Lactase Enzyme Supplementation In Lactose Intolerance

About lactose intolerance

Lactose intolerance is defined as the inability to digest and absorb lactose, a type of sugar found in milk and other dairy products. It is characterized by the presence of abdominal pain, bloating, borborygmi, and diarrhea induced by lactose. A recent NIH conference defined it as ‘the onset of gastrointestinal symptoms following a blinded, single-dose challenge of ingested lactose by an individual with lactose malabsorption, which are not observed when the person ingests an indistinguishable placebo’. Lactose intolerance is mainly related to the primary and secondary lactase deficiency.¹Deng Y, Misselwitz B, Dai N, Fox M. Lactose Intolerance in Adults: Biological Mechanism and Dietary Management. Nutrients. 2015;7(9):8020-8035.    ²Misselwitz B, Pohl D, Frühauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterology Journal. 2013;1(3):151-159.    Lactose is a disaccharide sugar from milk and milk products from all mammals and is digested by enzyme lactase found in the mucosal brush border surface of the human intestine. Lactose intolerance is found in about 25% of people in Europe; 50-80% of people of Hispanic origin, from south India, black people, and Ashkenazi Jews; and approximately 100% of people in Asia and American Indians.³Bhatnagar S, Aggarwal R. Lactose intolerance. BMJ: British Medical Journal. 2007;334(7608):1331-1332.    According to a multicenter study its prevalence in India was reported to be 66.6% in the subjects from two South Indian centers at Trivandrum and Pondicherry, while in a North Indian center in New Delhi it was much lower to 27.4%.⁴Tandon RK, Joshi YK, Singh DS, Narendranathan M, Balakrishnan V, Lal K. Lactose intolerance in North and South Indians. Am J Clin Nutr. 1981 May;34(5):943-6.    The most common cause of lactose malabsorption is non-persistence of enzyme lactase. Lactase non-persistence is a common condition in which the expression of this enzyme decreases during infancy. Contrastingly, congenital lactase deficiency is a rare condition that presents with severe symptoms in newborns. Additionally, it may also occurs secondary to acquired conditions including small bowel bacterial overgrowth, infectious enteritis, inflammatory bowel disease, drugs, gastrointestinal surgery, short bowel syndrome, or radiation enteritis, conditions that lead to either reduction of absorptive capacity or downregulation of lactase expression in the small intestine.²Misselwitz B, Pohl D, Frühauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterology Journal. 2013;1(3):151-159.

The deficiency of lactase can thus be classified as primary, secondary, congenital, and developmental depending on its cause. This classification is important as it relates to diagnosis, prognosis, and treatment of lactose intolerance.³Bhatnagar S, Aggarwal R. Lactose intolerance. BMJ: British Medical Journal. 2007;334(7608):1331-1332.    Intolerance to alcohol adversely affects the quality of life of affected individuals. The condition should therefore be adequately diagnosed and managed to ease the normal living of the sufferers.⁵Casellas F, Aparici A, Pérez MJ, Rodríguez P. Perception of lactose intolerance impairs health-related quality of life. Eur J Clin Nutr. 2016 Sep;70(9):1068-72.

Diagnosis

Diagnosis of lactose intolerance should be made in patients with abdominal symptoms that appears after ingestion of milk and milk products. The symptoms may include abdominal pain, bloating, borborygmi, and diarrhea. However, a few patients may also presents with nausea, constipation or a range of systemic symptoms including headaches, fatigue, loss of concentration, muscle and joint pain, mouth ulcers, and urinary difficulties. The symptoms can be disabling enough to interfere with routine life. Symptom improvement after elimination of milk products and worsening after reintroduction confirms the diagnosis. In contrast, self-reported food intolerance is also common which is often encountered by a large proportion of the community in population-based studies, with frequency rates ranging from 9.5 to 25% and is even higher in patients with functional gastrointestinal diseases such as irritable bowel syndrome. However, a definitive diagnosis is not possible based on clinical presentation alone, since various double-blind trials have shown that the association of self-reported lactose intolerance and the occurrence of symptoms after lactose ingestion are very poor, even in patients with lactase deficiency.¹Deng Y, Misselwitz B, Dai N, Fox M. Lactose Intolerance in Adults: Biological Mechanism and Dietary Management. Nutrients. 2015;7(9):8020-8035.    ²Misselwitz B, Pohl D, Frühauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterology Journal. 2013;1(3):151-159.    ³Bhatnagar S, Aggarwal R. Lactose intolerance. BMJ: British Medical Journal. 2007;334(7608):1331-1332.

