CLINICAL REVIEW
Clinical Implications of Lactose Malabsorption Versus
Lactose Intolerance
Michael Levitt, MD,* Timothy Wilt, MD, MPH,w and Aasma Shaukat, MD, MPH*
Abstract: The majority of the worlds adult population and an
estimated 80 million Americans are hypolactasic and hence mal-
absorb ingested lactose. Although lactose malabsorption is easily
identied, less readily assessed is the clinically important question
of how often does this malabsorption induce symptoms. This
review summarizes: (1) knowledge concerning the etiology and
diagnosis of hypolactasia and the pathophysiology of the symp-
toms of lactose malabsorption and (2) the results of well-controlled
trials of the symptomatic response of lactose malabsorbers to
varying dosages of lactose and the ecacy of therapeutic inter-
ventions to alleviate these symptoms. We conclude that the clinical
signicance of lactose malabsorption has been overestimated by
both the lay public and physicians in that commonly ingested doses
of lactose (ie, the quantity in a cup of milk) usually do not cause
perceptible symptoms when ingested with a meal. Symptoms occur
when the lactose dosage exceeds that in a cup of milk or when
lactose is ingested without other nutrients. Simple dietary instruc-
tion, rather than the use of commercial products to reduce lactose
intake, is recommended for the vast majority of lactose-mal-
absorbing subjects.
Key Words: diarrhea, hypolactasia, lactase deciency, lactose
intolerance, lactose malabsorption
(J Clin Gastroenterol 2013;47:471480)
T he milk sugar lactose is a disaccharide consisting of
galactose bound to glucose by a b-galactosidic linkage.
Small bowel assimilation of this disaccharide requires
hydrolysis to free glucose and galactose, a reaction cata-
lyzed by a brush border b-galactosidase (lactase). Low
lactase activity allows undigested lactose to reach the colon
where bacterial fermentation yields multiple products
including short chain fatty acids and gases [hydrogen (H2),
carbon dioxide (CO2), and methane (CH4)]. If sucient
lactose is malabsorbed, these fermentation products and
unfermented lactose cause symptoms of diarrhea, bloating,
atulence, and abdominal pain.
TERMINOLOGY
Although lactase deciency (or hypolactasia), lactose
malabsorption, and lactose intolerance are frequently used
interchangeably, these terms have dierent meanings.
From the *Minneapolis Veterans Aairs Health Care System, the
Section of Gastroenterology; and wCenter for Chronic Disease
Outcomes Research Minneapolis Veterans Aairs Health
Care System, the Section of General Internal Medicine and the
Minnesota Evidence-Based Practice Center, the Section of Internal
Medicine, University of Minnesota, Minneapolis, MN.
The authors declare that they have nothing to disclose.
Reprints: Michael Levitt, MD, Minneapolis Veterans Aairs Health
Care System, the Section of Gastroenterology, University of
Minnesota, 1 Veterans Drive, Minneapolis, MN 55417 (e-mail:
michael.levitt@va.gov).
Copyright r 2013 by Lippincott Williams & Wilkins
J Clin Gastroenterol  Volume 47, Number 6, July 2013
Lactase deciency indicates that the brush border lactase
activity is a small fraction of that of normal infants. Lactose
malabsorption means a sizable fraction of ingested lactose
is not absorbed in the small bowel. As lactose mal-
absorption usually results from lactase deciency, the
prevalence of these 2 entities is similar. Lactose intolerance
indicates that the lactose malabsorption causes symptoms.
Although malabsorption of moderate doses of lactose may
not cause discernible symptoms, lactose malabsorbers do
not necessarily suer from lactose intolerance. Thus, it is
crucial to dierentiate between subjects with lactose mal-
absorption versus lactose intolerance.
SOURCES OF DIETARY LACTOSE
Milk and milk products are the major dietary sources
of lactose. The lactose concentration in milk varies among
mammalsfrom trace quantities in Pacic pinnipeds (seals,
sea lions) to a high of about 7.5 g/100 mL in humans.1,2 The
lactose concentration of milk of cows, goats, and sheep is
about 5 g/100 mL. As the severity of lactose intolerance
symptoms is partially a function of the quantity of lactose
ingested, it is useful to have a working knowledge of the
lactose content of servings of various foods (Table 1). As
lactose exists in the water phase of milk, butter contains
virtually no lactose and hard cheeses provide r1 g of lac-
tose per 1 oz of serving. Thus, there is no physiological basis
for the complaint that lactose intolerance prevents a
lactose malabsorber from consuming mozzarella-laden
pizza (a concept used in advertisements for lactase supple-
ments). In addition to uid milk, the only commonly con-
sumed foods containing appreciable lactose are yogurt and
ice cream. Small amounts of lactose are also present in food
additives and medication excipients. The highest lactose
content per capsule or tablet is about 0.075 g3; thus, con-
sumption of 20 such tablets per day would provide only
about 1.5 g of lactose, which is the amount in 1 oz of milk.
LACTASE DEFICIENCY
Direct assessment of mucosal lactase activity requires
analysis of small bowel biopsies, an invasive and complex
procedure. However, lactose malabsorption nearly always
reects low lactase activity; thus, lactase deciency com-
monly is imputed from the simpler measurement of lactose
malabsorption. Lactase deciency may be genetically
mediated or secondary to the diseases that diusely injure
the small bowel mucosa, such as celiac disease or enteritis.
Loss of lactase activity secondary to these diseases fre-
quently is reversible with healing of the gut injury.
Although secondary lactase deciency is common in
countries with a high incidence of intestinal infections, in
developed countries lactase deciency nearly always is a
genetically determined trait.
