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Home , Lactose intolerance

Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2013; 17(Suppl 2): 18-25 intolerance: from diagnosis to correct management

T. DI RIENZO, G. D’ANGELO, F. D’AVERSA, M.C. CAMPANALE, V. CESARIO, M. MONTALTO, A. GASBARRINI, V. OJETTI

Department of Internal and , School of Medicine, Catholic University of the Sacred Heart, Rome, Italy

Abstract. Lactose and This review discusses one of the most relevant problems in gastrointestinal clin - ical practice: lactose intolerance. Lactose takes place in the small in - The role of lactase-persistence alleles the di - testine by the work of lactase-phlorizin hydro - agnosis of lactose the develop - ment of lactose intolerance symptoms and its lase, a protein expressed on the brush border of management. intestinal villi (with the highest expression in the Most people are born with the ability to di - mid-), fingerlike protrusions, which in - gest lactose, the major carbohydrate in crease the total surface area and , therefore , the and the main source of nutrition until weaning. ability to absorb different substrates. The Approximately, 75% of the worldʼs population lactase is encoded by LCT gene that maps on loses this ability at some point, while others can digest lactose into adulthood. Symptoms (2q21). Lactase has two active of lactose intolerance include , sites: the first hydrolyzes lactose in the two , and with a consid - and , making erable intraindividual and interindividual vari - them absorbable by the intestinal mucosa, the ability in the severity. second hydrolyzes phlorizin 1. Diagnosis is most commonly performed by typically occurs in the first part of the non invasive lactose breath test. the (jejunum ), which has low con - Management of lactose intolerance consists of two possible clinical choice not mutually ex - centrations of bacteria ; so just little portion of clusive: alimentary restriction and drug thera - lactose is fermented. py. Glucose and galactose are absorbed by intesti - nal into the blood-stream; glucose is Keywords: ultimately utilized as a source of energy and Lactose breath test, Diagnosis, Therapy. galactose, into the liver, becomes a component of glycolipids and glycoproteins 2. If the lactase enzyme is absent (alactasia) or deficient (hypolactasia), unabsorbed lactose mol - Introduction ecules osmotically attract fluid into the bowel lu - men, leading to an increased volume and fluidity of the intestinal content. In addition, the unab - Lactose is a sugar found in sorbed lactose passes into the colon, where it is mammalian milk; it makes up around 2 -8% of fermented by bacteria producing short-chain fat - milk (by weight), although the amount varies ty acids and gases (CO 2, CH4, H2) possibly lead - among species and individuals: 7.2 g/100 mL in ing to various gastrointestinal symptoms 3. mature human milk, 4.7 g/100 mL in cow’s milk but is negligible in the milk of some marine Human lactase . Lactose is a large sugar molecule that is made up of two smaller sugar molecules, glu - cose and galactose. Lactose is first broke down Since 8 weeks of gestation, lactase activity can into D(+)glucose and D(+)galactose by lactase be detected on mucosal surface in the human gut. enzyme, then absorbed by intestinal enterocytes The activity increases up to 34 weeks from birth, into the bloodstream. were lactase expression reaches its peak of expres -

