A 10-Year-Old Girl With Mild Elevation of Liver Transaminases

Case Presentation

A 10-year-old white girl presented for investigation of mildly elevated liver transaminases that were found incidentally while being evaluated for urticaria. There was no history of jaundice, abdominal pain, weight loss, diarrhea, fever, fatigue, failure to thrive, psychiatric, or neurologic symptoms. She only reported pruritus associated with the rash.

Her medical history was significant for chronic urticaria and multiple environmental allergies. The rash, which was described as maculopapular, erythematous, and associated with pruritus, responded well to antihistamine therapy. Past medical history was also significant for allergic rhinitis. There was no history of surgeries. Her only medication was cetirizine 10 mg by mouth daily. She had no known drug or food allergies. Immunizations were up to date. Social and family history were noncontributory.

On physical exam, the patient appeared well hydrated, well nourished, and had no complaints. She was at the 50th percentile for weight and 75th percentile for height. Vital signs were within normal limits for her age. Head, eyes, ears, nose, and throat exam was unremarkable. Heart and lungs exam was normal as well. The abdomen was soft, flat, and nontender with normal bowel sounds and without hepatosplenomegaly, ascites, or masses. Musculoskeletal and neurologic exam were normal. There was no evidence of skin rash.

Laboratory work-up revealed a normal complete blood count with minimal eosinophilia (white blood cell count, 6.7 cells/mcL³; segmented cells, 54%; lymphocytes, 37%; eosinophils, 5%) and normal hemoglobin (12.5 g/dL) and platelet count (308,000 cells/mcL). Basic metabolic panel was within normal limits. Her aspartate aminotransferase (AST) level was mildly elevated at 71–100 IU on repeat testing over 7 months, which was first noted prior to onset of cetirizine therapy. Serum alanine aminotransferase (ALT) was also mildly elevated at 36–67 IU (normal range for serum AST and ALT adjusted for age = 10–30 IU). Albumin, total protein, bilirubin, alkaline phosphatase, and gamma glutamyl transferase were all within normal limits for age.

• 1.What is the differential diagnosis?

  Many diseases may cause elevation of liver transaminases at this age. Infectious etiologies such as hepatitis A, B, or C, Epstein-Barr virus (EBV), or cytomegalovirus (CMV); metabolic disorders such as Wilson's disease and alpha-1-antitrypsin deficiency; and autoimmune hepatitis need to be considered. In view of the patient's history of urticaria, systemic lupus erythematosus should also be included in the differential diagnosis. In addition, nonalcoholic steatohepatitis, drug-induced hepatitis, and immune-mediated enteropathy are other forms of hepatitis and diagnoses that need to be considered.

Further Investigation

Additional laboratory investigations included an autoimmune liver panel, which was positive for antinuclear antibody (ANA) and negative for anti-smooth muscle, anti-F-actin, and anti-liver/kidney microsomal antibodies. The ANA titer was 1:160 and on repeat testing was 1:320, with a homogeneous pattern. Rheumatoid factor, anti-double-stranded DNA, and complement 3 levels were normal. Copper levels, viral serologies (hepatitis A, B, and C, EBV, CMV), and thyroid tests were all normal or negative. Liver ultrasound with Doppler showed normal liver echogenicity and size as well as normal blood flow.

• 2.What additional laboratory test would you perform at this point in the work-up to help establish the diagnosis?

  Serologic testing for celiac disease should be performed because this disease has been increasingly recognized as a potential cause of hepatitis.

Diagnosis

The patient underwent serologic testing for celiac disease.

The patient's celiac panel revealed a normal total immunoglobulin A (IgA) level (141 mg/dL) but was positive for IgA anti-tissue transglutaminase antibody (tTG; > 597.6 units [normal, < 20]) and IgA anti-endomysial antibody (EMA; 1:640 [normal, < 1:5]), prompting endoscopic evaluation; biopsies were obtained (Figure 1A, 1B).

Figure 1.

Stomach (A) and small bowel (B) biopsy. Light microscopy, hematoxylin and eosin staining. (Courtesy of Dr. E. Ruchelli, Department of Pathology, The Children's Hospital of Philadelphia)

The stomach biopsy (Figure 1A) showed moderate gastritis with lymphoplasmacytic infiltrate in the lamina propria extending into surface epithelium. The duodenal biopsy (Figure 1B) showed villous atrophy, crypt hyperplasia, intraepithelial lymphocytic infiltrate, and expansion of the lamina propria by plasma cells, consistent with a diagnosis of celiac disease.