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Levitt et al J Clin Gastroenterol  Volume 47, Number 6, July 2013

White Subjects
TABLE 1. Approximate Quantity of Lactose Per Serving of
Various Products 100
Products Lactose Per Serving
90
Milk (all types other than lactose reduced) 12 g/8 oz

Lactase Activity (units/gram Protein)

Yogurt 5.3 g/6 oz 80
Ice cream 3.7 g/0.5 cup
Hard cheese (cheddar, mozzarella) 0.01-0.9 g/1 oz
Butter Negligible 70
Medication excipients 0.02-0.075 g/tablet
60

Given the very high milk (lactose) intake/kg body 50

weight of newborn mammals, survival is dependent upon
the ability of newborns to digest/absorb lactose. High 40
concentrations of brush border lactase normally are present
in the small bowel of all newborn mammals with the 30
exception of the Pacic pinnipeds,4 the only mammals
whose milk does not contain appreciable lactose. However, 20
after weaning, about 75% of the worlds human population
(and all subhuman mammals) have a steep decline in 10
intestinal lactase synthesis that results in low brush border
lactase activity, despite continued exposure to lactose. Such 0
subjects are said to be lactase non-persistent. Roughly 25% 0 3 5 10 20 30 40 50 60 93
of humans are unique in that they retain infantile levels of Age in Years
lactase throughout adulthood and are termed as lactase
persistent. Figure 1 shows the results of the Herculean 70 Black Subjects
study of Welsh et al,5 in which they measured lactase
Lactase Activity (units/gram Protein)

activity of small bowel biopsies obtained from 348 white 60

and 55 African American subjects. The decline in lactase
activity in lactasenon-persistent white subjects occurred
after 5 years of age and was not complete, in that, 10% to
25% of the mean activity of infants was retained. It is not
known if the individual dierences in these low-retained
lactase activities translate into dierences in lactose toler-
ance. The majority of the African American subjects
became hypolactasic.
This prevalence of lactase persistence/nonpersistence is
strongly related to ethnicity, as illustrated in Figure 1. The
majority of adults of Asian, African, Latino, and Native
American descent are lactase non-persistent, whereas the
majority of whites are lactase persistent.6 However, there
are major dierences among whites, with individuals of
northern and middle European origin tending to be lactase
persistent, whereas the majority of subjects of southern
European and Mediterranean origin (eg, Greeks, Southern
Italians, and Jews) are lactase non-persistent. A brief
inquiry into a subjects ethnic background often allows the
clinician to make an educated guess regarding the like-
lihood that an individual is lactase non-persistent, keeping
in mind that lactase persistence is a dominant trait. Given
the ethnic composition of the US population, roughly 35%
of the adolescents and adults or about 80 million individ-
uals are lactase non-persistent.
Lactase synthesis is a function of the LCT gene located
on the long arm of chromosome 2.7 Inheritance of 2
defective alleles of this gene results in the very rare con-
dition of congenital lactase deciency. The expression of
LCT is regulated by a promoter located B14 kb upstream
from the LCT gene.8 The correlation between ethnicity and
lactase persistence/nonpersistence is linked to genetic var-
iations in this lactase promoter, not the LCT gene. Several
single nucleotide polymorphisms are associated with the
lactase persistence/nonpersistence phenotype. The wild-
type promoter, which results in the age-related reduction in
50
40
30
20
10
0
0 3 5 10 20 30 40 50 60 60+
Age in Years
FIGURE 1. Lactase activity at various ages of healthy white
(upper panel) and African American (lower panel) subjects.
Figure reproduced from Welsh et al.5 Copyright and approval to
publish by Elsevier.
lactase synthesis observed in the majority of humans, con-
tains cytosine/cytosine at position 13910 (C/C-13910). In
lactase-persistent individuals of northern European origin,
cytosine has been replaced in 1 or both alleles by thymine
(C-T substitution).9 This mutation eliminates the pro-
grammed reduction in activity of the promoter with age,
and lactase synthesis remains at the infantile level
throughout adulthood. Mutations other than the C-T
substitution have been identied in the promoter gene
in selected lactase-persistent African populations.10 Thus,
lactase nonpersistence does not reect a nonspecic
diminution of lactase synthesis with aging but rather a
highly engineered function of the lactase promoter gene
designed to diminish lactase synthesis after weaning.
The observation that lactase persistence correlates
closely with cultures that have a >5000 years history of

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J Clin Gastroenterol  Volume 47, Number 6, July 2013
herding animals11 raises interesting questions with regard to
the positive and negative survival value of intestinal lactase.
The availability of nonmaternal sources of milk in the
distant past in northern Europe must have provided a
survival value to subjects with the C-T (lactase persis-
tence) mutation; thus, this mutation became the predom-
inant genotype in this population group. However, what
was the dramatic survival value of being lactase persistent
when there was a nonmaternal source of milk? The obvious
answer is that survival was enhanced by the ability of lac-
tase-persistent subjects to consume more milk than their
lactasenon-persistent counterparts, and this milk supplied
some nutrient (calories, protein, or calcium) crucial to
survival. However, many populations have ourished
despite their lactase nonpersistence and low milk intake. In
addition, some studies12 have shown that lactasenon-per-
sistent adults tolerate large quantities of milk (1 quart daily)
without disabling symptoms. Seemingly, at some time in the
past, northern Europeans, presumably children, must have
survived primarily on milk.
A second question is what is the survival value of a
highly engineered gene that promotes lactase non-
persistence in adult mammals lacking a nonmaternal source
of milk? The standard postulate is that symptoms caused by
lactase nonpersistence prevents older siblings from con-
suming mothers milk needed for survival by the newborn.