18 Corresponding Author: Veronica Ojetti, MD, Ph.D; e-mail: [email protected] Lactose intolerance: from diagnosis to correct management sion. However, since the first month of life, lactase Sicily) were could reach 70% of populations 11,12 . activity starts to decrease ( lactase non persistance ) The “normal ” condition is represented by the loss and its decline is highly variable from weaning to of lactase expression, defined as “non-persistent ”. undetectable levels as a consequence of the normal In fact, in human life, the power supply is based maturational down-regulation of lactase activity 4-6 . exclusively on breast milk for the first few In humans, about 30% of the population has con - months of life. It is , therefore , understandable tinuous activity of lactase after weaning and in how the adjustment expression of the lactase gene adulthood ( lactase non persistance )2,7 . may predict its progressive decline in later stages of life. However, the genotype that determines the Hypolactasia persistence of lactase, is found only in Northern Europe populations, in some African and Arab nomadic tribes. In Europe, the persistence or not Hypolactasia, or lactase deficiency, a condi - persistence of the expression of lactase is associ - tion that determines the malabsorption of lactose, ated with the so-called point C/T occurs generally no earlier than 6-7 year age, but 13910. This consists in the substitution of a single is also sometimes much later 8, showing a steady nucleotide base in a sequence of DNA, that car - increase in prevalence even in the age groups ries regulatory on the lactase gene: genotype CC above 65 years 9. The kinetics of the reduction is associated with hypolactasia (lactase residual is and the amount of residual lactase have consider - approximately 10% compared to the levels of able variability between different ethnic groups birth), while the TT genotype with lactase persis - and even between individuals. However , the re - tence of activity. The presence of a CT genotype, duction of up to 50% of lactase is sufficient to instead, predisposes to the presence of levels of ensure effective digestion of lactose 10 . intermediate expression 13 . Hypolactasia, exists in three distinct forms: The secondary hypolactasia occurs, instead, congenital, primary and secondary. when a mucosal damage of bowel causes a tempo - The congenital is an autosomal recessive rary lactase deficiency. Typically, all diseases of (AR) condition characterized by severe diarrhea the small intestine, such as the Celiac or Crohn ’s with event of watery stools since the first intake disease, ulcerative , irritable bowel syn - of milk by the infant; it persists for all the life drome, radiation, immunological deficiencies, are and requires the complete exclusion of the capable of causing a secondary deficiency of lac - sources of lactose. This extremely rare condition tase, but more commonly bacterial or viral infec - has been described in about 40 cases, in which tions, parasitic infections (such as a ) or the non-lactase activity was caused by a non- drug treatment 6 induce a transient loss of enzyme sense mRNA. The deficiency of nutrients causes in the mucosa affected by the process inflammato - a delay in growth, with the rapid onset of dehy - ry or infectious. It is obviously a reversible condi - dration and alkalosis. tion requiring a lactose-free diet until it is restored The primary lactase deficiency ( lactase non to a normal intestinal mucosa 14 . persistance ) is an autosomal recessive (AR) con - dition resulting from the physiological decline of Lactose malabsorption lactase activity of intestinal cells and features a in coeliac patients large proportion of individuals. It is a well- known cause of abdominal disorders such as di - arrhea, bloating and flatulence. A recent study by our group demonstrated The primary hypolactasia is a condition ex - that a large proportion of patients with lactose tremely widespread in the world population, but malabsorption is affected by an otherwise silent with substantial variations between different eth - , a gluten-sensitive nic groups, the prevalence of disease is minimal caused by a permanent intolerance to gliadin and in Northern European populations (, Swe - its related proteins in individuals genetically sus - den, Germany, Austria, Switzerland, France, ceptible. Celiac disease damaging the brush bor - Great Britain, Holland, Ireland) and groups de - der causes a partial deficiency of lactase. scended from them, and is particularly high in Moreover, other data indicate that a large pro - Asia, Africa and Australia. In Italy, the lactase portion of patients with coeliac disease experi - non persistence effects average 40-50% of the enced a regression of lactose malabsorption after population, particularly in south (Campania and being on a gluten-free diet 15,16 . In some patient ’s

