Teenaged Boy With Epigastric Pain

Medscape

20-05-2025

Editor's Note:
The Case Challenge series includes difficult-to-diagnose conditions, some of which are not frequently encountered by most clinicians, but are nonetheless important to accurately recognize. Test your diagnostic and treatment skills using the following patient scenario and corresponding questions. If you have a case that you would like to suggest for a future Case Challenge, please email us at [e-mail] with the subject line "Case Challenge Suggestion." We look forward to hearing from you.
Background and Initial Presentation
A 13-year-old boy presents to the emergency department (ED) with a history of epigastric pain, vomiting, malaise, polyuria, and a 12-lb weight loss during the past 3 months. His parents have brought him to the emergency department today because his pain and vomiting are worsening. They report no history of hematuria, hematemesis, fever, or chills. They also do not note any other associated symptoms, prior surgeries, or medical conditions.
The patient was previously seen by his pediatrician and is undergoing a workup. Upper gastroendoscopy performed at a nearby hospital 2 weeks ago had revealed chronic gastritis with erosive changes in the antral region. Triple treatment for Helicobacter pylori , however, did not lead to any improvement. Abdominal ultrasonography also performed at that time showed mild nephrocalcinosis. Family history is negative for diabetes mellitus and porphyria.
Physical Examination and Workup
Upon physical examination, the child is thin and mildly ill-appearing. His temperature is 98.6°F (37°C); his pulse has a regular rhythm, with a rate of 80 beats/min; and his blood pressure is 120/70 mm Hg. The patient's respirations are regular and unlabored at 14 breaths/min.
The child is in mild distress secondary to his epigastric discomfort. The examination of the head and neck is normal, except that the oropharynx appears slightly dry. He has no dysmorphic facial features. His lungs are clear to auscultation, and normal respiratory effort is noted. The S1 and S2 heart sounds are normal, and no murmurs are detected. The abdomen is soft but tender to deep palpation in the epigastric region. The patient's extremities show no edema, and brisk capillary refill is noted. His skin is clear except in the gluteal region, where a nodular eczematous lesion is present. Routine laboratory tests reveal a normal complete blood count and normal values for sodium, potassium, chloride, bicarbonate, and magnesium. The patient's blood urea nitrogen and serum creatinine values are elevated (22.4 mg/dL and 1.8 mg/dL, respectively). The calcium level is elevated at 14.4 mg/dL, which is confirmed with an ionized calcium level of 7.2 mg/dL. The phosphorus level is low, at 5 mg/dL. Hepatic aminotransferase values are slightly elevated (aspartate aminotransferase, 61 U/L; alanine aminotransferase, 201 U/L) and the bilirubin level is 0.7 mg/dL. Alkaline phosphatase level is somewhat elevated at 137 IU/L. A chest radiograph is obtained (Figure).
Figure. Chest radiograph demonstrating combined hilar lymphadenopathy and reticulonodular interstitial infiltrates in the upper lung zone. (Note: This image is from a different patient with a similar condition.)
The patient is hospitalized. During the hospital course, additional laboratory tests are performed. The thyroid hormone levels are in the normal range, but the parathyroid hormone level is low, at 10.91 pg/mL (normal range, 15-65 pg/mL). Vitamin D metabolites are not measured. The serum angiotensin-converting enzyme (ACE) level is normal, at 32.7 U/L (normal range, 12-42 U/L). The results of a purified protein derivative test are negative. Urinalysis performed on several occasions shows a specific gravity of 1.003 and a pH of 5, with normal urinary sediment. Urinary culture findings are negative. On several occasions, marked hypercalciuria is observed, with a calcium level of 14 mg/kg and a urinary calcium/creatinine ratio (mmol/mmol) that ranges from 2.5 to 3.5. No glycosuria or aminoaciduria is noted.
Ultrasonography is performed, on which the parathyroid glands appear normal. Renal ultrasonography confirms mild nephrocalcinosis around the renal calices. A renal biopsy is performed. The specimen exhibits tubulointerstitial nephritis associated with tubular calcium deposits.
