Appendix Table D8Evidence table for blinded lactose intolerance treatment studies: Question 3 and 4

Author, Year, Study Design, Study Sponsorship, Country, Length of FollowupSubject Selection, Data Source, Methods to Measure Outcomes, Inclusion/Exclusion CriteriaSubject CharacteristicsTreatment-Active, Adherence EvaluationsTreatment- Control, Adherence EvaluationsOutcome assessment/Results and ConclusionsQuality of the Study
A. Commercially-available lactase/lactose hydrolysed milk, or non-lactose solutions
Montalto, 200554
RCT, crossover Sponsorship: not reported
Italy
Duration of symptom recording: 8 hours
Data source: 30 Italian subjects referred because of symptoms compatible with lactose intolerance with a positive lactose H2 breath test. Each patient underwent, in a random order, three H2 breath tests. An interval of at least 72 hours was allowed among successive tests (20 g lactose), to avoid the effect of colonic acidification.
Inclusion criteria: Symptoms compatible with lactose intolerance.
Methods to measure outcomes: Subjects kept a diary where they recorded occurrence of intolerance symptoms for 8 hours following milk ingestion.
Mean age (range): 43 (18–65)
Gender: women 63%.
Race/ethnicity: not reported
Comorbidities: not reported
Cointerventions: not reported
β-d-galactosidase from Kluyveromyces lactis
1) Test A -enzyme (3000 UI) added to 400 mL milk (lactose content 20 g) 10 h before milk consumption x 1 dose
2) Test B-enzyme (6000 UI) added 5 min before 400 mL milk (lactose content 20 g) consumption x 1 dose
Placebo before 400 mL milk (lactose content 20 g) plus aspartame (to simulate the taste of lactase-treated milk x 1 doseClinical score based on symptoms whose severity was indicated by a score for each symptom (0=absent; 1=mild; 2=moderate; 3=severe).
Conclusion(s): A significant reduction of the mean clinical score after both test A (0.36 ± 0.55) and test B (0.96 ± 0.85) versus placebo (3.77 ± 0.79) (P<0.001).
There was also a significant reduction after Test A versus Test B (P=0.03).
Allocation concealment: adequate (numbered containers, identical in shape and color)
Blinding: double + analysis by a blinded statistician.
Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Gremse, 200355
RCT, crossover Sponsorship: not reported
USA
Duration of symptom recording: 2 weeks
Data source: 30
American child subjects with lactose mal- digestion a positive lactose H2 breath test.
Inclusion criteria: Recurrent abdominal pain of childhood with at least 3 discrete episodes of abdominal pain severe enough to affect daily activities for 3 months or more.
Exclusion criteria: Organic causes of abdominal pain.
Methods to measure outcomes: Subjects and/or their parents recorded their symptoms daily in a diary that was collected at weekly intervals during each study period.
Mean age (range): 11 (3–17)
Gender: women 63%.
Race/ethnicity: black 53%, white 47%.
Comorbidities: not reported Cointerventions: not reported
240 mL Lactose‐free milk (LFM) to which lactase 2 g from Kluyveromyces lactis (Lactaid, Pleasantville, NY) was added to 2% homogenized milk (lactose content 12 g) taken for 14 days (2 week washout period)240 mL Milk (lactose content 12 g) 2% homogenized milk plus aspartame (to simulate the taste of lactase-treated milk) taken for 14 daysSymptom scores for the 14 day period (mean ± SEM).
Severity of symptoms was graded as: 0=none; 1=trivial, 2=mild; 3= moderate; 4=severe. Sum of the individual symptom scores was calculated for each 14-day study period and averaged for all subjects.
Significant increase in abdominal pain during the lactose ingestion period compared to the lactose-free period.
Conclusion(s): Authors conclude that ingestion of 12 g of lactose daily is associated with increased abdominal pain in susceptible children with lactose maldigestion.
Allocation concealment: unclear Blinding: Double Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Järvinen, 200356
RCT, crossover Sponsorship: not reported
Finland
Duration of symptom recording: 8 hours
Data source: 27 Finnish subjects who had experienced gastrointestinal symptoms after consuming milk or food containing lactose.
Inclusion criteria: lactose maldigestion based on rise in blood glucose <1.1 mmol/l within 1 hour after ingesting 50 g lactose dissolved in water.
Methods to measure outcomes: Gastrointestinal symptoms including flatulence, abdominal bloating, abdominal pain, borgorygmi and nausea were recorded on a questionnaire with a scale ranging from 0 (no symptoms) to 10 (very severe symptoms disturbing normal life) once every hour for the first 3 hours and then two more times (at 4–6 and 7–8 hours) until 8 hours had elapsed since the test meal.
Students and staff at a university. No further information provided.100 g chocolate sample consisting of lactose-free milk powder.100 g chocolate sample consisting of low-lactose milk powder (lactose content 2 g).
100 g chocolate sample consisting of whole milk powder (lactose content 12 g).
100 g chocolate sample consisting of whole milk (lactose content 12 g).
The chocolate sample was eaten in the morning between 8 and 10 o’clock after an overnight fast
Number of subjects reporting symptoms and mean symptom scores for individual gastrointestinal symptoms.
Conclusion(s): Numbers of subjects reporting GI symptoms did not differ significantly after eating chocolate samples.
Allocation concealment: unclear Blinding: described as “blinded,” no further details.
Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Suarez, 199857
RCT, crossover Sponsorship: Department of Veteran Affairs, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Dairy Council.
USA
Duration of symptom recording: 1 week
Data source: 31 American women subjects with lactose maldigestion a positive lactose H2 breath test plus 31 American women digester controls.
Inclusion criteria: Lactose maldigestion based on an increase in the breath-hydrogen concentration of >0.45 mmol/L (10 ppm) after the oral ingestion of a 250-mL aqueous solution containing 15 g lactose (0.18 mol/L) was used as the indicator of lactose maldigestion.
Exclusion criteria: Previously had gastrointestinal surgery, had significant intercurrent illnesses, had received antibiotic therapy within the past 2 months, or allergy to aspartame, milk, yogurt, or cheese.
Methods to measure outcomes: The occurrence and severity of symptoms (bloating, abdominal pain or cramps, and subjective impressions of rectal gas excretion) were self-rated by subjects on 2 occasions daily (for the periods from breakfast time to dinnertime and from dinnertime to bedtime) during the baseline and the 2 test periods.
Maldigestion group (n=31): Mean age 46.9 2.6 y
Gender: women 100%.
Race/ethnicity: Asian 29%; Hispanic 16%; black 6%; white 45%, of whom 4 were Jewish Digestion group
Mean age 49.4 ±2.4
Gender: women 100%.
Race/ethnicity: white 100%
Prior to the study, 23 women in the lactose mal- digestion group and 2 in the lactose digestion group believed that the ingestion of dairy products resulted in appreciable abdominal symptoms.
Lactose hydrolyzed products (LHP), lactose totaling 34 g daily. The lactose in fresh, low-fat milk was hydrolyzed by adding 1.07 g of a lactase preparation obtained from Kluyveromyces lactis 240 mL lactose hydrolyzed,1%-fat milk with breakfast and dinner; 1 serving (28 g) of a hard cheese at lunch and at dinner; and 240 mL low-fat, strawberry flavored, lactose-hydrolyzed yogurt at lunch.
Subjects ingested their regular diets with the exception of the additional dairy products. The dairy products provided <1300 mg Ca/d; it was assumed that the remainder of the diet provided <200 mg.
Conventional diary products (CDP) lactose totaling 34 g daily.
240 mL conventional, 1%‐ fat milk with breakfast and dinner; 1 serving (28 g) of a hard cheese at lunch and at dinner; and 240 mL (8 oz) lowfat, strawberry-flavored yogurt at lunch time
Severity of symptoms, (Mean ± SEM), ranked on a continuous scale from 0 to 5 as follows: 0 (no symptoms), 1 (trivial), 2 (mild), 3 (moderate), 4 (strong), or 5 (severe symptoms).
Women with lactose maldigestion reported significantly increased flatus frequency and subjective impression of rectal gas during the period of high lactose intake; however, bloating, abdominal pain, diarrhea, and the global perception of overall symptom severity were not significantly different between the 2 treatment periods.
Conclusion(s): Authors conclude that the symptoms resulting from lactose maldigestion are not a major impediment to the ingestion of a dairy-rich diet supplying <1500 mg Ca/day.
Allocation concealment: unclear Blinding: Double Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Xenos, 199858
RCT, crossover Sponsorship: not reported
Greece
Duration of symptom recording: 1 day
Data source: 8 Greek lactose intolerant volunteers.
Inclusion criteria: Rise in blood glucose levels <1.1 mmol/L above fasting level after ingestion of lactose (1 g/kg of body weight) and if intestinal symptoms occurred.
Methods to measure outcomes: Subjects completed questionnaire regarding symptoms 8 hours after consuming tests and then every 8 hours until 24 hours elapsed.
Symptoms were rated from 0=none to 4=severe.
Mean age 32 No other data were provided.Lactose treatment: β-D-galactosidase 100 u/mL + 100 g lactose dissolved in water. There was a washout period of 1 week between challenges.Matching placebo + 100 g lactose dissolved in water.Subjects reporting symptoms based on ratings (0=none to 4=severe), 8 hours after lactose challenge.
Conclusion(s): Subjective ratings of the severity of symptoms (cramps, belching, flatulence, diarrhea) were significantly decreased with the lactose treatment compared to placebo.
Allocation concealment: unclear Blinding: Double Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Suarez, 199759
RCT, crossover Sponsorship: Department of Veteran Affairs, the National Institute of Diabetes and Digestive and Kidney Diseases, and the National Dairy Council.
USA
Duration of symptom recording: 1 week
Data source: 19 American symptomatic lactase-nonpersistent (S-LNP) subjects self-described as “severely lactose intolerant,” plus 13 LNP subjects who denied lactose intolerance (A-LNP), and 10 lactase- persistent subjects who believed they were lactose intolerant (S‐ LP).