Various tests are available for the diagnosis of lactose intolerance including lactose tolerance test, hydrogen breath test and DNA based diagnostic test. Initially, the direct biochemical assay of the lactase activity from a jejunal sample was the most accurate method available for the diagnosis of lactose intolerance. This assay is performed with the help of a glucose oxidase reagent, which detects glucose liberated from lactose, with a cutoff value of 10 U/g proteins. However, due to the invasiveness of a jejunal biopsy, this method has been replaced by endoscopic duodenal biopsy. Contrastingly, lactose tolerance tests have been developed to confirm the ability of intestinal lactase to hydrolyze and absorb lactose, and to avoid intestinal biopsies. This test has a sensitivity of around 75%. In this test blood glucose levels were measured both before and after an oral load of lactose at prespecified time intervals, with a maximum rise of 20 mg/dL, indicative of lactose tolerance. Administration of oral ethanol is done before lactose load is used to inhibit galactose metabolism for the determination of the blood maximum rise of glucose (at least 20 mg/dl) and galactose (at least 10 mg/dl) which also indicates lactose tolerance. Therefore, galactose concentration in combination with glucose concentration improves the correlation with jejunal lactase activity than using only glucose maximum rise after lactose load.³Bhatnagar S, Aggarwal R. Lactose intolerance. BMJ: British Medical Journal. 2007;334(7608):1331-1332.    ⁶Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clinical and Experimental Gastroenterology. 2012;5:113-121.     Nevertheless, of all the indirect lactose tolerance tests currently available, hydrogen breath test is the most widely used which is a simple, low-cost and noninvasive technique. It is based on the fermentation of undigested lactose by intestinal flora, producing hydrogen, carbon dioxide and methane that are absorbed and eliminated by the lungs. The reliability of this test widely depends on the activity of bacterial flora.⁷Di Camillo M, Marinaro V, Argnani F, Foglietta T, Vernia P. Hydrogen breath test for diagnosis of lactose malabsorption: The importance of timing and the number of breath samples. Canadian Journal of Gastroenterology. 2006;20(4):265-268.   A DNA based diagnostic test and genetic tests are also available. Genetic test is a simple, noninvasive, and more comfortable examination that does not provoke symptoms of lactose intolerance and is less cumbersome. It provides a more direct result, i.e. a hypolactasia or lactase persistence genotype.⁶Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clinical and Experimental Gastroenterology. 2012;5:113-121.    Diagnostic algorithm for the diagnosis of lactose intolerance is given in figure 1.²Misselwitz B, Pohl D, Frühauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterology Journal. 2013;1(3):151-159.    ⁸Usai-Satta P, Scarpa M, Oppia F, Cabras F. Lactose malabsorption and intolerance: What should be the best clinical management? World Journal of Gastrointestinal Pharmacology and Therapeutics. 2012;3(3):29-33.

