ahmed yehya

LACTOSE INTOLERANCE
By: Ahmed Yehya hassan
supervised by: dr. aml abdelkader
academic year:2023
  Introduction
Lactose intolerance associated with primary or secondary lactase deficiency results from
abdominal pain and bloating, borborygmi, gas and diarrhea caused by lactose in dairy products.
The biological process and lactose malabsorption are well known and there are many studies,
including genetic, endoscopic and physiological testing. Lactose intolerance depends not only
on lactase expression, but also on lactose dose, gut microbiota, gut motility, small intestinal
bacteria, and sensitivity of the gut to fat and other fermentation products of lactose digestion.
Treatment for lactose intolerance may include a lactose-free diet and enzyme replacement
therapy. This only applies if the symptoms are related to dairy products; However, lactose
intolerance can be a nuisance due to differences in the absorbable, fermentable
oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) portion of the intake.

Affected by at least half of people with irritable bowel syndrome (IBS), this group must not only
restrict lactose but also have a low-FODMAP diet to improve bowel management. The long-
term effects of a dairy-free, low-FODMAP diet and stool microbiome have not been
determined. This review highlights recent advances in our understanding of the genetic basis,
biological mechanisms, diagnosis, and dietary management of lactose intolerance.

 Pathophysiology
The enzyme lactase-phlorizin hydrolase, more commonly known as lactase, is a β-galactosidase
responsible for the hydrolysis of lactose to the monosaccharides, glucose and galactose. These
are absorbed by intestinal enterocytes into the bloodstream (Figure 1), glucose is ultimately
utilized as a source of energy and galactose becomes a component of glycolipids and
glycoproteins. The enzyme has two active sites, one hydrolysing lactose and the other phlorizin
(an aryl α-glucoside) and a range of dietary glycolipids. A number of actions of the phlorizin site
are useful in humans and this explains why some enzyme activity is retained following the usual
decline in enzyme expression after weaning from breast milk
Figure 1
In lactase persistence, lactase-phlorizin hydrolase in the brush border efficiently hydrolyses
lactose into galactose (Gal) and glucose (Glu) and is rapidly absorbed into the bloodstream
taking luminal water with it. Hydrolysis typically occurs in the jejunum, which has low
concentrations of bacteria 101–4 mL−1; thus, little lactose is fermented.

Lactase is present on the apical surface of enterocytes in the small intestinal brush border with
the highest expression in the mid-jejunum. It is secured by its C-terminal end with most of the
molecule protruding into the gastrointestinal lumen. The enzyme is produced as a 220 kDa
precursor peptide, which undergoes considerable post-transcriptional modification during
transport to the cell surface as the mature 150 kDa protein. Luminal factors also contribute to
final modification of the protein to produce the active enzyme by cleavage of two further amino
acids by pancreatic trypsin.

By week 8 of gestation, lactase activity can be detected at the mucosal surface in the human
intestine. Activity increases until week 34 and by birth, lactase expression is at its peak.
However, within the first few months of life, lactase activity starts to decrease (lactase
nonpersistence). In most mammals, it declines at variable rates following weaning to
undetectable levels as a consequence of the normal maturational down-regulation of lactase
activity. In humans, approximately 30% of the population has continued lactase activity beyond
weaning and into adulthood (lactase persistence).7 This happens mainly in people of north
European descent and relates geographically to the introduction of dairy farming approximately
10 000 years ago. Recent analysis of archaeological DNA suggests that genetic lactase
persistence was rare in Northern Europeans prior to dairy farming. The so-called ‘culture-
historical hypothesis’ proposes that the high prevalence of lactase persistence in Northern
Europeans occurred as a result of a more recent selection process enabling populations to rely on
mammalian milk as an important component of the diet particularly at time of poor harvest. An
opposing hypothesis ‘reverse cause’ proposed that dairy farming and milk consumption was
adopted by those with pre-existing lactase persistence but evidence from archaeological DNA
suggests that this is less likely.

Hypolactasia, or lactase deficiency, exists in three distinct forms: congenital, primary and
secondary. Congenital lactase deficiency is associated with the least lactase activity. It is a
lifelong disorder characterized by failure to thrive and infantile diarrhoea from the first exposure
to breast milk. Congenital lactase deficiency is extremely rare, with only around 40 cases having
been reported. It is a single autosomal recessive disorder, but very little is known about the
molecular basis. The only treatment is complete avoidance of lactose from birth. Lactase
nonpersistence (primary lactase deficiency), as described above, occurs in the majority of
humans. Secondary or acquired lactase deficiency refers to the loss of lactase activity in people
with lactase persistence. It occurs as a result of gastrointestinal illness that damages the brush
border of the small intestine, e.g. viral gastroenteritis, giardiasis or coeliac disease. This is
usually reversible.