Inclusion criteria: Individuals who reported GI symptoms after one cup of milk. Lactose maldigestion based on an increase in the breath-hydrogen concentration of >10 ppm after the oral ingestion of a 250-mL aqueous solution containing 15 g lactose was used as the indicator of lactose malabsorption, hence LNP.
Exclusion criteria: Inconsistent GI symptoms (bloating, abdominal pain, flatulence, or diarrhea), prior gastrointestinal surgery or other significant illnesses, received antibiotic therapy within the past 2 months, or inability to consume aspartame.
Methods to measure outcomes: Subjects rated symptoms (bloating, borborygmi, abdominal pain or cramps, and subjective impressions of rectal gas excretion) on 4 occasions daily (morning, noon, afternoon, night) during the baseline and the 2 test periods. Subjects also recorded diarrhea, and each passage of flatus.
S-LNP Group (n=19)
Mean age 34 ±22 years (range 18–43)
Gender: women 53%.
Race/ethnicity: Asian 63%; black 11%; Hispanic 5%; white 21%
A-LNP Group (n=13)
Mean age 35.9 ±11 years (range 25–69)
Gender: women 38%.
Race: Asian 69%; black 8%; Hispanic 15%; white 8%
S-LP Group (n=10)
Mean age 35.9 ±11 years (range 25–69)
Gender: women 38%.
Race/ethnicity: Asian 69%; black 8%; Hispanic 15%; white 8%
240 mL lactose hydrolyzed milk (lactose totaling 11.8 g, 23.6 daily), consumed at breakfast and dinner. The lactose in fresh, low-fat milk was hydrolyzed by adding 1.07 g of a lactase preparation obtained from Kluyveromyces lactis to 1 L milk.
A washout period of 7 days between treatments.
240 mL regular milk (lactose totaling 11.8 g, 23.6 daily), plus aspartame (to simulate the taste of lactase-treated milk, consumed at breakfast and dinner.Mean symptom severity scores ranked scale on a scale as follows: 0=none; 1=trivial; 2= mild; 3=moderate; 4= strong; 5= severe.
Extracted from graph Neither LNP group had a significant increased in symptoms during the regular milk period compared to the lactose hydrolyzed milk period. S-NLP subjects reported significantly greater gaseous symptoms compared to A-NLP during both feeding periods.
Conclusion(s): Authors concluded lactase-nonpersistent subjects can tolerate two cups of milk per day without appreciable symptoms.
Allocation concealment: unclear Blinding: Double Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Vesa, 199760
RCT, crossover Sponsorship: Finnish Association of Agronomists
Finland
Duration of symptom recording: 2 days
Data source: 30 Estonian subjects with lactose maldigestion.
Inclusion criteria: Lactose maldigestion based on measuring of urinary galactose concentration after ingesting 50 g lactose with 150 mg ethanol/kg body weight, with symptom followup during the test day.
Exclusion criteria: No gastrointestinal diseases, were not on medications, on antibiotics at least two months prior to study, or had irritable bowel syndrome.
Methods to measure outcomes: On test days, after consuming milk, subjects noted symptoms (flatulence, nausea, abdominal bloating, abdominal pain) on a questionnaire with a visual analog scale (VAS).
Mean age (range): 46 (18–74)
Gender: women 90%.
Race/ethnicity: not reported
Comorbidities: not reported
Cointerventions: not reported
200 mL lactose-free milk (0.1% fat) x 2 daily (lactose totaling 0 g over 2 days)200 mL fat-free milk (0.1% fat) x 2 daily, (lactose totaling 19.6 g over 2 days)
200 mL high-fat milk (4.9% fat) x 2 daily (lactose totaling 19.6 g over 2 days)
Milk-free period over 5 days
Percentage of subjects who experienced symptoms during the test day after each lactose dose
The sum of symptoms was higher during all milk periods than during the milk-free period (P<0.01).
There were no statistically significant differences in the occurrence or severity of symptoms during the fat-free milk period compared with the high-fat milk period.
Conclusion(s): A marked difference in the fat content of milk did not affect the symptoms of lactose intolerance.
Allocation concealment: unclear Blinding: Double blinding attempted, although it was noted that full fat milk can be readily discerned from fat- free milk.
Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Vesa, 199661
RCT, crossover Sponsorship: not reported
Finland
Duration of symptom recording: 1 day
Data source: 39 Finnish subjects with lactose maldigestion and 15 lactose digesters.
Inclusion criteria: Lactose maldigestion based on a positive lactose H2 breath test (39%) or lactose tolerance test with ethanol (61%). Lactose maldigesters who experienced at least moderate gastrointestinal symptoms, i.e., loose stools, abdominal pain, abdominal bloating, or flatulence, were selected for in the study group.
Exclusion criteria: No gastrointestinal diseases or on antibiotics one month prior to study.
Methods to measure outcomes: On test, for 12 h after consuming milk, subjects noted symptoms (flatulence, abdominal bloating, abdominal pain, borborygmi, and loose stools) on a questionnaire with a visual analog scale (VAS)
1. Lactose maldigesters (n=39)
Mean age (range): 47.2 (27–70)
Gender: women 62%.
Race/ethnicity: white 100%.
2. Lactose digesters (n=15)
Mean age (range): 38.3 (25–54)
Gender: women 66%.
Race: white 100%.
Comorbidities: 5 hypertensives and one diabetic.
Cointerventions: not reported
200 mL fat-free, lactose-free milk x 1 serving (lactose was separated chromatographically). The taste of the milk was disguised with 0.2 g lemon flavoring and the sweetness and osmolarity of the test milks were equalized with glucose.200 mL fat-free, lactose-free milk x 1 serving (lactose was separated chromatographically) plus 0.1%/3‐ galactosidase was added to ensure that it contained no traces of lactose.
Milk 1. plus 0.5 g lactose
Milk 2. plus 1.5 g lactose
Milk 3. plus 7 g lactose
Percentage of subjects who experienced symptoms during the test day after each lactose dose.
Maldigesters reported significantly more abdominal bloating and abdominal pain than the digesters.
There was no difference in the mean severity of the reported symptoms between the test milks and the lactose-free milk in the group of lactose maldigesters, of whom one-third did not experience any symptoms from any of the test doses. The same proportion (64%) of the maldigesters experienced symptoms after both the lactose-free milk and the milk with 7 g lactose.
Conclusion(s): Gastrointestinal symptoms in most lactose maldigesters are not induced by lactose when small amounts (0.5–7.0 g) of lactose are included in the diet.
Allocation concealment: unclear Blinding: Double Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Saurez, 199562
RCT, crossover Sponsorship: Department of Veterans Affairs, National Institute of Diabetes and Digestive and Kidney Diseases, and the University of Minnesota
USA
Duration of symptom recording: 1 week
Data source: 30 American subjects who reported severe lactose intolerance with consistent related symptoms. Subjects were classified as having lactose mal‐ absorption if their breath H2 concentrations increased by more than 10 parts per million (ppm) (0.93 x 10−6 g of H2 per liter of air or 0.45 μmol per liter). The ability of the colonic flora to produce hydrogen through fermentation in response to carbohydrate malabsorption was tested in seven of the nine subjects who were able to absorb lactose after they ingested 10 g of lactulose.
Exclusion criteria: Subjects were excluded if they did not report consistently having symptoms after drinking less than 240 ml of milk; if they had undergone gastro-intestinal surgery, had other major illnesses, or received antibiotic therapy within the previous two months; or if they indicated that they could not consume aspartame.
Methods to measure outcomes: Subjects rated the occurrence and severity of gastro‐ intestinal symptoms experienced during the 24-hour period after each test meal.
Lactose mal- absorbers (n=21)
Mean age (range): 29.4 (18–50)
Gender: women 62%.
Race/ethnicity: white 38%; Asian 33%, Hispanic 24%; black 5%.
Lactose absorbers (n=9, those with increase in H2 <10 ppm)
Mean age (range): 25.1(18–45)
Gender: women 56%.
Race/ethnicity: white 89%; East Indian 11%
Comorbidities: not reported
Cointerventions: not reported.
Hydrolyzed low-fat milk (HM) (lactose content <0.05 g) by adding 1.07 g of lactase from Kluyveromyces lactis (Lactaid, Pleasantville, NY) to 1 liter of milk at breakfast daily for a one-week period.Low-fat milk (lactose content 12.1 g) to plus aspartame (to simulate the taste of lactase-treated milk) at breakfast daily for a one- week period.Intensity of daily gastrointestinal symptoms over the one week period (mean ± SEM), 0=none; 1=trivial; 2=mild; 3=moderate; 4=strong symptoms; and 5=severe.
Diarrhea or loose stool was defined as “an urgent, watery defecation.” In Subjects recorded each passage of flatus.
During the study periods, gastrointestinal symptoms were minimal. When the periods were compared, there were no statistically significant differences in the severity of these four gastrointestinal symptoms.
Conclusion(s): People who identify themselves as severely lactose-intolerant may mistakenly attribute a variety of abdominal symptoms to lactose intolerance. When lactose intake is limited to the equivalent of 240 ml of milk or less a day, symptoms are likely to be negligible and the use of lactose-digestive aids unnecessary.
Allocation concealment: unclear Blinding: double Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Johnson, 199363
RCT, crossover
Sponsorship: The National Dairy Board In cooperation with the National Dairy Council
USA
Duration of symptom recording: unclear
Data source: 45 lactose‐ maldigesting and lactose intolerant African Americans. All subjects claimed to have GI symptoms after consuming one cup of milk or less.
Inclusion criteria: Subjects who had an increase in hydrogen concentration from baseline of ≥ 20 ppm.
