A., a 2-year-old white female, presents to her primary physician with complaints of constipation and abdominal pain. A. was born fullterm and had no problems throughout infancy. She was exclusively breastfed until 9 months of age and gained appropriate weight until then. At 9 months, A.’s mother began introducing Cheerios, rice cereal, and canned baby food. One month later, A. developed abdominal pain and distention after meals. Over the past year, A. has continued to have abdominal pain with meals, despite cutting back on juice and milk. She stools once per week and has developed painful ulcers inside her mouth.
On physical exam, A. is a fussy, thin girl in no acute distress. She is afebrile and vital signs are stable. Her weight is at the 10th percentile and her height is at the 40th. At her 18-month checkup, weight and height had both been at the 40th percentile. Physical exam is remarkable for a distended abdomen with hyperactive bowel sounds. She has 2 small ulcers inside her mouth. Initial laboratory results include a normal BMP and a hematocrit of 29. Her stool is negative for blood.
Discussion: Celiac disease (CD), an autoimmune intolerance to gluten, occurs in 1% of the United States population. It is also seen with increasing frequency in patients of Northern African, Middle Eastern, and South Asian descent. CD is the result of an autoimmune reaction between dietary gluten and the tissue transglutaminase (TTG) autoantibody, which occurs in patients with the HLA-DQ2 or HLADQ8 haplotype. The reaction leads to villous blunting, crypt hyperplasia, and an increase in intraepithelial lymphocytes in the small bowel.
The clinical presentation of a child with CD is diverse, ranging from asymptomatic siblings to patients with behavioral changes. Common gastrointestinal symptoms include failure to thrive, oral ulcers, vomiting, abdominal distention, constipation, and chronic nonbloody diarrhea. Extra-intestinal manifestations of CD include short stature, dermatitis herpetiformis, osteopenia/osteoporosis, arthritis, hepatitis, iron-deficiency anemia, peripheral neuropathy, epilepsy, and pubertal delay.
CD is associated with other autoimmune and genetic disease— approximately 10% of patients with type 1 diabetes mellitus or trisomy 21 have the disease. Patients with Turner syndrome and Williams syndrome have an increased incidence of CD. Many of these patients may initially have negative serology, but periodic testing is warranted, because serologically positive tests may occur in many patients.
Diagnosis involves obtaining a celiac panel while the child is consuming gluten. The panel includes total serum IgA and IgA tissue transglutaminase, and IgA endomysial antibody levels. If the panel is positive, one should perform endoscopy with duodenal biopsy, the gold standard of diagnosis. The biopsies are histologically staged based on the Marsh classification. Type 0 is normal intestinal mucosa, type 1 shows increased intraepithelial lymphocytes, type 2 is type 1 + hyperplastic crypts, and type 3 is type 2 + villous blunting (subdivided into 3a, 3b, and 3c, based on the degree of atrophy.)
A CD diagnosis is appropriate if a patient has positive serology
and duodenal biopsies staged as type 1 or higher. Patients with normal
biopsies and positive serology are not classified as having CD but should
Therapy for CD involves lifelong avoidance of gluten. Gluten naturally occurs in wheat, barley, and rye, and in oats through crosscontamination. Once a patient begins a gluten-free diet, improvement in intestinal and extra-intestinal symptoms often begins within a few weeks. Avoidance of gluten leads to a complete symptomatic, physical, and histological normalization. A baseline bone-density scan is recommended at diagnosis. Follow-up testing requires obtaining a celiac panel, CBC, CMP, free T4, and vitamin D levels 6 months after the patient begins a gluten-free diet. Once levels are within normal limits, yearly testing is appropriate.
It is vital to counsel patients on the importance of maintaining a lifelong gluten-free diet, as many resume consuming gluten after symptom resolution. Noncompliant patients risk failure to thrive, GI malignancies (primarily enteropathy-associated T-cell lymphoma), osteoporosis, thyroid disease, and other autoimmune diseases. As physicians, we should be aware of the difficulties patients and families have in maintaining a gluten-free diet, and we should discuss the emotional and financial challenges in order to facilitate compliance. A team approach is often necessary to ensure that the patient is able to maintain strict adherence to a gluten-free diet.
Patient A. was found to have CD after her celiac panel was confirmed by a duodenal biopsy, which revealed type 3a histology. Patient A.’s symptoms reversed after approximately 1 month of a gluten-free diet, and growth began to improve. Follow-up labs 6 months later revealed improved TTG and EMA levels and were normalized within 1 year.
Amy Feldman, MD, wrote the “Make the Diagnosis” section in the last issue, on which this article is based.
References and Suggested Readings
Jatla M, Bierly P, Hlywiak K, Autodore J, Verma R. Overview of celiac disease: differences between children and adults.
Pract Gastroenterol 2008;32(4):18-34.