19 T. Di Rienzo, G. D’Angelo, F. D’aversa, C. Campanale, V. Cesario, M. Montalto, A. Gasbarrini, V. Ojetti intraluminal deficit, which brings to the damage ated with a normalization of the majority of pre - of the brush border, could be associated with viously positive lactose, and sorbitol many diseases, as chronic , chronic breath test. These findings suggest that, in pres - , (IBS) and ence of SIBO, the large amount of intestinal small intestinal bacterial overgrowth (SIBO). bacteria may unspecifically ferment sugars, IBS is a common chronic disorder of un - causing an abnormal H2 production and conse - known origin, characterized by abdominal pain, quently , a misleading diagnosis of lactose, fruc - bloating and alternating with diar - tose or sorbitol malabsorption. An alternative rhoea 17-19 . Abnormal visceral sensation, altered hypothesis could be that the bacterial over - motility and psychosocial factors may play a role growth leads to a damage of the small bowel in the occurrence and severity of IBS 17,18 . mucosa, thus , inducing a transient enzymatic or carrier protein deficiency and , then , multiple SIBO and lactose intolerance sugar’s malabsorption. After SIBO eradication the intestinal mucosa comes back to play its normal functions , and the sugar ’s malabsorption Small intestinal bacterial overgrowth (SIBO) disappear . Similarly, Pimentel et al reported that is a condition characterized by abnormally high while the number of IBS patients with true lac - bacterial population level in the small intestine, tose intolerance was low (16%), a much higher exceeding 10 6 organisms/mL 20 . SIBO is clinically number (58%) had an abnormal lactose breath characterized by symptoms such as abdominal test result and there was a significant correla - pain, flatulence, diarrhea and/or signs of malab - tion between lactulose (SIBO) and lactose sorption, comparable to those observed in IBS breath test result 19 . Normalization of lactulose pts 21 . Recent findings suggested that SIBO may breath test after neomycin treatment was associ - play a role in IBS: in particular, some trials re - ated with a significant reduction in IBS symp - ported a high prevalence of SIBO in IBS (78 - toms. These studies showed that the prevalence 84%) and a significant improvement in IBS of true lactose malabsorption was lower than symptoms after eradication 22,23 . Lactose 24-27 , fruc - the prevalence of abnormal LBT in SIBO thus tose and sorbitol malabsorption 28,29 , have also suggesting that the expansion of gut bacterial been blamed for IBS symptoms. Sugar malab - flora proximally results in abnormal interaction sorption could be primary (congenital enzymat - of substrate and gut bacteria leading to a posi - ic/carrier deficiency) or acquired (developing af - tive lactose BT 33 . ter intestinal damage: acute , med - In conclusion, LBT can be useful in the man - ications, celiac disease, Crohn’s disease, agement of patients presenting with IBS symp - others) 30 . When carbohydrates are not properly toms, in order to detect and treat a possible SI - hydrolyzed and absorbed , they cause in the bow - BO. The presence of SIBO should be always as - el a high bacterial production of short-chain fatty sessed at first, before searching sugar malabsorp - acids and gas, with the onset of a syndrome char - tion and specific sugars-free diets. Lactose, fruc - acterized by meteorism, abdominal pain and diar - tose and sorbitol BT could become a useful diag - rhea, thus , mimicking IBS symptoms. Hydrogen nostic approach in SIBO-negative or eradicated lactose, fructose and sorbitol BTs are commonly patients with refractory symptoms 19,34 . used to detect specific sugar’s malabsorption. There is a recent interest in fructose intolerance Symptoms of lactose intolerance as a possible explication for unexplained gas - trointestinal symptoms 31 . In fact, IBS patients showed a similar pattern of malabsorption in var - Malabsorption of sugar does not necessarily ious tested fermentable substrates 29 . For many mean lactose intolerance ; in fact, the develop - patients, bacterial overgrowth could be responsi - ment of gastrointestinal symptoms such as ab - ble for the association between sugar intolerance dominal pain, flatulence, , bloating, and and IBS rather than true sugar intolerance. In - diarrhea, only occur in about one-third of “mal - deed, Nucera et al 32 showed a regression of lac - absorbers” 35 . However, the undigested lactose tose (86.6%), fructose (97.5%), and sorbitol causes a rise in the osmotic load in the intestinal (90.9%) malabsorption after SIBO eradication . lumen, leading to an increased excretion of elec - The normalization of Lactulose breath test trolytes and fluids. Lactose intolerance is clini - one month after antibiotic treatment was associ - cally characterized by abdominal pain and bloat -

