Sucrase-Isomaltase Deficiency

By Kristin Dermody & Sara Murkowski
NAFWA HOME

Sucrase-Isomaltase: Digestive Function

n Brush border disaccharidase

n Required for hydrolysis of dietary sucrose

n Catalyzes degradation of sucrose to monosaccharides for intestinal absorption

n The digestive tract is can only absorp CHO’s in form of monosaccharides

n Let’s take a moment to talk carbs…

CHO 101

n Monosaccharides

n Glucose, Fructose, Galactose

n Readily absorbed across intestinal lumen

n Disaccharides

n Sucrose (glucose+fructose)

n Lactose (glucose+galactose)

n Maltose (glucose+glucose)

n Starches (polysaccharides)

n Contain 15-30% amylose, 70-85% amylopectin

CHO Digestion and Absorption

In lumen

n Starch à maltose + maltriose + á-limit dextrins

n Amylase

At brush-border

n Maltose/maltriose à glucose

n Glucoamylase (maltase)

n Sucrase-isomaltase

n á-limit dextrins à glucose

n Sucrase-isomaltase

n Sucrose à glucose + fructose

n Sucrase-isomaltase

n Lactose à glucose + galactose

n Lactase

Congenital Sucrase Isomaltase Deficiency

n An autosomal recessive human intestinal disorder

n Characterized by fermentative diarrhea, abdominal pain and cramps upon ingestion of sucrose, some starches

n Symptoms are consequence of absent/drastically reduced enzymatic activities of the sucrase-isomaltase complex

Multiple Forms of CSID

n 5 Distinct phenotypes documented

n Complete lack of sucrase in all forms

n Isomaltase activity varies depending on phenotype

n Genetic variability likely cause for large range in severity of symptoms among affected patients

Incidence and Prevalence of CSID

n The congenital absence of digestive enzymes is a rare disorder affecting about 0.2% North Americans

n Due to varying severity of disease, definite incidence and prevalence is uncertain

n CSID most common among congenital digestive enzyme deficiencies

n CSID is most common in Canadian Inuits and natives of Greenland.

Pathophysiology of CSID

n Rare inborn error of metabolism

n Results from mutation of sucrase-isomaltase at cellular level

• Mutations prevent completion & transport of enzyme to brush border enterocytes

n SI deficiency results in increased luminal disaccharides and consequent osmotic diarrhea

What are the Symptoms?

n Watery diarrhea

n Abdominal cramps

n Flatulence

n Bloating

n Occasional Vomiting

n Highly similar to lactose intolerance!

Symptoms are Conditional

n Severity of Sx’s dependent on:

n Distinct phenotype of CSID

n Quantity of sugar consumed

n Colonic bacterial activity

n Absorptive capacity of colon

n Rate of gastric emptying

n Small bowel transit time

n Symptoms typically more severe in infants than adults

n More rapid passage of CHO content through small intestine and colon

n Greater degree of malabsorption in infants than adults

Clinical Manifestations

n Severe chronic diarrhea

n Lethargy

n Fatigue

n Failure to thrive

Nutritional Implications

n Malabsorption of CHO

n Weight loss

n Dehydration

n Electrolyte imbalance

n Poor POs

n Ultimately, malnutrition!

Detection & Diagnosis of CSID

n First onset of symptoms generally at weaning from breast milk

n Sucrose and starch is introduced in form of fruit juices and solid foods

n Early observations noted in infants fed modified milk formulas with sucrose or polycose

Diagnostic Criteria

n Lab Studies

n Stool Analysis

• +Reducing substances

• +Acidic stool (pH lower than 5.5)

n Urinalysis

• Differential urinary disaccharidases

n Procedures

n Sucrose tolerance test

n CHO hydrogen breath test

• Fermented CHO load in large intestine releases hydrogen that is absorbed into blood and released by lungs

n Small bowel biopsy

• Measures intestinal disaccharidases

• Final, most definitive test

A Mysterious Diagnosis

n Correct diagnosis of CSID often long and difficult

n Symptoms similar in other diseases

• IBS

• Cow’s milk or soy protein allergy

• Cystic fibrosis

• Celiac disease

n Patients diagnosed as adults recount h/o feeding difficulties during infancy

Disease Progression

n Sucrose intolerance usually improves w/ age

n Symptoms of starch intolerance often disappear within first years of life

n However, patients do not “grow out” of CSID!

