentration was 16.0 mg/dL (273.7 mcmol/L), and abdominal ultrasonography demonstrated "a collapsed gall bladder without dilatation of the intrahepatic or extrahepatic bile ducts." You diagnosed breast milk jaundice and on follow-up visits every few days you noted a gradual reduction in total bilirubin. Physical examination demonstrates an alert, icteric infant whose weight is 4.2 kg. She has a firm liver edge palpable 1.5 cm below the right costal margin and a spleen tip palpable 2 cm below the left costal margin. You obtain the following laboratory data:WBC 10.5 Hgb 9.5

TBili 8.5 DBili 4.5 mg/dL ALT 140 AST 70 Alk Phos 450

Of the following, the MOST appropriate next diagnostic test is

1. abdominal CT scan

2. alpha-1-antitrypsin assessment

3. intraoperative cholangiography

4. percutaneous liver biopsy

5. urine succinylacetone measurement

Answer D • The infant described in the vignette has direct hyperbilirubinemia, which is defined by

a serum direct bilirubin concentration of more than 1.0 mg/dL (17.1 mcmol/L) with total bilirubin values of less than 5.0 mg/dL (85.5 mcmol/L) or greater than 20% of the total bilirubin for values greater than 5.0 mg/dL (85.5 mcmol/L). Direct hyperbilirubinemia indicates cholestasis and is an abnormal finding that requires additional evaluation. Immediate evaluation of hepatobiliary integrity in this infant is critical to determine if the direct hyperbilirubinemia is a consequence of extrahepatic biliary atresia. Recent studies have shown the best surgical outcomes for infants who have biliary atresia when the diagnosis is established by 30 to 45 days of age. By 7 weeks, as seen for the infant in the vignette, physical examination may show findings consistent with hepatic fibrosis (firm liver edge) and portal hypertension (splenomegaly). Therefore, even while additional tests are obtained to determine alternate causes, biliary atresia must be ruled out urgently, and a liver biopsy is essential. Histologic sections demonstrate portal tract bile ductular proliferation, a pathognomonic sign of extrahepatic biliary tract obstruction.

Other causes of neonatal cholestasis include infections and metabolic diseases. Measurement of urinary succinylacetone (to rule out tyrosinemia) and alpha-1-antitrypsin (to assess for possible alpha-1-antitrypsin deficiency-associated liver disease) are part of the standard evaluation for neonatal cholestasis and, in this infant, are indicated if the liver biopsy rules out biliary atresia.

• Although the "gold standard" for identifying extrahepatic biliary tract obstruction remains percutaneous liver biopsy, recent data indicate that biliary tract ultrasonography, conducted by an experienced ultrasonographer, may be helpful. The finding of a "triangular cord sign," which represents the fibrous remnant of an obliterated extrahepatic biliary tree, recently was shown to be highly specific for biliary atresia. Other diagnostic modalities, including magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography, currently are being investigated. Abdominal computed tomography scan may suggest an absent or atretic gallbladder, but this imaging study has not proved to be of significant value in the evaluation of biliary atresia.

Hepatobiliary scintigraphy, using a radiolabeled derivative of iminodiacetic acid, has long been touted as an important adjunct to the evaluation of neonatal cholestasis. Although definitive evidence of radiolabel excretion into the small bowel may confirm biliary tract patency, the study has a significant incidence of both false-positive and false-negative results.

At surgery, the diagnosis of extrahepatic biliary atresia can be confirmed via intraoperative cholangiography, which is followed by dissection of the atretic, extrahepatic biliary tree to the liver hilum. A portoenterostomy (Kasai procedure) is performed, with anastomosis of a Roux-en-Y jejunal limb to the porta hepatis.

A number of medical therapies, including corticosteroids and ursodeoxycholic acid, have been suggested as means to enhance bile flow in the postoperative period. For those patients in whom bile flow is achieved, cholangitis remains a significant cause of both short- and long-term morbidity. As a preventive measure, prophylactic antimicrobial therapy has been used widely after portoenterostomy, but the efficacy of this therapeutic approach has yet to be confirmed.

•Early diagnosis greatly enhances the likelihood of successful portoenterostomy that establishes bile flow and allows patients a prolonged survival period with their native livers. Any formula-fed infant who is noted to be jaundiced at the 2-week health supervision visit should be assessed for cholestasis by initially obtaining a fractionated (total and direct reacting) bilirubin value. For nursing infants, in whom breast milk-associated jaundice may result in a prolonged period of indirect hyperbilirubinemia, this evaluation may be delayed until 3 weeks of age, if findings on physical examination are normal, the infant has no history of dark-colored urine or light-colored stools, and the infant can be monitored reliably.

American Board of Pediatrics Content Specification(s):Know the diagnostic tests for biliary atresia

• Know the management of biliary atresia

• You are caring for a 16-year-old girl who has juvenile idiopathic arthritis. Her musculoskeletal symptoms have come under good control using naproxen sodium. Recently, however, she has been complaining of vague abdominal pain and occasional loose bowel movements. Physical examination demonstrates an alert, cooperative adolescent in no distress whose vital signs are normal for her age. She has mild, direct tenderness in the epigastric region, and rectal examination produces a scant amount of brown stool that is positive on fecal occult blood test. Laboratory data include:

Hemoglobin, 10.5 WBC 4.5 ESR 25 Albumin 3.4 g/dL

Of the following, the MOST appropriate long term additional medication for this patient is

1. celecoxib

2. ibuprofen

3. methotrexate

4. misoprostol

5. sucralfate

Answer D

• Nonsteroidal anti-inflammatory drugs (NSAIDs) remain first-line therapy for the management of many rheumatic diseases because of their anti-inflammatory and analgesic properties. However, chronic use is associated with an increased frequency of gastrointestinal complaints, peptic ulceration, and complications that include bleeding and perforation. NSAID-related small bowel enteropathy may result in enteric losses of both blood and protein. Although the arthritis symptoms of the 16-year-old girl described in the vignette are under control with naproxen, she has developed symptoms that are consistent with an NSAID-induced gastroenteropathy. To prevent NSAID-related complications, several treatment strategies have been recommended as either therapeutic adjuncts or alternatives to standard, cyclooxygenase-1 (COX-1) inhibitory NSAID therapy, including switching to a COX-2 selective inhibitor or adding a gastric cytoprotective agent. The synthetic prostaglandin-2 analog misoprostol, a cytoprotective agent, has demonstrated efficacy in reducing the frequency of gastric and duodenal ulcers among pediatric patients who require long-term NSAID therapy. Because misoprostol can cause abortion or premature birth in women who are pregnant, it should not be prescribed unless the possibility of pregnancy has been excluded and the patient is able to use an effective form of contraception. Furthermore, when other prostaglandin effects are of concern in this clinical setting, the addition of a proton-pump inhibitor has been shown to be as effective as misoprostol in preventing NSAID-induced mucosal damage. 