Exclusion criteria: Chronic constipation and other GI problems, regular cigarette smokers, and subjects on antibiotic therapy. Methods to measure outcomes: Subjects were to record symptoms after ingestion (time period unclear)
Ages ranged from 12–40 in the eligible population.
Gender: not reported but mostly female (70%) in the eligible population.
Race/ethnicity: black 100%
Comorbidities: not reported
Cointerventions: not reported
315 mL hydrolyzed milk (lactose content 0 g) by adding 30 drops of lactase (Lactaid, Pleasantville, NY) to of milk.
Subjects took 3 samples, either HM twice and M once or the opposite on 3 different days, assigned in a random order.
315 mL milk (lactose content 16.4 g) plus artificial sweetener (to simulate the taste of lactase- treated milk)
Subjects took three samples, either M twice and HM once or the opposite on 3 different days, assigned in a random order.
absorption.
33% (n=10) reported symptoms consistent with lactose mal‐ absorption with both HM and milk.
Conclusion(s): Authors conclude that the cause of milk intolerance in up to 1/3rd African Americans claiming symptoms after ingestion of a moderate amount of milk cannot be due to its lactose content.
Allocation concealment: unclear
Blinding: double Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Lin, 1993 Study 264
RCT, crossover
Sponsorship: Thompson Medical Co., Inc. and the Minnesota Agricultural Experiment Station
USA
Duration of symptom recording: 8 hours
Data source: 11
American adults similarly characterized as maldigesters as in Study 1 by breath hydrogen analysis following a 50-g lactose load and by past experience with intolerance symptoms following the consumption of dairy foods
Inclusion and exclusion criteria: Same as Study 1. Methods to measure outcomes: Subjects kept a similar diary to Study 1, except that symptoms of bloating, abdominal cramps, nausea, abdominal pain, diarrhea and gas were self-scored by subjects at baseline and 4 and 8 hr on a 1–5 scale (none to worst ever experienced).
Age range: 18–60
Gender: women 91%.
Race/ethnicity: not reported
Comorbidities: not reported
Cointerventions: not reported
50 g of lactose dissolved in 200 ml of water plus β‐ galactosidase (β‐ gal) enzyme preparations
1) Lactogest soft gel capsules × 2 (Thompson Medical Inc, New York, New York),
2) Lactogest capsules × 4
3) Lactaid caplets × 2 (Lactaid Inc, Pleasantville, New Jersey) or
4) DairyEase chewable tablets x
2 (Glenbrook Laboratories, New York, NY)
50 g of lactose dissolved in 200 ml of water plus two soft gel vitamin E capsules containing 420 rag/capsule of α-tocopherol in soybean oil as a Placebo (Pharmacaps Inc, Elizabeth, New Jersey)Symptom scores, expressed as the sum of mean scores rating symptoms from 1 (none) to 5 (worst ever experienced) at baseline and 4 and 8 hours after challenge.
Conclusion(s): Symptom scores for bloating, cramping, nausea, pain, diarrhea, and flatus were not significantly different between treatments and the control.
Allocation concealment: adequate (small brown coded envelopes)
Blinding: double
Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Funding: Some industry support
Nielsen, 198465
RCT, crossover Sponsorship: Danish Medical Research Council
Denmark
Duration of symptom recording: 1 day
Data source: 9 lactose intolerant Danish children
Inclusion criteria: Subjects had to fulfill two of the following:
1) An increase in blood glucose during a lactose tolerance test (2 g of lactose per kilogram of body weight);
2) Diarrhea, borborygmus, and/or flatulence during a lactose tolerance test;
3) Low or no lactase activity in an intestinal biopsy specimen taken at the ligament of Treitz. Exclusion criteria: Subjects with acute or chronic diarrhea or other GI orders. Methods to measure outcomes: At 10 times during the 24 test periods, a 0 was recorded in the scoring chart to indicate no symptoms and a 1 was recorded if symptoms or defecation was observed by the children’s parents.
Median age (range): 10 (9–16)
Gender: female 33%.
Ethnicity: 6 subjects immigrants from Korea, Pakistan, or Turkey (plus 3 native Danes)
Comorbidities: No subjects had renal or endocrine disorders or hereditary diseases.
Cointerventions: None received any medicine during the period of examination.
One half liter of hydrolyzed milk (HM) (lactose content 1.25 g) by adding 2 mL of lactase from Kluyveromyces fragilis (Lactozym 3000 L, Novo Industri A/S, Bagsvaerd, Denmark), given after 8 hours of fastingOne half liter of ordinary milk (lactose content 25 g) given after 8 hours of fastingSummation of observed symptoms from the scoring charts of the 9 subjects.
Conclusion(s): Children had significantly fewer clinical symptoms and signs within 24 hours after consuming lactose-hydrolyzed milk compared to regular milk.
Allocation concealment: unclear
Blinding: double
Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Funding: non- industry
Lybeck Sørensen, 198366
RCT, crossover Sponsorship: Not reported
Denmark
Duration of symptom recording: 8 hours
Data source: 35 symptomatic lactose intolerant Danish adults from Latin America.
Inclusion criteria: Lactose intolerance based on a lactose tolerance test (not defined), with no known disorders of the gastrointestinal tract.
Exclusion criteria: lactose tolerance
Methods to measure outcomes: Subjects completed questionnaire concerning the development of symptoms (borborygmus and meteorism, colic attacks, flatulence, and/or diarrhea) based on the following: 0=no symptoms; 1=slight; 2=moderate; 3=severe. The total symptom score was calculated as the sum of the score for each person.
Mean age (range): 32 (20–60)
Gender: women 54%.
Race/ethnicity: Latin American 100%
Comorbidities: not reported
Cointerventions: not reported
250 and 500 mL low-lactose milk (lactose content 1.6 g), 86% of the lactose was removed by ultrafiltration and replaced with the addition of maltodextrose.
48 hours between tests.
250 and 500 mL skim milk (SM) (lactose content 11.3 g).Frequency of symptoms in percent following milk ingestion.
Conclusion(s): Ingestion of 500 mL low-lactose milk resulted in significantly fewer symptoms compared to regular skim milk. After ingestion of 250 mL low-lactose milk there was a tendency to fewer symptoms but the difference was not statistically significant.
Allocation concealment: unclear
Blinding: double Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Rask Pedersen, 198267
RCT, crossover Sponsorship: NOVO Industries supplied the lactase and performed the HPLC analyses Denmark Duration of symptom recording: 1 day
Data source: 11 symptomatic lactose intolerant Danish adults.
Inclusion criteria: Rise in blood glucose levels <1.4 mmol/L above fasting level after ingestion of 50 g lactose with symptoms (abdominal cramp, meteorism, and/or diarrhea).
Methods to measure outcomes: On a 24 hour diary sheet, subjects reported abdominal symptoms based on the following. 0=none; 1= mild/moderate; 2= severe. For diarrhea, No diarrhea=formed stools; mild/moderate= ≤ 3 liquid/soft stools; severe= ≥ 4 liquid/soft stools.
Mean age: 43
Gender: women 64%.
Race/ethnicity: not reported
Comorbidities: not reported
Cointerventions: not reported
500 mL low-lactose milk (lactose content 3.75 g), 85% hydrolyzed by adding 2 mL of lactase from Kluyveromyces fragilis (Lactozym 3000 L, Novo Industri A/S, Bagsvaerd, Denmark) to of milk x 1 dose.500 mL ordinary milk (lactose content 25 g), x 1 dose.Number of subjects reporting symptoms after ingestion
Conclusion(s): There was a significant reduction in abdominal symptoms after ingestion of lactose-hydrolyzed milk compared to regular milk.
Allocation concealment: unclear
Blinding: double
Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Reasoner, 198168
RCT, crossover Sponsorship: University of Rhode Island and Shadow Research Foundation, Inc.
USA
Duration of symptom recording: 1 week
Data source: 9 symptomatic American adults from an outpatient clinic and 5 milk tolerant controls.
Inclusion criteria: Subjects with a blood sugar <20 mg/100 mL after ingestion of 50 g lactose and had symptoms when challenged with 250 mL of skim milk.
Methods to measure outcomes: Subjects rated the occurrence and severity of gastro‐ intestinal symptoms experienced during the 24-hour period after each test meal. 0=none; 1= mild; 2=moderate; and 3=severe. Number of days that the subject responded per week was totaled. A quotient was then calculated, giving a symptom index for the week.
“Milk-intolerant” (n=9)
Mean age (range): 41 (22–60)
Gender: women 44%.
Race/ethnicity: not reported
Comorbidities: 2 subjects had LI due to Crohn’s disease (one also had an intestinal resection), and one subject had a subtotal gastrectomy.
Cointerventions: not reported “Milk-tolerant” (n=5)
Mean age (range): 33 (22–48)
Gender: women 60%.
Race/ethnicity: not reported
Low-lactose milk (lactose content ~2.9 g/d) x 1 week), 74–91% hydrolyzed with lactase (Maxilact 40,000, GB Fermentation, Des Plains, Illinois). Average weekly consumed was 1.79 L.1) Skim milk (lactose content ~28.5 g/d) x 1 week. Average weekly consumed was 1.58 L. 2) Skim milk + glucose (simulates the taste of lactase- treated milk) x 1 week. Average weekly consumed was 1.8 L. 3) Sweet acidophilus milk x 1 week. Average weekly consumed was 1.50 L.Abdominal symptom responses trans‐ formed into a numerical value.
Numbers correlate with the following: 0 to 0.33 = none to mild; 0.34 to 0.66 = moderate; 0.67 to 1.0 = severe.
Conclusion(s): Lactose-hydrolyzed milk significantly reduced pain and gas symptoms in the “Milk-intolerant” group compared to regular skim milk.