For effective utilization of lactose without symptoms of intolerance, only 50% of lactase activity
is necessary and it is present only at the level that it is required, as is the case for other intestinal
disaccharides.

For many years, it was thought that lactase persistence in humans was the ‘wild-type’ pattern. As
the lactase nonpersistence phenotype is expressed in other mammals, this is now considered to
be the ancestral type whilst lactase persistence is because of a mutation.
  Symptoms of lactose intolerance

Lactose maldigestion occurs when lactose is not absorbed in the small intestine. It passes through
the gastrointestinal tract to the colon, where, in some subjects, it then leads to symptoms of
lactose intolerance.

The typical symptoms of lactose intolerance include abdominal pain, bloating, flatus, diarrhoea,
borborygmi, and on some occasions, nausea and vomiting. In a few cases, gastrointestinal
motility is decreased and subjects can present with constipation possibly as a consequence of
methane production. Animal models have shown a marked reduction in the major migratory
complexes of the gut when infused with methane, slowing gut transit.41

Abdominal pain and bloating are typically caused by colonic fermentation of unabsorbed lactose
by the bacterial microflora leading to the production of short chain fatty acids (SCFA), hydrogen,
methane and carbon dioxide, thus increasing gut transit time and intracolonic pressure
Acidification of the colonic contents and an increased osmotic load resulting from the
unabsorbed lactose in the ileum and colon lead to a greater secretion of electrolytes and fluid and
a rapid transit time resulting in loose stools and diarrhoea.

In lactase nonpersistence, there are several possible mechanisms for the common symptoms
found in patients. First, unabsorbed lactose passing through the colon has a high osmotic load
leading to increased water and electrolytes in luminal contents, speeding transit and softening
stool. Secondly, unabsorbed lactose is hydrolysed to galactose (Gal) and glucose (Glu) by
bacterial β-galactosidase present in lactic acid bacteria. These monosaccharides are then
available for bacterial fermentation by ileal and colonic flora to short chain fatty acids with by-
products of hydrogen and carbon dioxide, causing bloating in the small bowel and flatulence in
the colon. Thirdly, reduction in carbon dioxide by certain bacterial strains to methane could,
theoretically, lead to constipation through a reduction in small intestinal major migratory
complexes.
Care should be taken when subjects describe systemic symptoms as whilst these may be
coincidental, they could be an indication of cow’s milk protein allergy, which affects as many as
20% of patients with symptoms suggestive of lactose intolerance. Cow’s milk protein allergy is
rare in adults; Truelove and Wright showed that a few ulcerative colitis patients benefited from
exclusion of dairy products but this work has never been repeated. Aside from bloody diarrhoea,
extra-intestinal symptoms occur and may include muscle and joint pain, headaches, dizziness,
lethargy, difficulty with short-term memory, mouth ulcers, allergies (eczema, pruritis, rhinitis,
sinusitis and asthma) cardiac arrhythmia, sore throat, increased frequency of micturition, acne
and depression.

Some patients do not associate their symptoms of lactose intolerance with foods and in one
study, 52% of patients did not relate their symptoms with the intake of lactose. In addition,
substantial amounts of lactose given to patients with proven lactase nonpersistence and a history
of lactose intolerance who were properly blinded, did not cause significant symptoms.
Furthermore, in symptomatic patients, excluding lactose does not always eliminate symptoms
probably because there is another underlying cause, e.g. irritable bowel syndrome (IBS).

 Clinical Diagnosis of Lactose Malabsorption and Intolerance

Problems with lactose absorption have been described, detected and diagnosed in several ways
and this can lead to confusion among doctors and patients Lactase deficiency is defined as
markedly reduced brush-border lactase activity relative to the activity observed in infants.
Lactose malabsorption occurs when a substantial amount of lactose is not absorbed in the
intestine. Because lactose malabsorption is nearly always attributable to lactase deficiency, the
presence of this condition can be inferred from measurements of lactose malabsorption such as
an increase of glucose in the blood or an increase of hydrogen in the breath. The term lactose
intolerance is defined by patient reports of abdominal pain, bloating, borborygmi, and diarrhea
induced by lactose. Less often it can present with nausea or constipation and a range of systemic
symptoms, including headaches, fatigue, loss of concentration, muscle and joint pain, mouth
ulcers, and urinary difficulties however, it is unclear whether these atypical symptoms are
directly due to lactose ingestion, or related to the presence of so-called “functional diseases”,
such as irritable bowel syndrome (IBS), which is often accompanied by multiple somatic
complaints. Certainly, it is not possible to make a definitive diagnosis on clinical presentation
alone because double-blind trials have shown that the association of self-reported lactose
intolerance and the occurrence of symptoms after lactose ingestion are very poor even in patients
with lactase deficiency