20 Lactose intolerance: from diagnosis to correct management

Determination of genotypes ing. The unabsorbed lactose is fermented by gut microflora with a production of short chain fatty acids (SCFA), and gases (H2, CH4), thus in - Genomic DNA was extracted from peripheral creasing colonic distention and accelerating the venous blood. A positive genetic test for lactase oro-cecal transit time. Patients also complain non-persistence indicates a decline in lactase ac - flatus, diarrhea, borborygmi, and sometimes, tivity but does not give information on actual pa - nausea and . More rarely there is in - tient symptoms. Meanwhile, a lactose breath test creased production of with a delayed with intolerance symptoms gave clear informa - transit time and a consequent constipation. Some tion about the clinical aspect. Genotyping of lac - authors have reported that the clinical presenta - tose tolerance tests has limitations. In children, tion of lactose intolerance is not restricted to gut genotyping could only be used as a rule-out test symptoms. Neurological symptoms such as since it does not tell anything about the age at headache, vertigo, memory impairment, lethargy which a child with the CC genotype begins to de - or cardiac arrhythmia can develop even in less crease lactase expression. In patients where sec - than 20% 5,36 . One of the possible factors respon - ondary hypolactasia is suspected, e.g. coeliac dis - sible for these systemic symptoms can be the ease, genotyping should be done together with production of toxic metabolites, generated by tolerance tests. Although, more studies are needed lactose in colonic bacteria 5,37 , that to prove that the C-13910T SNP is a causative can alter cell signaling mechanism. When sys - DNA variant, and not merely a highly associated temic complaints are present, it is important to marker, the test is still useful for clinical exclude to cow’s milk protein, which is purposes 45 . The present real-time PCR method of - attendant in up to 20% of patients with symp - fers several advantages over the RFLP method. It toms of lactose intolerance . There is consider - is less laborious and the risks for PCR contamina - able intraindividual and interindividual variabili - tions are fewer. Furthermore, several steps in the ty in the severity of gastrointestinal symptoms, method could be automated. The method is suited according to the amount of lactose ingested and for a clinical laboratory, and in this sense compa - the patient’s ability to digest it. Fat content of rable to pyrosequencing or minisequencing 13,46 . lactose-containing food oro-cecal transit time, The genetic analysis identified a single nucleotide visceral sensitivity contributes to this variabili - polymorphism that shows complete association ty 38 . Valid evidence is missing for a relationship with the lactase non-persistence/persistence 39 and between symptoms and amount of lactose in - is characterized by a C to T change in the position gested 2,38 . 13910 of the lactase phlorizin hydrolase (LPH) Lactose doses of 15 -18 g are well tolerated gene. In particular, it has been shown that the when offered together with other nutrients. With genotype C/C -13910 is associated with adult- higher doses than 18 g, intolerance becomes pro - type hypolactasia, whereas genotypes C/T -13910 gressively more frequent, and quantities over 50 and T/T -13910 are associated with lactase persis - g elicit symptoms in most individuals 39,40 . tence. Moreover, these three genotypes perfectly correlate with the level of the lactase activity in 13,47 Diagnosis of lactose intestinal biopsy samples , and their L:S ratio . malabsorption Other diagnostic tests available are: • Lactose tolerance test (LTT): In this test pa - tient ’s drinks 50 g of lactose dissolved in wa - Different methods have been used for the di - ter. Samples of capillary blood to test the agnosis of lactose malabsoprtion. The gold stan - plasma glucose concentration were taken at – dard for the diagnosis of adults-type hypolactasia 5, 0, 15, 30, 45 and 60 min. The average of is the measurement of lactose, and mal - the –5 and 0 min determinations was used as tase activities and the determination of the lac - the pre-challenge glucose concentration. Glu - tose to sucrase ratio (L:S) in intestinal biop - cose was measured in whole blood on a plas - sies 41,42 . ma-calibrated Hemocue 201 (Hemocue AB, However, it seems too invasive for the diag - Angelholm, Sweden). A maximal plasma-glu - nosis of such a mild condition and its results may cose increase of 1.4 mmol/l or higher indicate be influenced by the irregular dissemination of lactose tolerance . The digestion of lactose de - lactase activity throughout the small intestine termines the elevation of blood glucose: the mucosa 14,43,44 . absence of such increase indicates failure ab -

