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Inflammatory bowel disease in early
childhood and adolescence: special
considerations
Petar Mamula, MD*,
Jonathan E. Markowitz, MD, MSCE,
Robert N. Baldassano, MD
University of Pennsylvania School of Medicine, The Children’s Hospital
of Philadelphia, Philadelphia, PA 19104, USA
The similarities between adult and pediatric patients diagnosed with
inflammatory bowel disease (IBD) are obvious and numerous. In this article
the authors describe some of the IBD features unique to the pediatric
population. These features could potentially have significant impact both in
research as well as clinical management of patients with IBD.
Epidemiologic data derived from studies in the pediatric population have
a potential to enable us to develop better understanding of IBD etiology,
especially environmental factors, as well as clinical features, which then may
allow for prediction of natural disease course. The diagnosis of IBD in
children comes often at a vulnerable time of growth and development.
Despite the increased nutritional needs related to the rapid periods of growth
during childhood and adolescence, many pediatric patients afflicted with IBD
will paradoxically demonstrate decreased appetite, increased metabolism,
and decreased absorptive capacity. Clinical presentation is often uncharac-
teristic, and environmental and genetic factors have a strong potential to
influence the natural history of disease [1,2]. As a result, IBD may have
profound effects on weight gain, linear growth, and bone mineralization,
some of which may not be reversible. Additionally, delayed sexual de-
velopment may have significant adverse effects on self-esteem and socializa-
tion. Beyond treating the overt symptoms of disease, therapy in children with
IBDmust be directed toward overcoming nutritional deficiencies to allow the
Gastroenterol Clin N Am
32 (2003) 967–995
* Corresponding author. Division of GI & Nutrition, The Children’s Hospital of
Philadelphia, 34th Street & Civic Ctr. Blvd., Philadelphia, PA 19104.
E-mail address: [email protected] (P. Mamula).
0889-8553/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved.
doi:10.1016/S0889-8553(03)00046-3
maximal potential for growth. These issues add a level of complexity to the
management of a child or adolescent with IBD. Finally, there is the issue of
health care transition to adult oriented health system. This issue was the main
topic of several recent conferences that emphasized the need for a de-
velopment of uniform guidelines designed to help both patients and their
families, as well as health care providers through this process.
Epidemiology
IBD is recognized as one of the most significant chronic diseases to affect
children and adolescents [3]. Pediatric IBD population-based epidemiolog-
ical studies are sparse for several reasons: high cost; potential for surveillance
error; and difficult execution because of the large number of patients needed,
and the results are often difficult to compare because of different criteria and
design [4,5]. In the United States most of the data come from large tertiary
care centers with a potential for a bias because of referral practice.
Recognizing the need for a large pediatric IBD registry, which would
allow for centralized data collection and would simplify execution of true
epidemiological studies, a pediatric consortium of six IBD centers was
formed. The goal for this registry is to grow into a nation-wide project and its
potential is in providing relevant information relating to risk factors
associated with IBD, true epidemiologic distribution and trends, clinical
features, and natural history [6]. The pediatric population is ideal for this
type of research for various reasons. Environmental factors potentially
leading to IBD may occur early in life; modification of early environment
may be attempted; patients with early onset disease tend to show more
aggressive disease with a stronger genetic influence; and access to patient’s
relatives is easier than in adult population [6]. Epidemiologic data on the age
of onset of IBD in 1074 pediatric patients from pediatric consortium are
presented in Fig. 1 [7]. Up to 31% of children in this series had a member of
extended family with IBD, while 4% and 12% had a sibling, or parent with
a history of IBD, respectively.
Overall, the sex distribution of IBD among children indicates slightly
increased preponderance of Crohn’s disease (CD) in boys [8], while ulcerative
colitis (UC) affects both sexes equally. At the Center for Pediatric IBDat The
Children’s Hospital of Philadelphia the authors follow approximately 1100
children with IBD. The demographic data on a sample of 425 children seen at
the main hospital site during the last 12 months supports previously noted
distribution as presented in Table 1. The age distribution follows a bimodal
pattern of incidence with the first peak in the second and third decades, and
a smaller peak in the sixth decade [9–11]. Up to 30% of all patients with IBD
are diagnosed during childhood [3]. Most recently, a well-designed pediatric
epidemiologic study of IBD in the United States was performed [12]. Data
were prospectively collected on 193 newly diagnosed patients with IBDin the
968 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
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969 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
state of Wisconsin sine January of 2000. Surprisingly high incidence rate of
4.5 per 100,000 was found in Crohn’s disease while the incidence rate for
ulcerative colitis was 2.2/100,000. This is in agreement with the impression
that during the last several decades incidence of IBD is increasing, more so
for CD than UC [10]. Analysis of time trends indicates a rapid rise in
incidence of Crohn’s disease from the 1960s to 1980s with subsequent
stabilization [13], although some studies indicate a continuing rise in recent
years [4,10,14]. The incidence of ulcerative colitis showed a more stable
pattern, although again with a tendency for an increase over the years [10,14].
Pediatric incidence studies fromEurope indicate similar patterns of increased
incidence for both types of IBD, although lower than in adults (Table 2)
[5,15–27]. The incidence rates for pediatric IBD range from 0.2 to 8.5 per
100,000 for CD and 0.5 to 4.3 per 100,000 for UC.