However, lactase deciency in whites does not become
manifest until after age 5 (Fig. 1), seemingly too late an age
to protect the newborn. In addition, as evidenced by
domestic pets, lactase nonpersistence does not result in milk
aversion. A second purely speculative postulate is that
lactase deciency prevented the absorption of environ-
mental toxins containing a b-galactoside linkage.
LACTOSE MALABSORPTION
When lactase activity is a small fraction of that of
infants, ingested lactose is incompletely hydrolyzed and
hence malabsorbed. There have been few direct measure-
ments of lactose digestion/absorption in the human gut. We
measured lactose absorption from analyses of aspirates
obtained from a mercury-weighted tube passed through the
mouth to the terminal ileum.13 Lactose malabsorbing sub-
jects absorbed a mean of 52% (range, 42% to 77%) of a
12.5 g dose of lactose. Thus, the residual lactase activity of
lactasenon-persistent subjects (Fig. 1) permits absorption
of an appreciable fraction of a limited dose of lactose. It is
not known whether the 12.5 g lactose dosage saturates
lactose hydrolyzing ability; such saturation would cause an
increased percentage malabsorption of larger lactose dos-
ages. Lactase-persistent subjects malabsorbed about 5% of
the 12.5 g dose.
Measurement of Lactose Malabsorption
The techniques commonly used to assess lactose
absorption in the clinical setting involve measurements of
blood glucose or breath H2 concentrations after lactose
ingestion. A blood glucose increase of <20 mg/100 mL
after ingestion of a large (50 to 100 g) dose of lactose has
been used as evidence of lactase deciency. Blood glucose
measurements have largely been supplanted by breath H2
testing. This noninvasive methodology is based on the
rationale that: (1) increased H2 production after lactose
ingestion only occurs when this sugar is delivered to colon
where it undergoes bacterial fermentation to H2 and (2) this
r 2013 Lippincott Williams & Wilkins
Lactose Malabsorption Versus Lactose Intolerance
H2 is absorbed from the colon and excreted in expired air in
a concentration sucient to give a recognizable breath
signal. Given the widespread usage of breath H2 measure-
ments in clinical practice, it is important to recognize the
limitations of this methodology. The accuracy of the tech-
nique depends upon minimal H2 release from lactose fer-
mentation in the small bowel. The one direct assessment of
small and large bowel H2 release after lactose instillation
(measurements obtained by aspiration of intestinal gas)
showed negligible small bowel H2 release relative to that in
the colon in 6 healthy controls.14 However, small bowel H2
production was appreciable in 1 subject with severe bacte-
rial overgrowth of the small bowel. It follows that the
frequency of bacterial overgrowth in the population
undergoing breath H2 testing is an important determinant
of the validity of this test. On the basis of the nding of a
breath H2 increase within 90 minutes of ingestion of lac-
tulose (a nonabsorbable disaccharide), it has been proposed
that small bowel overgrowth is present in >50% of subjects
with irritable bowel syndrome (IBS),15,16 a group likely to
undergo breath testing for lactose malabsorption. If cor-
rect, breath H2 testing for lactose malabsorption loses its
clinical utility. However, small bowel transit time of
unabsorbed disaccharide is more rapid than commonly
appreciated. When 10 g of lactulose plus a nonabsorbable
form of 99mTc was fed to healthy controls, g camera
measurements showed that the meal arrived in the cecum
within 90 minutes of ingestion in the majority of subjects.17
Thus, timing of the rise in breath H2 does not reliably
distinguish a small bowel versus a colonic site of H2
production. In addition, cultures of the small bowel are
positive in only a small fraction of IBS patients18,19 sug-
gesting that conclusions drawn from lactulose testing may
have grossly overestimated the frequency of bacterial
overgrowth. A second potential source of error with breath
H2 testing is the inability of colonic bacterial fermentation
reactions to release sucient H2 to raise the breath con-
centration to a level diagnostic of malabsorption. Such
subjects have been termed H2 nonproducers. However,
subjects who excrete large quantities of CH4 tend to have a
low breath H2 response to carbohydrate (lactulose) mal-
absorption.20 Methanogens utilize H2 released by other
bacteria. Thus, most H2 nonproducers in reality appear
to be H2 overconsumers. Assessing increases in both
breath H2 and CH4 increases the sensitivity of the breath
test for lactose malabsorption, but it is not clear to what
extent specicity is reduced.
Assessing the accuracy of H2 breath measurements for
lactose malabsorption requires comparison with the results
of an independent gold standard technique, eg, intestinal
lactase activity. Newcomer et al21 compared blood glucose
and breath H2 measurements after ingestion of 50 g of
lactose with the lactase activity of biopsies from 20 lactase
non-persistent and 20 lactase-persistent subjects. A breath
H2 concentration of Z20 ppm within 4 hours of lactose
ingestion perfectly distinguished subjects with high versus
low lactase activity, whereas there was overlap in blood
glucose measurements. This study, published in 1972, pro-
vided the impetus for the widespread clinical use of breath
H2 testing. However, subsequent studies have suggested
that false-negative breath tests, ie, symptoms without a
diagnostic rise in breath H2, may be a not uncommon
phenomenon. The exact frequency of this false negativity is
not clear because most studies do not have a gold standard
comparator. Lactulose-feeding studies have been used to
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Levitt et al
assess the accuracy of breath H2 testing. Failure to produce
a diagnostic breath H2 signal after the ingestion of this
nonabsorbable disaccharide provides irrefutable evidence
of a false-negative breath test for lactulose malabsorption.