• Celecoxib is a selective COX-2 inhibitor. Both as monotherapy and coupled with proton pump inhibitors (PPIs), COX-2 inhibitors have demonstrated reduced gastrointestinal adverse effects during management of rheumatologic diseases. However, several COX-2 inhibitors have been removed from the market because of potential cardiovascular complications, so that their use must be balanced against potential risks. Furthermore, the safety and effectiveness of COX-2 inhibitors in long-term use have not been confirmed in children. Ibuprofen is a COX-1 inhibitor that has a similar risk profile to that of naproxen. Methotrexate, a tetrahydrofolate reductase inhibitor, is a potent immunomodulator that may be used as second-line therapy in patients who have rheumatic diseases that cannot be controlled by alternative medications. Finally, sucralfate is a locally acting agent that forms a protective gel over inflamed and ulcerated gastroduodenal mucosa, thus accelerating healing. It often is employed as adjunctive therapy in the treatment of peptic ulcer disease, and its potential use for the girl in the vignette would be solely during acute management.

Adult studies have documented endoscopically confirmed ulcer prevalence rates as high as 15% to 30% among patients receiving NSAIDs, with the highest rate of ulceration occurring during the first 6 months of therapy. Overall, the incidence of NSAID-related gastroduodenal complications has been estimated at 2% per year. Dyspepsia appears to be the most common symptom accompanying long-term treatment, affecting up to 25% of patients. In a retrospective review of 700 children who had juvenile idiopathic arthritis and were treated with a variety of anti-inflammatory drugs, 0.8% developed symptoms of a secondary NSAID gastropathy. Although frank peptic ulceration and associated complications of bleeding and perforation are not frequent events in pediatric patients, they are of particular concern because NSAID-induced ulcers often are not preceded by typical symptoms of ulcer disease.

• The mechanism responsible for gastric and small intestinal mucosal damage from NSAIDs is likely multifactorial and includes reduction in local blood flow, direct irritant effects, and inhibition of mucosal healing. As stated previously, NSAIDs are inhibitors of COX-1, a constitutive enzyme of the gastric mucosa that mediates synthesis of prostaglandins such as PGE-2. Such inhibition leads to reductions in gastric blood flow, mucus production, and bicarbonate secretion and results in impaired gastroduodenal mucosal barrier function. Misoprostol, a PGE-2 analog, exerts its gastrointestinal cytoprotective effects by directly countering a primary mechanism responsible for the damaging effects of naproxen and other COX-1 inhibitors. Among pediatric patients receiving NSAIDs, coadministation of misoprostol has been shown to be an effective strategy to reduce gastrointestinal symptoms and increase hemoglobin concentrations.

Because the girl in the vignette displays signs and symptoms consistent with peptic ulcer disease, immediate management may include diagnostic endoscopy. Confirmation of gastroduodenal damage should prompt therapy with a PPI. In fact, although not offered as an option, the addition of a PPI has been shown to be effective in reducing gastrointestinal complications among patients requiring anti-inflammatory medications.

American Board of Pediatrics Content Specification(s):Understand the mechanism of injury by which nonsteroidal anti-inflammatory drugs may produce gastrointestinal symptoms

• A mother brings her 18-month-old child to the emergency department because of increased sleepiness. She reports that he has had several episodes of vomiting without fever or diarrhea over the past 24 hours for which she has given him two doses of ondansetron. This afternoon she had difficulty awakening him from his nap. On physical examination, the child is pale and arousable but prefers to sleep. His temperature is 37.0°C, heart rate is 130 beats/min, respiratory rate is 24 breaths/min, and blood pressure is 90/60 mm Hg. His pupils are 4 mm and normally reactive. His lungs are clear, and his abdomen is nontender and mildly distended, with hypoactive bowel sounds. While you are examining him, he has an episode of bilious emesis.

Of the following, the MOST likely explanation for this patient's signs and symptoms is

1. intussusception

2. ondansetron toxicity

3. sepsis

4. viral gastroenteritis

5. volvulus

Answer A • The child described in the vignette is exhibiting signs and symptoms that suggest the

presence of intussusception, the clinical condition in which a segment of intestine telescopes into an adjacent portion. The most common form of intussusception occurs when the terminal ileum "intussuscepts" into the more proximal bowel, but intussusception can occur in any segment of the intestine. Although intussusception is seen most frequently in male infants between 3 and 12 months of age (mean incidence, 8 months), it is the most common cause of bowel obstruction in children between 3 months and 6 years.

Intussusception should be suspected in any child who presents with some combination of the classic triad of signs and symptoms that includes episodic cramping pain that causes the patient to draw up the legs, a palpable sausage-shaped mass in the right abdomen, and "currant jelly" stool (loose stool mixed with dark, clotted blood and mucus). However, only 15% to 20% of children have all three of these findings, and one third of children have no evidence of hematochezia. Because of the variability of presentation, a high level of suspicion is needed to recognize intussusception in children who have more vague abdominal signs and symptoms such as vomiting and abdominal pain. The diagnosis also should be considered in a child who presents with unexplained lethargy or pallor, which may be the only presenting sign(s).

• Evaluation of the patient in whom intussusception is suspected may include abdominal radiographs that, in rare cases, demonstrate a soft-tissue mass in the right abdomen or the "target sign," which is the radiographic view of a cross-section of the intussusception. Abdominal ultrasonography is more diagnostically useful, with sensitivity and specificity approaching 100%. In cases where the diagnosis is not in question, contrast or air enema is both diagnostic and therapeutic.

Ondansetron has a very wide therapeutic range, and the likelihood of toxicity is extremely low. In toxicity studies, no end-organ damage was seen in animals given 30 to 100 times the recommended dose. In addition, minor adverse effects are uncommon, with headache and diarrhea reported most frequently. Sepsis is unlikely in the absence of fever. Bilious emesis should prompt evaluation for more serious causes of abdominal symptoms than viral gastroenteritis. If bilious emesis and lethargy occur in patients who have volvulus, the abdominal examination would reveal marked distension and tenderness.