Allocation concealment: unclear
Blinding: double
Intent-to-treat analyses:100% followup
Study withdrawals adequately described: no withdrawals reported
Unger, 198169
RCT, crossover Sponsorship: not reported
USA
Duration of symptom recording: 1 day
Data source: 24
American lactose malabsorbers (determined by breath hydrogen test) and 75 lactose absorbing adolescent volunteers. Subjects were to report all symptoms during breath hydrogen test period. Presence of ≥ 1 GI symptom was considered a positive response to lactose.
Methods to measure outcomes: Symptomatology questionnaires were given to subjects each day after the test beverage was consumed. One or more relevant symptoms occurring between one and 24 hours indicated a positive response to the dairy drink for that test day. The 4 symptoms (bloating, flatulence, cramps, diarrhea) indicative of lactose intolerance were rated according: 0=none; 1=mild; 2=moderate; 3=severe
Mean age (range): 24 (18–46)
Gender: women 49%.
Race/ethnicity: white 87% (northern European n=65; southern- European n=8; Jewish n=14), Asian 10%, black 3%.
240 or 480 mL lactose-free chocolate dairy drink.240 or 480 mL lactose-containing (lactose content 10.8–21.6 g) chocolate dairy drink.Subjects reporting symptoms during 24 hours after consumption.
Conclusion(s): 12.5% of lactose malabsorbers were symptomatic after consuming 240 mL of lactose-free solution versus 33.3% after consuming 240 mL lactose solution.
Allocation concealment: Blinding: double
Intent-to-treat analyses: Study withdrawals adequately described:
Cheng, 197970
RCT, crossover Sponsorship: Chile Foundation
Chile
Duration of symptom recording: 1 day
Data source: Chilean volunteers from the Santiago penitentiary. 15 were lactose intolerant and 16 were lactose tolerant controls.
Inclusion criteria: Lactose intolerance, determined by blood glucose analysis [<20 mg/100 considered deficient lactase activity] and developed symptoms after ingestion of 50 g lactose.
Methods to measure outcomes: A standard questionnaire was applied twice daily. All symptoms, attributable or not to lactose intolerance, were recorded. No symptoms = 0, mild (symptoms present but not interfering with daily activities or <2 liquid bowel movements) = 1, severe (symptoms present and interfering with daily activities or caused great discomfort or >2 liquid bowel movements) = 2. No data on statistical analyses.
Lactose intolerant subjects (n=15)
Mean age (range): 27 (19–34)
Gender: men 100%
Race/ethnicity: Latin American 100%.
Lactose tolerant subjects (n=16)
Mean age (range): 27 (18–38)
Gender: men 100%
Race/ethnicity: Latin American 100%.
Comorbidities: not reported
Cointerventions: not reported
500 mL low lactose milk (lactose content 0.5 to 1.25 g), hydrolyzed with lactase (galactosidase, Maxilact, Enzyme Development Corporation, New York, NY), x 2 daily for 1 month.500 mL skim milk (lactose content 25 g), sweetened with sucrose to imitate taste of low-lactose milk. All subjects received at least 4 of these tests.Results are expressed as the number of times a score was given to each symptom during the experiment.
Conclusion(s): Lactose intolerant subjects had more symptoms and more severe symptoms with skim milk.
Allocation concealment: unclear
Blinding: noted as double, unclear if milks were given out randomly.
Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Jones, 1976 Study 271
Single blind RCT no masking to taste, crossover
USA
Duration:8 hours Funded by National Dairy Council and NY State Agriculture Experiment station hatch project
Data Source: 17
American volunteers who reported symptoms after ingesting 25 g lactose but not after placebo.
Inclusion criteria: LI on basis of rise in blood glucose of less than 25 mg/100mL after 50 g lactose injection
Mean age 24 (range 20–34)
Gender: women 41%
Race/ethnicity: Asian 41%; black 18%; Latin- American 12%;
Other 29%
Comorbid: none
Co-intervention: none
60% reduced skim milk 500 ml (10 g lactose) 60% reduced lactose whole milk 500 ml (10 g lactose). Placebo 250 ml (saccharin, lemon juice water)Regular skim milk 500 ml (25 g lactose). Regular whole milk 500 ml (25 g lactose)Sum of score of bloating, gas, cramps and diarrhea on scale: 0-none, 1=mild, 2= moderate, 3=severe.
Conclusion(s): 1) Lower lactose milk better tolerated;
2.) No differences in tolerance between test beverages
Allocation concealment: unclear
Blinding: single no masking
Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Studies in which subjects were not noted to be symptomatic at baseline or symptoms were not required for study inclusion (based on biochemical measures only)
Lin, 1993 Study 164
RCT, crossover Sponsorship: Thompson Medical Co., Inc. and the MinnesotaAgricultur al Experiment Station
USA
Duration of symptom recording: 8 hours
Data source: 20 “healthy” American lactose maldigesters adults based soley on breath hydrogen test. Inclusion criteria: Breath hydrogen concentration to >20 ppm (>1.80 × 10 −6 g H2/liter air) after ingestion of 400 ml of low-fat (2%) milk containing approximately 20 g of lactose.
Exclusion criteria: Pregnant or lactating, had prior gastro‐ intestinal surgery, had illness that would interfere with the experiment, or had used antibiotics within the past 30 days.
Methods to measure outcomes: Subjects kept a dairy of symptoms and self- rated gas, stomach pain and/or cramps and diarrhea and/or loose stool for each hour from 0 to 8 hours following the test meal. Scores are expressed as the mean of the sum of scores rating symptoms from 0 (none) to 5 (severe) for each hour from baseline to 8 hr after the challenge.
Age range: 25–40
Gender: women 50%.
Race/ethnicity: not reported
Comorbidities: not reported
Cointerventions: not reported
400 ml of low-fat (2%) milk (lactose content 20 g) plus β-galactosidase (β‐ gal) enzyme preparations
1) Lactogest soft gel capsules x 2 (Thompson Medical Inc, New York, NY), 2) Lactogest capsules x 4
3) Lactaid caplets x 2 (Lactaid Inc, Pleasantville, New Jersey) or 4) DairyEase chewable tablets
2 (Glenbrook Laboratories, New York, NY)
400 ml of low-fat (2%) (lactose content 20 g) plus two soft gel vitamin E capsules containing 420 rag/capsule of α‐ tocopherol in soybean oil as a Placebo (Pharmacaps Inc, Elizabeth, New Jersey)The difference in symptom scores (from baseline), based on the summation of observed symptoms from the scoring charts (on a 0 = none to 5 = severe scale) of the 20 subjects.
Conclusion(s): Symptoms were significantly less severe with all the β‐ galactosidase products.
Allocation concealment: adequate (small brown coded envelopes)
Blinding: double
Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Brand, 199172
RCT, crossover Sponsorship: Not reported
Australia
Duration of symptom recording: 4 hours
Data source: Six healthy adult Australian subjects with lactose malabsorption. Subjects were not noted to be symptomatic at baseline.
Inclusion criteria: Diagnosis of lactose malabsorption was based on the results of a challenge with 300 mL whole milk containing 14 g lactose after an overnight fast based on a peak breath hydrogen excretion >20 ppm. Methods to measure outcomes: At hourly intervals they rated their symptoms (cramps, flatulence, and diarrhea) on a scale of 0, no symptoms; 1, mild; 2, moderate; and 3, severe.
Mean age (range): 33 (29 to 44)
Gender: female 83%.
Ethnicity: The 6 subjects were immigrants from Indonesia, Japan, Malaysia, and Laos.
Comorbidities: not reported
Cointerventions: not reported
300 mL 50% lactose reduced milk (Lacto Lo) (lactose content 2.4 g)
300 mL 80% lactose reduced milk (Cotee) (lactose content 1 g)
300 mL 80% lactose reduced milk (Balance) (lactose content 1 g)
300 mL 95% lactose reduced milk (Digestelact) (lactose content <0.25 g)
300 mL whole milk (lactose content 4.8 g), tested twice in each individual (n = 12).
After an overnight fast the subjects consumed 300 mL of each of five milk products in a single-blind fashion and random order on separate occasions 3–5 d apart.
Number of subjects who reported specific symptoms.
Conclusion(s): The results suggest that a 50% level of lactose reduction in milk may be adequate to relieve the signs and symptom s of milk intolerance in the majority of healthy adults with lactose malabsorption.
Allocation concealment: unclear
Blinding: single
Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Cavalli-Sforza, 198673
RCT, crossover Sponsorship: Parmalat Spa
Italy
Duration of symptom recording: 1 day
Data source: 80 Italian adults, data from 71 subjects: 40 lactose malabsorbers and 30 lactose absorbers.
Inclusion criteria: Adults free from gastrointestinal diseases and diabetes.
All subjects were give lactose tolerance test (50 g lactose in 200 mL water). Subjects were defined as lactose malabsorber if maximum increase in blood glucose concentration above fasting level was <20 mg/dL.
Methods to measure outcomes: Questionnaire was given to subjects to indicate whether they experienced diarrhea, flatulence, bloating, or abdominal pain during the 24 hours after consuming the milk test. Symptoms were rated mild = 1, moderate = 2 or severe = 3 in intensity. A total for the 4 symptoms could range from 0 to 12.
All subjects (N=80)
Mean age (range): 34 (18 to 69)
Gender: female 66%
Ethnicity: not reported
Comorbidities: not reported
Cointerventions: not reported
Regular whole hydrolyzed milk (lactose content 0.5 g/dL) and fat content of 3.2 g. Regular skim hydrolyzed milk (lactose content 0.65 g/dL and fat content of 0.10 g.) Each type of milk was taken on 4 consecutive days in Increasing quantities: 125, 250, 500, 1000 mL. The larger quantities could be divided into 2 to 6 intakes during the day.Regular whole milk (lactose content 4.9 g/dL) and fat content of 3.3 g. Regular skim milk (lactose content 5.10 g/dL and fat content of 0.15 g; 12.75 per milk serving)Symptom response to the intake of the 4 milk types, percent of cases.