Extrapolation from lactulose testing (assuming similar fer-
mentation pathways for lactulose and lactose) indicates
that false-negative tests for lactose malabsorption may
occur in 6% to 27% of subjects.20
Clinical application of breath H2 testing is poorly
standardized in that various lactose dosages, methods of
breath collection, and H2 criteria for malabsorption are
used. Thus, it is not possible to provide a widely applicable
estimate of the frequency of false-negative breath tests,
other than that this frequency is not negligible, perhaps on
the order of 10%. The frequency of false-positive tests is
not known.
Lactose Intolerance
The symptoms of lactose intolerance, ie, diarrhea,
abdominal pain, bloating, and atulence, are thought to be
manifestations of lactose reaching the colon. Thus, by
denition, a lactose-intolerant subject must be a lactose
malabsorber.
The colonic mucosa has a high hydraulic permeability,
ie, the gut cannot maintain an appreciable osmotic gradient
between blood and lumen. Thus, to the extent that lactose
and its fermentation products create nonabsorbable lumi-
nal osmoles, water moves from the blood to render luminal
contents isotonic. Failure to absorb 12 g of lactose would
deliver 33 mOsm of lactose to the colon, which would
hold about 100 mL of water in the lumen. A hypothetical
bacterial fermentation of this lactulose to four 3-carbon
fatty acids produces a 4-fold increase in osmotic load. If the
fatty acids were in the ionized form, associated cations
would further double this osmotic load, and the 800 mL of
retained water from malabsorption of 12 g of lactose would
cause appreciable diarrhea. However, within limits the
colonic mucosa rapidly absorbs organic acids produced
during the fermentation of lactose. To the extent that these
fermentation products are eciently absorbed, fermenta-
tion prevents rather than aggravates diarrhea associated
with lactose malabsorption.
Hammer et al22 quantied the diarrheal response to
increasing quantities of malabsorbed disaccharide when
healthy subjects ingested 45, 90 or 125 g of lactulose per day
in divided doses with meals (Table 2). The ingestion of 45 g
of lactulose increased fecal water excretion by only 96 mL
over baseline, one fourth of that expected from osmotic
activity of lactulose, indicating that 75% of the lactulose
was removed from the lumen through absorption of the
fermentation products. The eciency of this process
dropped to about 66% with a 90 g dose of lactulose, and to
only about 10% with a 125 g dose. Thus, the ability of the
colon to remove osmoles generated from lactulose became
TABLE 2. Increase in Fecal Water Relative to That Predicted From Varying Dosages of Lactulose
Fecal Measurement (g/d) Basal Diet
Fecal weight
Fecal water
Fecal water attributable to lactulose
Fecal water predicted from osmotic activity of lactulose
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J Clin Gastroenterol  Volume 47, Number 6, July 2013
saturated as the dose was increased from 90 to 125 g/d. Of
clinical interest was the modest increase in fecal water
(96 mL/d) with the daily ingestion of 45 g of lactulose, a
quantity roughly equivalent to that of the lactose in a quart
of milk. (As lactose is partially absorbed by lactasenon-
persistent subjects, 45 g of lactose would deliver less dis-
accharide to the colon than would the 45 g of lactulose.)
Thus, in the absence of massive milk ingestion, lactose
malabsorption is very unlikely to be the sole cause of severe
diarrhea.
Gaseous complaints, ie, bloating, abdominal pain, and
atulence, are more common than is diarrhea in lactose
malabsorbers. The rate of release of gas by colonic fer-
mentation reactions may be prodigiousone major bacte-
rial fermentation pathway releases 2600 mL of CO2 and
4000 mL of H2 during the metabolism of 12.5 g of lactose.23
Because the normal excretion rate of gas per rectum
usually is <1000 mL/d,24 the addition of 6600 mL to this
excretion would induce serious atulence. However, CO2 is
very rapidly absorbed and is also utilized by other bacteria
to synthesize acetate. H2 is less rapidly absorbed but is
eciently consumed by other bacteria.25 Thus, only a small
fraction of the gas produced in the colon is excreted per
rectum. A variety of factors inuence the perception of
gaseous symptoms resulting from lactose malabsorption.
The ratio of gas removed from the lumen through
absorption versus rectal excretion decreases as the rate of
release increases26; thus, atulence may increase out of
proportion to the quantity of lactose malabsorbed. In
addition, the gaseousness resulting from a given load of
malabsorbed disaccharide varies between individuals and at
dierent times in the same individual, presumably because
of dierences in fermentation. Lastly, the discomfort per-
ceived by an individual to a given volume of bowel gas may
dier because of variations in visceral sensitivity.
How lactose is ingested inuences the symptomatic
response of the lactose malabsorber. Lactose consumed in
an aqueous solution is rapidly emptied from the stomach
with resultant rapid small bowel transit. The larger the
nonabsorbable disaccharide load, the faster the small bowel
transit, with a mean small bowel transit time of only
40 minutes noted for a 20 g dose of lactulose.27 Although
not well studied, such rapid transit presumably limits the
hydrolysis/absorption of lactose by lactasenon-persistent
subjects. In addition, rapid intestinal transit results in the
colonic delivery of a large compact lactose bolus that may
overwhelm the mechanisms that reduce the osmoles and gas
produced by the colonic bacteria. Lactose in milk may be
better tolerated than lactose in aqueous solution,28 and
milk intake with other foods seemingly is better tolerated
than milk alone (Tables 3 and 4). Presumably additional
nutrients slow gastric emptying and small bowel transit
such that lactose is better hydrolyzed/absorbed and is
delivered at a slower rate to the colon. It is also likely that
Basal Diet Plus Lactulose (g/d)
45 90 125
142 264 550 1307
106 202 383 1184
96 277 972
375 830 1041
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TABLE 3. Symptomatic Response* of Adolescents and Adult Lactose Malabsorbers to Varying Dosages of Lactose Ingested With
Nutrients Other Than Milk in Blinded, Controlled Trials
Daily Lactose Dosage (g)
References No. 2 10 20 30 40 50 60 70
Jones et al29 16 NS NS ++
Cheng et al30 15 ++
Rorick and Scrimshaw31 23 NS
Newcomer et al32 59 NS NS ++
Suarez et al33 21 NS
Vesa et al34 30 NS
Suarez et al35 19 NS
Suarez et al36 31 +
Hertzler and Savaiano12 18 NS NS NS NS NS
Data derived from Evidence Report/Technology Assessment Number 192, Lactose Intolerance and Health. AHQR Publication No. 10-E004, February
2010.