n While enzyme deficiency remains, pt’s become more tolerant over time

Disease Management

n Dietary restriction

n Elimination of sucrose, glucose polymers, starches in 1^st year of life

n After 2-3 years, strict starch restriction can be liberalized as tolerated

n Pharmacotherapy

n Sacrosidaise (Sucraid)

• Yeast derived oral form of the sucrase enzyme

• Significantly increases sucrose and starch tolerance

• What is the drug’s efficacy? Research says…

Sacrosidase Therapy For CSID

n Purpose:

n To determine if sacrosidase prevented sx’s of diarrhea, abd cramps, gas, bloating in pt’s with CSID

n Methods:

n 28 subjects (5mo-11yo)

n Randomized, double-blind trial

• Phase 1: 3 sucrose breath H2 tests

• 3 single-dose treatments (placebo, sacrosidase, sacrosidase + milk)

• Phase 2: Dose-response phase

• 4 multidose treatments

• 10 days FS sacrosidase (1:10; 1:100; 1:1000)

n Data collected (Phase 2)

• # stools/d, severity of symptoms (for each concentration of enzyme administered + normal diet)

• Baseline period symptoms (sans enzyme therapy + sucrose/starch-free diet)

n Data Analysis

• ANOVA model

• Non-parameter Wilcoxin signed-rank test

Sacrosidase Therapy For CSID

n Results

n Phase 1:

• Breath H₂ excretion decreased significantly with sacrosidase, sacrosidase + milk (compared to placebo)

n Phase 2:

• Significant treatment differences between higher concentrations vs. lower concentrations

• Higher concentations -> fewer symptoms

n Conclusion

n “Sacrosidase is a safe, effective, well-accepted treatment to prevent GI symptoms in patients with CSID consuming a normal diet”

How Does This Apply?

n Sacrosidase

n The active ingredient in Sucraid®

n Sucraid®

n Approved by FDA – 1998

n Oral solution used as a replacement for pt’s w/o enzymes needed to properly break down and absorb sucrose and isomaltose

Milk Allergy: A Brief

n “The immune system's response to one or more of the proteins found in cow's milk”

n 2-3% of infants are allergic to milk but most tend to outgrow it within the first few years

n 60% milk allergic children outgrow it by the age of four

n 80% outgrow it by the age of 6

Goats’ Milk: What’s the deal?

n Trace amounts of casein

n Slightly less lactose than cows milk

n More easily digestible than cow’s milk

n Higher amounts of short chain fatty acids

n If allergic to cows’ milk…

What About A Milk Allergy?

n Sometimes a milk allergic person can use goat’s milk or soy milk

n Both milks can be allergenic

n Many people allergic to cow’s milk are also allergic to goat’s milk

References

n Indications – Congenital Sucrase-Isomaltase Deficiency. http://www.orphan-europe.com/1038815774.print. Orphan Europe, 2002

n Davis, M.B., et al. Mapping of the gene encoding human sucrase-isomaltase (SI) to chromosome 3q25-26. Cytogenet. Cell Genet. 46:604, 1987.

n Disaccharide Intolerance I. OMIM, Johns Hopkins University http://www.ncbi.nlm.nih.gov/entrez/query.

n Ritz V, et al. Congenital sucrase-isomaltase deficiency because of an accumulation of the mutant enzyme in the endoplasmic reticulum. Gastroenterology. 125(6):1678-85, 2003.

n Psychogenic polydipsia with hyponatremia: report of eleven cases. Am J Kidney Dis. 1987 May;9(5):410-6.

n Arch Intern Med. 1995 May 8:155(9):953-7.