Conclusion(s): Lactose malabsorbers had significantly fewer symptoms with skim milk vs. whole milk. The authors found, contrary to earlier findings, that fat seemed to contribute to milk intolerance in lactose malabsorbers rather than reduce it.
Allocation concealment: unclear
Blinding: double
Intent-to-treat analyses: no, 74 of 80 completed study satisfactorily but data only for 71 (3 refused to drink milk at room temperature)
Study withdrawals described: yes
Rosado, 198474
RCT Sponsorship: Limited, industries provided the enzymes (SugarLo Co. (Pleasantville, NJ) and G.B. Fermentation (Kingstree, SC))
USA/Mexico
Duration of symptom recording: 1 day
Data source: 50
Mexican adults were enrolled, 25 lactose malabsorbers and 25 absorbers.
Inclusion criteria: No inclusion criteria, subjects unselected. Methods to measure outcomes: Subjects completed symptom questionnaire document presence or absence of 4 gastrointestinal symptoms (abdominal cramps, gas/flatulence, vomiting, and/or diarrhea). Absence of all 4 symptoms = lactose tolerance. 0 =absent; 1=mild; 2=moderate; 3=severe, except for diarrhea which was always marked a 3.
Total points were then summed for each of the treatment periods. A score ≥ 4 = major symptomaology, ≤ 3 = minor.
Exclusion criteria: recent history or concurrent use of antibiotics or recent gastrointestinal disease.
Age range: 19–53
Gender: women 64%.
Race/ethnicity: Mostly Mexican with various degrees of European and Indian descent.
Comorbidities: NR
Cointerventions: NR
1) LactAid 1g combined with 360 mL milk, reconstituted from powdered whole milk (lactose content 18 g)
2) 360 mL pre- hydrolyzed milk. A minimum of 72 hours between tests.
360 mL milk, reconstituted from powdered whole milk (lactose content 18 g)Number of subjects reporting symptoms (minor or major).
Conclusion(s): Addition of LactAid significantly reduced symptoms of intolerance among the 25 lactose malabsorbers subjects.
Allocation concealment: unclear
Blinding: double
Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Funding: industry supplied supplies
Haverberg, 198075
RCT, crossover Sponsorship: National Dairy Council
USA
Duration of symptom recording: 1 day
Data source: 67
American lactose malabsorbing (determined by blood glucose analysis) and 43 lactose absorbing adolescent volunteers.
Classification was based on biochemical vs. subjective symptomatic response to lactose.
Methods to measure outcomes: Subjects reported abdominal symptoms on a questionnaire containing yes/no or multiple choice questions regarding symptoms over 24 hours after consumption.
Occurrence of diarrhea, ≥ 2 mild GI symptoms or ≥ 1 moderate or severe symptom was noted as a positive response of intolerance to the test drink.
Age range: 14–19
Gender: not reported
Race/ethnicity: black 53%, white 40%; Latin
American 7%.
Comorbidities: not reported
Cointerventions: not reported
240 or 480 mL lactose-free chocolate dairy drink.240 or 480 mL lactose-containing (lactose content 10.8–21.6 g) chocolate dairy drink.Number of subjects reporting symptoms during 24 hours after consumption 18% of lactose malabsorbers were symptomatic after consuming 240 mL of lactose-free solution versus 28% after consuming 240 mL lactose solution.
Conclusion(s): Results indicate that most of the individuals who reported GI symptoms after consuming the beverages did so due to other reasons besides the lactose content.
Allocation concealment: unclear
Blinding: double
Intent-to-treat analyses:100% followup
Study withdrawals adequately described: no withdrawals reported
Kwon, 198076
RCT, crossover Sponsorship: National Dairy Council
USA
Duration of symptom recording: 1 day
Data source: 45 American lactose malabsorbing (determined by blood glucose analysis) and 42 lactose absorbing adolescent volunteers. Classification was based on biochemical vs. subjective symptomatic response to lactose. Methods to measure outcomes: Subjects reported abdominal symptoms on a questionnaire containing yes/no or multiple choice questions regarding symptoms (bloating, flatulence, cramps, or diarrhea) over 24 hoursafter consumption by checking 1=none; 2= mild; 3=moderate; and 4=severe. Presence of ≥1 symptom was considered as a positive intolerant response.All subjects (N=87)
Age range: (14–19)
Gender: not reported
Race/ethnicity: black 30%, white 64%; Asian 6%.
Comorbidities: not reported Cointerventions: not reported
240 or 480 mL lactose-free chocolate dairy drink.240 or 480 mL lactose-containing (lactose content 10.8 or 21.6 g) chocolate dairy drink.Number of subjects reporting symptoms during 24 hours after consumption Among lactose malabsorbers, 27% were symptomatic after consuming 240 mL of lactose-free solution versus 9% after consuming 240 mL lactose solution.
Conclusion(s): Factors other than lactose malabsorption may be responsible for a significant proportion of mild symptoms of “milk intolerance” in an adolescent population similar to this study.
Allocation concealment: unclear
Blinding: double Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Rorick, 197977
RCT, crossover Sponsorship: National Dairy Council
USA
Duration of symptom recording: 1 day
Data source: 87 American elderly volunteers, in which 23 were lactose malabsorbers (determined by breath hydrogen analysis after ingestion of 25 g lactose) and 64 lactose absorbers.
Inclusion criteria: Subjects with no known gastrointestinal disease.
Methods to measure outcomes: Subjects were interviewed the following morning after the test and were asked to state the occurrence severity of gas, bloating, cramps, or diarrhea during the previous afternoon. Symptom severity was based as follows: none; mild (noticeable, but not troublesome); moderate (troublesome, but not seriously uncomfortable); severe (uncomfortable, could not carry out normal activities).
All subjects (N=87)
Mean age (range): 77 (60–97).
Gender: women 77%
Race/ethnicity: Northern/western European ancestry 76% (35% of the malabsorbers), Jewish 11% (30%), black 8% (22%), Southern Italian 5% (13%).
Comorbidities: not reported Cointerventions: not reported
240 mL lactose-free chocolate dairy drink.240 mL lactose- containing (lactose content 10.8 g) chocolate dairy drink.Number of subjects reporting intolerance to test drinks based on GI symptoms during the afternoon after consumption. Symptom frequency was not significantly different between beverages in both malabsorbers and absorbers. Conclusion(s): Authors conclude factors other than lactose malabsorption appeared to be responsible for the symptoms of intolerance reported and most may have been psychosomatic in origin.Allocation concealment: unclear
Blinding: double Intent-to-treat
analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Lisker, 197878
RCT, crossover Sponsorship: Programa Nacional de Alimentos of the Consejo Nacional de Ciencia Y Tecnología de México.
Mexico Duration of symptom recording: 6 hours
Data source: 150 Mexican volunteers, in which 97 were lactose malabsorbers (determined by blood glucose analysis [<25 mg/dl considered deficient lactase activity] after ingestion of 50 g lactose).
Inclusion criteria: Subjects with no known gastrointestinal disease, diabetes. Methods to measure outcomes: Symptoms were rated according: 1+ if mild; 2+ if moderate; 3+ if marked. Symptoms were scored as severe if diarrhea was present or if a cumulative rating of other symptoms (abdominal cramps, bloating, flatulence) was 4+. Cumulative rating less than 4+ was considered mild
All subjects
(N=150)
Mean age (range): 24 (16–50).
Gender: women 41%
Race/ethnicity: Mexican 100% 60 of the volunteers had previously participated in lactose mal‐ absorption studies and were also aware they could tolerate at least 250 mL of milk at one time without difficulty. Comorbidities: not reported Cointerventions: not reported
250 mL lactose-free milk plus 7.1 glucose. Powdered chocolate added to mask flavors.250 mL regular milk (lactose content 12.5 g). 250 mL regular milk plus additional 25 g lactose added (lactose content 37.5 g).Conclusion: Authors concluded that lactose-intolerant subjects are indeed lactose-intolerant and that the frequency of abdominal symptoms that occur in persons with lactose malabsorption increases directly with the lactose content in milk.Allocation concealment: unclear
Blinding: double Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Paige, 197579
RCT, crossover Sponsorship: Maternal and Child Health Services and National Institutes of Health
USA
Duration of symptom recording: 90 minutes
Data source: 22 lactose‐ malabsorbers and 10 lactose absorber African American volunteers. Malabsorption was based on blood sugar rise of 26 mg/mL following ingestion of lactose load (50 g/m2 of body surface)
Inclusion criteria: no overt gastrointestinal or metabolic disease, Methods to measure outcomes: Symptoms voluntarily mentioned were recorded. Subjects were not specifically asked if they developed any symptoms commonly associated with lactose intolerance.
All subjects (N=32)
Age range: 13–19.
Gender: not reported
Race: black 100%.
Comorbidities: not reported
Cointerventions: not reported
240 mL whole milk, 90% hydrolyzed (lactose content 1.2 g) by adding lactase from Saccharomyces lactis 240 mL. whole milk, 50% hydrolyzed (lactose content 6 g) by adding lactase from Saccharomyces lactis.240 mL whole milk (lactose content 12 g).Number of subjects reporting symptoms during 90 minutes after consumption. 90% hydrolyzed milk (n=22): 3 including 2 from the whole milk group)
90% hydrolyzed milk (n=18): none Whole milk (n=22): 3 Conclusion(s): Authors concluded hydrolyzed milk may serve as alternative to milk in subjects with low lactase levels.