A recent hypothesis regarding the etiology of IBD supports the
multifactorial theory encompassing genetic predisposition, internal and
external environmental influences, and immune system disorder [6]. Genetic
factors are well recognized with a high rate of concordance between
monozygotic twins (44.4%) compared with dizygotic twins (3.8%) [28], and
frequent multiple family members [29]. Increased genetic influence in early
onset CD, or perhaps genetic anticipation, may account for the fact that
patients with CD below 20 years of age have a family history of this disorder
in 30% of cases, while only 13% of patients diagnosed later have a family
history. The newly discovered NOD2 gene associated with CD supports the
interaction between genetic predisposition and the environment since this
gene regulates immune responses to bacterial products [30,31]. Other studies
evaluated environmental factors, housing with hot tap water and a separate
bathroom, and lowinfant mortality rate coincide with the higher incidence of
CD. These results may suggest that clean environments delay exposure to
Table 1
Demographic data on a sample of 425 children with inflammatory bowel disease
Demographic
characteristics
Crohn’s disease and
indeterminant colitis (%)
Ulcerative colitis
(%)
Male 204 (48) 42 (10)
Female 123 (29) 56 (13)
0–5 years old 12 (3) 3 (1)
6–9 years old 26 (6) 8 (2)
10–13 years old 69 (16) 32 (7)
14–17 years old 136 (32) 35 (8)
18–23 years old 84 (20) 20 (5)
White 268 (63) 80 (19)
African American 43 (10) 14 (3)
Hispanic 3 (1) 0
Asian 1 (< 1) 1 (< 1)
Other 11 (3) 4 (1)
Total number 327 (73) 98 (27)
970 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
enteric infections, resulting in failure of the normal immunologic maturation
process necessary to develop oral tolerance later in life [32–34].
Clinical presentation
The presentation of IBD in children and adults depends on the disease
location and the extent of inflammation [35]. The most commonly
encountered gastrointestinal symptoms are abdominal pain and diarrhea.
The list of presenting clinical features compiled from several studies is
presented in Table 3 [3,15,36–43]. Abdominal pain can be located anywhere
in the abdomen, although in patients with CD it occurs frequently in the
right mid quadrant, whereas in patients with UC it is located in the lower
abdomen. Diarrhea may be associated with blood in the stool, more so in
UC. Other gastrointestinal symptoms include loss of appetite, weight loss,
nausea, vomiting, and perianal disease. Features like growth and pubertal
Table 2
Epidemiologic studies in pediatric Crohn’s disease and ulcerative colitis
Incidence
Author Country Time period CD UC
Langholz et al [15] Denmark 1962–1987 0.2 2
Barton et al [17] Scottland 1968–1983 2.3 1.6
Armitage et al [20] Scottland 1981–1995 2.5 1.3
Olafsdottir et al [26] Norway 1984–1985 2.5 4.3
Lindberg et al [5] Sweden 1984–1986 1.2 1.4
1993–1995 1.3 3.2
Hildebrand et al [18] Sweden 1984–1985 1.7 1.7
Askling et al [16] Sweden 1990–1998 3.8 2.1
Cosgrove et al [19] United Kingdom (Wales) 1983–1988 1.3 0.7
1989–1993 3.1 0.7
Hassan et al [23] United Kingdom (Wales) 1995–1997 1.4 0.8
RCPHC [27] United Kingdom 5.3
Sawczenko et al [22] United Kingdom/R. of Ireland 1998–1999 5.2
Tourtelier et al [21] France 1994–1997 1.6 0.6
Gottrand et al [24] France 1984–1989 2.1 0.5
Bjornsson et al [25] Iceland 1990–1994 8.5
Kugathasan et al [12] United States 2000 4.5 2.2
Table 3
Frequency of common presenting symptoms
Symptom Crohn’s disease (%) Ulcerative colitis (%)
Abdominal pain 62–95 54–76
Diarrhea 52–78 67–93
Hematochezia 14–60 52–97
Weight loss 43–92 22–55
Fever 11–48 4–34
971 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
delay may cause confusion during the diagnostic process especially if they
are predominant. These topics will be discussed separately.
Delay in diagnosis of IBD in the pediatric population continues to be
a concern, even with increasing incidence and heightened awareness of IBD.
Mean delay for CD in children is reported to be between 7 to 11 months, in
UC between 5 to 8 months, and in IC 14 months [21,37,44]. At the same
time the delay in adult population is even longer and is measured in years
[45]. The time lag between onset of symptoms and correct diagnosis of
Crohn’s disease appears to be prolonged if the disease affects more proximal
bowel, and if presenting symptoms do not include diarrhea. The diagnosis is
particularly difficult when the presenting symptoms are uncharacteristic and
consist mainly of extraintestinal manifestations.
Extraintestinal manifestations
Up to 35% of pediatric IBD patients in some series have at least one
extraintestinal manifestation as a presenting sign [46,47]. Common
symptoms in a series of pediatric IBD patients from Israel, included
anorexia, joint complaints, and anemia [48]. See list below for extraintestinal
manifestations seen in children with IBD. These manifestations may also be
noted concurrently with, or after the diagnosis of IBD is made [46].
Skin
Erythema nodosum
Pyoderma gangrenosum
Perianal disease
Metastatic Crohn’s disease
Mouth
Cheilitis
Stomatitis
Aphtae
Liver
Primary sclerosing cholangitis
Hepatitis
Cholelithiasis
Pancreas
Pancreatitis
Kidney
Nephrolitiasis
Obstructive hydronephrosis
Enterovesical fistula
Urinary tract infection
Amyloidosis
Growth
Delayed growth
972 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
Delayed puberty
Bone
Osteoporosis
Eye
Uveitis
Episcleritis
Conjunctivitis
Lungs
Pulmonary vasculitis
Fibrosing alveolitis
Vascular
Vascultis
Thrombosis (pulmonary, limb, cerebrovascular)
Joints
Arthralgia
Arthritis
Ankylosing spondylitis
Blood
Iron deficiency anemia
Anemia of chronic disease
Thrombocytosis
Autoimmune hemolytic anemia
Vitamin B12 deficiency
General
Fever
Fatigue
Weight loss
Anorexia
Skin manifestations include erythema nodosum and pyoderma gangre-
nosum. Erythema nodosum is more common in CD and affects 3% of
pediatric patients with CD [49]. It is estimated that 75% of the patients with
erythema nodosum ultimately develop arthritis [50]. Pyoderma gangreno-
sum, on the other hand, is more common in patients with UC and affects
less than 1% of patients.