Lack of agreement between objective and subjective assessment of lactose intolerance

There are various methods for diagnosing lactose malabsorption and intolerance Testing of
lactase activity in mucosal biopsies from the duodenum is regarded as the reference standard for
primary and secondary lactase deficiency however, limitations include the inhomogeneous
expression of lactase and the invasiveness of the test. Genetic tests may be useful for identifying
lactase persistence in some European populations as the T-13910 allele is ~86%–98% associated
with lactase persistence in European populations however other SNPs are present in Arabian and
African populations Future genetic tests will likely cover a range of genetic polymorphisms,
potentially eliminating this limitation. A further limitation of both biopsy and genetic tests is that
no assessment of symptoms is made. This impacts on the clinical relevance of these
investigations because, as addressed above, only a proportion of patients with lactase deficiency
develop abdominal symptoms after ingesting lactose
Table 1
Summary of tests for lactose malabsorption and lactose tolerance
Lactose Lactase Activity at
H2-Breath Test Genetic Test
Tolerance Test Jejunal Brush Border

Increase of H2 in Increase of blood Enzymatic activity of

Genetic-13910C/T
Test principle respiratory air after sugar after lactose lactase enzyme in
polymorphism
lactose challenge challenge biopsy sample

<1.1 mmol/L C:C13910 lactase non-

Cut off >20 ppm within 3 h <17–20 IU/g
within 3 h persistence

Availability Good Excellent Variable Rare

Rapid GI-transit, Rapid GI-transit,

False positives (incorrect
small-intestinal impaired glucose Rare (<5%) in Caucasians Probably rare
diagnosis)
bacterial overgrowth tolerance

False Non-H2-producers.
Fluctuations in All causes of secondary Patchy enzyme
negatives malabsorption Full colonic
blood sugar lactose malabsorption expression
wrongly excluded adaptation

Cannot be excluded, Can be excluded

Cannot be
Secondary causes kinetic of H2-increase Cannot be excluded (histopathology at
excluded
can be suggestive same procedure)

Symptom assessment Possible Possible Not possible Not possible

Method of choice for Rarely performed Definitive in Caucasians. Reference standard for
assessment of lactose due to inferior Less in other populations. detection of lactase
Comment
malabsorption and sensitivity and Not suitable in secondary deficiency (primary or
intolerance specificity lactase deficiency. secondary)

Cost Low Lowest High Highest

Lactose digestion and the association of maldigestion with symptoms can be assessed by the H2-
breath test and the lactose tolerance test however, the former is confounded by fluctuations of
postprandial blood sugar. The H2-breath test can be false positive in the presence of small
intestinal bacterial overgrowth; however, a larger problem is false-negative tests due to the
presence of hydrogen non-producing bacteria in the colon (2%–43%) This problem of “hydrogen
non-production” can be mitigated to some extent by examining patient reports of symptoms after
the test dose. Patients with “false positive” breath tests complain of symptoms directly after
ingestion. Those with “true positive” lactose intolerance complain of symptoms only after the
substrate has entered the colon (usually 50–100 min). Another possibility is to combine the
biopsy or genetic test (in Caucasians) with the H2-breath test; however, this is an expensive and
time-consuming approach.

 Treatment

Management of lactose intolerance consists of dietary modification, lactase supplementation, and

treating an underlying condition in people with secondary lactase deficiency.

Dietary Modification: Lactase-containing milk products and calcium supplements are

recommended. Limiting the dietary intake of lactose by avoiding the intake of lactose-containing
products improves the symptoms of the disease. The following products contain lactose and,
therefore, must be avoided:

1. Soft and processed cheese

2. Buttermilk
3. Cream
4. Milk
5. Ice cream
6. Sour cream
7. Whey
8. Pancakes and waffles
9. Mashed potatoes
10. Butter
11. Margarine
12. Custard and pudding

Yogurt contains varying amounts of lactose and may cause symptoms in some patients. Greek
yogurt has the least. Yogurt culture microorganisms can produce β-galactosidase as part of their
lactose utilization pathway. This may promote lactose digestion in vivo. Plant-based milk
alternatives are becoming more available; however, technological issues, palatability, and
nutritional balance remain concerns. Probiotics have been observed to improve symptoms, such
as the DDS-1 strain of Lactobacillus acidophilus. Calcium and vitamin D supplements should
also be recommended. In patients with secondary lactase deficiency, treatment should be directed
at the underlying cause.
Lactase Supplements: Lactase enzyme supplements contain lactase which breaks down lactose in
milk and milk-containing products. They are available as lactase enzyme tablets or drops.