Other findings include interstitial infiltration by mononuclear cells, interstitial fibrosis, tubular necrosis, and atrophy. Dystrophic calcifications are present in some of the tubules.
Negative results are obtained for immunoglobulin (Ig) A, IgG, IgM, and C3 on immunofluorescence analysis. Immunohistochemical analysis reveals inflammatory cellular substrate CD68, macrophages, and lymphoid population. No glomerular abnormalities are evident.
The clinical picture of this patient was dominated by nonspecific constitutional symptoms, such as malaise, vomiting, abdominal cramps, and weight loss. He had no history of maculopapular rashes, erythema nodosum, arthritis, chronic lymphocytopenia, hepatomegaly, splenomegaly, lymphadenopathy, or uveitis. He also did not have any coughing or exertional dyspnea. The child did have vomiting and polyuria, which were caused by hypercalcemia.
The renal biopsy specimen indicated acute tubulointerstitial nephritis associated with tubular calcium deposits, without glomerular abnormalities. In addition, the chest radiograph demonstrated combined hilar lymphadenopathy and reticulonodular interstitial infiltrates in the upper lung zone. The chest radiography findings, when considered along with the hypercalcemia, rash, and renal biopsy results, are consistent with stage 2 radiographic sarcoidosis.[1]
Symptoms of Fanconi syndrome in children are failure to thrive, growth retardation, and rickets, which does not describe this patient. Diagnosis is by demonstrating glucosuria, phosphaturia, and aminoaciduria.[2]
Although a variety of glomerular lesions, including IgA nephropathy, are described as glomerular damage in sarcoidosis, they are not distinguishable from their primary form.[3] Moreover, this patient has a tubulointerstitial nephritis which is seen more often in sarcoidosis than IgA nephropathy (the latter is typically more a glomerulonephritis).
Bartter syndrome, a rare inherited salt-losing renal tubular disorder, is associated with secondary hyperaldosteronism with hypokalemic and hypochloremic metabolic alkalosis and low to normal blood pressure,[4] which does not describe this patient.
Discussion
Hypercalcemia and/or hypercalciuria may occur in less than a third of cases of pediatric sarcoidosis.[1] Measuring baseline serum calcium levels is recommended to screen for abnormal calcium metabolism in patients with sarcoidosis, even in asymptomatic patients.[5]
A rare cause of clinically manifested hypercalcemia is vitamin D intoxication, but it is associated with significant morbidity. It may be caused by endogenous synthesis of 1,25-dihydroxyvitamin D from subcutaneous fat necrosis, granulomatous disease, or by excessive exogenous vitamin D intake.[1] Hypercalcemia may also result from primary hyperparathyroidism or from increased levels of parathyroid hormone-related protein caused by certain malignancies.[6] Lastly, hypercalcemia may occur in patients with hypophosphatemia, vitamin A intoxication, or blue-diaper syndrome, or it may occur in association with use of certain medications, most notably hydrochlorothiazide and other thiazide diuretics.[6]
An intact parathyroid hormone (PTH) level at the time of hypercalcemia is pivotal in narrowing the differential diagnosis. If the PTH level is high, the child must be thoroughly investigated for the cause of hyperparathyroidism and may require urgent surgical intervention. If the PTH level is low (as it was in this patient), additional calciotropic hormones may be assayed if appropriate testing is available. Identifying the abnormal calciotropic hormone might allow diagnosis of the specific cause, elucidation of the mechanism for the hypercalcemia, and optimal treatment.[7]
Sarcoidosis is a multisystem disorder characterized by an increased cellular immune response to an unknown antigen and the formation of noncaseating granulomas in affected tissues. Although the lungs and lymph nodes are the predominant sites affected by sarcoidosis, other organs, such as the eyes, bone marrow, kidneys, liver, and spleen, may also be involved.[1,8] Cases of extrapulmonary sarcoidosis affecting the kidneys are rare; most such cases present with nephrocalcinosis or nephrolithiasis. Renal failure is an extremely uncommon manifestation.[1]
As noted previously, an intact PTH level at the time of hypercalcemia is important in narrowing the differential diagnosis. If the PTH level is high, the child must be completely investigated for the cause of hyperparathyroidism and may need urgent surgery. If the PTH level is low (as it was in this patient), additional calciotropic hormones may be examined if appropriate testing is available. Identification of the abnormal calciotropic hormone might facilitate diagnosis of the cause, clarification of the mechanism for the hypercalcemia, and appropriate treatment.[7]
Hypercalcemia in sarcoidosis is relatively uncommon.[1] It is usually caused by the autonomous production of 1,25-dihydroxyvitamin D (calcitriol) by macrophages within the granuloma. These macrophages can convert 25-hydroxyvitamin D, produced by the liver, into calcitriol by possessing the 1-alpha-hydroxylase enzyme. Calcitriol then travels to the intestinal cells and promotes luminal absorption of calcium and phosphate into the circulation. Hypercalcemia is accompanied by hypercalciuria and, eventually, nephrocalcinosis (as seen in this case). Hypercalcemia may also eventually cause renal failure both by causing dehydration and by inducing renal vasoconstriction, thereby reducing the glomerular filtration rate.[1,6]
Excess PTH production can produce significant bone loss, which is not seen in this patient.[7] High levels of magnesium are not directly linked to sarcoidosis.