Mouth ulceration is the most common oral manifestation of IBD. It is
more common in CD, frequently associated with skin and joint lesions, and
together with skin and eye manifestations often parallels the activity of
disease [36].
Ophthalmologic manifestations occur in about 4% of the adult
population with IBD, but less frequently in children and adolescents with
UC and CD [51]. The most common ocular findings are episcleritis and
anterior uveitis.
Arthritis is the most common extraintestinal manifestation in children
and adolescents, occurring in 7% to 25% of pediatric IBD patients [52].
973 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
The arthritis is usually transient, non-deforming synovitis, asymmetric in
distribution, and involves the large joints of the lower extremities. In
adults, the arthritis occurs when the disease is active, but in children the
arthritis may occur years before any gastrointestinal symptoms develop [53].
Hepatobiliary manifestations in children may precede the onset of IBD,
accompany active disease, or develop after surgical resection of all diseased
bowel [54]. Hepatic manifestations include elevation of aminotransferases,
chronic active hepatitis, granulomatous hepatitis, amyloidosis, fatty liver,
and sclerosing cholangitis. Chronic active hepatitis develops in less than 1%
of children with IBD [55]. Colitis at the time may be asymptomatic,
although the hepatitis may proceed to cirrhosis. Sclerosing cholangitis
develops in 3.5% of pediatric patients with UC, usually with extensive
disease, and less than 1% of pediatric patients with CD [55]. In a series of 36
pediatric patients with IBD who developed sclerosing cholangitis only four
had CD and 32 had UC [56]. The authors suggest heightened endoscopic
surveillance once the diagnosis of IBD is made in the setting of sclerosing
cholangitis since the time to dysplasia may be accelerated, as noted in three
pediatric patients who underwent proctocolectomy because of dysplasia.
Endoscopic retrograde cholangiopancreatography and magnetic resonance
cholangiopancreatography have significantly improved the ability to
diagnose this disease in the pediatric population.
The urologic manifestations of IBD include nephrolithiasis, hydro-
nephrosis, and enterovesical fistulae. Nephrolithiasis is a common renal
complication in pediatrics, and occurs in approximately 5% of the children
with IBD [3]. It usually is the result of fat malabsorption that occurs with
small bowel CD. Dietary calcium binds to malabsorbed fatty acids in the
colonic lumen and free oxalate is absorbed. This results in hyperoxaluria
and oxalate stones [57]. In patients with an ileostomy, increased fluid and
electrolyte losses may lead to a concentrated, acidic urine and the formation
of uric acid stones. External compression of the ureter by an inflammatory
mass or abscess may lead to hydronephrosis. Enterovesical fistulae, which
are more common in males, may present with recurrent urinary tract
infections or pneumaturia.
Thromboembolic disease is a rare but severe complication of IBD. Both
UC and CD are thought to be associated with a pro-thrombotic state with
enhanced parameters of coagulation [58]. Several different coagulation
abnormalities have been reported in patients with IBD, imparting an
increased risk for thrombotic vascular disease over the general population:
increased fibrinogen, thrombocytosis and abnormal platelet activation,
accelerated thromboplastin generation, elevation of factors V and VIII,
decreased antithrombin III, protein S and C deficiency, elevated anti-
cardiolipin antibodies, high plasma factor VII coagulant activity, resistance
to activated protein C, and prothrombin gene mutation (G20210) [59–61].
Thromboembolic complications are reported in 1.3% to 6.4% of pediatric
patients with IBD [58,60]. In the adult population, pulmonary, abdominal,
974 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
and peripheral veins and arteries are more commonly involved than cerebral
or retinal vessels. In pediatric IBD patients, cerebral and retinal vessels seem
to be affected more frequently than other sites, and thrombosis in these sites
carries a better prognosis than in adults. Most patients have active disease at
the time of the thromboembolic event, more so in children than in the adult
population.
Other extraintestinal manifestations may develop because of the side
effects of treatment. Those include pancreatitis, pericarditis, alopecia, osteo-
porosis, cataracts, acne, hepatitis, anemia, neutropenia, fibrosing alveolitis,
interstitial pneumonitis, and peripheral neuropathy. For example, pancreati-
tis may result from therapy with 5-aminosalicylic acid, 6-mercapto-
purine, corticosteroids and methotrexate; and peripheral neuropathy may
occur with metronidazole therapy, whereas corticosteroid therapy is associ-
ated with acne, cataracts, and osteoporosis.
Disease distribution and natural history of IBD
in children versus adults
The anatomic distribution of IBD is an important clinical feature, which
when thoroughly documented and described allows for improved compar-
isons of response to therapy and natural history among reported studies.
Crohn’s disease
In 139 adult patients with CD at the time of diagnosis 27% had small
bowel, 28% large bowel, and 43% ileocolic disease [62]. The extent of
disease progressed with time and, eventually 75% of patients had ileocolic
disease, whereas 88% underwent at least one operation. Pooled data of 14
pediatric studies with a total of 1153 children with CD revealed isolated
small bowel disease in 38%, small bowel and large bowel in 38% and large
bowel alone in 20% of cases [63]. In children 10 years of age and younger
40% had ileocolonic disease, which over time increased to 60%, and 43% of
patients required surgery [39]. In the authors series of children 5 years of age
and younger, isolated small bowel disease was seen in 11%, small bowel and
large bowel in 59%, and isolated large bowel disease in 30% of cases [64].