 Conclusions
Primary lactase deficiency can be regarded as the commonest “genetic disease” in the World,
although, in truth, loss of lactase expression in adulthood represents the normal “wild-type” and
lactase persistence the abnormal “mutant” state. Additionally, in secondary lactase deficiency, the
ability to digest lactose can be lost due to infection, surgery and other insults. Whatever the
cause, lactose malabsorption causes symptoms by several mechanisms: unabsorbed lactose leads
to osmotic diarrhea; products of its bacterial digestion lead to secretory diarrhea and gas can
distend the colon. Diagnosis of lactose malabsorption is based on detection either of the genetic
mutation, loss of lactase activity in the enteric mucosa or evidence of malabsorption in the blood
or breath. However, the presence of lactose malabsorption does not necessarily imply that
abdominal symptoms are related to this process. The majority of healthy individuals with lactase
deficiency tolerate up to 20 g lactose without difficulty. Instead, diagnosis of lactose intolerance
requires concurrent assessment of lactose digestion and abdominal symptoms.

Recent studies have provided important new insight into the complex relationship between
lactase deficiency, lactose malabsorption and symptom generation. This work has shed light on
the wider issue of food intolerance as a cause of symptoms in irritable bowel syndrome and
related conditions. Understanding the biological mechanism for food intolerance to lactose and
FODMAPs will help clinicians make a definitive diagnosis and guide rational dietary and
medical management. Ongoing studies will provide high quality evidence to document the
efficacy and long-term effects of these strategies.

 References

1. Vesa T.H., Marteau P., Korpela R. Lactose intolerance. J. Am. Coll. Nutr. 2000;19(Suppl.
S2):165S–175S. doi: 10.1080/07315724.2000.10718086. [PubMed] [CrossRef] [Google Scholar]

2. Swallow D.M. Genetics of lactase persistence and lactose intolerance. Ann. Rev. Genet.
2003;37:197–219. doi: 10.1146/annurev.genet.37.110801.143820. [PubMed] [CrossRef] [Google
Scholar]
3. Enattah N.S., Sahi T., Savilahti E., Terwilliger J.D., Peltonen L., Jarvela I. Identification of a
variant associated with adult-type hypolactasia. Nat. Genet. 2002;30:233–237. doi:
10.1038/ng826. [PubMed] [CrossRef] [Google Scholar]

4. Wang Y., Harvey C.B., Pratt W.S., Sams V.R., Sarner M., Rossi M., Auricchio S., Swallow
D.M. The lactase persistence/non-persistence polymorphism is controlled by a cis-acting
element. Hum. Mol. Genet. 1995;4:657–662. doi: 10.1093/hmg/4.4.657. [PubMed] [CrossRef]
[Google Scholar]

5. Poulter M., Hollox E., Harvey C.B., Mulcare C., Peuhkuri K., Kajander K., Sarner M.,
Korpela R., Swallow D.M. The causal element for the lactase persistence/non-persistence
polymorphism is located in a 1 Mb region of linkage disequilibrium in Europeans. Ann. Hum.
Genet. 2003;67:298–311. doi: 10.1046/j.1469-1809.2003.00048.x. [PubMed] [CrossRef]
[Google Scholar]

6. Hogenauer C., Hammer H.F., Mellitzer K., Renner W., Krejs G.J., Toplak H. Evaluation of a
new DNA test compared with the lactose hydrogen breath test for the diagnosis of lactase non-
persistence. Eur. J. Gastroenterol. Hepatol. 2005;17:371–376. doi: 10.1097/00042737-
200503000-00018. [PubMed] [CrossRef] [Google Scholar]

11.Savaiano DA, Levitt MD. Milk intolerance and microbe-containing dairy foods. J Dairy Sci
1987; 70: 397– 406.

12. Bayless TM, Paige DM, Ferry GD. Lactose intolerance and milk drinking habits.
Gastroenterology 1971; 60: 605– 8.