Management

Treatment of lactose intolerance should not only aim at reducing malabsorption but also at improving gastrointestinal symptoms. Reduction of lactose intake is usually recommended since various studies suggest that patients with self-reported lactose intolerance can consume at least 12 g lactose without experiencing symptoms. The treatment should also include maintenance of adequate intake of calcium, thus preventing secondary bone disease caused by a milk-restricted diet.¹Deng Y, Misselwitz B, Dai N, Fox M. Lactose Intolerance in Adults: Biological Mechanism and Dietary Management. Nutrients. 2015;7(9):8020-8035.     ²Misselwitz B, Pohl D, Frühauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterology Journal. 2013;1(3):151-159.    ⁶Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clinical and Experimental Gastroenterology. 2012;5:113-121.    The selection of therapy should be based on the underlying type of deficiency. Therefore, it is important to differentiate between primary and secondary lactase deficiency. In secondary deficiency a temporary lactose-free diet is required only until a complete recovery of the causative pathological condition is obtained. On the other hand, in primary deficiency, a different therapeutic strategy should be considered due to irreversibility of the condition.⁹Montalto M, Curigliano V, Santoro L, et al. Management and treatment of lactose malabsorption. World Journal of Gastroenterology: WJG. 2006;12(2):187-191.   Therapeutic strategies for the management of lactose intolerance include both pharmacological and non-pharmacological options.⁸Usai-Satta P, Scarpa M, Oppia F, Cabras F. Lactose malabsorption and intolerance: What should be the best clinical management? World Journal of Gastrointestinal Pharmacology and Therapeutics. 2012;3(3):29-33.    Treatment algorithm for the management of lactose intolerance is described in figure 2.⁹Montalto M, Curigliano V, Santoro L, et al. Management and treatment of lactose malabsorption. World Journal of Gastroenterology: WJG. 2006;12(2):187-191.

Non-pharmacological approach

Non-pharmacological treatment options consist of lactose restricted diet or the use of milk in which the lactose has been pre-hydrolyzed via treatment with lactase supplements. Ingestion of milk together with other foods, consumption of fermented and matured dairy products, distribution in milky snacks, are other known options. Additionally, colonic adaptation by increasing lactose load is another attractive approach in the management of lactose intolerance. This is supported by the observation that introduction of lactose to the diet causes temporary and transient symptoms in individuals. Since lactase from intestinal brush border is not an inducible enzyme, the reduction in symptoms may be explained by colonic adaptation.

Pharmacological approach

Pharmacological treatment strategies include enzyme replacement therapy with lactase from nonhuman sources to hydrolyze lactose, probiotics, gut decontaminating agents and antimicrobials. There exist multiple commercially available lactase supplements containing variable amounts of beta-galactosidase from a variety of sources. Probiotics are living microorganisms that are nonpathogenic and have beta-galactosidase or lactase intracellularly and may aid in the digestion of lactose ingested by the host.⁸Usai-Satta P, Scarpa M, Oppia F, Cabras F. Lactose malabsorption and intolerance: What should be the best clinical management? World Journal of Gastrointestinal Pharmacology and Therapeutics. 2012;3(3):29-33.

Role of lactase enzyme supplementation in the treatment of lactose intolerance

Enzyme supplementation therapy with lactase from non-human sources is an important adjunct to diet therapy in patients with lactose intolerance.¹⁰. Swagerty DL Jr, Walling AD, Klein RM. Lactose intolerance. Am Fam Physician. 2002 May 1;65(9):1845-50.   ¹⁴. Di rienzo T, D’angelo G, D’aversa F, et al. Lactose intolerance: from diagnosis to correct management. Eur Rev Med Pharmacol Sci. 2013;17 Suppl 2:18-25.   ¹⁵Ibba I, Gilli A, Boi MF, Usai P. Effects of exogenous lactase administration on hydrogen breath excretion and intestinal symptoms in patients presenting lactose malabsorption and intolerance. BioMed Research International 2014 (2014);Article ID 680196:7 pages.    This exogenous lactase is obtained from several microbial sources (yeasts or fungi) with aim to hydrolyze the dietary lactose, and has been found to be highly effective in decreasing the symptoms of lactose intolerance.