Perianal disease is seen in 11% to 18% of children with CD [8,65], while in
children younger than 5 years of age the documented rate was significantly
higher at 34%, similar to adult rate of 36% to 46% [64,66–71]. Upper
gastrointestinal CD is seen in 30% to 40% of children, while endoscopic
studies have shown even higher rates of up to 80% [3,72,73].
The studies of natural course of CDin adults more likely indicate a benign
course if patients stay in remission in the year after diagnosis [74]. However,
predicting the course is difficult until 2 years into the course of disease [75].
Early age at diagnosis was shown to be associated with more complicated
disease in adults [11], although a more recent study indicated that age had no
975 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
influence on change of location or behavior of the disease [76]. Studies on the
natural course of disease in children with CD are lacking. In one study
children with ileal disease had a better prognosis than ones with ileo-colonic
disease [49]. In a series of 100 consecutively diagnosed prepubertal patients
from Toronto, one third had mild disease never requiring corticosteroid
therapy, and one third had at least one exacerbation requiring corticosteroids
[77]. An additional 19% of patients had chronically active disease, but
achieved sustained remission with the use of immunomodulatory or surgical
therapy, and 10% of patients had chronically active steroid-dependent, or
steroid-refractory disease. In the same series, 36% of patients required
surgical therapy, which is significantly less than reported in earlier studies
[78,79]. The proportion of pediatric patients with CD requiring surgery was
28% in a recent study and it was shown to decrease over time, which was
mainly attributed to advances in medical therapy [5]. After the year of
diagnosis about 50% of patients with CD will be in a remission during any
given year [15], and less than 1% of patients have only a single episode of
disease activity [42].
In the series of 639 Swedish children with IBD, 8%of patients were 5 years
of age and younger and almost half of these patients carried a diagnosis of
indeterminate colitis (IC) [5]. The number of children diagnosed with IC is
higher than that seen in the adult population. In a large multi-center adult
study in Europe, 5% of adult patients were diagnosed with IC and a similar
proportion of 6% was seen in a series of 475 patients newly diagnosed with
IBD in Netherlands [80]. In the pediatric series of older children, 14% to
23% were diagnosed with IC [16,18,81]. In the authors’ experience with
82 children diagnosed with IBD at 5 years of age and younger, 23% were
diagnosed with IC [64]. Reasons for this difference are unclear, but one
possible explanation is a longer duration of disease in adults with a better
chance of establishing the specific diagnosis of CD or UC. Also, pediatric
gastroenterologists have in the past exhibited a less aggressive approach to
colonoscopy. During the period from 1984 to 1995 in the study of pediatric
IBD by Lindberg et al [5], the percentage of diagnoses made by colonoscopy
as opposed to rectosigmoidoscopy increased significantly from 50% during
1984 to 1986 to 90% in 1995. With recent more extensive colonoscopy and
histologic sampling of the terminal ileum, the proportion of children
diagnosed with IC is likely to decrease.
Ulcerative colitis
In UC, the distribution of disease is categorized as distal disease (disease
involving the rectum, or rectumand sigmoid colon), left-sided disease (disease
extending beyond the recto-sigmoid region), and pancolitis (disease involv-
ing the whole large intestine). In a large cohort of 1116 adult patients the
disease distribution was 63% with distal and left-sided colitis and 37% with
pancolitis [82]. Data compiled from several studies indicated that 14%
976 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
to 37% of adult patients have pancolitis, 36% to 41% left-sided colitis, and
44 to 49% involve the rectum/sigmoid colon [9]. Barton et al [63] found that
the distribution of disease in a group of 37 Scottish children with UC
corresponded with seven additional studies in 357 aggregate patients.
Proctitis was present in 22% of patients, left-sided colitis in 35%, and
extensive disease or pancolitis in 43% of patients. Most recent pediatric
epidemiologic study in 60 newly diagnosed patients with UC indicated high
proportion of 90% of patients with pancolitis [12]. The course and prognosis
of idiopathic ulcerative proctosigmoiditis was studied in 85 young patients
whose symptoms had begun before the age of 21 and the results were
compared with those in onset of similar disease as adults. The natural history
of proctosigmoiditis in young patients was found to be somewhat different
from that in adults, being characterized by a greater tendency to proximal
extension (38% versus 10%). When the disease remained confined to the
rectosigmoid region, the course and prognosis were no different than in
adults. Extension of the disease was unpredictable in individual patients, but
occurred in 73%of patients within 5 years fromthe onset of symptoms [83] in
contrast to proximal extension that was noted in 27% of adult patients in
a separate study [84].
In a study by Langholz et al [15] comparing clinical features and natural
history of UC in Swedish children and adults, abdominal pain was more
frequently found in children. The distribution of the disease was pancolitis
in 29%, and proctitis in 25% of children, compared with 14% and 46%
in adults, respectively. The cumulative colectomy rate after 20 years in
childhood onset UC was 29%, which was the same as in adults. Extension
of the disease was noted in 65% of the pediatric patients, and 70% of pa-
tients were in remission during 1 year. In a study at the Cleveland Clinic, pan-
colitis was seen in 63% of patients, left-sided colitis in 22%, and proctitis
in 15% [85]. In the largest reported series of 171 children with UC, 22%
had proctosigmoiditis, 36% left sided colitis, and 43% pancolitis [86]. Mild
disease was initially seen in 43%, and moderate to severe in 57% of patients.