Due to persistent elevation in liver enzyme levels for more than 1 year after a strict gluten-free diet was initiated and after normalization of celiac antibody levels, a liver biopsy was performed. Results of liver biopsy were normal (not shown).

Extraintestinal Manifestations of Celiac Disease

Patients with celiac disease can present with various extraintestinal manifestations, including hematologic (iron-deficiency anemia and megaloblastic anemia secondary to nutritional deficiencies, abnormal coagulation due to vitamin K deficiency), neurologic (ataxia, depression, seizures, autistic-like behavior, headaches, peripheral neuropathy), rheumatologic (arthritis or arthralgias sometimes associated with systemic lupus erythematosus or rheumatoid arthritis), hepatic (hepatitis), cardiac (pericarditis), dental/oral (dental enamel hypoplasia, aphthous lesions), endocrine (short stature, delayed puberty), infertility and miscarriage, bone (decrease in bone density), and skin (dermatitis herpetiformis) complications.

Clinical Course and Discussion

The patient was maintained on a gluten-free diet. Her growth and development continued to be adequate for age. On follow-up laboratory studies, her tTG, EMA, ALT, and ANA levels normalized while AST continued to be minimally elevated at 49 IU (upper normal, 37 IU) 3 years post diagnosis. Her bone density scan revealed reduced mineral density and she was started on calcium supplementation. The patient was also referred to an allergist to further evaluate her chronic urticaria, which was not thought to be dermatitis herpetiformis or related to celiac disease. The elevated ANA levels were believed to be nonspecific in the setting of an autoimmune condition.

Celiac disease, also known as celiac sprue or gluten-sensitive enteropathy, is an immune-mediated disorder characterized by chronic inflammation of the small intestinal mucosa. The etiology of celiac disease is most likely multigenic. A genetic predisposition (HLA-DQ2/HLA-DQ8) is required, but exposure to wheat, barley, and rye triggers the disease. Although the pathogenesis of the disease is not fully understood, gluten is thought to induce mucosal damage, both by a direct toxic effect and by initiating a cascade of immunologic responses.

Celiac disease has been described worldwide. Its prevalence in most countries ranges from 0.5/100 to 1/100. The distribution of celiac disease is bimodal, with a first peak at 6–24 months of age and a second peak in the fourth and fifth decades of life. It may present at any age, from infancy to adulthood. Mucosal injury doesn't necessarily correlate with the gravity of symptoms, as this case demonstrates. In fact, some patients have significant abnormalities found on small bowel biopsy, yet have no clinical manifestations of the disease. There are essentially 3 different presentations of celiac disease: classic or early onset, atypical or late onset, and asymptomatic. Patients with classic or early-onset celiac disease usually present before 2 years of age with gastrointestinal symptoms and complications, such as failure to thrive, diarrhea, constipation, vomiting, decreased appetite, and abdominal distention. The diagnosis of classic celiac disease is usually less challenging than diagnosis of the atypical type, in which extraintestinal symptoms predominate. Asymptomatic patients are classified either as silent or latent celiac disease. Patients who present with no symptoms but with abnormal biopsies and serologic markers are classified as silent-type. Often, these patients are tested due to a high risk for celiac disease (ie, first-degree relatives of patients with celiac disease, patients with trisomy 21, or type 1 diabetes mellitus). Patients with latent celiac disease are asymptomatic, with normal biopsies but positive serology. These patients may develop mucosal changes and symptoms over time and with further exposure to gluten. Celiac disease has been associated with diseases such as type 1 diabetes mellitus, Williams syndrome, dermatitis herpetiformis, selective IgA deficiency, thyroid autoimmune disease, autoimmune hepatitis, trisomy 21, exocrine pancreas insufficiency, cystic fibrosis, alpha-1-antitrypsin deficiency, and inflammatory bowel disease.