Allocation concealment: unclear
Blinding: double Intent-to-treat
analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Jones 1976, Study
171
Single blind RCT no masking to taste, crossover
USA
Duration:8 hours Funded by National Dairy Council and NY State Agriculture Experiment station hatch project
Hypothesis: 1. milk with lower lactose better tolerated than regular milk, 2. compare symptoms after whole, skim milk, and lactose solutions
Data Source: 16 American adult volunteers Inclusion criteria: LI on basis of rise in blood glucose of less than 25 mg/100mL after 50 g lactose injection Methods to measure outcome: Asked about any symptoms of bloating, gas, abdominal cramps and diarrhea on 0–3 point scale, summedMean age 25
(range 23–55)
Gender: women 31%
Race/ethnicity: Asian 25%; black 19%; Latin‐ American 13%; other 44%
Comorbid: none Co-intervention: none
1. 50% lactose reduced skim milk 591 ml (30 g lactose) 2. 75% lactose reduced skim milk 591 ml (15 g lactose)Regular skim milk 591 ml (50 g lactoseSum of score of bloating, gas, cramps and diarrhea on scale: 0-none, 1=mild, 2= moderate, 3=severe. Conclusion(s):
1) Lower lactose milk better tolerated;
2.) Whether milks were given with or without food had no significant effect on symptoms
Allocation concealment: unclear Blinding: single no masking Intent-to-treat
analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
B. Prebiotics or probiotics
I. Studies where subjects were reported to be symptomatic at baseline in addition to LI testing
Newcomer, 198380
RCT, crossover Funding: US national diary council and NC State University Dairy Foundation
USA
Duration: 10 weeks Hypothesis: Unfermented acidophilus milk is better tolerated than regular milk
Data source: 28 US volunteers
Inclusion criteria: No symptoms and negative hydrogen breath test for controls and symptoms and positive hydrogen breath test for cases (defined as H2 excretion of. 30 ml/min after 50gm lactose plus symptoms)
Methods to measure outcomes: Subjects kept a diary for scoring 0–4; 0=no trouble, 1=slight symptoms, 2=mild s/s, 3= moderate, 4= severe) for 4–10 weeks Loss to followup: none
Range age: 18–69
Gender: NR
Race: NR
Comorbid: 5/18 cases also had IBS Co-intervention: none
Unfermented acidophilus milk: 2% milk with L. acidophilus added for approx 7x10(6) colony/ml (one 8 oz glass with three meals, 3x/day for total of 720 ml/day)2% milk: 3 8 oz glasses per day, one with each meal for total of 720 ml/dayMedian of cumulative s/s score over 10 weeks as sum of diarrhea+pain+gas+ borborygmi over 5 2‐ week periods for LI group
Conclusion(s): No difference in tolerance of regular milk vs. unfermented acidophilus milk
Allocation concealment: unclear
Blinding: double Intent-to-treat
analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
II. Studies where subjects did not have symptoms of LI at baseline or not reported and only underwent breath/other testing
Lin, 199881
RCT, crossover Sponsorship: National Science Council of Taiwan
Taiwan
Duration of symptom recording: 8 hours
Data source: 20 Taiwanese subjects.
Inclusion criteria: Maldigesters were classified on the basis of a rise in breath hydrogen concentration of >20 ppm after ingestion of 400 ml of milk containing approximately 20 g of lactose. Methods to measure outcomes: Subjects rated symptoms on a 0‐ 5 (none to severe) scale for each hour from hour 1 to hour 8 following each of the diets.
No information on age and gender provided.
Comorbidities: not reported Cointerventions: not reported
1) 400 ml of 2% low-fat milk containing L. acidophilus at a cell concentration of 108 CFU/ml;
2) 400 ml of 2% low-fat milk containing L. acidophilus at 109 CFU/ml;
3) 400 ml of 2% low-fat milk containing L. bulgaricus at 108 CFU/ml;
4) 400 ml of 2% low-fat milk containing L. bulgaricus at 109 CFU/ml. All milk products were non- fermented.
400 ml of 2% low- fat milkSymptom scores are expressed as the mean of the sum of stomach pain, gas, and diarrhea scores rated from 0 to 5 (none to severe) for each hour from 0 to 8 hr after consumption of the diets.
Conclusion(s): Non- fermented milks containing L. bulgaricus 449 at 108 and 109 CFU/ml were effective in reducing symptoms.
Allocation concealment: unclear
Blinding: double Intent-to-treat
analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Mustapha, 199782
RCT, crossover Sponsorship: Minnesota-South Dakota Diary Foods Research Center United States
Duration of symptom recording: 8 hours
Data source: 11 lactose maldigesting American subjects
Inclusion criteria: Maldigesters were classified on the basis of a rise in breath hydrogen concentration of >20 ppm after ingestion of 400 ml of milk containing approximately 18 g of lactose. None had any GI illness or had taken antibiotics in the prior three months of the study. Methods to measure
outcomes: Subjects rated symptoms on a 0‐ 5 (none to severe) scale for each hour from hour 1 to hour 8 following each of the diets. Diarrhea was monitored 24 hours after diet.
Age range: 25–42
Gender: women 55%.
Race/ethnicity: not reported
Comorbidities: not reported
Cointerventions: not reported
1) 400 mL L. acidophilus 4356 (b-galactosidase (b-gal) activity 1.22; lactose content 15‐ 16 g).
2) 400 mL L. acidophilus B (b‐ gal) activity 0.81; lactose content 15‐ 16 g).
3) 400 mL L. acidophilus N1 (lowest b-gal activity 0.50; lactose content 15‐ 16 g).
4) 400 mL L. acidophilus E (b‐ gal) activity 0.79; lactose content 15–16 g).
400 mL low fat milk (b-gal activity 0; lactose content 15 g)Mean symptom response 0–5 (none to severe), summed from hour 1 to hour 8.
Conclusion(s): Acidophilus milk containing L. acidophilus N1 was the most effective of the four strains in improving lactose digestion and tolerance.
Allocation concealment: unclear
Blinding: double Intent-to-treat
analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Jiang, 199683
RCT, crossover
Sponsorship: Minnesota Agricultural Experiment Station
USA
Duration of symptom recording: 1 day with 3 days in b/w
Hypothesis: HB after ingestion of milk with different strains of B. longum
Data source: 15 American volunteers
Inclusion criteria: lactose maldigesters on basis of rise of >20ppm after ingestion of 400 ml of milk (16 gm lactose) on hydrogen breath test using Levitt/Donaldson method.
Methods to measure outcomes: ranked scale of symptoms for abdominal pain, flatulence, borborygmi, diarrhea and meteoism: 0=none, 1=slight, 2=mild, 3=moderate, 4=moderately severe, 5= severe summed for hours 1–8. flatus frequency: mean num of gas passages over 8 hours, plus hydrogen breath test mean reading over 8 hours
Age range: 24–42, mean 29.7
Gender: women 8(52%).
Race: white 100%
Comorbidities: no
GI disorders
Cointerventions: not reported
3 test meals:
1) 400 ml 2% milk with Bifidobacterium longum appd.r6 from m- MRS broth containing lactose
2) 400 ml 2% milk with B. longum appd.r6 from Sanofi biomed as a concentrated frozen culture
3) 400 ml of bifidus milk with B. longum ATCC 15708 from m-MRS broth containing lactose
One meal 400 ml of 2% milkMean symptom response 0–5 (none to severe), summed from hour 1 to hour 8.
Conclusion(s): Consumption of milk containing appd.r6 grown with lactose resulted in significantly less flatulence vs. milk or the milk containing appd.r6 grown with both lactose and glucose. Authors concluded that milks containing B. longum might reduce symptoms from lactose malabsorption when the culture is grown in a medium containing only lactose to induce a higher β- galactosidase level and increase rate of lactose uptake.
Allocation concealment: yes
Blinding: double Intent-to-treat
analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Vesa, 199684
RCT crossover France
Funding: Yoplait Sodima, France Duration of symptom recording: 8 hours
Hypothesis: Addition of L. bulgaricus to increase lactase activity may make milk easier to tolerate compared to yogurt and milk with L. acidohpilus and bifidobacterium
Data source: 15 Healthy French volunteers (reported 14)
Inclusion criteria: lactase deficient by hydrogen breath test Methods to measure outcomes: symptom score 0–4 (0=no symptoms, 1=mild, 2=moderate, 3= fairly strong, 4=very strong symptoms) for abdominal bloating, flatulence, abdominal pain and loose stool compared mean+/−SE and sum of symptoms
Age range: 20–45
Gender: women 11 (73%)
Race: 100% Caucasian
Comorbidities: none
Cointerventions: not reported
3 fermented dairy products each with 18gm lactose in 250 ml water:
1) Ofilus (Yoplait, France; has L. acidophilus and bifidobacterium ) 320 ml
2) Bulgofilus (ofilus bacteria+ L. bulgaricus) 400 ml
3) Yoplait yogurt 500 ml
Lactulose 10gm in 250 ml waterConclusion(s): Significantly less bloating with bulgofilus compared to lactulose and sum score less with bulgofilus compared to lactuloseAllocation concealment: unclear Blinding: unclear if double Intent-to-treat analyses: no 15 enrolled, 14 reported Study withdrawals adequately described: 1 withdrawal reported Industry funding
Lerebours, 198985
RCT, parallel study Sponsorship: none reported.
France
Duration of symptom recording: unclear
Data source: 16 healthy subjects born in Cameroon.
Inclusion criteria: lactose intolerance on the basis of an increase in breath hydrogen concentration >20 ppm after ingestion of 440 mL milk containing 18 g lactose. Only two subjects experienced mild flatulence after milk ingestion.
Methods to measure outcomes; No methods reported.
Age range: 20–53
Gender: NR
Race: black 100%.
Comorbidities: not reported
Cointerventions: not reported
125 g yogurt (n=8) three times daily (breakfast, bunch, and dinner) (lactose content 18 g/d)
Meals were given over 8 consecutive days.
125 g fermented‐ then-pasteurized milk (FPM) (n=8) without living acid bacteria times daily (breakfast, bunch, and dinner) (lactose content 18 g/d)Presence or absence of symptoms.