American Board of Pediatrics Content Specification(s):Recognize the presence of intussusception

• You are called to see a 16-year-old girl who underwent scoliosis surgery 6 days ago. She is receiving parenteral nutrition via peripheral vein and morphine for pain. This morning she began complaining of severe upper abdominal pain and vomiting. Physical examination demonstrates a well-developed adolescent in moderate distress whose temperature is 38.7°C, heart rate is 90 beats/min, and blood pressure is 130/66 mm Hg. Her abdomen is mildly distended, with moderate fullness and tenderness in the right upper quadrant and epigastrium. Laboratory data include:

Hemoglobin 11.5 WBC 15.5

AST 100 ALT 120 Gamma-glutamyl transpeptidase 180 Amylase 70 Lipase 80

Of the following, the MOST appropriate diagnostic test is

1. abdominal CT scan

2. abdominal ultrasonography

3. hepatobiliary scintigraphy

4. MR cholangiopancreatography

5. upper gastrointestinal endoscopy

Answer B • During recovery from major surgery or trauma, the acute onset of upper abdominal pain

should alert the clinician to several diagnostic possibilities, including peptic ulcer and inflammatory pancreatic and gallbladder diseases. The adolescent described in the vignette, who recently underwent spine surgery, has developed a febrile illness associated with right upper quadrant fullness and tenderness. Laboratory studies show elevations in the white blood cell count, gamma-glutamyl transpeptidase, and aspartate and alanine aminotransferases but near-normal pancreatic enzyme values. Acute calculous or acalculous cholecystitis is the most likely cause of these findings. No single diagnostic test is universally reliable for evaluating cholecystitis, and clinical assessment often is the most important factor guiding management. Once cholecystitis is suspected, however, the diagnostic study of first choice is abdominal ultrasonography. Typical ultrasonographic findings in acute cholecystitis include identification of gallstones (in calculous cholecystitis) or biliary sludge; evidence of bile ductular dilatation; and a distended, thick-walled gallbladder. One study reported that a wall thickness of more than 3.5 mm was a reliable indicator of cholecystitis. In the absence of cholelithiasis or other ultrasonographic signs of calculous or acalculous cholecystitis, hepatobiliary scintigraphy can assess biliary excretion and gallbladder function accurately in many cases. Unfortunately, prolonged fasting and parenteral nutrition are associated with false-positive results. If results of these tests are inconclusive, other helpful studies include magnetic resonance imaging and computed tomography scans. These tests may be more helpful than ultrasonography in determining other sources of abdominal sepsis, but because of its relative reliability and cost, ultrasonography remains the initial study of choice. Endoscopic intervention (endoscopic retrograde cholangiopancreatography) may be considered if choledocholithiasis is suspected.

• Cholecystitis is defined as inflammation of the gallbladder wall. Both chronic and acute cholecystitis are diagnosed most frequently in adults as a complication of cholelithiasis, a condition affecting more than 20 million Americans annually. In the pediatric population, gallbladder disease, although much less common, occurs with the greatest frequency in adolescents who have underlying hemolytic disorders leading to gallstone formation and in oral contraceptive users. In the setting of cholelithiasis, acute cholecystitis is the consequence of cystic duct obstruction that results in gallbladder inflammation and distension. Production and release of biliary lysolecithins further exacerbate the inflammatory process.

Although no history of hemolytic disease or other disorder predisposing to gallstone formation has been cited for the girl in the vignette, her recent surgery, need for parenteral nutrition support, and ongoing pain management using narcotic analgesia as well as her physical findings necessitate evaluation for acalculous cholecystitis. This acute inflammatory disorder has been associated with both medical and surgical conditions, in which intravenous alimentation, narcotic administration, and prolonged fasting contribute to biliary stasis and hypofunction. Reports have described the occurrence of acute acalculous cholecystitis in both adults and children undergoing spinal surgery, but the disorder may develop following any surgical procedure or systemic illness exhibiting the previously noted risk factors. Following diagnosis, the condition may be managed medically, employing a combination of antibiotics, gastric decompression, and parenteral alimentation, but cholecystectomy often is required.

• Because the clinical presentation of postoperative acalculous cholecystitis may be nonspecific, significant delays in diagnosis and treatment may occur, resulting in gallbladder necrosis, perforation, and abscess. For adults who have chronic systemic illness, the mortality rate associated with these complications has been reported as high as 50%. Frequent findings among children who have acute cholecystitis include jaundice in approximately 40% and a right upper quadrant mass in about 25%. Although several laboratory tests yielded abnormal results for the girl in the vignette, the white blood cell count, serum bilirubin, and liver function profile may be normal early in the course of disease.

American Board of Pediatrics Content Specification(s):Recognize the presence of cholecystitis in children

• You are evaluating a 4-month-old male infant because of worsening postprandial emesis. When born at term following an uncomplicated pregnancy and delivery, he weighed 3.4 kg. At 4 weeks of age, he began having frequent episodes of spitting-up after meals, which prompted one visit to the local emergency department, where abdominal ultrasonography was performed. Since that time, the baby has continued to have frequent postprandial emesis. His diet is 4 to 5 oz of a standard cow milk-based formula every 4 hours. On physical examination, the alert, vigorous, and happy infant is wearing a formula-stained bib and weighs 6 kg. Of note is a small umbilical hernia.

Of the following, the MOST appropriate next step is

1. administration of lansoprazole 1 mg/kg/day

2. administration of ranitidine 3 mg/kg BID

3. an upper GI series

4. thickening of formula with rice cereal

5. trial of a hypoallergenic infant formula

Answer D • The otherwise healthy and thriving 4-month-old infant described in the vignette presents

with recurrent, postprandial regurgitation that has been present since 1 month of age. Initially, vomiting prompted an ultrasonographic evaluation, presumably to rule out infantile pyloric stenosis. Considering the duration of symptoms, the infant's healthy appearance, and his appropriate weight gain, the most likely clinical diagnosis is gastroesophageal reflux (GER). The primary management objective should be to reduce, if possible, the frequency and severity of vomiting episodes, and the intervention most likely to achieve this goal is feeding of thickened infant formula combined with reduced volumes of feedings.

GER during early infancy is a physiologic state associated with the delayed maturation of gastrointestinal motility and function. Etiologic factors include immaturity of the anatomic antireflux barrier, reduced esophageal capacitance and gastric compliance, delayed gastric emptying, and perhaps most prominently, increased transient lower esophageal sphincter (LES) relaxations. During postnatal life, the frequency and severity of reflux episodes decreases in parallel with the maturation of LES function, so that by 1 year of age, clinical symptoms of GER are reported in fewer than 10% of infants.