*Symptom severity after ingestion of lactose relative to control.
NS indicates not statistically signicant; + , moderate; + + , severe (see text for denition of severity).

lactose given in divided doses throughout the day is better
tolerated than lactose provided as a single dose.
MAXIMAL DOSE OF LACTOSE TOLERATED BY
LACTOSE MALABSORBERS
A question of major clinical importance is what dose
of lactose is required to induce appreciable symptoms (ie,
intolerance) in lactose malabsorbers. If this dosage were less
than the quantity most lactasenon-persistent subjects
consume or wish to consume, lactose intolerance becomes a
minor clinical problem. Although lactase nonpersistence
and malabsorption are diagnosed by objective testing,
documentation of lactose intolerance is based on an indi-
viduals subjective impression of his/her symptomatic
response to lactose. These symptoms, ie, bloating, dis-
tention, abdominal discomfort, and diarrhea, are common
in the absence of lactose malabsorption, particularly in
patients with IBS, and subjects with self-diagnosed lactose
intolerance frequently are not lactose malabsorbers.33,48 In
addition, these symptoms are highly susceptible to psy-
chological factors, as evidenced by the very high placebo
response rate of individuals with IBS type symptoms.49
Thus, truly reliable demonstration that a subject is lactose
intolerant requires multiple time-consuming double-blinded
tests showing that the subject has more symptoms after
some dosage of lactose than with an indistinguishable
control. As such testing is not performed, studies of the
tolerable doses of lactose and the ecacy of treatments for
lactose malabsorption have assessed subjects with demon-
strated malabsorption plus/minus self-diagnosed lactose
intolerance, not proven lactose intolerance.
We recently reviewed the worlds literature on various
aspects of lactose intolerance to serve as background data
for an NIH Consensus Conference concerning Lactose
Intolerance and Health.50,51 Topics reviewed included the
maximal dose of lactose tolerated by lactose malabsorbers
and the ecacy of various interventions for lactose intol-
erance symptoms. Studies included in this review were
double-blinded, placebo-controlled, randomized trials pub-
lished in English between 1965 and December 2009 that
assessed lactose-induced symptoms (not simply breath
H2 or blood glucose responses). The best controlled studies
compared symptoms with a lactose-hydrolyzed beverage as

TABLE 4. Symptomatic Response* of Adolescents and Adult Lactose Malabsorbers to Varying Doses of Lactose Ingested as a Single Dose
Without Nutrients Other Than Milk in Blinded, Controlled Trials
Daily Lactose Dosage (g)
References No. 2 10 20 30 40 50
Jones et al29 17 NS + ++
Stephenson and Latham37 19 NS + ++
Kwon et al38 45 NS +
Reasoner et al39 9 + ++
Rask Pedersen et al40 17 +
Lybeck Srensen et al41 35 NS NS NS + ++
Rosado et al42 25 +
Cavalli-Sforza and Strata43 40 +/ +/ +
Brand and Holt44 26 +
Johnson et al45 45 +
Hertzler et al46 13 NS ++
Montalto et al47 20 ++
Data derived from Evidence Report/Technology Assessment Number 192, Lactose Intolerance and Health. AHQR Publication No. 10-E004, February
2010.
*Symptom severity after ingestion of lactose relative to control.
NS indicates not statistically signicant; + / , minor; + , moderate; + + , severe (see text for denition of severity).

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Levitt et al
the control versus articially sweetened lactose/milk to
disguise the greater sweetness of hydrolyzed versus intact
lactose.
Pooling of the results of studies of the dosage of lac-
tose tolerated by lactose malabsorbers was complicated by
the use of dierent enrollment criteria, lactose dosing reg-
imens and techniques to assess the severity of symptoms
(poststudy interview, numerical rating of individual symp-
toms, or summation of all symptoms, etc.). When possible,
we rated the severity of symptoms (bloating, atulence,
abdominal pain, and diarrhea) as negligible (no statistically
signicant dierence vs. control), minimal (1 symptom
signicantly increased but r20% of the maximal severity
reportable for that symptom), mild (1 or more symptoms
signicantly increased to >20% to r33% of maximal
severity), severe (1 or more symptoms increased to >33%
of maximal severity). In studies where such a numerical
system was not applicable, our subjective evaluation of
reported symptom severity was used. Tables 3 and 4 sum-
marize data from 21 blinded studies that evaluated the
dierence in symptoms reported by lactose malabsorbing
adolescents and adults after the consumption of lactose or
milk versus an indistinguishable control. When ingested
with other nutrients (Table 3), daily lactose dosages of up to
18 g (1.5 cups of milk) were tolerated without a statistically
signicant increase in symptoms. As the dosage was
increased above 20 g, a signicant increase in symptoms
versus control was frequently observed. Lactose consumed
as a single dose in the fasting state (Table 4) occasionally
produced minimal symptoms with a dose of 12 g, and a
greater symptomatic response was observed with increasing
dosages. Anecdotal claims that some groups of mal-
absorbers (eg, elderly, blacks, Asians) are particularly
intolerant of lactose were neither supported nor refuted by
available evidence.
