Enzyme and Transport Defects

Enzyme and Transport Defects

Sandy T. Hwang

Robert J. Shulman


Pathophysiology and Clinical Findings

Disorders of carbohydrate absorption are linked integrally with dysfunction of the small-intestinal mucosal carbohydrate-digesting enzymes: lactase, sucrase, alpha-dextrinase, trehalase, and glucoamylase. Lactase activity increases substantially between 35 weeks’ gestation and birth. Lactase is the only enzyme capable of hydrolyzing lactose. Sucrase and alpha-dextrinase are two enzymes that are linked covalently in the intestinal brush border and develop full activity in early fetal life. Sucrase can hydrolyze sucrose, maltose, and the 1,4 bonds in glucose polymers and starches. Alpha-dextrinase can hydrolyze maltose but not sucrose, and it is the only enzyme that can hydrolyze the 1,6 bonds found in starches. Trehalose, a carbohydrate found in mushrooms and insects, is hydrolyzed by trehalase. Glucoamylase activity also is developed early in gestation and can hydrolyze maltose and the 1,4 linkages from the nonreducing ends of starches (i.e., glucose polymers, complex starches). If lactose, sucrose, trehalose, and maltose are not hydrolyzed and absorbed, they remain as osmotically active molecules in the lumen of the bowel. Unabsorbed glucose
polymers and starches have a similar but smaller effect inversely proportional to molecular size. All disorders associated with significant carbohydrate malabsorption can induce a net secretion of water that increases the rate of intestinal transit and can decrease the absorptive capacity for other nutrients. The result is watery diarrhea and cramping that cease if patients are not fed.

Malabsorbed carbohydrate passes into the colon, where it is converted by bacterial fermentation to fatty acids, which also are osmotically active, and to hydrogen gas. These conversion products are absorbed partially; some of the hydrogen gas is excreted in breath. When carbohydrate is malabsorbed beyond the capacity of bacterial fermentation, the result is acid stools (pH less than 6) and fecal carbohydrate loss (i.e., stools positive for reducing substances, such as glucose).

Disorders of carbohydrate digestion or absorption may or may not be associated with failure to thrive in infancy, depending on the degree of exposure to the offending carbohydrate. Nutritional or growth abnormalities do not result if the diet is nutritionally adequate and contains little or no offending carbohydrate.

Primary Disorders

Infants with the rare condition of congenital lactase deficiency are symptomatic at birth if a lactose-containing diet (e.g., breast milk, formula) is fed. Lactose tolerance appears to increase during childhood for reasons that are not understood entirely. Late-onset lactase deficiency, an autosomal recessive trait, develops between ages 3 and 5 years. It occurs in 5% to 20% of white children and 70% to 75% of black children in North America, in 74% of Hispanic children, and in 55% of Filipino children. Evidence suggests that the decline in lactase activity can be due to changes in gene transcriptional regulation or posttranslational processing. Although lactose malabsorption also occurs in late-onset deficiency, lactose intolerance—characterized by watery diarrhea, abdominal pain, and/or cramping—may not be present, because symptoms depend in part on patients’ subjective response to gas and pain, the lactose load, the rate of gastric emptying, and, in some cases, the residual lactase activity.

In North America, the incidence of sucrase and alpha-dextrinase deficiency is 0.2%. In this autosomal recessive disorder, patients have a defect in the posttranslational processing of the enzymes; sucrase activity is absent, and dextrinase activity is partially or completely absent. Usually, patients become symptomatic in infancy when a sucrose-containing diet is introduced. As with congenital lactase deficiency, patients appear to develop tolerance to sucrose with age.

Trehalase deficiency is a rare autosomal recessive condition particularly prevalent in the Greenland Inuit population (10% to 15%). Symptoms have been reported after the ingestion of large amounts of mushrooms.

A recently identified condition, glucoamylase deficiency, is included in the differential diagnosis of chronic diarrhea in children. Usually, the activity levels of sucrase, dextrinase, maltase, and lactase are normal. Significant growth failure is not a common feature.

