Keywords
primary lactase deficiency - persistent diarrhea
Introduction
Around the world, diarrhea is the second leading cause of death in children under
the age of 5 years, taking the lives of 760,000 children each year, according to the
World Health Organization (WHO, 2013). The great majority of diarrhea episodes last
less than 1 week. When diarrhea persists for more than 14 days, it is called persistent
or chronic diarrhea. In resource-limited (developing) countries, persistent diarrhea
(PD) is most common in children younger than 2 years of age, and especially in children
under 1 year,[1] but can also occur in older children. In the developing world, chronic diarrhea
is typically associated with serial enteric infections and malnutrition. In developed
countries, chronic diarrhea is more likely to be induced by underlying disease-causing
malabsorption or maldigestion. These prolonged episodes are important not only because
of the discomfort of having diarrhea but also because of the association with malnutrition
and increased risk of death.[2] As a result, diarrhea is a major cause of malnutrition, and malnourished children
are more likely to fall ill from diarrhea. Lactose intolerance is a common complication
of diarrhea in infants with malnutrition and a cause of treatment failure.[3] Malnourished children commonly have a reduced activity of intestinal lactase, the
enzyme responsible for the digestion of lactose,[4] and it has been suggested that feeding them this disaccharide can retard nutritional
recovery. A large proportion of children with PD are seen in the wake of lactation
failure and following the introduction of animal milk feeds.[5] The most common clinical problem encountered in dietary selection is possible lactose
intolerance. The consequence of lactose malabsorption and continued milk feeding include
osmotic diarrhea and increased stool output. Reduced intake of nutrients, maldigestion,
and malabsorption increase nutrient losses, and the effects of the inflammatory response
also contribute to adverse outcomes. Given the propensity of PD in the younger age
group, it is natural that milk forms a major part of the dietary intake in these children.
However, some of these children may be lactose intolerant, possibly contributing to
the high rate of unfavorable treatment outcomes. Genetically regulated reduction of
lactase enzyme activity or lactase nonpersistence is determined by racial or ethnic
factors and is the underlying mechanism of lactose malabsorption in healthy individuals.
Lactase nonpersistence is most frequent in Asian and African populations; in contrast,
the majority of Caucasians, particularly of northern European background, maintain
elevated lactase activity into adulthood.
Aim
This study was therefore designed to establish the prevalence of primary lactase deficiency
and associated factors among mildly malnourished children with PD.
Methods
This was a prospective cohort study. The study population consisted of mildly malnourished
children with PD aged 3 to 24 months admitted to Globalmed Pediatric Clinic between
October 2014 and September 2015. The Gomez classification of malnutrition was used.
A mildly malnourished child was one whose weight-for-height was less than 75 to 90%
of the National Centre for Health Statistics/WHO reference median. The study included
78 malnourished children with PD aged 3 to 24 months. The study population was divided
into two age groups: 3 to 12 months age group and 13 to 24 months age group. Fifty
children were in the age group of 3 to 12 months and 28 children were in the age group
of 13 to 24 months. Forty-three children in the study group were females and 35 were
males ([Table 1]).
Table 1
Distribution by age and sex
|
3–12 mo age group (50 children)
|
13–24 mo age group (28 children)
|
|
31 females
|
12 females
|
|
19 males
|
16 males
|
The prevalence of lactose intolerance in the study population was explored on the
basis of a precoded and pretested structured questionnaire and a genetic test for
primary lactose malabsorption. Characteristics that were explored during the study
period were each child's anthropometric measurements, birth order, duration of breastfeeding,
immunization status, diarrhea episodes in the previous 3 months, abdominal distention,
vomiting, previous problems with cow's milk, average frequency of stool in 24 hour,
watery stool, antibiotic use during diarrhea, and dehydration. EDTA (ethylenediaminetetraacetic
acid) blood samples, 2 mL, were obtained and posted to laboratory to undergo a genetic
test for primary lactose malabsorption. Two LCT gene mutations are associated with lactase expression, C −13910 (C at position -13910
upstream of the LCT gene) and G −22018 (G at position-22018), are related to lactase nonpersistence,
whereas T −13910 and A −22018 are related to lactase persistence. The CC genotype
is associated with physiological loss of lactase activity. The test was considered
positive if (examination of polymorphism – 13910C > T [relative to LCT gene]) homozygous CC genotype was consistent with primary lactase deficiency. Bacteriological
studies of stool samples were performed to identify major diarrheagenic bacteria,
including Salmonella spp, Shigella spp, Yersinia enterocolitica, Campylobacter, Clostridium difficile, and enteropathogenic Escherichia coli (EPEC). Quick Stripe Adeno/Rota rapid test (Savyon Diagnostics Ltd.) were performed
for determination of rotaviruses and/or adenoviruses in stool samples. Data were coded
and entered into a computerized database. All data collected were checked for completeness
and accuracy and were cleaned before analysis. The analysis was performed using the
Statistical Package for Social Sciences (SPSS 22; SPSS Inc.) software. Continuous
variables were expressed as mean ± standard deviation, and categorical variables were
expressed as frequencies. The analysis of continuous variables was performed using
Student's t-test and that of categorical variables was performed using Fisher's exact test. Voluntary
informed consent was obtained from the parents/caretakers before participating in
the study. Confidentiality was maintained throughout the study. Correlation analysis
was performed by Spearman rank correlation. Results were summarized in texts and [Table 2].