The data in Table 3 indicate that the quantity of lac-
tose that commonly might be consumed with a meal (18 g
or 1.5 cups of milk) usually is tolerated without perceptible
symptoms. A similar conclusion was reached in a system-
atic review of the literature by Savaiano et al.52 Less well
studied is the tolerance to lactose when taken in divided
doses with meals. To determine whether the maximal rec-
ommended daily intake of calcium (1500 mg) could be
supplied primarily as dairy products, Suarez et al36 fed
adult females (31 lactose malabsorbers and 31 lactose
absorbers) 1 cup of milk at breakfast and dinner, 1 cup of
yogurt at lunch, and 2 oz of cheese (34 g of lactose and
1100 mg of calcium/d) for 1 week. During a control week,
subjects consumed lactose prehydrolyzed products. The
only symptom signicantly altered during lactose ingestion
was an increase in daily rectal gas passages from an average
of 11 to 17 per day in lactose malabsorbers. However, this
gaseousness did not signicantly inuence the subjects controls of the same racial background.5659 These results
global assessment of the overall acceptability of the 2
feeding periods. The majority of lactose absorbers and
malabsorbers indicated a preference to obtain their calcium
by some mechanism (eg, calcium supplements) other than
the dairy-rich diet. Thus, there is limited desire by most
adult women (independent of absorber status) to consume
dairy products in a quantity that might provoke severe
lactose intolerance symptoms. The study of Hertzler and
Savaiano12 provided the most startling evidence of the
ability of malabsorbers to tolerate lactose when consumed
in divided dosages with the 3 major meals. Lactose was fed
in incrementally increasing quantities over a 10-day period
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J Clin Gastroenterol  Volume 47, Number 6, July 2013
to 20 lactose malabsorbers who believed they were lactose
intolerant. The initial and 10th day dosages were 42 and
70 g/d (equivalent to 1.5 quarts of milk daily!). No sig-
nicant dierences in diarrhea or gaseous complaints were
observed on any day of the lactose-feeding period versus
the low lactose control period. The authors attributed this
remarkable lactose tolerance to an adaptation of the fecal
ora to lactose. If these results could be extrapolated to the
entire population of malabsorbers (which seems unlikely),
lactose intolerance would be a non-problemprovided lac-
tose was ingested in divided doses on a daily basis.
On the basis of annual per capita US sales, we calcu-
lated that the daily consumption of the average American
is 236 mL of uid milk plus yogurt, 60 g of ice cream, and
30 g of cheese.53 These foods provide an average per capita
lactose intake of 16 to 17 g/d. This average value is inu-
enced by many factors such as age (children consume more
lactose than adults) and ethnicity (African Americans
consume less lactose than whites). The lack of symptoms
observed in controlled studies when this quantity of lactose
was ingested with meals raises the question of how and why
the general public and physicians seemingly overestimate
the frequency and severity of symptoms caused by com-
monly ingested doses of lactose. The initial techniques used
to diagnose lactose malabsorption (blood glucose and
breath H2 testing) utilized 50 to 100 g of lactose fed as a
single dose to fasting subjects. As indicated in Tables 3 and
4, such a dosing regimen commonly causes appreciable
symptoms. Extrapolation from these studies likely led to
misconceptions concerning the ability of lower dosages of
lactose to induce similar symptoms. It is also possible that
the individual lactose malabsorber became symptomatic
after ingestion of very large quantities of milk on some
occasion, and this indiscretion led the subject to believe
that much smaller dosages of lactose caused similar prob-
lems. Lastly, the symptoms of lactose intolerance and IBS
overlap, and patients with IBS often misattribute their
symptoms to lactose intolerance, a misattribution fostered
by innumerable articles in the lay press concerning the
symptomatic potential of lactose and commercial adver-
tisements for products touted to be of value for lactose
intolerance.
Before dismissing the clinical importance of lactose
intolerance, the problem of outliers must be considered.
For example, does the well-described visceral hyper-
sensitivity of IBS subjects render them uniquely susceptible
to lactose-induced symptoms? Subjects with IBS are more
likely to have self-diagnosed lactose intolerance versus that
of controls54; however, such a self-diagnosis does not
accurately predict that the subject will be a lactose
malabsorber.55 Multiple studies have found a similar
prevalence of lactose malabsorption in IBS subjects versus
indicate that: (a) IBS subjects overestimate the importance
of lactose malabsorption as a cause of their symptoms and
(b) an appreciable fraction of individuals diagnosed as IBS
are not otherwise healthy individuals suering from lactose
malabsorption. However, these observations do not exclude
the possibility that lactose malabsorption plays a role
in IBS by aggravation of the underlying intestinal
pathophysiology. Such a role would be best elucidated
through well-blinded studies showing that lactose restric-
tion does or does not improve symptoms in IBS subjects
who are lactose malabsorbers. Several such variably
blinded studies have demonstrated no or minimal
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J Clin Gastroenterol  Volume 47, Number 6, July 2013
improvement.6062 In contrast, while not the usual
blinded study, Bohmer and Tuynman63 rst assessed
lactose absorption in 70 IBS subjects, who all then went on
a lactose-restricted diet. A sizable decrease in abdominal
symptom score was observed in the 17 subjects who were
lactose malabsorbers, whereas the lactose absorbers showed
no such improvement. (The subjects purportedly had no
knowledge of the results of their lactose malabsorption
status.) This paper, published 12 years ago, remains the
strongest piece of evidence that lactose restriction might
have a role in the treatment of gastrointestinal complaints
of IBS subjects. Given the conicting results of published
studies, the possibility that lactose malabsorption aggra-
vates IBS symptoms requires further study.