Regurgitation (the passage of gastric contents into the oropharynx) and vomiting (expulsion of gastric contents from the mouth) are associated with diverse clinical problems. Clearly, any infant who has a vomiting history should be assessed carefully for the presence of "red flags" that might suggest a serious, underlying clinical condition.

• Regardless of associated symptoms, any infant whose vomiting episodes commence after 6 months of age must be evaluated further for a non-GER diagnosis. In general, however, infants who have a history of chronic postprandial emesis and whose history and physical examination findings do not encompass the warning signals of a non-GER diagnosis should receive the diagnosis of uncomplicated infant GER. Accordingly, the infant in the vignette need not undergo further diagnostic studies. In particular, the use of barium upper gastrointestinal radiographic examinations should be limited to those cases where concerns of swallowing function or anatomic integrity (eg, oropharyngeal dysphagia, esophageal stricture, intestinal malrotation, or atresia) are paramount. Contrast studies are not helpful for evaluating GER.

Most importantly, parents should be reassured and educated regarding the generally benign nature of this problem. For infants who have uncomplicated reflux, neither dietary nor pharmacologic intervention has been demonstrated to accelerate maturation of the LES or influence natural history. Nevertheless, several studies have shown that the feeding of thickened infant formula is an effective clinical strategy that results in reduced frequency and severity of vomiting episodes. A variety of approaches may be used to achieve formula thickening, including the use of rice cereal, dietary gums, and commercially available "antireflux" formulas. The efficacy of thickened feedings may be enhanced further by reducing feeding volumes. If thickened feedings do not result in symptomatic improvement or if associated atopic symptoms are demonstrated, a 2-week trial of a hypoallergenic protein hydrolysate formula may be considered.

•Considerable controversy surrounds pharmacologic intervention in GER. Abundant evidence indicates that the use of so-called prokinetic drugs (eg, metoclopramide) does not alter the clinical course and, therefore, has little, if any, role in management. Furthermore, the adverse effect profiles of most of these drugs make their use during infancy problematic. Although studies in preterm infants indicate that erythromycin, a macrolide antibiotic that exerts a motilin agonist effect in subtherapeutic doses, may be useful in the management of selected cases of refractory GER, this agent has not been evaluated for uncomplicated reflux. A recent physician survey found that a considerable number of infants who have presumptive diagnoses of clinical GER receive empiric trials of acid-reducing medications, either histamine2-receptor antagonists (eg, ranitidine) or proton pump inhibitors (PPIs) (eg, lansoprazole). These agents have demonstrated considerable efficacy in the treatment of symptomatic GER and in the healing of reflux esophagitis in older children and adults, but double-blind, placebo-controlled studies in infants have failed to show an effect on symptoms such as irritability, back arching, or feeding refusal. Nevertheless, in cases where suspected esophageal symptoms occur in conjunction with recurrent emesis, a brief trial of acid-reducing medication may be considered. The use of these drugs must be tempered by emerging data indicating that long-term PPI use is associated with an increased incidence of complications, including candidal esophagitis and community-acquired pneumonia. Clinical trials aimed at determining the safety and efficacy of PPIs in infants are ongoing. However, current recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition do not support the routine use of these drugs in the management of infant GER.

American Board of Pediatrics Content Specification(s):Know the treatment for gastroesophageal reflux

• A 6-month-old infant presented in the newborn period with intestinal malrotation and mid-gut volvulus. Emergency surgery resulted in resection of his entire small bowel, except for 7 cm of duodenum. He has been maintained on parenteral nutrition since then and is listed for small bowel transplantation at the regional transplant center. His parenteral nutrition regimen provides 120 kcal/kg per day and includes 20% dextrose, 3 g/120 kcal per day amino acids, and 3 g/kg per day lipids. He has had increasing jaundice over the past month. On physical examination, the alert, afebrile, and icteric infant has a firm liver edge palpable 3.5 cm below the right costal margin. Laboratory data include:TBili 12.5 DBili 8.0 ALT 200 AST 150

Gamma-glutamyl transpeptidase 180

Of the following, the MOST appropriate treatment is to

1. add phenobarbital 5 mg/kg/day orally

2. add ursodeoxycholic acid 20 mg/kg/day orally

3. decrease amino acids to 1.5 g/120 kcal/day

4. decrease dextrose to 10%

5. decrease lipids to 1.0 g/kg/day

Answer E • Parenteral nutrition (PN) is a life-sustaining therapy for patients whose limited gastrointestinal

function does not permit adequate enteral absorption of nutrients. Despite its ability to maintain nutritional status and support growth, long-term PN has been associated with numerous serious and sometimes life-threatening complications, including bloodstream infections due to bacterial and fungal contamination of central venous catheters, metabolic derangements, and PN-associated liver disease (PNALD). The infant described in the vignette has PNALD, an extremely challenging problem that is especially common in patients who have short-bowel syndrome, for reasons that are not completely understood. Although the causes of hepatocellular dysfunction and cholestasis (indicated by direct hyperbilirubinemia and elevated gamma-glutamyl transpeptidase values) in this clinical setting may be multifactorial, current data suggest that excess intravenous lipids or specific elements in lipid emulsions play a major role in the pathogenesis of PNALD. Accordingly, the most reasonable approach for the infant in the vignette is to decrease the amount of infused lipid.

For the patient who has an extremely short bowel, PN serves as a "bridge therapy." Because the infant in the vignette retains only a short length of duodenum, the prognosis is dire for achieving any significant small bowel adaptation that can lead to recovery of intestinal absorptive function. Therefore, long-term survival clearly depends upon a successful small intestinal transplant. For patients in whom residual bowel length is sufficient to undergo adaptive change and support some level of fluid and nutrient absorption, early reintroduction of enteral feedings remains the best option for limiting the occurrence and severity of PNALD.

Careful ongoing clinical assessment is essential for all patients receiving PN to identify and treat potential complications of this therapy. In addition to routine biochemical monitoring scrupulous attention must be paid to strict adherence to aseptic technique, both in parenteral fluid preparation and central line care. Ideally, central venous catheter access, including care required for routine dressing changes, should be carried out only by personnel trained and credentialed in line management. Such precautions should limit PN-associated complications, although PNALD remains a vexing and often unavoidable problem.

