Pediatrics

Disaccharidase Deficiencies

OVERVIEW: What every practitioner needs to know

Are you sure your patient has disaccharidase deficiencies? What are the typical findings for this disease?

Disaccharidase deficiencies are caused by the decreased hydrolysis of the disaccharides (double-sugars) by the disaccharidase enzymes (lactase; maltase-glucoamylase; sucrase-isomaltase; palatinase and trehalase). These enzymes are localized in the brush border membrane of the small intestinal epithelial cells. Lactose and sucrose are the most common disaccharides in the diet. The decrease in enzyme activities can be due to an inherited or congenital deficiency or can be acquired as the consequence of small intestinal mucosal damage.

The reduced hydrolysis of these double sugars results in an osmotic effect in the proximal small intestine that leads to increased fluid, sugar, and other nutrient load to the terminal ileum and colon where bacterial fermentation produces gases (H2, CH4, CO2) and short chain fatty acids. Increased intestinal gas may occur 30 minutes to hours after ingestion of the sugar, and the distension of bowel wall leads to crampy abdominal pain. The osmotic effect may be large enough to cause diarrhea, which is explosive when gas also accompanies the liquid stool.

Developmental disaccharidase deficiencies occur in pre-term infants. The most important disaccharidase in the newborn period is lactase. This has relatively low activity before 32 weeks of gestation and rises progressively thereafter to high activity levels in term infants.

The most common symptoms of disaccharidase deficiencies include abdominal pain, bloating, and flatulence. A less common but still frequent symptom is diarrhea.

What other disease/condition shares some of these symptoms?

There are multiple other conditions and diseases leading to similar symptoms. These include aerophagia, overeating, high fructose intake, excessive intake of beans/ legumes, chewing gums containing sorbitol or Xylitol, medications with high sugar content, antibiotics, acarbose (Precose), Orlistat (Xenical, Alli), excessive fiber supplements, and ingestion of certain spices.

Intestinal mucosal damage associated with many diseases results in secondary disaccharidase deficiencies. The most frequent cause of mucosal damage is celiac disease that can affect 1% of the population. Other acquired diseases are rotavirus enteritis, giardia infestation, eosinophilic gastroenteritis, Crohn's disease, small intestinal bacterial overgrowth, tropical sprue, post-infectious gastroenteropathy, autoimmune enteropathy and pancreatic insufficiency.

Mucosal damage also occurs with graft versus host disease, immunodeficiencies, chemotherapy, radiation injury. Congenital mucosal abnormalities manifesting in the newborn period include microvillus inclusion disease, Tufting enteropathy, and genetic defects such as congenital glucose-galactose malabsorption and congenital chloridorrhea.

What caused this disease to develop at this time?

Lactase deficiency is the most common disaccharidase deficiency and may be primary or secondary. Primary causes are trehalase deficiency, maltase-glucoamylase deficiency, sucrase-isomaltase deficiency, sucrase-isomaltase deficiency which is onset from birth and related to sucrose or starch intake, primary adult type hypolactasia which is onset from 3 years up to early adulthood, and the rarely case of congenital lactase deficiency.

Primary (adult-type) hypolactasia is the most frequent form of lactase deficiency. It is the result of a programmed reduction of lactase synthesis after three years of age and affects approximately half of the world’s population. Primary congenital lactase deficiency is a rare disorder that manifests in early infancy.

Secondary deficiencies of lactase are common and present after depletion of mature enterocytes from an underlying disorder or disease process. Sucrase-isomaltase deficiency is the second most common disaccharidase deficiency. It usually presents after weaning from breast milk, when sucrose or starch intake increases. This enzyme is needed to hydrolyse sucrose, as well as limit dextrins from starches. Trehalase deficiency is less common and presents when mushrooms are ingested.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A review of patient history, physical examination, breath test, lactose intolerance test, stool reducing substance test, osmotic gap, fecal pH, stool electrophoresis, and a dissaccharidase assay are all common studies for diagnosing disaccharidase deficiency. (See Table I.)

Table I.

