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Chronic diarrhea in a 5-year-old girl: pitfall in routine laboratory testing with potentially severe consequences.


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 [10.sup.9]/L; reference interval, 4.5-13.5 X [10.sup.9]/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 [3.056.38 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[degrees]C; height, 110 cm (43.3 in, 38th percentile); weight, 19 kg (41.9 lb, 48th percentile).



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); PC[O.sub.2], 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.


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.


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 [H.sub.2] 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 per formed 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 bodyweight (maximal dose, 25 g) as a 100-g/L solution in water, which is administered over a 5- to 7-min period (4-6). Hydrogen gas can be measured by 2 methods: (a) real-time measurement with an [H.sub.2]-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 [H.sub.2] 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 [H.sub.2] concentration is considered the cutoff for fructose malabsorption (3-6).

Clinical symptoms do not appear to correlate with the degree of [H.sub.2] 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 [H.sub.2] 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 (4-6), especially because of the lack of a reference method.


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 9822.3 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.

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.



* Hydrogen breath tests have become an important diagnostic tool in identifying patients who experience carbohydrate malabsorption.

* HFI can be discriminated from fructose malabsorption by a typical nutrition history (strict avoidance of sweets and fruit) and the symptoms of recurrent hypoglycemia.

* Although HFI is a rare condition, physicians performing fructose breath hydrogen tests need to rule out HFI before testing.

* If hereditary fructose intolerance cannot be ruled out by nutritional history, genetic testing for HFI is advisable (e.g., sequence analysis of exons 2-9 of the ALDOB gene), which leads to a definitive diagnosis in more than 90% of all HFI cases.

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.


(1.) Gitzelmann R, Steinmann B, van den Berghe G. Disorders of fructose metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. Vol. 1. 7th ed. New York: McGrawHill; 1995. p 905-34.

(2.) Sanchez-Gutierrez JC, Benlloch T, Leal MA, Samper B, Garcia-Ripoll I, Feliu JE. Molecular analysis of the aldolase B gene in patients with hereditary fructose intolerance from Spain. J Med Genet 2002;39:@56.

(3.) Barnes G, McKellar W, Lawrance S. Detection of fructose malabsorption by breath hydrogen test in a child with diarrhea. J Pediatr 1983;103:575-7.

(4.) Simren M, Stotzer P0. Use and abuse of hydrogen breath tests. Gut 2006;55:297-303.

(5.) Romagnuolo J, Schiller D, Bailey RJ. Using breath tests wisely in a gastroenterology practice: an evidence-based review of indications and pitfalls in interpretation. Am J Gastroenterol 2002;97:1113-26.

(6.) Gibson PR, Newnham E, Barrett JS, Shepherd SJ, Muir JG. Review article: fructose malabsorption and the bigger picture. Aliment Pharmacol Ther 2007;25:349-63.

(7.) Peuhkuri K, Poussa T, Korpela R. Comparison of a portable breath hydrogen analyser (Micro H2) with a Quintron MicroLyzer in measuring lactose maldigestion, and the evaluation of a Micro H2 for diagnosing hypolactasia. Scand J Clin Lab Invest 1998;58:217-24.

(8.) Chambers RA, Pratt RT. Idiosyncrasy to fructose. Lancet 1956;271:340.

(9.) Santer R, Rischewski J, von Weihe M, Niederhaus M, Schneppenheim S, Baerlocher K, et al. The spectrum of aldolase B (ALDOB) mutations and the prevalence of hereditary fructose intolerance in Central Europe. Hum Mutat 2005;25:594.

(10.) Costa C, Costa JM, Deleuze JF, Legrand A, Hadchouel M, Baussan C. Simple, rapid nonradioactive method to detect the three most prevalent hereditary fructose intolerance mutations. Clin Chem 1998;44:1041-3.


C.M. Frank Kneepkens

Unlike glucose and galactose, fructose is absorbed passively. Fructose absorption by the apical transporter GLUTS requires a concentration gradient, which is maintained both by the active absorption of nutrients and water and by fructose transport out of the enterocytes by the basolateral transporter GLUT2. After excretion into the portal blood stream, fructose is rapidly metabolized in the liver. Whether a given amount of fructose is absorbed adequately is a matter of local conditions. Fructose is better absorbed as a part of a meal or in a mixture with actively absorbed molecules such as glucose and amino acids.

The breath hydrogen test (BHT) has given us a tremendous amount of insight into the fate of ingested carbohydrates, including fructose. Many, if not most, healthy children are not able to completely absorb a test dose of fructose. Consequently, fruit juices containing fructose in excess of glucose, such as apple juice, might especially lead to symptoms of carbohydrate intolerance and toddlers' diarrhea. Obviously, this "condition" is essentially different from the inborn error of metabolism, hereditary fructose intolerance.

The case report by Wenzel et al. addresses 2 important points. First, the authors rightly point out that the fructose BHT is not innocuous under all circum stances. It should be preceded by careful evaluation of the patient's history with reference to the possibility of hereditary fructose intolerance. Second, the clinical usefulness of the fructose BHT is limited. Because healthy children also "malabsorb" fructose, the diagnostic sensitivity of the test is low. When the child's history suggests a role for fructose, the clinician, instead of performing a BHT, should provide the parents with dietary advice aimed at normalizing the child's feeding pattern and excluding fruit juices from the diet. It is seldom, if ever, necessary to eliminate other sources of fructose. The effect of the diet on the symptoms is sufficient proof.