The lungs and lymph nodes are the predominant sites that are affected by sarcoidosis,[9] and also the liver in children,[8] although other organs, including the eyes, bone marrow, kidneys, and spleen, may additionally be involved.[1,8,9]
Pediatric sarcoidosis is a rare disease, with an estimated incidence of 0.6 to 1.02 per 100,000 children.[8] Two distinct forms of childhood sarcoidosis appear to exist. Older children usually present with a multisystem disease similar to the adult manifestation, with frequent lymphadenopathy and pulmonary involvement. They also show generalized signs and symptoms, such as fever and malaise. In contrast, early-onset childhood sarcoidosis is a unique form of the disease characterized by the triad of rash, uveitis, and arthritis, usually in patients who are younger than 4 years.[9]
Pulmonary disease and abnormal findings on chest radiography are more common in children with sarcoidosis aged 8-15 years, compared with those younger than 4 years.[9] Bilateral hilar adenopathy is the most common finding on chest radiography in children; it occurs in almost all cases. It is typically symmetrical, although rarely it may occur unilaterally. Pulmonary parenchymal involvement is common and most often appears radiographically as an interstitial pattern; however, nodular, alveolar, and fibrotic patterns have also been noted. Of note, although chest radiography may be sufficient for the diagnosis, high-resolution chest CT may be helpful in evaluating lung changes[1,9] and is superior to conventional CT for detecting and demonstrating diagnostic findings in the lungs.[10]
Other uncommon manifestations include pleural effusion, pneumothorax, pleural thickening, calcification, and cor pulmonale, and atelectasis.[1] The serum ACE level is increased in many patients with sarcoidosis. Sensitivity and specificity as a diagnostic test is limited. The serum ACE level may be normal in patients with active disease.[9]
Many children with sarcoidosis have palpable peripheral lymph glands. The lymph nodes generally are firm, nontender, discrete, and easily movable. They neither ulcerate nor form draining sinuses. The glands involved most often are the cervical, axillary, epitrochlear, and inguinal glands. In the neck, the posterior triangle nodes are affected more frequently than the nodes in the anterior triangle. The enlarged peripheral lymph nodes are the most accessible tissue for biopsy. Hepatosplenomegaly often occurs in children with sarcoidosis at some point in their clinical course, but clinically significant hepatic dysfunction is rare. Mild elevation in biochemical liver function test values is common (as it was in this patient), but severe liver involvement is uncommon in children.[9]
Ocular involvement is very common in children with sarcoidosis, and a complete ophthalmologic evaluation, including a slit-lamp examination, is essential (particularly in young children). Sarcoidosis may affect any part of the eye or orbit. Anterior uveitis (also called "iritis" or "iridocyclitis") is the most frequently noted lesion.[9] The patient should be examined for a decrease in visual acuity, eye pain, a red eye, or any other visual aberration that can indicate a posterior or anterior uveitis.[8]
Sarcoid-associated uveitis can be acute or chronic and may vary from an isolated iridocyclitis to a bilateral panuveitis syndrome. If left untreated, the disease may cause synechiae, corneal opacities, glaucoma, and, eventually, blindness.[1,9]
Renal involvement is not well characterized in published series of childhood sarcoidosis. Histopathologic studies have revealed epithelioid granuloma formation, interstitial infiltration by mononuclear cells, interstitial fibrosis, tubulitis, tubular atrophy, mesangial hyperplasia, glomerular fibrosis, and vascular involvement.[9]