In glucose and galactose malabsorption (an autosomal recessive disease), hydrolysis of carbohydrates proceeds normally, but patients lack the ability to absorb glucose or galactose (carbohydrates that appear to have a common transport mechanism). The defect appears to be a mutation in the sodium glucose cotransporter gene. Often, the disorder is associated with abnormal renal tubular glucose transport, which results in a decreased threshold for glucose reabsorption. Symptoms occur if the diet contains lactose, sucrose, maltose, or starches.

Isolated fructose malabsorption has been described. Often, symptoms of abdominal pain, bloating, and diarrhea follow the malabsorption of such fructose-containing foods as fruits and fruit juices. Symptoms do not develop after the ingestion of sucrose. Clinical evidence suggests this condition can coexist with glucose–galactose malabsorption.

Secondary Disorders

All the entities described must be differentiated from secondary carbohydrate intolerance, which results from damage to the enzyme-containing villous epithelial cells. Usually, lactase is the enzyme affected most severely because of its normally low activity and the slow rate of recovery, compared with that of the other enzymes. In contrast to sucrose and maltose, the rate-limiting step in lactose absorption is hydrolysis, not absorption. Lactase deficiency in infancy results commonly from enteric virus infections (e.g., rotavirus) or small-intestinal bacterial pathogens. A clinically significant deficiency may last from 3 to 4 weeks after an episode of acute gastroenteritis. Celiac disease and iron deficiency are other disorders that may be associated with lactase deficiency in older infants and children. If mucosal injury is severe, sucrase, alpha-dextrinase, and glucoamylase can be affected. In the worst cases, glucose absorption is impaired as a consequence of the reduced surface area available for absorption resulting from blunted and damaged villi.

Diagnosis and Treatment

An accurate diet history is critical in the diagnosis of carbohydrate intolerance. Often, the diagnosis can be confirmed by exclusion of the suspected carbohydrate from the diet, followed by rapid abatement of the symptoms (Fig. 363.1). Confirmatory evidence of carbohydrate malabsorption includes acid stools (i.e., pH less than 6, measured with Nitrazine paper on a fresh stool sample) and, in severe cases, stools positive for glucose. Stools are glucose positive because of bacterial breakdown of the disaccharides to their component sugars.

The diagnosis of carbohydrate malabsorption can be confirmed with an oral tolerance test, but this is neither sensitive nor specific. The hydrogen breath test is a more useful diagnostic tool. In the oral tolerance and the breath hydrogen tests, a 2-g load of the carbohydrate per 1 kg of body weight is administered as a 20% solution. In response to the oral tolerance test, a rise in blood glucose of less than 25 mg/dL is presumptive evidence of carbohydrate malabsorption, as is a rise in breath hydrogen greater than 10 parts per million over baseline. A definitive diagnosis is achieved when normal histology (in the primary disorders) or abnormal histology (in the secondary deficiencies) is found and enzyme activity is absent in a small-intestinal biopsy specimen obtained perorally.

The treatment of choice for the primary disorders is exclusion of the offending carbohydrate from the diet, presumably for life. However, tolerance generally improves with age, and small amounts of the carbohydrate can be consumed without clinical symptoms. Lactose intolerance can be overcome when meals are supplemented with the lactase enzyme obtained from the fungus Aspergillus oryzae (Lactrase, Lactaid). Sucrase and alpha-dextrinase intolerance can be improved by adding fresh bakers’ yeast (Saccharomyces cerevisiae) to meals. A more palatable alternative is liquid yeast sucrase (Sucraid). The exclusion of starches from the diet improves symptoms in glucoamylase deficiency. Glucose and galactose malabsorption requires the use of fructose as the dietary carbohydrate, because fructose transport by facilitated diffusion is unaffected in this disorder. Fructose malabsorption requires the removal of free fructose from the diet.

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Jul 24, 2016 | Posted by in ORTHOPEDIC | Comments Off on Enzyme and Transport Defects
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