•All major nutrients infused in PN solutions, as well as other factors (eg, infection, hepatic accumulation of bile acids) have been implicated in the pathogenesis of PNALD. However, advances in the composition and delivery of nutrients to infants receiving PN have resulted in amino acid profiles that mimic those during breastfeeding, and control of carbohydrate intake avoids hyperglycemia and wide swings in blood glucose values. Recently, increased focus has been placed on the role of intravenous lipids in the pathogenesis of PNALD. Both excess lipid administration and phytosterols, present in soybean emulsions used for PN, have been postulated as causative factors. Reducing infused lipids to 1.0 g/kg per day in this infant should ameliorate PNALD at least partially while preventing the onset of essential fatty acid deficiency. One recent study in two infants reported dramatic improvement in PNALD following replacement of the standard omega-6 fatty acid-based lipid infusate with a phytosterol-free omega-3 fatty acid emulsion.

Control of carbohydrate and protein intake, as demonstrated in the vignette, should limit PN-associated metabolic derangements. Accordingly, these major nutrients are much less likely to be implicated in the pathogenesis of PNALD in this infant, and reduction in parenteral glucose or amino acid intake would not be expected to ameliorate cholestasis. Early studies suggested that phenobarbital enhances bile salt-independent biliary flow. However, its efficacy in this condition has not been demonstrated, and this therapy is not recommended for use in any pediatric cholestatic state. Ursodeoxycholic acid is a bile acid that does not form micelles, undergoes enterohepatic circulation, and increases hepatocellular bile excretion. However, the extreme short bowel with absent ileum (the site of active bile salt reabsorption) described for the infant in the vignette precludes its effectiveness.

American Board of Pediatrics Content Specification(s):Know the complications of and understand how to monitor parenteral nutrition

A 17-year-old boy is referred to you by his school because of obesity. He has been in good health, except for a rapid increase in weight for the past 2 years. During that time, his parents have noted a change in his behavior, and they are concerned about his poor school performance. Because of declining grades and some difficulty in concentrating on his studies, the young man recently was diagnosed with attention-deficit disorder and has been treated with methylphenidate. Physical examination demonstrates a well-developed, obese adolescent, whose height is 170 cm and weight is 80 kg. The only other findings of note are a firm liver edge palpated 2 cm below the right costal margin and a palpable spleen tip. Initial laboratory results include:

Hgb 13.0 AST 60 ALT 55 ALK Phos 280 TBili 3.5 ESR 30

Because of these results, you obtain the following additional studies: HepA Ab neg, HepBsAb pos, HepBsAg neg, HepC Ab neg, Alpha-1-antitrypsin, 220 mg/dL (normal, 150 to 350) Serum ceruloplasmin, 22 mg/dL (normal, 20 to 60)

Of the following, the MOST appropriate next study is:

1. abdominal ultrasonography

2. Epstein-Barr virus titers

3. liver biopsy

4. serum copper measurement

5. slit lamp examination

Answer E• The adolescent boy described in the vignette presents with obesity, behavioral changes, and elevations in

transaminases. Results of laboratory studies are consistent with immunity to hepatitis B and no evidence of either hepatitis A or C infection. In addition, the alpha-1-antitrypsin value is normal, serum ceruloplasmin is just above the lower limit of normal, and erythrocyte sedimentation rate (ESR) is 30 mm/hr. Based on these clinical and biochemical data and the knowledge that serum ceruloplasmin is an acute-phase reactant that may be increased in the presence of an elevated ESR, Wilson disease (WD) must be ruled out. This may be achieved by performing both a slit lamp examination to determine the presence of Kayser-Fleischer (K-F) rings (Item C140A), the manifestation of copper deposition in Descemet membrane of the cornea, and a 24-hour urine copper determination. The serum copper concentration is not of diagnostic significance for WD in this clinical setting, and the presence of K-F rings, in conjunction with a 24 hour urine copper value of greater than 40 mcg is sufficient to diagnose WD. A liver biopsy (for copper content) may not be required. Abdominal ultrasonography may demonstrate hepatosplenomegaly in this case but will provide no further diagnostic clues. Assessment for other possible viral causes, including Epstein-Barr virus infection, is not indicated unless WD is excluded.

• WD, also known as hepatolenticular degeneration, was described initially in 1912 by Kinnear Wilson. If untreated, WD is a fatal disorder characterized by chronic liver disease leading to cirrhosis along with progressive neurologic deterioration. It is inherited in an autosomal recessive pattern and results from an abnormal ATP7B gene on chromosome 13. This gene encodes a metal-transporting P-type adenosine triphosphatase (ATPase), which is expressed primarily in hepatocytes and functions in the transmembrane transport of copper. Absent or reduced function of ATP7B protein resulting from this genetic abnormality leads to reduced hepatocellular excretion of copper into bile and the failure to incorporate copper into the copper-carrying protein, ceruloplasmin. Excessive hepatic copper accumulation causes hepatocellular injury that leads to inflammatory and, ultimately, cirrhotic changes. Eventually, copper is released into the bloodstream and deposited in other organs, including the brain, kidneys, and cornea (hence the appearance of K-F rings).

Answer E• The clinical presentation of WD may be subtle or overt, depending upon the age at presentation and

extent of copper-induced organ damage. The clinical characteristics of symptomatic WD patients are listed in (Item C140B). During childhood and early adolescence, other than cases diagnosed on the basis of family history (16% in one series), the overwhelming majority of patients present with evidence of hepatocellular dysfunction without neurologic sequelae. In most pediatric series, the mean age of presentation is around the end of the first decade. Children who have WD are usually evaluated because of hepatomegaly (82% of patients in one recent series) or persistent transaminase elevations, although in one series from the United Kingdom, acute liver failure was the presenting sign in almost 50% of patients. Among older adolescents and adults, psychiatric disturbances and neurologic dysfunction become apparent, with such signs found in 10% to 40% of reported cases by the end of the second decade. With increasing age, the psychoneurologic picture tends to predominate.

• For the patient who presents with signs of persistent hepatic dysfunction, irrespective of associated psychiatric or neurologic signs and symptoms, further evaluation follows an established practice guideline that is approved by the American Association for the Study of Liver Diseases. The diagnostic algorithm is based on three initial determinations: 1) K-F rings by slit lamp examination, 2) serum ceruloplasmin, and 3) 24-hour urine copper excretion. The diagnosis of WD is established in patients who present with K-F rings, a serum ceruloplasmin less than 20 mg/dL (200 mg/L), and a 24-hour urine copper excretion of greater than 40 mcg. For patients who do not meet the diagnostic criteria, a WD diagnosis may be confirmed by determining hepatic copper content on a percutaneous liver biopsy sample. A hepatic copper concentration of greater than 250 mcg/g dry weight is diagnostic for WD.