Source of lactase impacts the pH stability of final preparation, which decides the dosage, efficacy, safety and cost. The good source is Aspergillus oryzae. European Food Safety Association (EFSA) and the United States Food and Drug Administration (USFDA), both approve and recommend Aspergillus oryzae. Lactase from A. oryzae source is considered GRAS (Generally Regarded as Safe).¹⁶Scientific Opinion on lactose thresholds in lactose intolerance and galactosaemia. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). EFSA Journal 2010;8(9):1777.   ¹⁷Enzyme Preparations Used in Food (Partial List). Available at: http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/EnzymePreparations/default.htm [Accessed on 16/11/2017].   ¹⁸GRAS Notice (GRN) No. 510. Available at: https://google2.fda.gov/search?q=lactase+from+aspergillus+oryzae&client=FDAgov&site=FDAgov&lr=&proxystylesheet=FD Agov&requiredfields=-archive%3AYes&output=xml_no_dtd&getfields=* [Accessed on 16/11/2017].    Lactase preparations from A. oryzae are stable in an acidic environment and are practically pH independent. High activity throughout the GI tract, even in lower stomach where pH is less than 3.5, is unlike other formulations which are unstable at pH of less than 3.5.¹⁹Park YK, De Santi MSS, Pastore GM. Production and characterization of β-galactosidase from Aspergillus Oryzae. Journal of Food Science 1979;44(1):100–103.   

Several studies conducted in the past in different populations have shown that lactose supplementation is an effective available way to increase the dairy consumption, and promote health of lactose intolerant people.²⁰He M, Yang Y, Bian L, et al. Effect of exogenous lactase on the absorption of lactose and its intolerance symptoms. Wei Sheng Yan Jiu. 1999; 28(5):309-11.    Furthermore, it is also likely to prevent complications of reduced calcium intake, vitamin deficiency, and to ensure a better quality-of-life. In an Asian study,²⁰He M, Yang Y, Bian L, et al. Effect of exogenous lactase on the absorption of lactose and its intolerance symptoms. Wei Sheng Yan Jiu. 1999; 28(5):309-11.    investigators evaluated the effects of exogenous lactase on lactose malabsorption and its intolerance symptoms, and to identify the available way to improve lactose absorption. Healthy adults with a history of lactose intolerance were screened by 25 gm lactose tolerance test, and those with higher hydrogen expired and/or lactose intolerance symptoms were selected for evaluation. These selected individuals were challenged twice with “400 ml low fat milk” and “400 ml low fat milk + 9000FCC lactase” separately in three days interval. Concurrently, breath hydrogen concentration and intolerance symptoms were tested in four hours following the challenge. The results of the study showed that exogenous lactase administration could significantly decrease the incidence of lactose malabsorption (the abnormal expiration of hydrogen decreased from 100% to 48.9%; Figure 3) and milk intolerance symptoms (from 51.1% to 13.3%; Figure 4). Overall, the study thus potentiated that lactose malabsorption and symptoms of intolerance result from the reduced enzyme activities of individuals, and that exogenous lactase supplementation can improve this lactose absorption and intolerance symptoms.

Sanders et al²¹Sanders SW, Tolman KG, Reitberg DP. Effect of a single dose of lactase on symptoms and expired hydrogen after lactose challenge in lactoseintolerant subjects. Clin Pharm. 1992;11(6):533-8.    investigated the effect of a single dose of oral lactase on symptoms, breath hydrogen concentration, and glucose absorption in lactose-intolerant subjects challenged with lactose. The findings showed that single doses of a chewable lactase tablet were able to reduce the concentration of expired hydrogen and symptoms of lactose intolerance after a lactose challenge. Subjects of the study included volunteers whose breath hydrogen concentrations increased ≥ 20 ppm on a lactose challenge test and who met other admission criteria as well. After fasting, subjects were given three chewable lactase tablets or placebo tablets in a randomized, double-blind, crossover manner. In addition, subjects also consumed ~236 ml of whole milk in which 37.5 gm of lactose powder was dissolved (total lactose content, 50 gm). There was at least one week washout period between the lactose challenges. For evaluation, breath hydrogen and plasma glucose concentrations were measured before and at intervals after the challenges. Moreover, subjects were asked to complete symptom-evaluation questionnaires every 8 hours for 4 days. Overall, a total of 24 subjects completed the study. The results showed that the maximum mean breath hydrogen concentration was significantly lower after lactase treatment than after placebo treatment. In 21 subjects, the area under the hydrogen concentration-time curve was found to be lower after lactase than after placebo. There were no significant differences in the plasma glucose levels. Furthermore, subjective ratings of the symptoms’ severity (abdominal cramping, belching, flatulence, and diarrhea) were noted to be lower during the first eight hours after challenge in lactase-treated subjects; ratings for bloating were lower during the next eight hours as well.