Ninety percent of patients in the mild group had cessation of symptoms
within 6 months, compared with 81% in the moderate to severe group. The
response was independent of disease distribution and the overall 5-year risk
for surgery was 19%. During any subsequent year of follow-up 55% of
patients were symptom-free, 38% had chronic intermittent symptoms, and
7% had continuous symptoms. In their review Hofley and Piccoli [42]
reported that 10% of children had only a single episode, 20% had
intermittent symptoms, 50% had chronic symptoms but were not in-
capacitated, and 20%had incapacitating disease. Ten percent of patients had
fulminant colitis defined as less than 6 bloody bowel movements, abdominal
tenderness, fever, weight loss, anemia, leukocytosis, and low albumin.
Disease in patients with early onset of UC has been reported to have
variable courses. In young children (< 10 years of age) with UC 11% of
patients had severe, 37% moderate, and 53% mild disease [87]. Eventually
977 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
89%had total colonic disease within 2 to 10 years of the disease, from75%at
the presentation. An early study indicated that mild disease at presentation
was usually followed by a mild course [88]. In the authors’ series of 36
children with UC less than 5 years of age, 60% had proctitis and left-sided
disease, while 40% had pancolitis [64]. Four patients (11%) required
colectomy. In a series of patients diagnosed with UC before the age of 20,
22% required surgery after a mean follow up of 18 years [89], whereas up to
73% of steroid dependent patients with pancolitis required the same [90].
Nutritional aspects of IBD
Treatment of children and adolescents with IBD is often based on
experience first obtained in the adult population. Treatments become
available in the adult population before the pediatric population, and many
treatments never receive a formal pediatric indication. For many aspects of
IBD, this is acceptable. However, there is a particular aspect of IBD for
which there is no adult equivalent—the effects on growth and development.
It is widely accepted that IBD has significant effects on nutritional status.
A combination of decreased intake and increased metabolic demands
present an especially large burden for the body afflicted with IBD. The
situation is exacerbated by the already increased nutritional demands to
maintain normal growth and maturation. When IBD is active during critical
periods of growth, it is extremely difficult to compensate for the increased
demands with oral intake alone [91–93]. The effects of poor nutrition during
childhood are long lasting, making the recognition and treatment of
malnutrition a critical aspect for the care of children with IBD.
By the time most children are diagnosed with IBD, they are already
malnourished to a degree. Up to 85% of children with CD, and as many as
65% of those with UC, will have growth failure at the time of diagnosis [94].
The earliest sign of growth failure may be decreased linear growth, with
almost 90% of children and pre-pubertal adolescents demonstrating reduced
height velocity before diagnosis, almost one-half of whomdevelop alterations
in growth before the development of gastrointestinal symptoms [95].
Poor intake may be the most important contributor to malnutrition in
IBD [3,96,97]. Several studies have documented that dietary intake is
chronically deficient in most growth-retarded children with Crohn’s disease
[93,98,99]. Nausea, abdominal pain, bloating, and diarrhea may cause
patients with IBD to limit their intake. Anticipation of these symptoms may
lead to behavioral conditioning and anorexia, which may be further
exacerbated by depression [100].
Nutritional status can be markedly improved with calorie supplementa-
tion. Intravenous nutrition administered during acute exacerbations can
maintain fluid and electrolyte status and arrest some of the early catabolism
of protein stores [101,102]. Growth retardation also responds to enterally
978 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
administered calories, as evidenced by a series of patients in whom caloric
intake was increased through nasogastric feedings [103]. By improving
caloric intake over a 1-year period, significant improvement was seen in both
height and weight velocity revealing that calorie supplementation alone is
adequate to promote growth in many cases. Even short-termenteral nutrition
is adequate to induce improvement in weight gain. Lean body mass increased
in a series of adolescents with IBD, based on radiolabeled leucine metab-
olism, after only 3 weeks of increased enteral calories when protein intake
was increased from 2.3 to 3.2 g/kg body weight per day [98].
Despite the opportunity to intervene with nutritional therapy, however,
some consequences of malnutrition during childhood may be irreversible.
When adjusting height for genetic potential based on parental height, many
patients with CD never achieve expected levels [97] as demonstrated by
measuring body composition in 132 subjects with CD and 66 controls, aged
5 to 25 years. In this population, adjusted height Z-scores were significantly
lower than predicted heights. These findings were most pronounced in male
patients, in whom the average adjusted height Z-score was a full standard
deviation below expected.
Growth assessment
Accurate assessments of growth and nutritional status are the corner-
stone for successful treatment. When dealing with growth measurements in
children, inaccuracy of even 1 or 2 cm of height measurement can drastically
change interpretations. Therefore, trained personnel, under standard
conditions should perform growth assessments. The same scale should be
used for serial assessments, a stadiometer should be used for all height
assessments, and the patient should be assessed wearing a similar amount of
clothing each time (most easily accomplished with the patient disrobed).
Growth irregularities in children with IBD have been measured in various
ways, including weight for age, height for age, height and weight adjusted Z-
score, height velocity, and various anthropometric measures, such as head
circumference, midarmcircumference, and triceps skinfold thickness [94,104].
The need for specialized training and equipment precludes the use of all these
assessments with each visit; accurate measurements of height and weight
usually suffice for clinical purposes. Height and weight measurements should
be plotted on a standard growth curve, which allows comparison against an
age-matched population. Height and weight deficit calculations expressed as
a ratio of the actual height or weight divided by the expected value based on
the 50th percentile for age, can give insight into the duration of malnutrition.