Approach to Diagnosis
Study Method Indicators for Diagnosis
Patient History Review of Chart Frequently the child is without complaints first thing in the morning, but 1 to 3 hours after ingesting milk or other dairy products develops distension and crampy abdominal pain that is relieved by passing flatus or upon defecation.
Patient Examination Palpitation of Lower Quadrants Pain may reveal palpable gas or fluid in the RLQ overlying the cecum and illicit characteristic borborygmi.
Breath Test Following an overnight fast and a basal collection of exhaled breath, the test substrate is ingested. Further collections of exhaled breath are obtained at 30 minute intervals for up to 3 hours. An elevation of at last 20 parts per million (ppm) for hydrogen or 10 ppm for methane above the basal level is indicative of a positive test for disaccharidase deficiency. The presence of abdominal pain or diarrhea during the test is supportive evidence for a positive test. The advantage of this test is it reflects the absorptive capacity of the entire small intestine for the substrate used. The disadvantages are that the test is time consuming and requires a separate study for each individual sugar under consideration. A small number of individuals do not produce hydrogen or methane and hence will give a false negative result. Typically these cases will manifest symptoms of pain or diarrhea during the test but are without a rise in breath hydrogen or methane levels.
Lactose Intolerance Test This test is based on serial blood glucose measurements following ingestion of lactose. The specificity of the LTT ranges from 77–96% and sensitivity from 76–94%. The LTT is rarely used since the introduction of breath tests.
Stool Reducing Substance Test Unabsorbed sugars can be detected in the stool. Clinitest tablets give a positive reaction with glucose, galactose, fructose, maltose, and lactose (reducing sugars). The test is not very sensitive and a positive result merely indicates the presence of an unabsorbed sugar in the stool but cannot identify the specific sugar. False negative tests may occur due to prior bacterial fermentation of the sugar in the colon. Clinitest tablets cannot detect sucrose, lactulose, sorbitol, and mannitol as these are non-reducing sugar or sugar alcohols.
Osmotic Gap The osmotic gap is best determined by measuring the stool electrolytes and using the calculation gap= 290- 2x(Stool Na+ + K+). Diarrhea secondary to disaccharidase deficiency typically results in an increased stool osmotic gap (>125 mOsm/kg). The osmotic gap provides an indirect indication of a disaccharidase deficiency and does not identify the causative sugar.
Fecal pH A low fecal pH is characteristic of diarrhea caused by carbohydrate malabsorption. In experimentally induced diarrhea a fecal pH of <5.3 indicates carbohydrate malabsorption is the major cause of diarrhea. ApH of >5.6 suggests carbohydrate malabsorption is not the only cause of diarrhea.
Stool Electrophoresis This test can identify a specific unabsorbed sugar in the stool unless it has been fully fermented by the colonic bacterial flora. This test is time consuming and expensive and hence is seldom used.
Disaccharidase Assay Determination of disaccharidase enzymes levels can be obtained from a single small intestinal biopsy specimen. The test is offered by only a few laboratories in the United States and worldwide. The advantage of this test is that it can directly measure the activity of all the disaccharidases with the exception of trehalase. The disadvantage is that it requires an endoscopy and biopsy of the small intestinal mucosa. The test also does not reflect the absorptive capacity of small intestine for the individual sugars and the results can be misleading in cases where the intestinal mucosal abnormality is patchy, as for example, in celiac disease.

Would imaging studies be helpful? If so, which ones?

A plain abdominal x-ray demonstrating gaseous distension of the large intestine can be seen in disaccharide malabsorption. However, this is a non specific finding and hence imaging studies have no role in the diagnosis of disaccharidase deficiencies.

Confirming the diagnosis

See Figure 1. Algorithm for the diagnosis of the most frequent disaccharidase deficiency: lactose malabsorption

Figure 1.

Algorithm for the diagnosis of the most frequent disaccharidase deficiency: lactose malabsorption.

If you are able to confirm that the patient has disaccharidase deficiency, what treatment should be initiated?

Complete dietary elimination of the symptom causing disaccharidase is curative. However, this cure is not always possible as there are many hidden sources of these sugars in foods and medications. In addition, complete elimination of lactose products can lead to inadequate calcium intake.

Yogurt may be tolerated by lactase-deficient individuals and provides a good source of calcium. If lactose is ingested with high fat meal the symptoms may be less severe due to slower gastric emptying. Consuming whole milk or chocolate milk, rather than skim milk, and drinking milk with meals can reduce symptoms of lactose intolerance presumably as a result of prolongation of gastric emptying. Alternatively, supplementation of dairy products with lactase of microbiologic origin may be suggested.