The ability of commonly ingested dosages of lactose to
induce symptoms has not been studied in a well-dened
group of IBS subjects under strictly blinded conditions.
However, 2 studies in which the enrollment criterion was
severe self-diagnosed lactose intolerance (symptoms with
milk in cereal or coee) found no signicant increase in
symptoms versus during 1-week feeding periods with 1 cup
of milk with breakfast or 1 cup of milk at breakfast and 1 at
dinner.33,35 These subjects likely had IBS. A blinded study
of the tolerance to ingestion of various dosages of lactose in
IBS subjects with lactose malabsorption (similar to the
studies shown in Table 3) would shed light on the likelihood
that a lactose-restricted diet might be of value in IBS
subjects.
TREATMENT OF LACTOSE INTOLERANCE
We also reviewed existing literature regarding the
ecacy of various treatments for lactose intolerance for the
NIH Consensus Conference. Despite the enormous liter-
ature on the treatment of lactose intolerance, a search of
nearly 2500 abstracts and full-text articles revealed only 24
studies that fullled the criteria of well-controlled, blinded
studies of the ecacy of various interventions in lactose
malabsorbing subjects. As lactose intolerance was not
documented pre-enrollment, the ecacy of interventions
may have been evaluated in subjects who did not have
intolerance to the dosage of lactose tested. Pooling the
results of these studies was hampered by the same problems
previously noted for determining the tolerable lactose
dosagevariable enrollment criteria, lactose dosing regi-
mens, and outcome measurements. Most studies did not
correct for multiple comparisons, and other criteria of high-
quality randomized-controlled studiesconcealed alloca-
tion and intention to treat analysiswere rarely reported.
With these caveats in mind, we assessed 4 categories of
treatments for lactose intolerance symptoms: lactose-
reduced products, colonic adaptation, probiotics, and
antibiotics (rifaximin).
Lactose-reduced Products
We identied 17 studies29,30,3336,3941,45,47,6469 that
assessed lactose-reduced products and 1 study60 that com-
pared treatment with lactase capsules versus placebo. As
discussed previously, lactose malabsorbing subjects tolerate
a 12 g dose of lactose. Thus, it is not surprising that 5
studies33,34,41,65,66 using lactose-reduced products showed
little or no ecacy over conventional milk containing
B12 g of lactose (Table 5). One study64 with this dosage
showed a statistically signicant improvement in 1 symp-
tom (reduced abdominal pain), but the mild improvement
r 2013 Lippincott Williams & Wilkins
Lactose Malabsorption Versus Lactose Intolerance
was of questionable clinical importance. Studies with >15 g
lactose dosages showed mixed results, with no clear dose-
response relationship (Table 6). One study47 showed stat-
istically signicant improvement in overall symptom score,
although the clinical signicance of dierences was not
clear. The remaining studies either did not report, or did
not show improvement in overall symptom score.
Improvement in individual symptoms of abdominal pain,
diarrhea, or atulence, respectively, was reported in
5,3941,68,70 2,40,70 and 636,3941,67,70 of the 14 studies. The
other 5 studies showed no signicant dierence between
intervention and placebo for overall or individual symptom
scores. Assuming that lactose intolerance is a true entity, ie,
lactose in sucient quantity induces symptoms, it follows
that lactose-reduced products should be eective. However,
the results of published controlled studies are inconsistent,
likely because of the use of insucient lactose dosages and
limitations in methodology.
Probiotics and Yogurt
Only 1 study met our inclusion criteria. Newcomer
et al71 randomized 18 subjects to 720 mL of acidophilus
unfermented milk (milk with B36 g lactose and added
Lactobacillus acidophilus 106) or the same amount of reg-
ular 2% milk. The study did not nd any dierence in
overall symptom score between the acidophilus milk and
regular milk. Most other studies were excluded because
they enrolled subjects with abnormal H2 breath testing, but
symptoms compatible with lactose intolerance were either
not required or not reported before enrollment. Most of
these studies were not designed to measure improvement in
symptoms, but to test improvement in malabsorption
measurements (breath H2 or blood glucose). Inclusion cri-
teria were variable, as were the type, source, and concen-
tration of yogurt and probiotics studied, making it dicult
to interpret ecacy for management of lactose intolerance
symptoms.
