Editorial article
Diagnosis of lactose intolerance
Diagnóstico de la intolerancia a la lactosa
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Its absorption depends on the correct activity of the lactase enzyme found at the edge of the mucus brush (microvilli) of the small intestine. The lactase hydrolyses the lactose, thus allowing the passage of the carbohydrates through the intestine to reach the blood flow. The activity of lactase in mammals is at its peak during breast-feeding, falling off after weaning, which causes a reduction in the capacity to absorb lactose.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a> This fact, genetically defined, also takes place in the majority of humans and is known as primary hypolactasia or lactase nonpersistence (LNP).<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a> The lactose that is not absorbed in the small intestine passes rapidly to the colon, where it is metabolised by the intestinal flora, which produces short-chain fatty acids and gas, primarily hydrogen (H<span class="elsevierStyleInf">2</span>), carbon dioxide (CO<span class="elsevierStyleInf">2</span>) and methane (CH<span class="elsevierStyleInf">4</span>), which are responsible for the symptoms of lactose intolerance (LI).<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">It is frequent in day-to-day clinical practice to confuse the terms malabsorption and LI, a fact that can lead to erroneous treatment of the patient. Lactose malabsorption (LM) is defined as inefficient digestion of lactose, which can be due to a primary cause (LNP) or secondary to other acquired intestinal pathologies, such as bacterial overgrowth, giardiasis or coeliac disease.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> LI is defined as the presence of clinical symptoms, such as abdominal pain, explosive diarrhoea, swelling, flatulence, bowel sounds and/or vomiting associated with LM, when milk of products contained milk are ingested.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">5</span></a> However, malabsorption of this sugar does not always translate into the development of symptoms of intolerance; in fact, only between a third and half of patients with LM are also intolerant.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">There are different diagnosis methods for LM, from the determination of the activity of the lactase by means of jejunal biopsy, absorption tests (overload of lactose [TTL] or gaxilosa [LacTEST<span class="elsevierStyleSup">®</span>]), malabsorption (hydrogen breath test with lactose [HBTL] and analysis of faecal pH), genetic studies and even symptom surveys after the ingestion of lactose.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Currently there is no “gold standard” test for the diagnosis of LM. The <span class="elsevierStyleItalic">activity of lactase in jejunal biopsies</span> was put forward as such; however, it is too aggressive a test for the study of a mild disease and its results could be influenced by an irregular spread of the lactase activity throughout the small intestine mucus.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">oral lactose tolerance test</span> (LTT) is an indirect test, with minimal invasion, which consists of the determination of glycaemias in the bloodstream, at predefined intervals (baseline, 30, 60, and 120<span class="elsevierStyleHsp" style=""></span>min) after the administration of an oral overload of lactose (25–50<span class="elsevierStyleHsp" style=""></span>g). Recently it has been possible to show that the test can be shortened to 60<span class="elsevierStyleHsp" style=""></span>min without affecting its diagnostic efficacy, with the financial saving this entails<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">8</span></a>; and even to 30<span class="elsevierStyleHsp" style=""></span>min with a minimum change in its diagnostic capacity (which would affect only 2.2% of patients).<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">9</span></a> LM is considered pathological when the increase in the levels of glycaemia after the administration of the overload is not greater than 20<span class="elsevierStyleHsp" style=""></span>mg/dl (1.11<span class="elsevierStyleHsp" style=""></span>mmol/l), with regard to the baseline value, in all determinations. Low reliability in diabetic patients and those with slowed-down gastric evacuation is the main shortcoming; however, it contributes clinical value when registering the symptomatology caused by exposure to 50<span class="elsevierStyleHsp" style=""></span>g of lactose in patients with LM. In adults it shows a sensitivity and specificity which oscillates between 75% and 96%.