21 T. Di Rienzo, G. D’Angelo, F. D’aversa, C. Campanale, V. Cesario, M. Montalto, A. Gasbarrini, V. Ojetti

sorption of lactose. This test is burdened by lactose administered was 25 g for adults and 1 the onset of severe gastrointestinal symptoms mg/kg in children. End-alveolar breath samples in patients with lactose intolerance to high were collected immediately before lactose inges - dose of lactose administered 48 . tion and every 30 min for 4 h using a two-pack • Quick lactose test (QLT): a new method for system. Samples were analyzed immediately for the endoscopic diagnosis of adult-type hypo - H2 using a model of solid sensor gas-chromato - lactasia, has been developed over the last few graph. Results were expressed as parts per million years. This test is based on a colorimetric reac - (p.p.m.). H2-LBT was considered positive for tion that develops when the endoscopic biopsy lactose malabsorption when an increase in H2 from the post-bulbar is incubated value more than 20 parts per million (p.p.m.) over with lactose on a test plate. The color reaction the baseline value was registered 51 . Some re - develops within 20 min after hydrolysis of lac - searcher or clinician suggested to perform the test tose in patients with normolactasia (positive directly with milk. However the use of galenic result), while no reaction develops in patients preparations is required for standardized test ac - with severe hypolactasia (negative result) 49 . cording to available guidelines. QLT comparison of genetics and exhibition Problems good correlation between the different techniques (sensibility 95-100%, specificity 100%) 49 . Our It is possible to find false-negative breath group compared the efficacy of the QLT with the tests, due to the inability of colonic flora to pro - H2 lactose BT. Our results showed a valid correla - duce H2 after ingestion of non-absorbable carbo - tion between the two techniques, with a concor - hydrates, or after a recent use of antibiotics. dance rate of 81%. This percentage became higher False-positive breath tests are less frequent and and reached 96% when we considered CH4 and are mainly due to small bowel bacterial over - H2 production. In our study, the QLT seems to be growth or abnormal oral microflora 52 . able to identify the subgroup of patients with In both adults and children , we propose to adult-type hypolactasia and low H2 production record and score the most common GI symptoms that is not identified by the commonly used H2 (abdominal pain, bloating, flatulence and diar - BT. The former is also simpler and less expensive rhea) during and 8 h after the test, by a visual- than the genetic tests. Based on these observations analogue scale (VAS). QLT could be a reliable test for the diagnosis of It is important to underline the fact that not all adult-type hypolactasia, with a sensitivity higher patients with lactose malabsorption present intol - than that of the BT and comparable to that of the erance symptoms during the test . more difficult to perform genetic tests 50 . Management of lactose intolerance Lactose breath test Management of lactose intolerance consists of Lactose BT represents an indirect test for lactose two possible clinical choice not mutually exclu - malabsorption, and it is commonly considered the sive: alimentary restriction and drug therapy. most reliable, non-invasive and inexpensive tech - The usual behavior for this condition is the nique. Based on several different studies, lactose avoidance of milk and products from the di - BT shows good sensitivity (mean value of 77.5%) et. However , this restriction leads to a reduction and excellent specificity (mean value of 97.6%) 43,44 . of intake of substances such as calcium, phospho - rus and vitamins and may be associated with de - How the test look like? 53 creased bone mineral density . This diet should To minimize the basal hydrogen excretion, pa - be given only in patients with gastrointestinal tients were asked to have a carbohydrate-restrict - symptoms of intolerance (diarrhea, bloating, ab - ed dinner on the day before the test and to be fast - dominal pain, flautulence), so defined “lactose in - ing for at least 12 h on the testing day. Before tolerants” not also in “lactose malasorbers”. starting the test patients did a mouth wash with 20 In primary hypolactasia milk and dairy prod - ml of chlorhexidine 0.05%. Smoking and physi - ucts are forbidden for 2-4 weeks, time required for cal exercise were not allowed for 30 min before remission of symptoms. Then, should recommend and during the test. End-alveolar breath samples a gradual reintroduction of dairy products low in were collected before lactose ingestion. Dose of lactose up to a threshold dose of individual toler -