Colonic Adaptation
The rationale for this intervention is that colonic
bacteria adapt to chronic lactose exposure with an increase
in fecal b-galactosidase activity and decreased H2 produc-
tion. The latter is thought to reect the proliferation of
lactose-fermenting organisms such as Bidobacteria that do
not produce H2. The clinical implications of this colonic
adaptation have been tested in 2 controlled studies. Hertzler
and Savaiano12 randomized 20 individuals to receive
incrementally increasing doses of lactose or dextrose for 10
days (nal dosage 70 g/d). The symptomatic response to
25 g of lactose was then tested, the subjects were then
crossed-over to the opposite treatment, and the process
repeated. Comparison of the symptomatic responses to 25 g
lactose after the dextrose and lactose-feeding periods
showed a statistically signicant decrease in atulence with
lactose adaptation, but no signicant dierences in
abdominal pain or diarrhea. The second study72 random-
ized 46 lactose malabsorbers to ingest either 34 g of lactose
or sucrose for 13 days. The symptomatic response to a 50 g
challenge dose of lactose was determined before and after
the feeding periods. Comparison of the prefeeding and
postfeeding scores showed similar signicant reductions in
symptoms after both the lactose-feeding and sucrose-feed-
ing periods, which the authors attributed to the placebo
eect of dietary manipulation (with no evidence for adap-
tation to lactose). Taken together, these studies provide
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TABLE 5. Efficacy of Lactose-reduced Products on Management of Lactose Intolerance Symptoms With Test Lactose Doses r12 g
Lactose Content (g) Signicant Improvement*
References No. Control Intervention Overall Symptom Score Abdominal Pain Diarrhea Flatulence
Gremse et al64 30 12 0 NS + NS NS
Jarvinen et al65 27 12 0 and 2 NS NS NS NS
Vesa et al67 39 0.5, 1.5, 7 0 NS NS NS NS
Suarez et al33 21 12 < 0.5 NS NS NS
Lybeck Srensen et al41 35 11.3 1.6 NS NS NS NS
Unger et al66 24 10.8 0 NS
*NS, P > 0.05; + , P < 0.05.

inconclusive evidence to support the role of colonic adap-
tation as an eective strategy to treat lactose intolerance.
Rifaximin
The single controlled study73 using this antibiotic
enrolled 40 patients with lactose malabsorption and self-
diagnosed lactose intolerance. Sixteen subjects were
randomized to 10-day treatment with rifaximin (800 mg/d),
16 to a 40-day lactose-free diet, and 8 were given 10 days of
placebo. Compared with baseline, there was reduced
abdominal pain, diarrhea, bloating, and distention at day
40 for the rifaximin group. Similar decreases were seen for
the lactose-free group. The clinical signicance of the
change in score is not clear.
APPROACH TO PATIENT WITH SYMPTOMS
COMPATIBLE WITH LACTOSE INTOLERANCE
Diagnosis
Patients complaining of otherwise unexplained diar-
rhea, bloating, distention, or atulence potentially could
have lactose intolerance, and many such subjects will
present with a self-diagnosis of lactose intolerance. The
results of the studies reported in this paper suggest that that
the rational (although not commonly used) diagnostic/
therapeutic approach to such patients is as follows. A
history of a perceived temporal relationship between lactose
ingestion and symptoms has limited reliability given the
demonstrated tendency of subjects to misattribute their
symptoms to lactose intolerance. Historical information
that is of value is the quantity of lactose commonly ingested
as a single dose and over the course of the day. If the
patient, like the average adult American, ingests very little
lactose (r1 cup of milk/d), lactose intolerance is highly
unlikely to be the cause of symptoms. In the absence of
massive milk ingestion (Z1.5 quarts of milk/d), moderate to
severe diarrhea never should be attributed to lactose mal-
absorption. H2 breath testing to diagnose lactose mal-
absorption has very limited utility. This testing provides
information on the patients ability to absorb lactose,
whereas the desired information is if the subject is lactose
intolerant (ie, if lactose is causing the symptoms). In addi-
tion, breath H2 testing has an appreciable false-negative
rate and an unknown false-positive rate. In populations
with a high (ie, Z70%) prevalence of lactase non-
persistence (eg, Asians, Africans), the accuracy of the
assumption that the subject is a lactose malabsorber
approaches the accuracy of the test. One situation in which
breath H2 testing might be indicated is the patient: (a) who
has a low chance of being lactase non-persistent based on
ethnicity and (b) who desires to consume large quantities of
lactose.

TABLE 6. Efficacy of Lactose-reduced Products on Management of Lactose Intolerance Symptoms With Test Doses of Lactose of >15 g
Lactose Content (g) Overall Symptom Signicance of Improvement*
References No. Control Intervention Score Abdominal Pain Diarrhea Flatulence
Montalto et al47 30 20 Z70% hydrolyzed +
Suarez et al35 19 24 0 NS NS NS
Vesa et al67 30 20 0 NS NS +
Johnson et al45 45 16 0 NS
Nielsen et al68 9 25 1.25 +
Cheng et al30 15 25 0.5-1.25 g
Lybeck Srensen 35 22.5 3.2 NS + NS +
et al41
Rask Pedersen et al40 11 25 3.75 + + +
Reasoner et al39 9 28.5 2.9 + +
Unger et al66 24 21.6 0
Jones et al29 17 25 10
Suarez et al36 31 34 2 NS NS NS +
Lin et al69 11 50 Lactodigest, DairyEase, or NS NS NS
2-4 Lactaid capsules with
milk (50 g)
Xenos et al70 8 100 Lactase 100 U/mL + 100 g + + +
lactose
*NS, P > 0.05; + , P < 0.05.

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J Clin Gastroenterol  Volume 47, Number 6, July 2013
Therapy
Given the results of the controlled trials reviewed in
this paper, the simplest and least expensive approach to
patients with lactose intolerance symptoms is counseling
with regard to the ability of the vast majority of subjects to
tolerate lactose if the dose is limited to 2 cups of milk (or its
lactose equivalent) daily, taken in divided doses with 2
meals. With such an intake, there is no need to use lactose-
reduced products or lactase supplements. Although data
are contradictory, it is possible that routine daily con-
sumption of lactose-containing products will be better tol-
erated than intermittent consumption. Subjects should
avoid drinking more than 1 cup of milk as a single dose,
particularly in the absence of consumption of other foods.
The unusual patient who wishes to ingest more than 2
servings of dairy products per day or dairy products with-
out other nutrients may benet from the use of lactose-
reduced products. A question that remains to be answered
is the utility of stringent lactose restriction as adjunctive
treatment in subjects with IBS.
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