In another study, Portincasa et al²²Portincasa P, Di Ciaula A, Vacca M, et al. Beneficial effects of oral tilactase on patients with hypolactasia. Eur J Clin Invest. 2008;38(11):835-44.    tested the effectiveness of single ingestion of a lactase preparation in adults with hypolactasia, previously assessed by lactose H₂-breath test. A total of 134 subjects – positive to hypolactasia – underwent lactose H₂-breath testing [performed by administering 500 mL of cow’s whole milk (25 gm of lactose)] plus either placebo, or low (6750 U) or standard (11,250 U) doses of the lactase. Of the 134 subjects, 25 subjects were lactose malabsorbers and 109 were lactose intolerant. A small subgroup of intolerant subjects underwent lactose breath test with both the doses. Appearance of gastrointestinal symptoms was monitored during the tests. The results showed that after lactase ingestion, there was a time-dependent change of H₂ in breath (Figure 5), and integrated H₂ levels were decreased by 74% (low dose) and 88% (standard dose) in intolerants (n=109). Lactase ingestion (both doses) resulted in a significant decrement in symptom score, with the total symptom score decreasing by 76% (low dose) and by 88% (standard dose). The authors thus concluded that a single oral administration of lactase is highly effective in decreasing the symptoms and hydrogen excretion of hypolactasia assessed by lactose H₂-breath test. Ingestion of lactase might therefore be a better option than exclusion diets in intolerant subjects with hypolactasia.

The above mentioned studies seem to clearly suggest that lactase supplementation with milk and dairy products could be an effective strategy in correcting the lactose maldigestion, and may represent a convenient approach in milk/lactose intolerance.¹¹Rosado JL, Solomons NW, Lisker R, Bourges H. Enzyme replacement therapy for primary adult lactase deficiency. Effective reduction of lactose malabsorption and milk intolerance by direct addition of beta-galactosidase to milk at mealtime. Gastroenterology. 1984 Nov;87(5):1072-82.

Conclusion

Lactose intolerance is a condition in which people have digestive symptoms including bloating, diarrhea, and gas, after ingestion of milk or milk products. Lactase deficiency and lactose malabsorption are the primary cause for the development of lactose intolerance. The therapeutic strategies for the management of the condition include restriction of lactose containing diet and administration of lactase enzyme supplementation. The lactase enzyme digests the lactose in the food and therefore reduces the chances of developing digestive symptoms.