A 12-year-old boy presents with a 3-year history of growth failure and poor weight gain. He was asymptomatic until the past 3 months, when he has described sharp postprandial abdominal pain. On physical examination, his weight is 28.5 kg and his height is 137 cm, both below the 5th percentile. He has moderate tenderness in the right lower quadrant of the abdomen, without guarding or rebound tenderness, and his perianal examination demonstrates a skin tag.
His laboratory testing includes normal thyroid function testing and tissue transglutaminase (TTG) IgA. His albumin is low (3.1 g/ dL) but comprehensive metabolic panel is otherwise unremarkable. His hemoglobin is 10.1 g/dL and his CRP is elevated at 2.2 mg/dL (0-0.9). There is a family history of colitis and rheumatoid arthritis.
An upper GI with small bowel follow-through demonstrates a nodular and narrowed terminal ileum (See Fig. 1). He undergoes upper endoscopy and colonoscopy, with visual and histological evidence of chronic inflammation in the stomach, terminal ileum, and colon. Granulomas are also noted on ileal biopsies. The patient is diagnosed with Crohn’s disease (CD).
Figure 1 Fig. 1: Nodular and narrowed terminal ileum
Discussion: The incidence of inflammatory bowel disease (IBD), particularly CD, has increased over the past few decades. Estimates from population-based studies suggest that approximately 400,000 children and adults in the United States have CD. Approximately 20-30% of all cases of CD are diagnosed before the age of 20 years.
Common clinical symptoms of IBD include abdominal pain, diarrhea, GI bleeding, nausea, vomiting, weight loss, poor appetite, perianal lesions, and fever. Extraintestinal manifestations include arthritis, arthralgia, uveitis, erythema nodosum, nephrolithiasis, and hepatobiliary disease. Growth failure frequently complicates pediatric Crohn’s disease and can often be the presenting complaint in an otherwise asymptomatic child. The earliest sign of growth failure is decreased linear growth velocity, which may be identified in as many as 88% of prepubertal patients with CD and often precedes the development of GI symptoms. It is imperative to perform a detailed history and physical examination to search for other manifestations of IBD when evaluating a child with growth failure.
The etiology of growth retardation in pediatric IBD is usually multifactorial, with nutritional, hormonal, and disease-related factors all contributing. Malnutrition is due to a combination of malabsorption, increased gastrointestinal losses, increased caloric requirements due to active disease, as well as inadequate intake, in part due to cytokine mediated anorexia. There is also evidence that proinflammatory cytokines associated with active inflammation directly inhibit growth. The use of chronic, daily corticosteroids for the treatment of CD can
also adversely affect linear growth.
Therapy for a child with CD and growth failure should focus on treatment of active disease as well as nutritional rehabilitation. Pharmacologic options include 5-aminosalicylates, steroids, immunomodulators such as 6-MP and methotrexate, antibiotics such as metronidazole, and biological therapies including infliximab (Remicade) and adalimumab (Humira). Of these options, only biological therapy has been proven prospectively to improve growth. Beneficial effect of methotrexate has been suggested by retrospective data. Significant improvement in height velocity post-operatively has been demonstrated in patients with growth failure and localized CD after intestinal
Another treatment option, chosen for this patient, is enteral nutritional therapy (EN). With EN, formula is administered, usually by overnight nasogastric administration, for 100% of the child’s nutritional needs. By providing more calories, EN effectively promotes weight gain and growth. Additionally, small prospective studies have suggested that EN also results in clinical remission in 70% of pediatric CD patients and promotes healing of the GI tract. Not allowing children to eat is a major impediment to compliance, so our center employs a unique
model of nonexclusive enteral nutritional therapy with 80-90% of nutritional needs being addressed with formula. This method allows the child to eat during the day. The leading hypotheses for how EN reduces disease activity are decrease in antigen load to the intestine or change in intestinal microflora. For patients who do not choose this
option, lower-volume nasogastric feeds in concert with medical therapy can help address nutritional deficits.
Our patient responded very well to 85% EN with improvement in weight gain, linear growth, and laboratory parameters, as well as a report of improved energy and resolution of the abdominal pain.
References and Suggested Readings
Grossman AB, Baldassano RN. Specific considerations in the treatment of pediatric inflammatory bowel disease. Expert Review of Gastroenterology and Hepatology. 2008;2:105-124.
Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn’s disease. Gastroenterology. 1998;95(6):523-7.
Walters TD, Griffiths AM. Growth impairment in pediatric inflammatory bowel disease. In: Mamula P, Markowitz JE, Baldassano RN, eds. Pediatric Inflammatory Bowel Disease, 1st Ed. New York: Springer Science and Business Media, 2008:103-118.