Conclusion(s): Although lactose malabsorption was higher with FPM than with yogurt, the subjects reported no gastrointestinal distress after consuming 1PM for 8 days but it must be stressed that only two subjects experienced mild symptoms after milk ingestion. These data indicate that besides lactose digestion, other factors are involved in inducing or preventing gastrointestinal distress during the consumption of dairy products by lactase- deficient subjects.
Allocation concealment: unclear
Blinding: double Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Martini, 198786
RCT crossover
Sponsorship: The National Dairy Board In cooperation with the National Dairy Council
USA
Duration of symptom recording:8 hours
Data source: 16 American healthy subjects.
Inclusion criteria: lactose intolerance on the basis of an increase in breath hydrogen concentration >20 ppm after ingestion of milk containing 20 g lactose. Methods to measure outcomes; intolerance symptoms were recorded by the subjects.
Age range: 18–26
Gender: male 100%
Race: NR
Comorbidities: not reported
Cointerventions: not reported
A. Flavored products (n=9)
1) 465 g strawberry flavored yogurt (lactose content 20 g)
2) 410 g ice milk (lactose content 20 g)
3) 400 g ice cream (lactose content 20g) B. unflavored products (n=8)
1) 455 g unflavored yogurt (lactose content 20 g)
2) 410 g unflavored yogurt FY-1 (lactose content 20 g)
3) 410 g unflavored yogurt FY-2 (lactose content 20 g)
4) 410 g unflavored yogurt FY-3 (lactose content 20 g) One subject received both products.
415 g whole milk (lactose content 20 g)Subjects reporting symptoms of gastrointestinal distress.
Conclusion(s): Subjects were free of symptoms after consuming flavored and unflavored yogurts.
Tolerance to frozen yogurt same as for ice cream and ice milk.
Allocation concealment: unclear
Blinding: single- blind (subjects were not informed of the identity of each product but no attempt to mask flavors was undertaken)
Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
Savaiano, 198487 RCT crossover, single blind (no attempt to mask flavor or texture)
USA
University of MN Agricultural Experiment Station, VA, NIH
Duration of s/s recording: 8 hours
Hypothesis: yogurt produces less symptoms than other milk products
Data source: 9
American healthy subjects.
Inclusion criteria: lactose intolerance on the basis of an increase in breath hydrogen concentration >20 ppm after ingestion of milk containing 20 g lactose.
Methods to measure outcomes; intolerance symptoms were recorded by the subjects, scale not reported. Symptoms reported were diarrhea, flatulence, abdominal pain
Age range: 20–28
Gender: NR
Race: NR
Comorbidities: not reported
Cointerventions: not reported
1) 500 gm yogurt
2) 420 gm sweet acidophilus milk
3) 465 gm cultured milk (buttermilk)
4) 500 gm pasteurized yogurt
410 gm milkNo symptoms reported when yogurt or pasteurized yogurt was fed. 4 and 5 of the nine reported symptoms with milk and sweet acidophilus milk respectively.
Conclusion(s): Yogurt is unique due to ability to enhance lactose digestion
Allocation concealment: unclear
Blinding: single (no attempt to mask flavor or texture)
Intent-to-treat analyses: 100% followup
Study withdrawals adequately described: no withdrawals reported
C. Modifications to diet or other therapies
Cappello, 20088
RCT
Sponsorship: not reported
Italy
Duration of symptom recording: 40 days
40 symptomatic Italian subjects with positive breath H2 test for lactose intolerance Methods to measure outcomes: Subjects filled in a questionnaire related to the intensity of symptoms (bloating, abdominal pain, flatulence and diarrhea).
Symptoms score referred to the 5 days preceding each evaluation and scored as: 0=absent; 1=mild (awareness of a symptom but easily tolerated); 2=moderate; 3=severe; and 4=very severe.
Mean age: 44
Gender: women 80%.
Race: Not reported
Comorbidities: not reported
Cointerventions: not reported
1) Rifaximin 800 mg/day x 10 days (n=14)
2) No-milk diet x 40 days (n=13)
Placebo (n=5) x 10 daysIntensity of symptoms at baseline, 10d and 40 d (mean ± SD). Conclusion(s): The total symptom score significantly improved after rifaximin and lactose-free diet.Allocation concealment: unclear
Blinding: partially open. blinding of rifaximin and placebo not reported Intent-to-treat analyses: no
Study withdrawals adequately described: no
Funding: not reported
D. Colonic adaptation studies
Hertzler, 199689
RCT, crossover Sponsorship: The National Dairy Board In cooperation with the National Dairy Council
USA
Duration of symptom recording: 10 days
Data source: 20 American lactose maldigesting subjects. Inclusion criteria: Healthy nonsmokers who had not used antibiotics in the preceding 2 months and reported no history of functional bowel complaints. Subjects were classified as lactose maldigesters based on a rise in breath hydrogen of >20 ppm (0.9 imol hydrogen/L air) after a challenge dose of lactose (0.7 g/kg body wt) administered after an overnight fast. Methods to measure outcomes: Subjects rated symptoms hourly during the breath hydrogen tests using a ranked scale: 0=none, 1=slight, 2=mild, 3=moderate, 4= moderately severe, 5= severe. Data are reported as the sum of hours 1–8. During the feeding periods, subjects recorded symptoms once per day each evening during the feeding periods using the same scale mentioned above.Mean age: 30
Gender: women 25%.
Race: Asian 70%, black, Latin- American, and white 10% each Comorbidities: not reported
Cointerventions: not reported
Dextrose for days 1–10 and crossed over to the other feeding period for days 12–21.
Initial dosage was 0.6 g · kg body wt−1 · d−1, which was increased by 0.2‐ g/kg increments every other day up to a maximum of 1.0 g · kg−1 · d−1. On days 11 and 22 an aqueous lactose challenge (0.35 g/kg) was administered after an overnight (>12 hours) fast. Breath hydrogen excretion and intolerance symptoms were monitored hourly for 8 hours after the challenge dose was consumed
Lactose for days 1‐ 10 and crossed over to the other feeding period for days 12–21.
Initial dosage was 0.6 g · kg body wt−1 · d−1, which was increased by 0.2‐ g/kg increments every other day up to a maximum of 1.0 g · kg−1 · d−1. On days 11 and 22 an aqueous lactose challenge (0.35 g/kg) was administered after an overnight (>12 hours) fast. Breath hydrogen excretion and intolerance symptoms were monitored hourly for 8 hours after the challenge dose was consumed.
Symptoms rating after lactose (L) or dextrose (D) feeding periods (mean ± SEM). The maximum possible score for any individual symptom would be 40 (a “5” rating each hour for 8 hours).
Conclusion(s): Authors concluded that there is colonic adaptation to regular lactose ingestion and this adaptation reduces lactose intolerance symptoms.
Allocation concealment: unclear
Blinding: noted as blinded, unclear if double-blinded Intent-to-treat
analyses: no Study withdrawals adequately described: no
E. Incremental lactose loads or studies examining different levels of lactose
Hertzler, 199690
RCT, crossover
Sponsorship: Minnesota Agricultural Experiment Station
USA
Duration of symptom recording: 1 day
Data source: 13 American lactose maldigesting subjects.
Inclusion criteria: Subjects were classified as lactose maldigesters based on a rise in breath hydrogen of >20 ppm (0.9 imol hydrogen/L air) during a challenge dose of lactose (20 g) after a 12 hours fast.
Methods to measure outcomes: Subjects rated symptoms of flatulence, abdominal pain, and diarrhea hours 1 through 8 following challenge dose. A ranked scale was used; 0=none, 1=slight, 2=mild, 3=moderate, 4= moderately severe, 5= severe.
Mean age: 32 (range 21 to 42)
Gender: women 46%.
Race: NR
Comorbidities: not reported
Cointerventions: not reported
Five treatment solutions consisting of lactose dissolved in 240 mL of tap water.
1) Lactose 0 g
2) Lactose 2 g
3) Lactose 6 g
4) Lactose 12 g
5) Lactose 20 g
Symptoms rating after each challenge dose (mean ± SEM). The maximum possible score for any individual symptom would be 40 (a “5” rating each hour for 8 hours).
Conclusion(s): Lactose maldigesters may be able to tolerate foods with ≤6 g lactose per serving such as hard cheeses and small servings (≤120 mL) of milk.
Allocation concealment: unclear Blinding: double-blinded Intent-to-treat analyses: no Study withdrawals adequately described: no
Newcomer, 197891
RCT, crossover
Sponsorship: National Institutes of Health and United States Public Health Service.
USA
Duration of symptom recording: 8 hours
Data source: 59 lactase deficient American Indians.
Inclusion criteria: lactase deficiency determined by breath hydrogen concentration to >20 mL/min after ingestion of 50 g (less for children) of lactose.
Methods to measure outcomes: A subject was considered to have a positive symptomatic response if he/she had ≥1 loose stools or had a grade 2+ or higher in at least one of the following symptoms: abdominal cramps/pain, bloating or gas, borborygmi, flatulence.
Symptoms were rated according: 0 = no trouble; 1+ = slight; 2+ = mild; 3+ = moderate, subject would normally avoid a breakfast causing these symptoms; 4+ = severe, subject would be unable to carry on usual activities.
Mean age (range): 18.7 (5–62). 44 were <18 years of age.
Gender: women 47%
Race/ethnicity: American Indian 100%
6 breakfasts randomly distributed. Sugar packets with lactose ranging from 0 to 18 g added to 8 ounces of Ensure drink.
Breakfast 1: 0 g lactose + 18 g glucose plus galactose (G+G).
Breakfast 2: 3 g lactose + 15 g G+G.
Breakfast 3: 6 g lactose + 12 g G+G.
Breakfast 4: 9 g lactose + 9 g G+G.
Breakfast 5: 12 g lactose + 6 g G+G.
Breakfast 6: 18 g lactose + 0 g G+G.
Number of subjects with symptoms.