Table 2
Correlation of CC genotype with clinical symptoms of lactose intolerance
|
Lactase persistence
|
Lactase nonpersistence
|
F
|
p-Value
|
|
ABS
|
Mean
|
Standard deviation
|
ABS
|
Mean
|
Standard deviation
|
|
≥2 diarrhea episodes in the previous 3 mo
|
12
|
0.32
|
0.471
|
24
|
0.92
|
0.272
|
35.10
|
0.0000
|
|
Abdominal distention
|
22
|
0.58
|
0.500
|
26
|
1
|
0.000
|
18.32
|
0.0001
|
|
Previous problems with cow's milk
|
20
|
0.53
|
0.506
|
22
|
0.85
|
0.368
|
7.61
|
0.0076
|
|
Vomiting
|
21
|
0.55
|
0.504
|
24
|
0.92
|
0.272
|
11.68
|
0.0011
|
|
Frequency of stool ≥8 motions in 24 h
|
|
5.29
|
1.088
|
|
9
|
0.849
|
T = –16.193
|
0.000
|
Abbreviation: ABS, Absolute value.
Results
The prevalence of primary lactase deficiency among the study children was 41% ([Figs. 1]
[2]
[3]).
Fig. 1 The prevalence of primary lactase deficiency among the study children.
Fig. 2 Age distribution by primary lactase deficiency.
Fig. 3 Sex distribution by primary lactase deficiency.
The reasons for PD in the lactose tolerant group were rotavirus infection (33.3%),
bacterial gastroenteritis (20.5%; EPEC, 7.7%; Shigella, 6.4%; Y. enterocolitica, 3.8%; Salmonella, 2.6%), and gastroenteritis of unknown etiology (5.1%). Only four children had rotavirus
infection in the lactose intolerant group ([Figs. 4] and [5]).
Fig. 4 Causative factors of persistent diarrhea in lactase persistent group.
Fig. 5 Pathogens associated with bacterial gastroenteritis.
Diarrhea episodes in the previous 3 months, abdominal distention, vomiting, previous
problems with cow's milk, and higher frequency of stool in 24 hours were significantly
associated with primary lactase deficiency. The correlation analysis demonstrated
that primary lactase deficiency had a significant positive correlation with the number
of diarrhea episodes in the previous 3 months (r = 0.556; p = 0.0000), abdominal distention (r = 0.490; p = 0.0000), previous problems with cow's milk (r = 0.331; p = 0.0076), and vomiting (r = 0.294; p = 0.0091).
Discussion
The 41% prevalence of primary lactase deficiency in the 78 mildly malnourished children
with PD was higher and was not significantly different in children's age groups (3–12
months and above 12 months) in contrast to other studies.[6] This might be explained by the difference in sample size and study population. Children
with primary lactase deficiency had a higher mean stool frequency (≥8 motions in a
24-hour period; p = 0.000), a finding consistent with one published by Ozmert et al in Turkey.[7] High prevalence of primary lactase deficiency among children having had two or more
diarrhea episodes in the previous 3 months (p = 0.000), as found in this study, has also been reported elsewhere.[6] Recurrent episodes of diarrhea result in repeated disruption of the intestinal villi
with shortened regeneration and maturation time, predisposing an individual to intestinal
lactase deficiency. Conversely, lactose intolerance prolongs and increases the severity
of diarrhea.[8]
Conclusion
The 41% prevalence of primary lactase deficiency in mildly malnourished children with
PD is relatively high. Clinical predictors of primary lactase deficiency in mildly
malnourished children include higher mean stool frequency (≥8 motions in one 24-hour
period [p = 0.000], having ≥2 diarrhea episodes in the previous 3 months [p = 0.0000], abdominal distention [p = 0.0001], vomiting [p = 0.0011], previous problems with cow's milk [p = 0.000; t = –16.193].
PD has become the major cause for diarrheal mortality in children from developing
countries. The relationship between diarrhea and malnutrition is bidirectional: diarrhea
leads to malnutrition, while malnutrition aggravates the course of diarrhea. Lactose
intolerance is a relatively common cause of PD. The most common cause of primary lactase
deficiency is lactase enzyme nonpersistence. Genetic testing is a new tool for the
diagnosis of lactase persistence. Prevalence of primary lactase deficiency among malnourished
children with PD in different regions of Georgia is the main topic of our investigation
and further studies.