In terms of liver involvement, a recent review article points out that hypertransaminasemia is the most common hepatic presentation of celiac disease; it has been described in up to 54% of children with a classic presentation at the time of celiac disease diagnosis.[1] The pathogenesis of liver disease in celiac disease is unclear. There are 2 proposed mechanisms: increased intestinal permeability facilitating entry of toxins, antigens, and inflammatory substances; and humoral-mediated immune responses, as anti tTG antibody is present in liver as well. The clinical presentation varies from asymptomatic to signs and symptoms of chronic liver disease, such as palmar erythema, finger clubbing, spider angiomata, jaundice, and organomegaly. The pathology ranges from isolated nonspecific elevation of liver enzymes to primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. The abnormal transaminases frequently improve on a gluten-free diet in 75% to 95% of patients. False-positive celiac serology in the setting of liver disease has been described, so intestinal biopsy confirmation of celiac disease is uniformly recommended. In another study, approximately 9% of patients with elevated transaminases of unclear etiology were later found to have celiac disease.[2] Liver biopsy showed a nonspecific reactive hepatitis. Additionally, the risk for liver disease in celiac disease was investigated in 13,818 adult patients and 66,584 age- and sex-matched reference individuals from a general-population cohort.[3] Celiac disease was associated with an increased risk for acute and chronic hepatitis, primary sclerosing cholangitis), fatty liver, biliary cirrhosis, and liver failure. Also, prior liver disease was associated with a statistically significant 4-fold to 6-fold increased risk of later developing celiac disease. Liver failure has also been described in association with celiac disease. A young woman with severe liver failure was considered for liver transplantation when additional testing revealed celiac disease.[4] After starting a gluten-free diet, the liver failure reversed. Another study described severe liver disease in 4 patients with untreated celiac disease and the occurrence of celiac disease in an additional 185 adults with previous liver transplantation.[5] Of the 4 patients with severe liver disease and celiac disease, each one had congenital liver fibrosis and hepatic steatosis and 2 had progressive hepatitis without known etiology. Hepatic dysfunction reversed in all patients when a gluten-free diet was initiated. In the transplantation group, 4.3% of patients were found to have celiac disease. The liver pathology included primary biliary cirrhosis, autoimmune hepatitis, primary and secondary sclerosing cholangitis, and congenital liver fibrosis. The study authors suggested investigation for celiac disease in patients with severe liver disease, as a gluten-free diet may prevent progression to hepatic failure.

Given that celiac disease may manifest with a range of clinical presentations, the most important factor at the time of diagnosis is having a high index of suspicion. There are 3 diagnostic tools employed in this setting: serologic tests, small bowel biopsy, and genetic (HLA) testing. Celiac disease is diagnosed when a patient has the typical positive serologic markers, with confirmation on small bowel biopsy. It is important to remember that serologic testing and biopsy must be done with the patient on a gluten-inclusive diet or the results may be falsely negative. The combination of serologic markers that seems to provide the most sensitivity and specificity for the diagnosis of celiac disease is the anti-endomysial IgA and tTG IgA antibodies. IgA deficiency is one of several conditions that may yield a false-negative result, and because IgA deficiency is often seen in patients with celiac disease, patients should have a total IgA level drawn at the same time that the antibody testing is done. Both serologic markers may be falsely negative in children younger than 2 years of age (because it takes a somewhat mature immune system to make some anti-self antibodies) or in IgA-deficient patients. These patients may be screened for celiac disease using an IgG-based antigliadin or tTG antibody. HLA haplotyping is required only in a very select subgroup of patients. In cases where the diagnosis is indeterminate based on inconclusive biopsy and serology results, HLA testing may help in classifying the patient as being at high or low risk for having celiac disease. The DQ2 and/or DQ8 markers are present in 97% of celiac disease patients. Therefore, patients negative for these 2 markers are very unlikely to have celiac disease.

The cornerstone of treatment for celiac disease remains the gluten-free diet. Prolamins, alcohol-soluble proteins of wheat, barley, and rye, need to be completely excluded from the diet. In the United States, oats are also avoided mainly because of concern regarding cross-contamination during manufacturing. An expert celiac disease dietitian is thus a key member of the treatment team. There are many hidden sources of gluten that are not always identified by parents or patients, such as soy sauce and some candies, medications, seasonings, and mouthwash, among others. Support groups for patients and families have also been shown to have a positive impact on treatment outcome. In addition to diet restrictions, patients may require supplementation with folic acid, calcium, vitamin D, zinc, and iron.

In summary, this case emphasizes the importance of clinicians maintaining a high index of suspicion for celiac disease, especially considering the wide array of signs, symptoms, and laboratory abnormalities with which a patient may present.