A.K. is a healthy 13-year-old boy who presents with a depressed mood. He reports a 10-pound weight loss and anorexia, but no nausea, vomiting, abdominal pain, or abnormal bowel habits. Examination reveals an emotionally flat teenager with normal vital signs, growth parameters, and physical findings. Screening labs including a CBC, TSH, and CMP are notable only for mild increases in transaminases (ALT 271, AST 125). A coagulation profile reveals a normal PT/INR. Over the ensuing months, AK’s depression resolves and his appetite rebounds. However, elevations in transaminases persist, prompting further workup. An ultrasound shows an average-sized liver with normal echogenicity and no splenomegaly. Laboratory studies for hepatotropic infections and autoimmune liver disease are unrevealing. A metabolic work-up
reveals a normal alpha-1 antitrypsin level with MM PI phenotype and a normal CK level. However, a ceruloplasmin level is below normal (10 mg/dL) and a 24-hour urine copper level is above normal (219.8 mcg). Collectively, these findings raise suspicion for Wilson disease, subsequently confirmed with a liver biopsy that reveals mild hepatitis with steatosis and an elevated tissue copper content (1,487 mcg/g).
Discussion: Wilson disease is an autosomal recessive disorder of copper transport that results in toxic accumulation of copper in the liver, brain, and other organs. The disease has a carrier rate of 1 in 90 and affects 1 in 30,000 people. Organ-specific manifestations vary with the age at presentation, which ranges from 3 to 73 years. Children typically present in early adolescence with isolated hepatic disease, while adults often present with neuropsychiatric complaints, such as psychosis, seizures, and movement disorders. When neuropsychiatric findings occur in children, they generally involve subtle changes, such as mood swings, and deterioration in school performance and/or handwriting.
The Western diet contains many foods that are rich in copper, including chocolate, nuts, mushrooms, shellfish, and organ meats. Although copper is a necessary component of several metabolic enzymes, its excess can damage cells by promoting free radical formation and lipid/protein oxidation. Normal enterohepatic metabolism ensures that the total body copper content is maintained within a safe range. Approximately 20% of dietary copper is absorbed in the intestine and delivered to the hepatocytes by the portal vein. Excess intrahepatic copper is processed into nontoxic complexes or excreted into the biliary system.
In Wilson disease, copper metabolism is impaired by a mutation in the ATP7B gene. This gene encodes a protein in the hepatocyte that 1) shuttles copper to the Golgi apparatus, where it is incorporated into ceruloplasmin; and 2) transports copper into the bile canaliculus. The defect in ATP7B decreases copper excretion, causing a toxic copper burden that triggers a vicious cycle of hepatocyte death and copper release. Over time, copper is released into the circulation and damages other organs. The ATP7B defect also impairs copper incorporation into ceruloplasmin, which causes an elevated fraction of unbound ceruloplasmin. Unbound ceruloplasmin is rapidly degraded, explaining the low level of serum ceruloplasmin in many Wilson disease patients. Hepatocellular damage can cause a broad spectrum of liver problems, including asymptomatic transaminase elevation and/or hepatomegaly, cholestasis, cirrhosis, and fulminant liver failure. The differential diagnosis, therefore, varies based on presentation. Initial laboratory testing should include a CBC, CMP with GGT, albumin, and PT/INR. In certain cases, copper-induced oxidative stress triggers a Coombs negative hemolytic anemia. Patients may also have a relatively low alkaline phosphatase level and ALT/AST ratio. While these findings are suggestive of Wilson disease, they are not diagnostic.
Current guidelines recommend initial evaluation of the serum ceruloplasmin and 24-hour urine copper levels. A slit lamp examination of the eyes to evaluate for the presence of copper granule deposition in the limbus (the Kayser-Fleischer ring, which appears to surround the iris, Fig. 2) also is advised. A serum ceruloplasmin level less than 20mg/dL is 80% sensitive and 94% specific for Wilson disease. When used alone, however, it is not adequate to render or exclude the diagnosis because hepatic inflammation of any etiology can increase ceruloplasmin, and impaired liver synthetic function can decrease it. Likewise, a 24-hour urine copper level that exceeds 100mcg is highly suggestive but not reliably diagnostic for Wilson disease. If any of these tests are abnormal, a liver biopsy should be performed. Steatosis,
mitochondrial changes, and a quantitative hepatic copper level >250 mcg/g are consistent with the diagnosis.
Figure 2: Kayser-Fleischer rings, caused by copper deposits where the cornea meets the sclera, are one of the most significant signs of Wilson disease. (Photo courtesy of Stephen E. Orlin, MD)
Treatment involves restriction of dietary copper and chelation therapy with D-penicillamine or Trientine. The latter is generally preferred because it is associated with fewer side effects. Zinc, which inhibits intestinal copper uptake and promotes copper excretion, may be used as alternative therapy in asymptomatic patients. Cases of
fulminant hepatic failure are managed with liver transplantation.
A.K. was treated with a combination of dietary restriction and Trientine. He remains asymptomatic with stable mild elevations in liver enzymes and no signs of extrahepatic copper accumulation.
References and Suggested Readings
Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease:
an update. Hepatology. 2008;47(6):2089-2111.
The Division of Gastroenterology, Hepatology and Nutrition at The Children’s Hospital of Philadelphia sees patients at our Main Campus in West Philadelphia and at several locations throughout the CHOP Care Network. To refer a patient to CHOP, please call us at 215-590-3630 and choose option 2.
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