• Once the diagnosis is confirmed, treatment with an appropriate copper-chelating agent should begin immediately. WD represents the uncommon situation of a metabolic disease for which a specific pharmacologic therapy, if begun early in the disease course, is associated with complete symptom resolution, normalization of laboratory values (except for serum ceruloplasmin), and an excellent long-term prognosis. For patients who have hepatic disease, penicillamine, the first copper chelator to be successfully used for the treatment of WD, is an effective agent. However, penicillamine has been supplanted by trientine as the drug of first choice. Trientine is also indicated as primary therapy for patients who have neurologic involvement with or without WD hepatopathy. When patients have been stabilized, with normal serum transaminase values, zinc, which interferes with intestinal copper absorption, may be used either alone or in combination with trientine, accompanied by a low copper-containing diet.

Item C140B. Clinical Manifestations of Wilson Disease

Hepatic Acute liver failureChronic hepatitisCirrhosisElevated serum transaminases (persistent)Hepatosplenomegaly

Neurologic Abnormal gaitChoreoathetoid movementsChronic headaches (migrainelike)DysarthriaDystoniaInsomniaParkinsonianlike rigidityPseudobulbar palsySeizuresTremors

Ophthalmologic Kayser-Fleischer ringsSunflower cataracts

Psychiatric Behavioral/personality changesDepressionNeurosesPsychosis

Renal (uncommon) AminoaciduriaNephrolithiasis

You are asked to see a 16-year-old boy who has jaundice. He was well until 2 months ago, when he developed symptoms of an upper respiratory tract infection and scleral icterus was noted. At that time, blood tests showed:

Hgb 14.5 Albumin, 4.2 AST 20 ALT 22 TBili 4.5 DBili 0.2

His respiratory symptoms resolved after 1 week and his jaundice cleared. At his office visit today, he appears well and is anicteric. Physical examination demonstrates no abnormalities. Follow-up laboratory evaluation documents:

Hgb14.2 Albumin 4.3 AST 22 ALT 20 Tbili 2.4 Dbili 0.1

Of the following, the elevated bilirubin in this patient MOST likely results from

1. alpha-1-antitrypsin deficiency

2. Crigler-Najjar syndrome

3. Dubin-Johnson syndrome

4. Gilbert syndrome

5. hepatitis A infection

Answer D• The mild increase in unconjugated bilirubin that becomes clinically apparent during an acute respiratory illness and

otherwise normal liver function test results described for the boy in the vignette represent a typical presentation for Gilbert syndrome (GS), a benign disorder of bilirubin conjugation. GS is an autosomal recessive condition resulting from a mutation in the UGT-1 gene that impairs the functioning of the enzyme UDP-glucuronyl transferase. Clinical jaundice is noted most often in adolescents and young adults during periods of fasting, intercurrent illness, or physical stress. Both daily and seasonal variations are seen, although hyperbilirubinemia is mild and, by definition, less than 6 mg/dL (102 µmol/L). Up to one third of patients have normal bilirubin values. Although GS has been reported to complicate other conditions associated with hyperbilirubinemia, including neonatal physiologic jaundice and the hemoglobinopathies, patients who have GS are otherwise healthy and exhibit no associated hepatic or hematologic abnormalities. No clinical sequelae are associated with GS. Accordingly, no further diagnostic testing is indicated for the boy in the vignette, and both he and his family should be reassured about the benign nature of the condition.

• Crigler-Najjar syndrome (types I and II) is an extremely rare, autosomal recessive condition caused by absent (type I) or limited (type II) UDP-glucuronyl transferase activity. The disorder generally presents in the first few days after birth. In type I disease, serum unconjugated bilirubin values of 25 to 35 mg/dL (425 to 600 mcmol/L) or higher are common, and infants are at high risk of developing kernicterus unless aggressive phototherapy is initiated early. In contrast, patients who have type II disease (and rarely may present at an older age) usually have unconjugated bilirubin concentrations of less than 20 mg/dL (350 mcmol/L) and respond dramatically to treatment with phenobarbital, an inducer of the partially active UDP-glucuronyl transferase enzyme. Another disorder of bilirubin metabolism that presents in the newborn period is Dubin-Johnson syndrome. This condition, along with Rotor syndrome, is a rare disorder of hepatocellular excretion of conjugated bilirubin. Characteristic findings include elevations in the direct-reacting (conjugated) bilirubin fraction but without other evidence of cholestasis or hepatic dysfunction.

• Alpha-1-antitrypsin (A1AT) deficiency is an autosomal recessive disorder that may present with a cholestatic picture in newborns who express the Pi ZZ phenotype, identified by a characteristic serum electrophoretic migration pattern. The condition is not strictly a deficiency syndrome, but rather results from misfolding of the A1AT protein, thus preventing its hepatocellular export. Available data indicate that only 10% of newborns who have the Pi ZZ phenotype develop symptomatic liver disease with a clinical picture of cholestasis and elevations in serum transaminases. In these infants, A1AT deficiency must be considered in the differential diagnosis of neonatal direct hyperbilirubinemia. Although 50% of older Pi ZZ patients may develop transaminase elevations at some point, clinical expression of the disorder usually is characterized by obstructive pulmonary disease. Finally, infection with the hepatotropic virus hepatitis A may be ruled out for this boy on the basis of normal serum transaminase values.

A mother brings in her 5-week-old infant girl because of feeding difficulties. The baby weighed 3,300 g when born at term, and she has breastfed exclusively. Approximately 2 weeks ago, the parents noted that the baby became increasingly irritable, particularly during feedings, and she began spitting-up 4 to 6 times per day. Physical examination demonstrates a well-developed, alert but irritable infant whose weight is 3.85 kg, heart rate is 180 beats/min, and respiratory rate is 70 breaths/min. Lung sounds are clear. On physical examination, you note a hyperdynamic precordium and a grade 2/6 holosystolic cardiac murmur. Chest auscultation yields normal results. You palpate a firm liver edge 5.0 cm below the right costal margin. The spleen is not palpable. You also note a 2x2-cm hemangioma on the abdominal wall. Results of laboratory tests include:

Hemoglobin, 9.8 White blood cell count, 4.8 Platelet count, 80

Peripheral blood smear: Burr cells and schistocytes noted

Electrolytes: normal TBili 1.6 CXr: mild cardiomegaly.