22 Lactose intolerance: from diagnosis to correct management ance. In secondary hypolactasia, associated with bacteria, initially breaks down unabsorbed lactose various intestinal disorders, diet is necessary only by hydrolysis to its monosaccharides, glucose and until the regression of these acquired disorders 54 . galactose, that may be absorbed. However, there In the case of unearned baby, milk without is a huge variability in the amount of lactase ac - lactose completely solves the problem. tivity in different probiotics. Ojetti et al 56 shows What is the dose tolerated in a placebo-controlled trial that the addiction of by lactose intolerant daily? tilactase to a lactose load improves gastrointesti - nal symptoms, and reduced hydrogen production Available data suggest that adults and adoles - during the LBT . Lactobacillus reuteri also is ef - cents with diagnosis of lactose intolerance could in - fective but lesser than tilactase. This probiotic gest at least 12 g of lactose in a single dose (equiva - may represent an interesting treatment option for lent to the lactose content in 1 cup of milk) without lactose intolerance since its use is simple , and its or with minor symptoms 54 . Other strategies that effect may last in the time after stopping adminis - should be suggested to patients are: to consume tration. On the other hand, probiotic is adminis - milk with other foods; to use fermented dairy prod - tered at a standard dosage, regardless of the ucts and ; to distribute the amount of milk dosage of lactose the patients are going to ingest. during the day to increase lactose dose assumption Other strategies for management of Lactose making colon able to an adaptation . Intolerance may include gut decontaminating Montalto et al 55 shows that low-dose lactose, agents and anti-microbials agent, such as rifax - such us in drugs, neither increase breath hydrogen imin. excretion nor causes gastrointestinal symptoms.

–C–o–n––f–li–c–t––o–f––in–– t–e–r– e–-––st Drug therapy The Authors declare that they have no conflict of inter - ests. Enzyme supplementation therapy with lactase from nonhuman sources to hydrolyze lactose is an - other important approach. Exogen lactase is ob - tained from oryzae (Lacdigest, References Italchimici, Pomezia, Rome, Italy) or from Kluyveromyces lactis (Silact, Sofar, Trezzano, Mi - CAMPBELL AK, W AUD JP, M ATTHEWS SB. 1) The molecu - lano, Italy ) are able to break down lactose into glu - 56 lar basis of lactose intolerance. Sci Prog 2005; cose and galactose to allow a better absorption . 88(Pt 3): 157-202. LOMER MC, P ARKES GC, S ANDERSON JD. The use of exogenous β-galactosidase in lac - 2) Lactose in - tose malabsorbers, also when added at mealtime, tolerance in clinical practice-myths and realities. Aliment Pharmacol Ther 2008; 27: 93-103. is efficacious and free of side effects. More re - SPOHR A, G UILFORD WG, H ASLETT SJ, V IBE -P ETERSEN G. 3) cently , the administration of probiotics endowed Use of breath hydrogen testing to detect experi - with a β-galattosidase activity was useful to treat mentally induced disaccharide malabsorption in patients with lactose intolerance. Probiotics are healthy adult dogs. Am J Vet Res 1999; 60: 836- 840. live microorganisms; some of them have a beta- KRETCHMER N. galactosidase that may aid in the digestion of lac - 4) Lactose and lactase-a historical per - spective. Gastroenterology 1971; 61: 805-813. MATTHEWS SB, W AUD JP, R OBERTS AG, C AMPBELL AK. tose ingested. These microorganisms can be 5) added to food products, such as milk and , Systemic lactose intolerance: a new perspective or used as supplements. Many bacterial families on an old problem. Postgrad Med J 2005; 81: 167-173. with over 500 species house our gastrointestinal VESA TH, M ARTEAU P, K ORPELA R. tract with the highest concentration in the colon. 6) Lactose intoler - ance. J Am Coll Nutr 2000; 19(2 Suppl): 165S- It has been demonstrated that malabsorbed lac - 175S. SAVAIANO DA, L EVITT MD. tose is salvaged by the distal ileal and colonic lac - 7) Milk intolerance and mi - tic acid bacteria. Lactobacillus, Bifidobacterium, crobe-containing dairy foods. J Dairy Sci 1987; 70: 397-406. Staphylococcus, Enterococcus, Streptococcus are SEPPO L, T UURE T, K ORPELA R, J ÄRVELÄ I, R ASINPERÄ H, 8) defined as “Lactic acid bacteria”, they ferment SAHI T. Can primary hypolactasia manifest itself lactose to produce lactate, hydrogen, methane, after the age of 20 years? A two-decade follow-up and short -chain fatty acids. In the process of fer - study. Scand J Gastroenterol 2008; 43: 1082- mentation, microbial lactase, present in lactic acid 1087.

23 T. Di Rienzo, G. D’Angelo, F. D’aversa, C. Campanale, V. Cesario, M. Montalto, A. Gasbarrini, V. Ojetti

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