In cases of short-term deficiencies, one can expect weight deficit (wasting),
while long-term malnutrition often results in height deficit (stunting) [104].
The value of an accurate height and weight measurement, however, goes
beyond these values at any one point in time. To thoroughly understand
whether a patient’s growth is normal it must be considered in the context of
979 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
the patient’s genetic potential, often assessed using mid-parental height
[105]. There is more value in following several growth points over time than
any individual value. Reduction in growth velocity may be evident in
patients who remain in the normal range on a standard growth curve [95].
Accordingly, growth velocity (rather than height for age percentile) has been
incorporated into the scoring system of the Pediatric Crohn’s Disease
Activity Index (PCDAI) (Fig. 2). This index has been developed and
validated by a group of senior pediatric gastroenterologists in 1991 [106] and
correlates well with the original Crohn’s Disease Activity Index (CDAI)
developed for adult patients [107].
Another important reflection of overall nutritional status is progression of
sexual development. Delay in the onset of pubertal development is common
among adolescents with IBD, and active disease could potentially delay the
onset of puberty indefinitely [108]. Once an adolescent enters puberty, changes
in disease activity can slow down or arrest its progression. These potential
derangements have important implications for the adolescent patient.
Once a patient has developed secondary sexual characteristics, growth
potential may be irreversibly lost, whereas those whose disease is in
remission before entering puberty generally experience improved height
velocity and catch-up growth [109]. Accurate staging of sexual development
can be accomplished by monitoring breast and pubic hair development in
girls and by monitoring genital and pubic hair development in boys [110].
Tanner stage should be regularly included as part of the evaluation of young
patients with IBD.
Nutrient deficiency
Althoughgrowthparameters andsexual development may give a very good
overall representation of nutritional status, vigilance is needed to avoid the
development of deficiencies in micro and macronutrients. Periodic assessment
of dietary intake through diet records is an easy way to assess whether patients
receive a diet sufficiently balanced in protein, carbohydrates, and fats and
whether it provides daily requirements in important micronutrients.
Particular attention should be paid to intake of iron. Up to 70% of
children and adolescents with IBD are iron deficient [111], because of
a combination of inadequate intake, decreased absorption, and increased
losses. Iron supplementation is commonly associated with gastrointestinal
side effects, which may decrease patient compliance [112]. It is important
therefore, to monitor both a patient’s intake of iron (through dietary
records) and objective parameters of iron deficiency such as hemoglobin
concentration, reticulocyte count, mean corpuscular volume, red blood cell
distribution width, and levels of iron, ferritin, and transferrin saturation.
Absorption of other micronutrients, in particular vitamin B12, folic acid,
vitamin D and calcium, may also be impaired under various conditions in
IBD, such as after intestinal resection or with the use of certain medications.
980 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
Bone disease in pediatric inflammatory bowel disease
Calcium homeostasis and bone growth is one of the most important
aspects of malnutrition in pediatric IBD. The acquisition of bone mineral
should occur throughout growth and development. It is now believed that
peak bone mass (PBM) is a major determinant of the risk for osteoporosis
later in life [113]. With at least 90% of PBM acquisition occurring during
Fig. 2. Height velocity chart (boys).
981 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
childhood and adolescence, 25% of which is during the time of peak height
velocity, anything that interferes with normal bone development during
childhood has the potential for lifelong implications [114]. Effective
prevention of osteoporosis and its consequences must therefore occur
during childhood, and identifying those patients at risk for abnormal bones
is of paramount importance.
Factors associated with bone disease in IBD include malnutrition and the
effects of cytokines and glucocorticoid therapy. Malnutrition can lead to
abnormalities in both calcium and vitamin D homeostasis. Vitamin D
deficiency is common among patients with IBD, and CD in particular, with
over 50% of patients demonstrating abnormal levels [115]. Calcium
deficiency may occur in the setting of decreased dairy intake because of
lactose intolerance and fat malabsorption, both of which may be related to
small bowel involvement in CD. Various inflammatory cytokines have been
implicated in the development of bone disease [116,117]. Glucocorticoid
therapy has negative impact on calcium homeostasis [118,119] and on bone
remodeling [120,121]. Corticosteroids also depress calcitonin levels, resulting
in further bone resorption [122]. Despite the negative effects of glucocorti-
coids on bone density, however, growth failure and significant bone disease
can be present before treatment with corticosteroids [123,124].
The prevalence of osteopenia in children with CD has been reported on
a series of 119 patients [125]. In this report, 70% of patients had bone
mineral density 1 standard deviation below age-matched norms, with nearly
one-third having scores 2 standard deviations below normal. A follow up
report found that the risk of having low bone mineral density was most
associated with hypoalbuminemia, the need for nasogastric or parenteral
nutrition, the use of the immunomodulator 6-mercaptopurine, and the use
of corticosteroids [126]. Specifically, an average corticosteroid dose of
7.5 mg per day, a cumulative lifetime dose of 5 g, or 12 months of life-
time exposure were associated with the worst bone density.
Calcium supplementation seems to be one of the best ways to prevent
bone disease. Even among normal children who receive the recommended
daily allowance of calcium, supplementation can result in improved bone
mineral density [127]. Furthermore, among children with inadequate calcium
intake, supplementation results in improved bone mineral density [128].
These results are reversible, however, because the benefits of supplementa-
tion disappears 18 months after supplementation is discontinued [129]. It
may be most important to begin supplementation early in childhood, as
success seems to decline as subjects enter puberty [127,130,131]. The
implications for pediatric patients with IBD are clear. Given that pediatric
patients with IBD are at risk for inadequate calcium intake, it is very likely
that they will benefit from supplementation, optimally given before puberty
starts. Further success in preventing bone disease may be seen with low
impact exercise programs that will compensate for decreased physical
activity in those whose disease is active [132].