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.

Department of Pediatric Gastroenterology, VU University Medical Center, Amsterdam, the Netherlands.

Address correspondence to the author at: Department of Pediatrics, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands.


Received November 20, 2008; accepted December 3, 2008.

DOI: 10.1373/clinchem.2008.118562


David A. Rudnick

The report by Wenzel and colleagues highlights the risks inherent in fructose tolerance testing and the challenges accompanying evaluation for hereditary fructose intolerance (HFI) (1). The rapid resuscitative intervention after fructose exposure described by the authors may have saved the child's life, and the authors should be commended for subsequent expeditious diagnosis of a rare disease. Nevertheless, a prospective consideration of the patient's history could have raised concern for HFI before fructose tolerance testing. Historically, the diagnosis of HFI was made by invasive and dangerous analyses, such as measurement of hepatic aldolase B activity or intravenous fructose tolerance testing. The reliability of enzyme analysis may be questionable, considering a report describing "transient hereditary fructose intolerance" (2) and our own experience with variable aldolase B activity in a patient considered for HFI, which together raise the concern that single measurements of low enzyme activity may have poor diagnostic specificity. The potential dangers of intravenous fructose infusion are illustrated by the reports of fatalities associated with the provision of fructose-based parenteral nutrition. These tests have largely given way to genetic approaches for diagnosing HFI. The identification of aldolase B mutations associated with HFI has led to PCR-based strategies that provide estimated diagnostic sensitivity of >95%. Such tests have also been used to estimate the population prevalence of HFI. Interestingly, these estimates (approximately I in 20 000 Caucasian individuals) are much higher than our own clinical experiences suggest, raising the possibility that HFI may often be undiagnosed. With these considerations in mind, many investigators now discourage fructose tolerance testing because of concern about the potential for severe toxicity and even death. This case reminds us of those dangers and supports the use of molecular genetic analysis whenever HFI is considered a possibility. Even when genetic analysis is uninformative, many do not use fructose tolerance testing but instead prefer dietary avoidance of fructose as a safer approach to assess the possible contributions of fructose on the symptoms of concern.

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.


(1.) Rudnick DA. Hereditary fructose intolerance. In: Johnson LR, ed. Encyclopedia of gastroenterology. San Diego: Academic Press; 2004. p 368-71.

(2.) Catto-Smith AG, Adams A. A possible case of transient hereditary fructose intolerance. J Inherit Metab Dis 1993;16:73-7.

Departments of Pediatrics and Developmental Biology, Washington University School of Medicine, St. Louis, MO.

Address correspondence to the author at: Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8208, St. Louis, MO 63110.

Received January 16, 2009; accepted February 3, 2009.

DOI: 10.1373/clinchem.2008.118570

Jurgen J. Wenzel, [1] Heidi Rossmann, [1] Ulrike Kullmer, [2] Bettina Oberman, [2] Eugen Mengel, [2] Karl J. Lackner, [1] and Johannes Lotz [1] *

[1] Institute for Clinical Chemistry and Laboratory Medicine; and [2] Department of Paediatrics, Johannes Gutenberg-University Mainz, Mainz, Germany.

* Address 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@zentrallabor.

Received May 6, 2008; accepted November 3, 2008.

DOI: 10.1373/clinchem.2008.110148
Table 1. Differential diagnosis of chronic diarrhea in childhood.

Functional and dietary Liquid stools in breast-fed babies
 Toddler syndrome
 Irritable bowel syndrome
Food intolerance Cow's milk intolerance
 Allergy to nutrients
Inborn errors of digestion Lactose malabsorption
 and absorption
 Fructose malabsorption
 Glucose--galactose malabsorption
 Sucrase--isomaltase deficiency
 Congenital CI--diarrhea
 Malabsorption of bile acids
 Malabsorption of lipids
 Atrophy of microvilli, dysplasia
 of intestinal epithelial cells
 Acrodermatitis enteropathica
Inborn or acquired deficiency Cystic fibrosis
 in pancreatic enzymes
 Hereditary pancreatitis
 Acquired pancreatic insufficiency
 Hypoplasia of the pancreas
Inborn metabolic diseases HFI
Autoimmune diseases Celiac disease
 Autoimmune enteropathy
Inflammatory bowel diseases Crohn disease
 Ulcerative colitis
Chronic enteric infections Bacteria (anatomic stasis, e.g.,
 stagnant loop syndrome,
 characterized by incomplete
 bowel obstruction and overgrowth
 of the small intestinal flora by
 anaerobic bacteria; functional
 Parasites (e.g., Giardia lamblia)
Iatrogenic Therapeutic diets
 Other drugs (e.g., excessive
 Short bowel syndrome
Endocrine diseases Hyperthyroidism
 Adrenal insufficiency
 Hormone-producing tumors
 Carcinoid syndrome (rare in children)
Immune defects Inborn or acquired
Vitamin deficiencies Folate and vitamin B12 deficiency
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Article Details
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Title Annotation:Clinical Case Study
Author:Wenzel, Jurgen J.; Rossmann, Heidi; Kullmer, Ulrike; Oberman, Bettina; Mengel, Eugen; Lackner, Karl
Publication:Clinical Chemistry
Article Type:Case study
Geographic Code:4EUGE
Date:May 1, 2009
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