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Clinical Case Study |
1 Institute for Clinical Chemistry and Laboratory Medicine; and2 Department of Paediatrics, Johannes Gutenberg-University Mainz, Mainz, Germany.
aAddress correspondence to this author at: Johannes Gutenberg-University Mainz, Institute for Clinical Chemistry and Laboratory Medicine, Langenbeckstr. 1, 55131 Mainz, Germany. Fax +49 6131 17 6627; e-mail lotz{at}zentrallabor.klinik.uni-mainz.de.
CASE
A 5-year-old girl was referred because of recurrent watery diarrhea, abdominal pain, and flatulence. She was the second of 3 children. Her 10-year-old sister was normally developed and healthy. Her younger brother has meningomyelocele and hydrocephalus.
At 1 year of age, the patient was admitted to the hospital for recurrent bronchitis, otitis media, food refusal, mild diarrhea, and abdominal distension since weaning. A sweat chloride analysis excluded cystic fibrosis. At that time, the patient’s laboratory results showed increased C-reactive protein (139 mg/L; reference interval, <5 mg/L) and moderate leukocytosis (14.6 x 109/L; reference interval, 4.5–13.5 x 109/L). Values for all other variables were within the reference intervals. Since then, the patient experienced recurrent abdominal pain, mild diarrhea, and occasional nausea. Stool samples were repeatedly analyzed for pathogenic bacteria without consistent relevant results. Beginning at the age of 3 years, the patient developed increasingly anomalous behavior, which included frequent episodes of fatigue and apathy, persistent enuresis, and encopresis (fecal soiling), delayed language development, inability to integrate in her kindergarten group, and continual food intake in parallel with the avoidance of sweets and fruit. Fasting glucose concentrations were measured several times, and all measurements were in the lower part of the reference interval [3.05–6.38 mmol/L (55–115 mg/dL)]. Interestingly, the parents were not aware of the patient’s eating habits, because the mother was largely occupied with the care of her youngest child. Consequently, the 2 older children helped themselves most of the time.
A physical examination revealed abdominal distension, but the findings for the patient were otherwise unremarkable: blood pressure, 112/62 mmHg; temperature, 36.2 °C; height, 110 cm (43.3 in, 38th percentile); weight, 19 kg (41.9 lb, 48th percentile).
DISCUSSION
additional patient data
Because of her chronic intestinal symptoms, the patient was referred to our laboratory to confirm or exclude fructose malabsorption, one of the most frequent causes of diarrhea in childhood (Table 1
). The fructose breath hydrogen test was performed as described below. At 15 min after the oral administration of fructose (19 g), the patient became sleepy. At 30 min after administration, she showed disturbed consciousness, exhibited low muscle tonicity, and became cold-sweaty. Only minutes later, the patient became comatose, exhibited seizures, and was severely hypoglycemic [blood glucose, 1.0 mmol/L (18 mg/dL)]. Values for blood gas variables were as follows: pH 7.28 (reference interval, pH 7.37–7.45); PCO2, 46.2 mmHg (reference interval, 32.0–43.0 mmHg); base excess, –4.7 mmol/L (reference interval, –2.0 mmol/L to +3.0 mmol/L). We noted increased concentrations of serum lactate (3.9 mmol/L; reference interval, 0.5–2.2 mmol/L) and transaminases [aspartate aminotransferase, 247 U/L; alanine aminotransferase, 78 U/L (reference intervals, <35 U/L)]. After an immediate infusion of a 100-g/L glucose solution, the patient recovered rapidly. The activities of these 2 aminotransferases normalized within 4 days.
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resolution of the case
Chronic diarrhea—often accompanied by abdominal pain, bloating, nausea, or flatulence—is a common complaint in pediatric outpatients (Table 1
). These symptoms, which occur in conjunction with the intake of sweets and fruit, are related to fructose malabsorption or hereditary fructose intolerance (HFI). In retrospect, the patient’s strict avoidance of fructose-containing food, combined with recurrent episodes of fatigue and apathy, persistent enuresis and encopresis, delayed language development, and the fact that the symptoms started at the time of weaning, suggests HFI as the most probable diagnosis in this patient (1). Because only limited information was available about the details of the patient’s history and because the main complaints were abdominal pain, bloating, and diarrhea (symptoms typical for fructose malabsorption), the fructose breath hydrogen test was performed. Severe hypoglycemia following fructose exposure, as well as signs of liver damage (increased liver enzyme values after fructose intake and normalization during the following days), made HFI much more likely than fructose malabsorption, which is not associated with either episodes of hypoglycemia or organ injury.
Direct sequencing of exons 5 and 9 of the ALDOB gene (aldolase B, fructose-bisphosphate) (2) confirmed HFI due to a homozygous G>C transition in exon 5. This mutation is common in HFI patients and encodes the substitution of a proline residue for alanine at position 149 (A149P).