References

1. Deng Y, Misselwitz B, Dai N, Fox M. Lactose Intolerance in Adults: Biological Mechanism and Dietary Management. Nutrients. 2015;7(9):8020-8035.
2. Misselwitz B, Pohl D, Frühauf H, Fried M, Vavricka SR, Fox M. Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment. United European Gastroenterology Journal. 2013;1(3):151-159.
3. Bhatnagar S, Aggarwal R. Lactose intolerance. BMJ: British Medical Journal. 2007;334(7608):1331-1332.
4. Tandon RK, Joshi YK, Singh DS, Narendranathan M, Balakrishnan V, Lal K. Lactose intolerance in North and South Indians. Am J Clin Nutr. 1981 May;34(5):943-6.
5. Casellas F, Aparici A, Pérez MJ, Rodríguez P. Perception of lactose intolerance impairs health-related quality of life. Eur J Clin Nutr. 2016 Sep;70(9):1068-72.
6. Mattar R, de Campos Mazo DF, Carrilho FJ. Lactose intolerance: diagnosis, genetic, and clinical factors. Clinical and Experimental Gastroenterology. 2012;5:113-121.
7. Di Camillo M, Marinaro V, Argnani F, Foglietta T, Vernia P. Hydrogen breath test for diagnosis of lactose malabsorption: The importance of timing and the number of breath samples. Canadian Journal of Gastroenterology. 2006;20(4):265-268.
8. Usai-Satta P, Scarpa M, Oppia F, Cabras F. Lactose malabsorption and intolerance: What should be the best clinical management? World Journal of Gastrointestinal Pharmacology and Therapeutics. 2012;3(3):29-33.
9. Montalto M, Curigliano V, Santoro L, et al. Management and treatment of lactose malabsorption. World Journal of Gastroenterology: WJG. 2006;12(2):187-191.
10. Swagerty DL Jr, Walling AD, Klein RM. Lactose intolerance. Am Fam Physician. 2002 May 1;65(9):1845-50.
11. Rosado JL, Solomons NW, Lisker R, Bourges H. Enzyme replacement therapy for primary adult lactase deficiency. Effective reduction of lactose malabsorption and milk intolerance by direct addition of beta-galactosidase to milk at mealtime. Gastroenterology. 1984 Nov;87(5):1072-82.
12. Ianiro G, Pecere S, Giorgio V, Gasbarrini A, Cammarota G. Digestive Enzyme Supplementation in Gastrointestinal Diseases. Current Drug Metabolism. 2016;17(2):187-193.
13. Medow MS, Thek KD, Newman LJ, Berezin S, Glassman MS, Schwarz SM. Beta-galactosidase tablets in the treatment of lactose intolerance in pediatrics. Am J Dis Child. 1990 Nov;144(11):1261-4.
14. Di rienzo T, D’angelo G, D’aversa F, et al. Lactose intolerance: from diagnosis to correct management. Eur Rev Med Pharmacol Sci. 2013;17 Suppl 2:18-25.
15. Ibba I, Gilli A, Boi MF, Usai P. Effects of exogenous lactase administration on hydrogen breath excretion and intestinal symptoms in patients presenting lactose malabsorption and intolerance. BioMed Research International 2014 (2014);Article ID 680196:7 pages.
16. Scientific Opinion on lactose thresholds in lactose intolerance and galactosaemia. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). EFSA Journal 2010;8(9):1777.
17. Enzyme Preparations Used in Food (Partial List). Available at: http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/EnzymePreparations/default.htm [Accessed on 16/11/2017].
18. GRAS Notice (GRN) No. 510. Available at: https://google2.fda.gov/search?q=lactase+from+aspergillus+oryzae&client=FDAgov&site=FDAgov&lr=&proxystylesheet=FDAgov&requiredfields=-archive%3AYes&output=xml_no_dtd&getfields=* [Accessed on 16/11/2017].
19. Park YK, De Santi MSS, Pastore GM. Production and characterization of β-galactosidase from Aspergillus Oryzae. Journal of Food Science 1979;44(1):100–103.
20. He M, Yang Y, Bian L, et al. Effect of exogenous lactase on the absorption of lactose and its intolerance symptoms. Wei Sheng Yan Jiu.1999; 28(5):309-11.
21. Sanders SW, Tolman KG, Reitberg DP. Effect of a single dose of lactase on symptoms and expired hydrogen after lactose challenge in lactoseintolerant subjects. Clin Pharm. 1992;11(6):533-8.
22. Portincasa P, Di Ciaula A, Vacca M, et al. Beneficial effects of oral tilactase on patients with hypolactasia. Eur J Clin Invest.2008;38(11):835-44.