Transcript QOD Development - Robert Wood Johnson Medical School

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 papilledema
No facial weakness or asymmetry
Normal cranial nerves
Upper extremities: Strength 4/5, normal deep tendon reflexes and
sensation
Lower 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.
2.
3.
4.
5.
Campylobacter jejuni
Clostridium difficile
Escherichia coli O157:H7
Salmonella type D
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.
2.
3.
4.
5.
abdominal CT scan
alpha-1-antitrypsin assessment
intraoperative cholangiography
percutaneous liver biopsy
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-1antitrypsin (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.
2.
3.
4.
5.
celecoxib
ibuprofen
methotrexate
misoprostol
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 16year-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 longterm 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 antiinflammatory 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 antiinflammatory 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.
2.
3.
4.
5.
intussusception
ondansetron toxicity
sepsis
viral gastroenteritis
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 sausageshaped 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.
2.
3.
4.
5.
abdominal CT scan
abdominal ultrasonography
hepatobiliary scintigraphy
MR cholangiopancreatography
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.
2.
3.
4.
5.
administration of lansoprazole 1 mg/kg/day
administration of ranitidine 3 mg/kg BID
an upper GI series
thickening of formula with rice cereal
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 doubleblind, 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 communityacquired 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.
2.
3.
4.
5.
add phenobarbital 5 mg/kg/day orally
add ursodeoxycholic acid 20 mg/kg/day orally
decrease amino acids to 1.5 g/120 kcal/day
decrease dextrose to 10%
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 PNassociated 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 PNassociated 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 welldeveloped, 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.
2.
3.
4.
5.
abdominal ultrasonography
Epstein-Barr virus titers
liver biopsy
serum copper measurement
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 longterm 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 coppercontaining diet.
Item C140B.
Clinical Manifestations of Wilson Disease
Hepatic
Acute liver failure
Chronic hepatitis
Cirrhosis
Elevated serum transaminases (persistent)
Hepatosplenomegaly
Neurologic
Abnormal gait
Choreoathetoid movements
Chronic headaches (migrainelike)
Dysarthria
Dystonia
Insomnia
Parkinsonianlike rigidity
Pseudobulbar palsy
Seizures
Tremors
Ophthalmologic
Kayser-Fleischer rings
Sunflower cataracts
Psychiatric
Behavioral/personality changes
Depression
Neuroses
Psychosis
Renal (uncommon)
Aminoaciduria
Nephrolithiasis
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.
2.
3.
4.
5.
alpha-1-antitrypsin deficiency
Crigler-Najjar syndrome
Dubin-Johnson syndrome
Gilbert syndrome
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.
2.
3.
4.
5.
abdominal ultrasonography
acid alpha-glucosidase assay
bone marrow aspiration
Coombs test
echocardiography
Answer A
•
The infant described in the vignette presents with anemia, thrombocytopenia, and clinical signs suggesting highoutput 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 highoutput 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 C176
Differential Diagnosis of Hepatomegaly in Infants and Children
Inflammatory
Autoimmune hepatitis
Bile acid synthetic and transport defects
Idiopathic neonatal hepatitis
Infection (bacterial, parasitic, viral)
Medications
Toxins
Infiltrative
Extramedullary hematopoiesis
Hemophagocytic syndromes
Leukemia, lymphoma
Metastatic neoplasms
Primary liver neoplasms (hepatoblastoma,
hemangioma)
Obstructive
Choledochal cyst
Cholelithiasis
Extrahepatic biliary atresia
Malignancy (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 failure
Peliosis hepatis (multiple causes)
Pericardial disease (restrictive)
Suprahepatic web of the inferior vena cava
Veno-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.
2.
3.
4.
5.
Campylobacter jejuni
rotavirus
Salmonella enteritidis
Salmonella typhi
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-toperson 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 childcare 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.
2.
3.
4.
5.
barium esophagography
intraesophageal pH monitoring
lansoprazole administration
ranitidine administration
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.