Of the following, the study that is MOST likely to demonstrate the cause of this infant’s symptoms is

1. abdominal ultrasonography

2. acid alpha-glucosidase assay

3. bone marrow aspiration

4. Coombs test

5. echocardiography

Answer A• The infant described in the vignette presents with anemia, thrombocytopenia, and clinical signs suggesting high-

output cardiac dysfunction. In addition to tachycardia and tachypnea, the most significant physical finding is hepatomegaly, with a liver edge palpated 5 cm below the right costal margin. The differential diagnosis of liver enlargement during infancy can include inflammatory, infiltrative, obstructive, storage, and vascular disorders (Item C176). This infant’s clinical findings suggest an intrahepatic hemangioma that necessitates abdominal ultrasonography.

• The additional hemangioma-related complications (high-output cardiac failure, thrombocytopenia, and hemolysis) exhibited by the infant point toward the development of the Kasabach-Merritt phenomenon, a rare consequence of large vascular lesions that is characterized by hemolytic anemia, thrombocytopenia, and coagulopathy.

• Hemangiomas are the most common soft-tissue tumors of infancy, with an occurrence rate of 5% to 10% and a female-to-male predominance of 3:1. Most hemangiomas are cutaneous lesions, and greater than 55% may be identified at birth. They typically undergo a rapid early proliferative phase, reaching their maximum size by 6 to 8 months, followed by a gradual spontaneous involution.

• Although rare, compared with cutaneous lesions, hemangiomas of the liver are the most common hepatic vascular lesions found in newborns that often are multiple and involve both lobes. They are frequently, but not always, associated with cutaneous hemangiomas. Indeed, the newborn who has multiple cutaneous lesions should undergo screening for visceral hemangiomatosis. Similar to cutaneous lesions, hepatic hemangiomas grow rapidly during early infancy. However, they are associated with significantly higher morbidity and mortality rates than cutaneous hemangiomas and frequently present clinically as the consequence of secondary anemia and high-output congestive heart failure.

Answer A• Ultrasonography with evaluation of blood flow by Doppler is a cost-effective, noninvasive technique that

demonstrates the high-flow pattern characteristic of the hemangioma, helping to differentiate this lesion from solid tumors and other vascular or lymphatic abnormalities. Acid alpha-glucosidase assay, bone marrow aspiration, Coombs test, and echocardiography may be used in the evaluation of hepatomegaly, but none can target the likely cause of this infant’s illness. The acid alpha-glucosidase assay is the diagnostic study of choice in the evaluation of Gaucher disease, a lipid storage disorder characterized not only by hepatomegaly but also by massive splenomegaly.  Bone marrow aspiration is routinely performed to evaluate suspected blood cell dyscrasias, other nonhematopoietic malignancies, and storage diseases but would not be helpful in this infant in whom intravascular hemolysis (schistocytes on smear) is a possibility. In neonatal hemolytic disorders, the peripheral blood smear Coombs test is used to evaluate blood group incompatibilities. Hemolysis, extramedullary hematopoiesis, splenomegaly, and hyperbilirubinemia are common findings; thrombocytopenia is unusual. Finally, echocardiography may demonstrate a high-output state in this infant, but hemolysis and thrombocytopenia would be unusual associated findings in congenital cardiac disease.

• Liver size is assessed best by physical examination using a digital percussion technique. Imaging studies are extremely useful for identifying structures of the hepatobiliary tract and intrahepatic lesions, but these techniques should not be employed routinely to determine liver size. In newborns, the mean liver span, assessed by percussion in the right midclavicular line, ranges from 4.5 to 5 cm. During normal development, liver size increases linearly with both body weight and height, and by 12 years of age, the mean normal span is 7 to 8 cm in boys and 6 to 7 cm in girls. Because the precise position of the liver in the right upper abdominal quadrant may vary from individual to individual and may be affected by an associated clinical condition (eg, low-lying liver in the presence of pulmonary hyperinflation), a liver edge that is palpated below the right costal margin does not necessarily indicate enlargement. When the liver edge is palpable, a distance below the right costal margin of more than 3.5 cm during the neonatal period and greater than 2 cm in older infants and children is considered abnormal, irrespective of associated signs and symptoms.

• Depending on patient age, the observation of hepatomegaly, in conjunction with a careful history and the presence of other physical findings, should determine the course of diagnostic evaluation. Although hepatomegaly may represent a transient observation accompanying a systemic viral illness, persistent liver enlargement warrants further evaluation. When the liver edge is firm (as in the vignette), a storage or infiltrative disorder must be considered.

Item C176Differential Diagnosis of Hepatomegaly in Infants and Children

Inflammatory Autoimmune hepatitisBile acid synthetic and transport defectsIdiopathic neonatal hepatitisInfection (bacterial, parasitic, viral)MedicationsToxins

Infiltrative Extramedullary hematopoiesisHemophagocytic syndromesLeukemia, lymphomaMetastatic neoplasmsPrimary liver neoplasms (hepatoblastoma,

hemangioma)

Obstructive Choledochal cystCholelithiasisExtrahepatic biliary atresiaMalignancy (primary and metastatic)

Storage Fat

Malnutrition (Kwashiorkor) Obesity (nonalcoholic fatty liver disease) Parenteral nutrition

Glycogen Diabetes Glycogen storage diseases Parenteral nutrition

Lipid (metabolic disorders) Diabetes Fatty acid oxidation defects Gaucher disease Niemann-Pick disease Wolman disease

Other Hemochromatosis Neonatal iron storage disease Wilson disease

Vascular Budd-Chiari syndrome (hepatic vein thrombosis)Congestive heart failurePeliosis hepatis (multiple causes)Pericardial disease (restrictive)Suprahepatic web of the inferior vena cavaVeno-occlusive disease

A 3-year-old boy presents with a temperature of 39.5°C and a first-time generalized seizure. Over the past 3 days, he has had 8 to 10 loose, liquid stools and abdominal pain. He attends child care, and several other children in the center have been reported to have diarrhea.

Of the following, the MOST likely cause of this child’s illness is infection with

1. Campylobacter jejuni

2. rotavirus

3. Salmonella enteritidis

4. Salmonella typhi

5. Shigella flexneri

Answer E• Acute onset of fever, abdominal cramps, and diarrhea (often with blood and mucus) over 3 days, as

described for the boy in the vignette, are suggestive of a bacterial gastroenteritis. The associated seizure and attendance at a child-care center support the diagnosis of Shigella infection.

• Campylobacter jejuni infection can present with fever and similar gastrointestinal symptoms but has not been associated with seizures. In addition, Campylobacter is typically transmitted from contaminated poultry; outbreaks in child-care centers are uncommon.