Corticosteroids remain the cornerstone of therapy for sarcoidosis, but immunosuppressive, cytotoxic, and immunomodulatory agents are viable therapeutic options for patients who do not respond to or experience adverse effects from corticosteroids. The published data most extensively documents treatment with methotrexate,[1,8] but favorable responses have been noted with leflunomide, azathioprine, and antimalarial and antimicrobial agents, as well as with tumor necrosis factor–alpha inhibitors. The dosage and the duration of corticosteroid therapy must often be individualized. Treatment is continued until the clinical manifestations of the disease resolve or show significant improvement.[9,11] For cutaneous sarcoidosis that cannot be controlled by local treatment, consideration of oral glucocorticoids is suggested.[11 More recently, repository corticotropin injection been suggested as an alternative in patients who are on high-dose prednisone.[9]
The patient in this case received prednisone, 1.5 mg/kg per day for 1 month, with gradual tapering of the dose over the following 4-5 months. Hypercalcemia and renal failure reversed completely, as did the pulmonary changes seen on radiography.
No recurrence was observed at 1-year follow-up. Renal nephrocalcinosis persisted, however, despite symptomatic and biochemical improvement. During corticosteroid therapy, measurement of the urinary beta-2-microglobulin concentration by sodium dodecyl sulfate polyacrylamide gel electrophoresis proved a valuable monitoring tool for assessing recovery of the tubular impairment.
Chest radiography obtained after 3 weeks of corticosteroid therapy showed resolution of the findings seen in the original chest radiograph.
This patient represents a rare case of sarcoidosis presenting with acute renal failure and hypercalcemia as the initial manifestations. Sarcoidosis should be considered in the differential diagnosis of hypercalcemia and renal failure,[1,9] occurring singly or in combination. Corticosteroids are useful for treatment.[1,8,9]
As noted previously, hypercalcemia in sarcoidosis is uncommon[1] and usually results from autonomous production of 1,25-dihydroxyvitamin D (calcitriol) by macrophages within the granuloma. These macrophages can convert 25-hydroxyvitamin D, produced by the liver, into calcitriol by possessing the 1-alpha-hydroxylase enzyme. At that point, calcitriol travels to the intestinal cells and facilitates luminal absorption of calcium and phosphate into the circulation. Hypercalcemia is accompanied by hypercalciuria and, eventually, nephrocalcinosis.[1,6,9]
A rare cause of clinically manifested hypercalcemia is vitamin D intoxication, which may be caused by excessive exogenous vitamin D intake.[1,6,9]
Hypercalcemia may also result from primary hyperparathyroidism or from increased levels of parathyroid hormone-related protein caused by certain malignancies.[1,6,9]
As noted previously, corticosteroids are the cornerstone of therapy for sarcoidosis,[1,9] but viable therapeutic options include immunosuppressive, cytotoxic, and immunomodulatory agents for patients who do not respond to or experience adverse effects from corticosteroids. Published data mainly documents treatment with the immunosuppressant methotrexate,[1,8] but favorable responses have been seen with leflunomide, mycophenolate mofetil, azathioprine, and antimalarial and antimicrobial agents, as well as with tumor necrosis factor-alpha inhibitors. Treatment options do not include fungicides, antiviral drugs, and antibiotics; granulomatous pulmonary infections caused by mycobacteria and fungi should have been ruled out.[1] For cutaneous sarcoidosis that is not controlled by local treatment, oral glucocorticoids could be considered.[11] For patients on high-dose prednisone, a suggested alternative is repository corticotropin injection.[9] The dosage and the duration of corticosteroid therapy must often be individualized. The treatment is continued until the clinical manifestations of the disease resolve or show significant improvement.[9,11]