Strict elimination of all sources of sucrose and fructose from the patient’s diet changed her life completely. During the subsequent months, she recovered quickly from all gastrointestinal symptoms. The patient is now 6 years old and is no longer tired. The apathy, enuresis, and encopresis have stopped, her language skills continue to progress, and she has integrated well in her new kindergarten group. Recently, a neuropsychiatric evaluation indicated typical intellectual (IQ 100) and behavioral development; therefore, the patient will be enrolled in a regular primary school.
fructose breath hydrogen test
Hydrogen breath tests have become an important diagnostic tool in identifying patients who experience carbohydrate malabsorption (3)(4). The principle of these tests is that after an oral loading dose, a restricted ability to reabsorb certain carbohydrates in the small intestine increases the amount fermented by bacteria in the large intestine. The H2 produced during this process readily crosses the intestinal epithelium into the circulation, and the amount detected in expired air can be used to infer impaired intestinal absorption.
The fructose breath hydrogen test is the method of choice to confirm or exclude fructose malabsorption. Depending on the age of the patient, the test is performed in a fasting state of at least 4–12 h. Patients should be instructed on the day before the test to abstain from fruit, juices, dairy, and other food containing high amounts of slowly absorbable or unfermentable carbohydrates. Smoking, teeth brushing, chewing gums, and physical exercise are not allowed 2 h before and during the test (5).
There is no consensus on how fructose breath hydrogen tests should be performed or interpreted. Children typically receive an oral fructose dose of 1 g/kg body weight (maximal dose, 25 g) as a 100-g/L solution in water, which is administered over a 5- to 7-min period (4)(5)(6). Hydrogen gas can be measured by 2 methods: (a) real-time measurement with an H2-sensing electrochemical cell, mostly with a portable device [Lacto FAN (Micro Medical) in our laboratory]; or (b) collection of expired air in gas-sampling bags and delayed measurement of H2 concentrations by gas chromatography (7). End-expiratory breath samples are analyzed before fructose ingestion (baseline) and at 10-min intervals until 2 h after ingestion. A 20-ppm increase in H2 concentration is considered the cutoff for fructose malabsorption (3)(4)(5)(6).
Clinical symptoms do not appear to correlate with the degree of H2 production but rather reflect the highly variable response of the gut–brain axis to the malabsorbed carbohydrate (6). Studies have demonstrated good qualitative test–retest reproducibility but only a moderately reproducible peak breath H2 concentration (6). The diagnostic sensitivity and specificity of the fructose breath hydrogen test are inherently difficult to determine, and most authors do not provide exact values (4)(5)(6), especially because of the lack of a reference method.
diagnosis
HFI is an autosomal recessive condition characterized by severe hypoglycemia, abdominal pain, and vomiting following the ingestion of fructose (1)(8). In European populations, the estimated incidence is approximately 1 in 20 000 (9). Mutations in the ALDOB gene on chromosome 9q22.3 have been identified as the genetic cause of the disease.
In HFI, clinical symptoms tend to arise at the time of weaning as fructose becomes a nutritional component. Continuous fructose administration leads to growth failure, hepatomegaly, and possibly even death due to metabolic acidosis, hypoglycemia, and liver failure. Fig. 1
summarizes the pathway of fructose metabolism and consequences of the aldolase B defect in HFI patients. In brief, impaired enzyme function allows fructose 1-phosphate to accumulate, primarily in hepatocytes, kidney cells, and the mucosa of the small intestine. Fructose 1-phosphate inhibits glucose formation by inhibiting gluconeogenesis and glycogenolysis, thereby promoting systemic hypoglycemia and ATP depletion.
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As in the current case, patients with HFI develop a protective aversion to fructose-containing foods; consequently, the condition may remain medically unrecognized. If patients are inadvertently exposed to large quantities of fructose, however, as in our case, they will experience severe hypoglycemia. Even fatal outcomes have been reported under such circumstances. Although the frequency of HFI is rather low, affected patients are probably more frequently found in the pediatric cohort presenting with abdominal symptoms; such patients are then referred for fructose breath hydrogen testing. Currently, there is an increasing trend to centralize testing for carbohydrate malabsorption in specialized metabolic-testing units and central laboratories, making it more likely for cases similar to ours to be revealed in a laboratory context. Recently, fructose malabsorption breath test kits have also been introduced for home use. In the light of this case, we strongly suggest avoiding the use of such tests. We recommend that metabolic-testing units be prepared for quick diagnosis (blood glucose measurement) and therapy (infusion of glucose solution) for hypoglycemic episodes. This case should alert physicians to obtain a detailed nutritional history before performing fructose breath hydrogen tests. Laboratories cannot assume that HFI has been excluded by the transferring physician. We recommend that the patient’s history include an interview regarding strict avoidance of fruits with a high fructose content (e.g., pears, apples, bananas, dates, grapes), detailed consequences of their ingestion, symptoms of hypoglycemia, and information about the absence of dental caries and fillings. If there is a history of systematic avoidance of fructose-containing foods along with episodes suggestive of hypoglycemia, fructose loading must be avoided. We recommend that the laboratory instead perform genetic testing for HFI, which leads to a definitive diagnosis in most cases, because only 3 missense mutations in the ALDOB gene account for 85%–95% of the HFI alleles in different Caucasian populations (A149P, A174D, and N334K) (9)(10). If no mutation is found despite a strong clinical suspicion of HFI, intravenous fructose loading can be performed under strict medical supervision after several weeks of fructose abstinence.
POINTS TO REMEMBER
Acknowledgments
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Authors’ Disclosures of Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.
Acknowledgment: The authors thank Carolin Neukirch for expert technical assistance.
References
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