n Hum Psychopharmacol. 2002 Jul; 17(5):253-5

n National Organization for Rare Disorders. www.raredisorders.org.

n Belmont, et al. Congenital Sucrase-isomaltase deficiency presenting with failure to thrive, hypercalcemia, and nephrocalcinosis. BMC Pediatrics. 2:1471-2431, 2002.

n Treem, et al. Sacrosidase therapy for congenital sucrase-isomaltase deficiency. J Pediatr Gastroenterol Nutr. 28 (2): 137-142, 1999

By Kristin Dermody & Sara Murkowski NAFWA HOME

Sucrase-Isomaltase: Digestive Function

n Brush border disaccharidase

n Required for hydrolysis of dietary sucrose

n Catalyzes degradation of sucrose to monosaccharides for intestinal absorption

n The digestive tract is can only absorp CHO’s in form of monosaccharides

n Let’s take a moment to talk carbs…

CHO 101

n Monosaccharides

n Glucose, Fructose, Galactose

n Readily absorbed across intestinal lumen

n Disaccharides

n Sucrose (glucose+fructose)

n Lactose (glucose+galactose)

n Maltose (glucose+glucose)

n Starches (polysaccharides)

n Contain 15-30% amylose, 70-85% amylopectin

CHO Digestion and Absorption

In lumen

n Starch à maltose + maltriose + á-limit dextrins

n Amylase

At brush-border

n Maltose/maltriose à glucose

n Glucoamylase (maltase)

n Sucrase-isomaltase

n á-limit dextrins à glucose

n Sucrase-isomaltase

n Sucrose à glucose + fructose

n Sucrase-isomaltase

n Lactose à glucose + galactose

n Lactase

Congenital Sucrase Isomaltase Deficiency

n An autosomal recessive human intestinal disorder

n Characterized by fermentative diarrhea, abdominal pain and cramps upon ingestion of sucrose, some starches

n Symptoms are consequence of absent/drastically reduced enzymatic activities of the sucrase-isomaltase complex

Multiple Forms of CSID

n 5 Distinct phenotypes documented

n Complete lack of sucrase in all forms

n Isomaltase activity varies depending on phenotype

n Genetic variability likely cause for large range in severity of symptoms among affected patients

Incidence and Prevalence of CSID

n The congenital absence of digestive enzymes is a rare disorder affecting about 0.2% North Americans

n Due to varying severity of disease, definite incidence and prevalence is uncertain

n CSID most common among congenital digestive enzyme deficiencies

n CSID is most common in Canadian Inuits and natives of Greenland.

Pathophysiology of CSID

n Rare inborn error of metabolism

n Results from mutation of sucrase-isomaltase at cellular level

• Mutations prevent completion & transport of enzyme to brush border enterocytes

n SI deficiency results in increased luminal disaccharides and consequent osmotic diarrhea

What are the Symptoms?

n Watery diarrhea

n Abdominal cramps

n Flatulence

n Bloating

n Occasional Vomiting

n Highly similar to lactose intolerance!

Symptoms are Conditional

n Severity of Sx’s dependent on:

n Distinct phenotype of CSID

n Quantity of sugar consumed

n Colonic bacterial activity

n Absorptive capacity of colon

n Rate of gastric emptying

n Small bowel transit time

n Symptoms typically more severe in infants than adults

n More rapid passage of CHO content through small intestine and colon

n Greater degree of malabsorption in infants than adults

Clinical Manifestations

n Severe chronic diarrhea

n Lethargy

n Fatigue

n Failure to thrive

Nutritional Implications

n Malabsorption of CHO

n Weight loss

n Dehydration

n Electrolyte imbalance

n Poor POs

n Ultimately, malnutrition!

By Kristin Dermody & Sara Murkowski
NAFWA HOME

n Elimination of sucrose, glucose polymers, starches in 1^st year of life

• Breath H₂ excretion decreased significantly with sacrosidase, sacrosidase + milk (compared to placebo)