Enzyme supplementation is available for lactose (many brands such as Lactaid©) and sucrose (Sucraid©, or fresh Baker's yeast) malabsorption.

For lactase deficiency, 1-2 capsules taken with milk or dairy products; pre-treat milk with 1-2 capsules/quart of milk; Liquid: 5-15 drops/quart of milk; Tablet: 1-3 tablets with meals.

For sucrose deficiency, Infants and Children =15 kg: 8500 international units (1 mL) per meal or snack; Children >15 kg and Adults: 17,000 international units (2 mL) per meal or snack.

If available a nutritional consultation may be beneficial. Congenital or primary disaccharidase deficiencies require life-long management. Secondary disaccharidase deficiencies may be transient and require treatment only until the cause is eliminated and the intestinal lining recovers.

What are the adverse effects associated with each treatment option?

There are no immediate adverse effects with elimination diets. In the long-term elimination of all dairy products can result in decreased calcium intake. Unless additional calcium is obtained from other food sources or supplements there is potential risk for decreased bone density. There is no significant risk associated with enzyme replacement therapy. To date no known adverse effects have been reported with Lactaid or Sucraid use.

What are the possible outcomes of disaccharidase deficiences?

Primary forms of lactase deficiency (congenital lactase deficiency or primary hypolactasia) will have complete symptom resolution if therapeutic recommendations are followed.

The outcome in cases of secondary disaccharidase deficiencies is dependent on the underlying cause of the intestinal mucosal damage. In cases where mucosal recovery is possible following treatment of the underlying cause (e.g., celiac disease) complete symptom resolution can be anticipated and eventually it should be possible to resume ingestion of all disaccharidases.

What causes this disease and how frequent is it?

Primary lactase deficiency is due to a genetically programmed gradual loss of intestinal lactase production that occurs after the early childhood in affected individuals. Epidemiological data demonstrate this condition is more common in certain ethnic groups and geographic locations. Data on the “lactase persistence gene” prevalence in different parts of the world were published in a paper by Itan et al. and are summarized (See Table II.)

Table II.

Wordwide Lactase Persistence based on Allele Frequency

How do these pathogens/genes/exposures cause the disease?

Congenital deficiencies of disaccharidases and the primary lactase deficiency are due to genetic variations. Congenital lactase deficiency is a rare disease that is inherited in an autosomal recessive fashion. Most cases have been reported from Finland. The human lactase gene is located on chromosome 2q21-22. The locus for congenital lactase deficiency has been linked to a 350-kilobase interval more than 2 megabases away from the lactase-phlorizin hydrolase gene.

The most common form of lactose deficiency is primary (adult-type) hypolactasia characterized by a decline in lactase activity starting after about 3 years of age. It is hypothesized that developmentally-regulated DNA-binding proteins down-regulate transcription or destabilize mRNA transcripts, causing decreased lactase expression after weaning.

The persistence of lactase is attributed to inheritance of an autosomal dominant mutation that prevents the normal maturational decline in lactase expression. A single-nucleotide polymorphism (SNP) -13910 T/C upstream of the coding gene has been found to be involved in the regulation of enzyme activity. In whites the CC genotype of the SNP -13910 T/C upstream of the lactase gene is associated with adult-type hypolactasia while the TC and TT genotypes are linked with lactase persistence. Several other variants have been identified very close to the -13910 position, which are associated with lactase persistence in the Middle East and Africa.

Congenital sucrase-isomaltase deficiency occurs in about 0.2% in North Americans of European origin and about 10% in the Eskimos of Greenland. It is an autosomal recessive disorder. The sucrase-isomaltase gene is located on chromosome 3 at locus 3q25-26. Affected individuals have undetectable intestinal sucrase activity and reduced isomaltase activity. It manifests during infancy after the introduction of sucrose in fruits and juices or glucose polymers in infant formula. The human maltase-glucoamylase gene (MGAM) is located on chromosome 7 at locus 7q34. Maltase-glucoamylase deficiency was detected with a prevalence of 1.8% in children with chronic diarrhea.