982 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
It remains controversial as to whether bisphosphonates have a role in the
treatment of pediatric patients with IBD. Effective in the prevention of
vertebral compression fractures associated with corticosteroid use [133,134],
these compounds are being considered as a potential treatment for bone
disease associated with IBD. One of these compounds, alendronate, was
shown to improve bone mineral density in adult patients with CD also sup-
plemented with calcium and vitamin D, as compared with a group receiving
placebo for 12 months [135]. Potential effects on bone remodeling, however,
raise some concern over the use of bisphosphonates in pediatric patients.
To date, long-termadverse effects of these medications on bone remodeling
have yet to be demonstrated in pediatrics [136]. There have also been studies
that have shown normal vertebral remodeling in children receiving bis-
phosphonate for other bone disorders [137]. Nevertheless, because of the
relative lack of data specific to pediatric IBD, use of these medications should
be limited to those with severe osteoporosis unresponsive to the proven,
better-studied modalities. Controlled trials of these medications are needed in
the pediatric IBD population, and it is likely that more information on the
long-term effects of bisphosphonates will be available soon.
Quality of life and coping strategies
Childhood and adolescence is a period of intense physical, emotional,
social and intellectual growth and change. The transition into adulthood is
a turbulent time when adolescents are finding their identity, improving their
social skills and cognitive abilities, and when their belief systems are being
shaped. To a great extent this development affects how they will respond to
events as adults later in life. This may explain why various psychologic and
social issues may be more pronounced in children and adolescents than
adults with IBD. Adults may be better equipped to express their wants,
needs, and feelings in a social situation or with their family. Furthermore,
adults may have developed problem-solving skills that allow them to adjust
to these situations better than children who have yet to develop these skills.
Physicians are becoming increasingly aware that traditional methods of
evaluating clinical status of patients with IBD may not accurately reflect how
patients feel about their illness, how they function on a day-to-day basis, and
their worries and concerns [138]. This is why health-related quality of life
(HRQOL), defined as ‘‘a global measure of the patient’s perceptions, illness
experience, and functional status that incorporates social, cultural, psycho-
logical, and disease-related factors’’ [139], becomes an important aspect
of care. HRQOL questionnaires have been studied extensively in adult pop-
ulations, but similar child and adolescent studies are lacking [140–145]. A
disease-specific quality of life measure that encompasses the issues unique to
pediatric population is currently being developed and validated.
The concerns of children and adolescents diagnosed with IBD mostly
overlap with those of adults, but some are unique to the pediatric
983 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
population. It has been reported that children initially deny that IBD
interfered with their lives, but with further probing, many admit frustration
and anger about their physical symptoms, unpleasant treatments, and the
lack of understanding of the illness by others [146]. Major concerns of
children are also energy level and body image [147,148]. Children often feel
a lack of control with their choices regarding a variety of activities ranging
from leisure and sports to school and employment. They believe they are
missing opportunities because of lack of energy, exacerbation of the disease,
and feelings of isolation. In a meta-analysis of different chronic diseases in
children, IBD had the most profound effect on mental health of all the
medical diseases reviewed [149].
When a child or adolescent is diagnosed with IBD parents and siblings
also have to learn how to cope with illness [150]. The dynamics of the family
may change by bringing more attention to the child with the illness, which
may cause jealous feelings in siblings. Parents may have worries and fears
about how the disease will affect the child’s future, potential problems at
school, side effects of medications, and feelings of guilt. The most common
concerns of siblings of IBD patients are that they are being kept in the dark
about the disease, fear about the disease and treatment, and feeling jealous
of parents’ overprotection of the ill child.
Children with IBD experience a multitude of stressors, including altered
physical appearance, decreased physical functioning, demanding treatment
regimens, pain, diarrhea and fecal incontinence, and school absences. Some
of the variability in children’s adjustment to illness may be because of
differences in the degree of disease severity, age, and sex of the child.
However, psychosocial factors also influence adjustment to IBD [151]. Thus,
the way a child responds to illness-specific stressors must be considered be-
cause this affects the course of the illness and the child’s overall adjust-
ment [152]. Understanding the role of coping strategies is thus essential
to facilitating maximal adjustment to a chronic illness.
Coping strategies are commonly classified as either problem-focused or
emotion-focused. Children who use problem-focused strategies cope by
gathering information [153]. They then make educated decisions regarding
howto most effectively manage the situation through direct action. Emotion-
focused strategies seek to manage somatic, subjective, and affective responses
to the stressor [154]. In this case, typical coping mechanisms include denial
and distraction. Social support has been found to positively influence the
quality-of-life of adolescents with IBD [155]. Gillman [156] notes that these
children with IBD may have difficulty recognizing or acknowledging
stressors, and may therefore continually use ineffective coping strategies.
A positive approach style includes problem-focused strategies of cognitive
restructuring and problem-solving, emotional regulation, and social support.
Anegative avoidance style includes emotion-focused strategies of distraction,
denial, wishful thinking, and resignation, also social withdrawal, blaming
others, and self-criticism. An additional factor determining adjustment to
984 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
illness is the presence of mental health issues such as anxiety and depression.
Underlying mental disorders may affect the way a child responds to her or his
stressors, and thus to her or his illness.
Multidisciplinary teams treating patients with IBD and their families need
to recognize the aforementioned concepts, and use this information
accordingly. Psychological treatment may be used to teach patients ways
to facilitate their adjustment and maintain their typical daily lives. For
example, these patients may be guided to use family and peer support to
adjust to changes in their appearance caused by medications. They may learn
to schedule activities when they feel most energetic, and to rest at other times.
