European Review for Medical and Pharmacological Sciences 2013; 17(Suppl 2): 18-25

Lactose 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 Medicine and Gastroenterology, School of Medicine,

Catholic University of the Sacred Heart, Rome, Italy

Abstract. This review discusses one of the

most relevant problems in gastrointestinal clin-
Lactose and lactase
ical practice: lactose intolerance. Lactose digestion 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 malabsorption 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-jejunum), fingerlike protrusions, which in-
gest lactose, the major carbohydrate in milk crease the total surface area and, therefore, the
and the main source of nutrition until weaning. ability to absorb different substrates. The enzyme
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
chromosome 2 (2q21). Lactase has two active
of lactose intolerance include abdominal pain, sites: the first hydrolyzes lactose in the two
bloating, flatulence and diarrhea with a consid- monosaccharides glucose and galactose, making
erable intraindividual and interindividual vari- them absorbable by the intestinal mucosa, the
ability in the severity. second hydrolyzes phlorizin1.
Diagnosis is most commonly performed by Hydrolysis typically occurs in the first part of
the non invasive lactose hydrogen breath test.
the small intestine (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 enterocytes into the blood-stream; glucose is
ultimately utilized as a source of energy and
Keywords: galactose, into the liver, becomes a component of
glycolipids and glycoproteins2.
If the lactase enzyme is absent (alactasia) or
Lactose breath test, Diagnosis, Therapy.

deficient (hypolactasia), unabsorbed lactose mol-

ecules osmotically attract fluid into the bowel lu-
men, leading to an increased volume and fluidity
of the intestinal content. In addition, the unab-
Introduction

Lactose is a disaccharide 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 (CO2, CH4, H2) possibly lead-
among species and individuals: 7.2 g/100 mL in ing to various gastrointestinal symptoms3.
mature human milk, 4.7 g/100 mL in cow’s milk
but is negligible in the milk of some marine
mammals. Lactose is a large sugar molecule that
is made up of two smaller sugar molecules, glu-
Human lactase
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: veronica.ojetti@tin.it

 Lactose intolerance: from diagnosis to correct management

sion. However, since the first month of life, lactase Sicily) were could reach 70% of populations11,12.
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 activity4-6. 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
persistence of lactase, is found only in Northern
Europe populations, in some African and Arab
nomadic tribes. In Europe, the persistence or not
Hypolactasia

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 polymorphism 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 later8, 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 years9. 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 lactose10. intermediate expression13.
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 colitis, 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 giardiasis) or
the non-lactase activity was caused by a non- drug treatment6 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 mucosa14.
persistance) is an autosomal recessive (AR) con-
dition resulting from the physiological decline of
lactase activity of intestinal cells and features a
large proportion of individuals. It is a well-
Lactose malabsorption

known cause of abdominal disorders such as di-

in coeliac patients
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- coeliac disease, a gluten-sensitive enteropathy
nic groups, the prevalence of disease is minimal caused by a permanent intolerance to gliadin and
in Northern European populations (Finland, 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 diet15,16. 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, fructose and sorbitol
many diseases, as chronic pancreatitis, chronic breath test. These findings suggest that, in pres-
hepatitis, irritable bowel syndrome (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 constipation alternating with diar- tose or sorbitol malabsorption. An alternative
rhoea17-19. 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 IBS17,18. mucosa, thus, inducing a transient enzymatic or
carrier protein deficiency and, then, multiple
sugar’s malabsorption. After SIBO eradication
the intestinal mucosa comes back to play its
normal functions, and the sugar’s malabsorption
SIBO and lactose intolerance

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 106 organisms/mL20. 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 result19. Normalization of lactulose
pts21. 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 eradication22,23. Lactose24-27, fruc- the prevalence of abnormal LBT in SIBO thus
tose and sorbitol malabsorption28,29, 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 BT33.
ter intestinal damage: acute gastroenteritis, 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 symptoms19,34.
used to detect specific sugar’s malabsorption.
There is a recent interest in fructose intolerance
as a possible explication for unexplained gas-
trointestinal symptoms31. In fact, IBS patients
Symptoms of lactose intolerance
showed a similar pattern of malabsorption in var- Malabsorption of sugar does not necessarily
ious tested fermentable substrates29. 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, nausea, bloating, and
and IBS rather than true sugar intolerance. In- diarrhea, only occur in about one-third of “mal-
deed, Nucera et al32 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

ing. The unabsorbed lactose is fermented by gut

microflora with a production of short chain fatty
Determination of genotypes
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 vomiting. More rarely there is in- tient symptoms. Meanwhile, a lactose breath test
creased production of methane 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 fermentation in colonic bacteria5,37, 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 allergy to cow’s milk protein, which is purposes45. 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 minisequencing13,46.
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
ty38. Valid evidence is missing for a relationship with the lactase non-persistence/persistence39 and
between symptoms and amount of lactose in- is characterized by a C to T change in the position
gested2,38. 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 individuals39,40. tence. Moreover, these three genotypes perfectly
correlate with the level of the lactase activity in
intestinal biopsy samples, and their L:S ratio13,47.
Other diagnostic tests available are:
• Lactose tolerance test (LTT): In this test pa-
Diagnosis of lactose

tient’s drinks 50 g of lactose dissolved in wa-

malabsorption

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, sucrase 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-
sies41,42. 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
mucosa14,43,44. 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 administered48. 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 duodenum 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
good correlation between the different techniques Problems
(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 microflora52.
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 tests50.

Management of lactose intolerance

Management of lactose intolerance consists of

Lactose breath test

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 dairy 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? creased bone mineral density53. 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 disorders54. 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 al56 shows
in a placebo-controlled trial that the addiction of
What is the dose tolerated tilactase to a lactose load improves gastrointesti-
by lactose intolerant daily? 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 symptoms54. 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 cheeses; 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 al55 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.
–––––––––––––––––––-––
Conflict of interest
The Authors declare that they have no conflict of inter-
Drug therapy
ests.
Enzyme supplementation therapy with lactase
from nonhuman sources to hydrolyze lactose is an-
other important approach. Exogen lactase is ob-
tained from Aspergillus oryzae (Lacdigest,
Italchimici, Pomezia, Rome, Italy) or from References
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T. Di Rienzo, G. D’Angelo, F. D’aversa, C. Campanale, V. Cesario, M. Montalto, A. Gasbarrini, V. Ojetti

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