Trehalase enzyme digests trehalose the disaccharide found in mushrooms, yeast and algae. The human trehalase gene (TREH) is located on chromosome 11 at locus 11q23. Isolated trehalase deficiency is reported to occur in 8% of the population of Greenland.

Drugs, inflammatory diseases and pathogens can cause direct damage to the enterocytes or adversely affect cell turnover in the small intestine.

Other clinical manifestations that might help with diagnosis and management.

Decreased bone density (controversial).

Poor weight gain (occasional and controversial).

What complications might you expect from the disease or treatment of the disease?

There is no complication associated with the management of disaccharidase deficiencies.

Are additional laboratory studies available; even some that are not widely available?

Genetic testing for the primary (adult-type) lactase deficiency is available in some commercial laboratories. There was a good correlation between the C/C(-13910) genotype and low lactase activity (<10 U/g protein) in the majority of children tested at 8 years of age and in every child older than 12 years of age, giving a specificity of 100% and sensitivity of 93% for the genetic test.

How can disaccharidase deficiences be prevented?

Primary causes of disaccharidase deficiencies cannot be prevented. When an index case is identified, genetic counseling and anticipatory guidance may be helpful in early identification of additional cases.

Some causes of secondary disaccharidase deficiencies are preventable. Use of rotavirus vaccine has been shown to significantly decrease the occurrence of disease and this in turn will decrease the incidence of acquired disaccharidase deficiency. Similarly, maintenance of appropriate nutrition during and after infectious gastroenteritis has been shown to minimize prolonged mucosal damage.

What is the evidence?

Response to dietary restriction as well use of supplements such as Lactaid for lactase deficiency, or Sucraid for Sucrase Isomaltase deficiency has been documented in studies and clinical practice.

Kolars, J. C., Levitt, M. D., Aouji, M., Savaiano, D. A.. "Yogurt - an autodigesting source of lactose". N Engl J Med. vol. 1. 1984. pp. 3.

(Yogurt a well-tolerated source of milk for lactase-deficient persons.)

Harms, H.K., Bertele-Harms, R.M., Bruer-Kleis, D. "Enzyme-substitution therapy with the yeast Saccharomyces cerevisiae in congenital sucrase-isomaltase deficiency". N Engl J Med. vol. 316. 1987. pp. 1306-9.

(Patients with congenital sucrase-isomaltase deficiency who consume sucrose can ameliorate the malabsorption by subsequently ingesting a small amount of viable yeast cells, preferably on a full stomach.)

Itan, Y., Jones, B. L., Ingram, C. J., Swallow, D. M., Thomas, M. G. "A worldwide correlation of lactase persistence phenotype and genotypes". BMC Evol Biol. vol. 10. 2010. pp. 36.

(Lactase persistence genotype data is currently insufficient to explain lactase persistence phenotype frequency in various parts of the world.)

Wang, L.H., Hartman, P.A. "The genetically programmed down-regulation of lactase in children". Gastroenterology. vol. 114. 1998. pp. 1230-6.

(Genetically programmed down-regulation of the lactase gene is detectable in children from the second year of life, although the onset and extent are somewhat variable.)

Troelsen, J. T., Olsen, J., Moller, J., Sjostrom, H. "An upstream polymorphism associated with lactase persistence has increased enhancer activity". Gastroenterology. vol. 125. 2003. pp. 1686-94.

(The molecular difference between lactase persistence and nonpersistence is caused by the mutation at position -13910)

Lebenthal, E., Khin Maung, U., Zheng, B. Y., Lu, R. B., Lerner, A. "Small intestinal glucoamylase deficiency and starch malabsorption: a newly recognized alpha-glucosidase deficiency in children". Journal of Pediatrics. vol. 124. 1994. pp. 541-6.

(Intestinal glucoamylase deficiency can be the cause of chronic diarrhea.)

Rasinpera, H., Savilahti, E., Enattah, N. S., Kuokkanen, M., Totterman, N., Lindahl, H. "A genetic test which can be used to diagnose adult-type hypolactasia in children". Gut. vol. 53. 2004. pp. 1571-6.

(Genetic test of C/T(-13910) polymorphism can be used as a first stage screening test for adult-type

Ongoing controversies regarding etiology, diagnosis, treatment

There are no real controversies.

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