They may get through episodes of pain by performing learned techniques
such as muscle relaxation and deep breathing, and by becoming attuned
to the specific techniques that are most helpful to their personal illness
experience. Educational intervention is crucial, to inform children and
adolescents about their medical condition so that they can use appropriate
coping strategies. Education may be achieved through informal conversation
with their parents and professional staff and through formal educational
programs and literature. Parents will also benefit from intensive education
about their children’s conditions and learning strategies to help them gain
control and adapt to living with a child with a chronic illness. Teaching
parents strategies to facilitate appropriate systemic involvement, such as
school participation with medications and special arrangements, will help
them gain their own sense of competency and control while simultaneously
helping to improve their children’s quality of life.
Team approach
Because of a complex nature of issues surrounding the care of a child or
adolescent with IBD it is necessary to adopt a multidisciplinary approach,
and devise an individual plan for therapy. In addition to parents, siblings,
and family members, teachers and school nurse should also be part of the
team. They should be informed about important aspects of IBD, especially
symptoms. The medical support team ideally should include physician,
nurses and nurse practitioners, nutritionist, social worker, and psychologist
(Fig. 3). The authors believe that a team effort is necessary to ensure
comprehensive, state of the art, care which allows IBD patients to achieve
appropriate levels of physical, mental, and social sense of well being.
Transition of the patient with inflammatory bowel disease
from pediatric to adult care
The needs of adolescents with chronic conditions and their health care
transition to adult-centered services have been a focus of interest of several
conferences during the last two decades. However, no clear model for
985 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
transition exists in the United States. Therefore, the American Academy of
Pediatrics sponsored a national invitational conference that made the health
care transition one of the priorities in an effort to assure comprehensive
community-based service systemfor all children and youth with special health
care needs by the year 2010 [157]. The consensus statement has identified these
critical initial steps: (1) identification of a health care professional who
assumes the responsibility for health care planning, (2) identification of the
core knowledge and skills required to provide transition services, (3) creation
of up-to-date medical summary that is portable and accessible, (4) creation of
a written health care transition plan, (5) application of the same guidelines for
primary and preventive care for all adolescents and young adults, and
(6) provision of affordable, continuous health insurance coverage.
What is transition? The position paper by the Society for Adolescent
Medicine defines transition as ‘‘the purposeful, planed movement of ad-
olescents and young adults with chronic physical and medical conditions
from child-centered to adult-oriented health care system’’ [158]. The passage
from adolescence to adulthood is a time of internal turmoil and intense
examination of personal goals and wishes. Being ill during this time of
growing and changing may cause frustration about the present and anxiety
about the future. The growing adolescent must be able to progressively shed
the sheltered environment of childhood and achieve self-reliance and
independent living as a decision-maker. For the chronically ill adolescent,
this period of transition can be stressful not only for the patient but also for
their families and their health care providers [158–162].
For the process of transition to be successful some prerequisites should be
met [163]. For example, adolescents have to be ready, should consent to
transition, and they should be educated about the important issues relating to
Fig. 3. Inflammatory bowel disease support team.
986 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
their condition and treatments. They should be able to recognize emergencies
and be aware of the support system available. The process of transition
should begin when a patient enters mid adolescence. The pediatric gastro-
enterologist should begin seeing adolescent patients without their parents
to build a relationship which promotes independence and self-reliance.
It is important to discuss with the patient and the family that in the future
they will need to transition to a gastroenterologist who is also trained in inter-
nal medicine with expertise in dealing with medical problems that occur
during adulthood, including pregnancy, fertility, and cancer surveillance.
During the transition several obstacles may be encountered [164].
Patients, parents, and other family members may feel threatened by changes
in the pattern of care, and resentful of the effort required to adjust to a new
setting and different staff. They frequently regard strong source of advocacy
form pediatric team as a permanent arrangement. In contrast, they may
perceive the internist who expects to care for an independent individual as
less involved or less sensitive to the developmental and social aspects of their
medical conditions. Health care providers may also feel ambivalent during
this period of change. The pediatrician may view the maturation of the child
as a professional and personal achievement, and find difficulty in relin-
quishing the patient to others whose style of practice he or she may not
know well. Internist–gastroenterologist may find patients with childhood
onset IBD immature and their families demanding.
Once the decision to pursue a transition program has been made the
pediatrician or pediatric gastroenterologist should have a well-thought
transition plan ready. They need to prepare a detailed medical summary
describing the course of the disease, therapy, allergies, and so on. Copies of
the relevant tests should also be prepared. The next step is to identify a skilled
gastroenterologist who cares for young adults. This individual must realize
that a young adult with childhood onset IBD may have a different set of
expectations than the young adult with recent onset of IBD. They may expect
for a gastroenterologist to spend more time with them than what is
customarily spent with other adult patients, which in some instances may
require reorganization of a practice to allow for additional time. These
patients may expect ready access to nurse practitioner or physician. They have
a heightened risk for the development of cancer and will require an increased
need for cancer surveillance. In a case where there is additional growth
potential present as a result of delayed puberty the pediatric gastroenterol-
ogist should remain on the team to provide necessary expertise [164].
A transition program should result in improved compliance with therapy
and effective planning of long-range life needs. These also include the need
for a benefits package to be designed covering issues of continuing health
insurance, life insurance, disability, and so on.
The successful transition from pediatric to adult health care systems is an
ongoing process, which should address medical, behavioral, and social
issues and not be seen as merely a transfer of care.
987 P. Mamula et al / Gastroenterol Clin N Am 32 (2003) 967–995
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