• Nontyphoidal Salmonella infections, such as S enteritidis, are acquired from animal reservoirs, including poultry and livestock. Transmission from contaminated meats and eggs is the usual source of outbreaks, although other foods, including ice cream, fruits, and cider, have been implicated. Secondary person-to-person transmission can occur. Transmission of nontyphoidal Salmonella from contact with pet reptiles is another important source of infections. Infection may range from asymptomatic to gastroenteritis with diarrhea, abdominal cramps, and fever. Seizures are not commonly associated with these infections. Salmonella bacteremia can occur in younger children (<1 year old).

• S typhi is a solely human pathogen that is rare in the United States. Infection is associated with crowding and poor hygienic conditions. Most cases in the United States are acquired during international travel. Typhoid fever is a protracted illness characterized by fever, constitutional symptoms, abdominal pain and tenderness, hepatosplenomegaly, rose spots on the skin, and changes in mental status.

• Rotavirus infection is transmitted by the fecal-oral route and can be found on multiple surfaces in child-care centers. Clinically, the illness is characterized by the acute onset of fever and vomiting, with watery diarrhea developing 24 to 48 hours later. Severe infection generally occurs in children 2 years of age and younger.

You are asked to see a 6-week-old infant who has just been hospitalized because of an apparent life-threatening event. The baby was delivered via cesarean section at term following an uncomplicated pregnancy because of failure of labor progression. He weighed 3,200 g. He was started on cow milk protein-based formula at birth. At about 2 weeks of age, he developed postprandial emesis, and these episodes have increased so that the baby spits up once or twice after each feeding. He currently consumes 6 oz of formula every 3 to 4 hours. Several hours ago, immediately after feeding, the baby appeared to be choking, stopped breathing, and developed perioral cyanosis. He expelled formula from his nose and mouth. The parents called 911, and the infant was brought to the emergency department, where he appeared active and alert and had a weight of 4,400 g. The infant was admitted for evaluation and observation.

Of the following, the MOST appropriate next step is

1. barium esophagography

2. intraesophageal pH monitoring

3. lansoprazole administration

4. ranitidine administration

5. reduced feeding volumes

Answer E• An apparent life-threatening event (ALTE) is an observer-dependent phenomenon that is characterized by a

combination of apnea, abnormal muscle tone (limpness, rigidity), choking, and color change (pallor, cyanosis, plethora). ALTEs typically are reported in infants at 1 to 2 months of age and are rarely described after age 8 months. Although specific causes are poorly understood, gastroesophageal reflux (GER) has been implicated. However, supportive data are conflicting, and the relationship between apnea and GER remains controversial. Accordingly, for the infant described in the vignette, whose clinical history otherwise suggests a diagnosis of uncomplicated GER that may be exacerbated by overfeeding, current best evidence suggests that the most appropriate approach to management is to reduce feeding volumes and increase feeding frequency.

• GER is defined by the passage of gastric contents into the esophagus, with or without regurgitation or vomiting. It is a normal physiologic process occurring several times per day in healthy infants, children, and adults. Most episodes are transient, last fewer than 3 minutes, occur in the initial 2 hours postprandially, and are followed by rapid esophageal clearance of the refluxate. Such brief, recurring GER events are generally unassociated with clinical signs or symptoms. During the first 3 postnatal months, regurgitation (defined as effortless passage of gastric contents into the mouth) or vomiting events (which may be projectile) are noted daily in 50% of infants. These GER episodes arise from several potential anatomic and physiologic mechanisms, the most prominent being repeated transient relaxations of the lower esophageal sphincter (LES). As in the vignette, a diagnosis of GER in infants is based solely upon a history of spitting-up. Formal intraesophageal pH monitoring is of no value in routine evaluation. This study should be reserved for assessing equivocal reflux cases or in an attempt to correlate symptoms with reflux episodes. Barium esophagraphy cannot quantify the extent or severity of GER and is used solely to document anatomic integrity.

• Symptoms and signs that have been associated with prolonged or increased GER include both respiratory and nonrespiratory events (Item C244). Although regurgitation or vomiting are not consistent findings in older patients who have GER-related complications, spitting-up, with or without expulsion of gastric contents from the mouth, is considered a necessary condition for reaching a clinical diagnosis of reflux during infancy.

Answer E• Early studies suggested that a mechanism for reflux-induced apnea involved acid stimulation of

pharyngeal and esophageal chemoreceptors, leading to laryngospasm. However, more recent large case series have failed to demonstrate a consistent GER-apnea link. Where respiratory status was monitored along with both esophageal pH and bioelectrical impedance in infants presenting with a history of apnea, only 15% of apneic episodes were correlated with GER. Furthermore, these episodes were as likely to occur with non-acid as with acid GER. Additional data have failed to demonstrate any clinical efficacy of acid reduction therapy in preventing or ameliorating apnea events. Thus, acid blockade with either a histamine-2-receptor antagonist (ranitidine) or a proton pump inhibitor (lansoprazole) is not indicated in this clinical setting.

• GER has also been implicated as a causative or exacerbating factor for other respiratory disorders. Where studied using esophageal pH monitoring, 60% to 70% of children who have reactive airway disease demonstrate pathologic reflux. However, whether this degree of GER is a primary problem or a secondary phenomenon caused by lung hyperinflation and downward movement of the diaphragm, leading to displacement of the LES into the chest accompanied by a reduction in LES pressure, is unclear. Several studies have attempted to assess the role of acid reduction therapy in ameliorating asthma symptoms in both children and adults, and most have failed to demonstrate consistent treatment efficacy. However, a few reports have shown improvement in asthma symptoms following acid blockade for patients who have poorly controlled asthma, especially those who have predominantly nocturnal symptoms.

• GER has been implicated in causing recurrent pneumonia and interstitial lung disease, especially in children who have significant neurologic impairment. In these cases, lung disease presumably results from failure of normal airway mechanisms to protect the lungs from aspirated gastric contents. Several case series have presented conflicting results regarding the efficacy of either medical or surgical GER therapy in improving lung function and reducing the risk of pneumonia in affected patients. Because gastroesophageal and respiratory function are closely linked, the finding of pathologic GER in patients who have chronic pulmonary disease is not surprising. In one report, 27% of patients who had cystic fibrosis reported symptoms of heartburn. However, where studied by pHometry, the prevalence of pathologic GER in cystic fibrosis was even higher. Accordingly, GER may be considered an exacerbating factor for children and adults who have a wide range of chronic respiratory disorders, but as previously discussed, the effectiveness of acid blockade on respiratory symptoms in these patients has not been clearly demonstrated.