Conclusion(s): A modest amount of lactose (1–1½ glasses of milk), when consumed with a meal, was well tolerated by lactase-deficient American Indians.
Allocation concealment: unclear
Blinding: double, symptoms assessed by “blinded observer” Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Stephenson, 197492
Un-blinded RCT, attempt made to mask to taste, crossover
USA
Duration:8 hours Funded by National Dairy Council and NY State Agriculture Experiment Station hatch project
Hypothesis: Higher doses of lactose poorly tolerated
Data Source: n=35 U.S. adults, with and without LI on basis of rise in blood glucose of less than 20 mg/100mL after 50 g lactose ingestion Methods to measure outcome: Asked about any symptoms of bloating, gas, abdominal cramps and diarrhea on scale of mild moderate and severe, summedMedian age 25 (23–55 range)
Gender: women 54%
Race/ethnicity: white 71%, non‐ white 29%
Co-morbid: none
Co-intervention: none
Day 1, all 35 got 50 gm lactose. Those with symptoms got 15, 30, 50 gm lactose in water or milk serially. Those with no symptoms got 100, 150 and 200 gm lactose in water and milk seriallyPlacebo 250 ml (saccharin, lemon juice water)Sum of score of bloating, gas, cramps and diarrhea on scale: 0=none, 1=mild, 2= moderate, 3=severe.
Conclusion(s): Most adults with lactose intolerance can tolerate up to 30 gm lactose
Allocation concealment: unclear Blinding: single no masking Intent-to-treat analyses: one person lost to followup Study withdrawals adequately described: yes, one withdrawal reported, data missing on up to 3 individuals in different groups
F. Studies with irritable bowel syndrome subjects
Parker, 200193
RCT, crossover
Sponsorship: NR
UK
Duration of symptom recording: 1 week
Data source: 122 British IBS patients were referred for a lactose hydrogen breath test.
The breath test was positive in 33 (27%) and negative in 89 (73%).
Subjects in the positive group were then placed on a low lactose diet for 3 weeks. The daily intake of lactose from this diet was <1 g.
Patients improving on the low lactose diet were given double-blind, placebo-controlled challenges to confirm lactose intolerance.
Methods to measure outcomes: Symptom score was based on eight variables: abdominal pain, daily bowel movements, urgency to defecate, consistency of feces, flatulence, headache, abdominal distension, and general well-being.
Each symptom was scored from 0 to 4, 0 being no symptoms and 4 most severe. Urgency was scored from 0 to 3.
The maximum cumulative score = 31.
Data for the 33 subjects with positive hydrogen breath test.
Mean age NR. Age <50 years 73%;
Gender: women 76%
Race/ethnicity White 85% (n=28), Asian 9% (n=3), Middle-Eastern 6% (n=2),
Comorbidities: not reported
Cointerventions: not reported
Three active tests were given in random order for 7 of 9 subjects improving on low- lactose diet: lactose 5 g, 10 g, or 15 g, and placebo mixed with 285 ml water and taken at breakfast on 2 consecutive days with 5 days' rest between each test.
Symptoms scores were completed daily for test and rest days. Subjects remained on low lactose diet during double-blind, placebo-controlled test period.
Conclusion(s): During double-blind phase, 2/7 subjects (29%) developed increasing symptoms with increasing doses of lactose.
Although 5 of the 7 were affected by 15 g lactose, 5 subjects had worse symptoms with 5 g than 10 g, suggesting that many LM patients can tolerate up to 12 g per day.
Patients with lactose intolerance were not distinguishable from others with IBS on the basis of symptoms, and treatment with a low lactose diet gave disappointing results.
Allocation concealment: unclear Blinding: double-blinded Intent-to-treat analyses: 100% followup although 2 subjects meeting eligibility did not participate for unknown reasons Study withdrawals adequately described: no withdrawals reported
Böhmer 199694
Sponsorship: not reported
The Netherlands
Duration of symptom recording: 6 weeks
Data source: 105 Caucasian Dutch subjects, 70 with IBS and 35 healthy controls
Inclusion criteria: Subjects were screened for lactose mal‐ absorption (LM) and were not aware of the test results. Diagnosis of IBS after exclusion of organic causes.
Subjects had to fulfill at least two criteria: visible abdominal distension; pain relief with defecation; more frequent stools at pain onset; looser stools at pain onset; passage of rectal mucus; and feeling of incomplete evacuation. Subjects were classified as lactose malabsorbers based on a rise in breath hydrogen of >20 ppm above basal level during a challenge dose of lactose (50 g) after a 12 hours fast.
Methods to measure outcomes: subjects scored symptoms (pain, flatulence, distension, diarrhea, mucus, incomplete evacuation) 0=no complaints, 1=mild; 2=moderate; and 3 as severe. A maximum cumulative score = 18.
IBS subjects (n=70 of which 17 had LM)
Median age (range): 35.7 years (18 to 59)
Gender: women 74%
Race/ethnicity: white 100%
Healthy control subjects (n=35)
Median age (range): 33 years (21 to 51)
Gender: women 74%
Race/ethnicity: white 100%
Lactose restricted dietCumulative symptom scores at 3 and 6 weeks, comparing IBS subjects with LM vs. IBS subjects without LM.
Conclusion(s): the mean symptom score of the IBS with LM showed a statistically significant decrease after 6 weeks of a lactose restricted diet.
Allocation concealment: unclear Blinding: double-blinded Intent-to-treat analyses: no dropouts reported Study withdrawals adequately described: none
Lisker 198995
RCT, crossover
Sponsorship: Mr. A. Kligerman, President of Sugar Lo/Lact Aid company (lactase and placebo vials)
Mexico
Duration of symptom recording: months: 3 months
Data source: 12 Mexican subjects with IBS whose diets regularly included milk.
Eight of the subjects were lactose mal-digesters (when challenged with 12.5 lactose and diagnosed by hydrogen breath test ≥ 20 ppm).
Inclusion criteria: 1) diagnosis of IBS based on chronic abdominal pain, altered bowel habits, and absence of organic disease; 2) regular diet included consumption of milk/dairy products ≥8 oz. glass of milk daily or equivalent lactose intake; 3) patients lived close enough to center to allow adherence to frequent interviews; and 4) showed proper compliance and reliability during first (control) month.
Methods to measure outcomes: Diary record of symptoms filled out daily. Symptoms included constipation, diarrhea, abdominal pain, abdominal distension, and flatulence.
Mean age (range): 49 years (24 to 72)
Gender: women 75%
Race/ethnicity: not reported
Comorbidities: not reported
Cointerventions: not reported
Treatment A group Lactase x 4 weeks, then placebo x 4 weeks, then lactase x 4 weeks.
Prior to 3 month study phase there was a 1 month non‐ intervention, control period.
Lactase (derived from Kluyveromyces lactis) was used in vitro (added in entirety to liter of milk the day before consumption) and in vivo (added at mealtime when consuming lactose- containing foods away from home)
Treatment B group Placebo x 4 weeks, then lactase x 4 weeks, then lactase x 4 weeks.
Prior to 3 month study phase there was a 1 month non‐ intervention, control period.
Symptoms noted as better, same, or worse for each intervention month
Conclusion(s): GI symptoms were found to be independent of lactase treatment. In this study population with a high prevalence of lactose deficiency, IBS symptoms appeared to be independent of lactose maldigestion.
Allocation concealment: unclear Blinding: double-blinded Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported
Newcomer 198380
RCT, crossover
Sponsorship: National Dairy Council and North Carolina State University Dairy Foundation
USA
Duration of symptom recording: 1 week
Data source: 79 American subjects, 61 lactase sufficient subjects with IBS and 18 lactase deficient (all had histories of milk intolerance) subjects.
There were also 10 healthy controls.
Inclusion criteria: lactase deficiency was diagnosed by an increase in the breath hydrogen ≥0.30 ml/min above basal level after challenge of 50 g lactose in 500 ml water.
IBS was diagnosed on the basis of a typical history and a minimal number of negative diagnostic studies.
Methods to measure outcomes: Symptom (diarrhea, abdominal pain/cramps*, gas/flatus*, rumbling*, constipation) diary at end of each day.
Diarrhea was yes/no, # stools per day.
Scored as following for *: 0=no trouble; 1=slight trouble; 2=mild; 3=moderate; 4=severe. Constipation was better, same, worse.
1) Lactase deficiency subjects (n=18)
Age range (18–69)
Gender: not reported
Race/ethnicity: not reported
2) lactase sufficient subjects with IBS (n=61)
Age range (20–82)
Gender: not reported
Race/ethnicity: not reported
3) healthy controls (n=10)
Age range (21–64)
Gender: not reported
Race/ethnicity: not reported
Lactase deficient subjects
Acidophilus milk (mean 1½ glasses daily) x 1 week (either week 1 or week 4).
2 week control period between weeks of starting new treatment Lactase sufficient subjects with IBS and controls Acidophilus milk (3 8 oz. glasses daily) x 2 weeks (either week 3 or week 7).
Three 2- week control periods (milk-drinking periods in between).
lactase deficient subjects Unaltered milk (mean 1½ glasses daily) x 1 week (either week 1 or week 4).
lactase sufficient subjects with IBS and controls Unaltered milk (3 8 oz. glasses daily) x 2 weeks (either week 3 or week 7).
Cumulative symptom indices for the 18 lactase deficiency subjects
Conclusion(s): There was no difference in the tolerance of the acidophilus and unaltered milks in the lactase deficient group. IBS subjects were also not helped by the ingestion of acidophilus milk.
Allocation concealment: unclear Blinding: double-blinded Intent-to-treat analyses: 100% followup Study withdrawals adequately described: no withdrawals reported

From: Appendix D, Evidence Tables

Cover of Lactose Intolerance and Health
Lactose Intolerance and Health.
Evidence Reports/Technology Assessments, No. 192.
Wilt TJ, Shaukat A, Shamliyan T, et al.

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