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">8</span></a> This high variability in the diagnostic profitability found in the literature is due to the lack of homogeneity when it comes to carrying out the test; in fact, and under the protection of the same concept of LTT, tests are included in which both the method of sample extraction (capillary and venous) and the cutting points (1, 1.11 or 1.39<span class="elsevierStyleHsp" style=""></span>mmol/l), the dose of lactose (25 or 50<span class="elsevierStyleHsp" style=""></span>g), determination times (30, 45, 60, 90 or 120<span class="elsevierStyleHsp" style=""></span>min) and even the aforementioned test for the calculation of diagnostic efficacy<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> are different. In any case, the experience of our group shows that it is still an effective test to assess LM or LI situations, economical and easily available in any basic level health centre.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">HBTL</span> detects in exhaled air the hydrogen produced by the bacterial fermentation of the lactose which has escaped the complete absorption in the small intestine. It is considered pathological when it shows an increase in the levels of hydrogen above 20<span class="elsevierStyleHsp" style=""></span>ppm with regard to the baseline values. It is the most widely-used indirect method of LM diagnosis, due to its reliability, low cost and that it is non-invasive<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a>; its sensitivity and specificity oscillate between 80% and 100% and 70% and 100%, respectively,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">12</span></a> and as in the case of LTT, it can contribute clinical value by exposing the patient to a lactose overload. However, in addition to requiring 240<span class="elsevierStyleHsp" style=""></span>min to carry out, and material which is not available in many centres, it is possible to encounter false negatives (due to the incapacity of the intestinal flora to produce H<span class="elsevierStyleInf">2</span> after the ingestion of non-absorption carbohydrates, or after the recent administration of antibiotics) and false positives (caused by bacterial overgrowth). At present a joint measurement of H<span class="elsevierStyleInf">2</span> and CH<span class="elsevierStyleInf">4</span> in exhaled air is carried out, to avoid false negatives derived from the existence of a non-H<span class="elsevierStyleInf">2</span>-producing methanogenic intestinal flora. It is a good diagnostic method, complete and not at all invasive, with a major role in the paediatric community and in patients with a phobia of venipuncture, but with the disadvantages listed above (mainly that it takes a long time to carry out).</p><p id="par0035" class="elsevierStylePara elsevierViewall">There is a genetic test that analyses two polymorphic positions (−13910 C/T and −22018 G/A) in the patient's DNA, located in the regulatory region of the lactose-hydrolase gene (LCT), which determine the persistence or not of the lactose-hydrolase enzyme in adults. The genotype CC-13910/GG-22018 is associated with the non-persistence of this enzyme and therefore with hypolactasia in adult Caucasian patients. The demonstration of a homozygote genotype CC-13910 is a good predictor of intestinal lactase activity, while heterozygote should be considered negative, because LM is a recessive condition. In different studies carried out on the Caucasian population, a high degree of agreement has been reached with regards to the HBTL for the diagnosis of LM.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">13</span></a> Its disadvantages are a high cost, its low availability, its slight usefulness in African, Arab or Asiatic populations, in addition to not providing clinical information after exposure to lactose.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a> To summarise, it is a test that can contribute to the diagnosis of LNP in certain populations, and its differentiation from secondary causes, but on its own it is incapable of assessing the state of LI. It could be an important mainstay in the future, within LM and LI diagnostic algorithms, but aspects such as availability and price could count against it.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">Gaxilosa test</span> is a non-invasive diagnostic method based on the oral administration of a synthetic analogue of lactose (4-galactosyl-xylose). The intestinal lactase fragmented in analogue in 2 physiological products: galactose and <span class="elsevierStyleSmallCaps">d</span>-xylose. The latter is absorbed passively in the small intestine and its levels can be measured effectively in the blood or urine with a simple colorimetric method.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">15</span></a> The total amount of xylose in urine is correlated to the enzymatic activity of the intestinal lactase. Gaxilosa has a good diagnostic capacity, with sensitivity and specificity above 90%, and its advantages with regard to other existing diagnosis systems are its simplicity of application, the absence of discomfort for the patient and its quantitative character.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">16</span></a> However, it does not supply information about tolerance, there being no correlation between the degree of malabsorption (quantified in this test) and the degree of critical intolerance. This test could play an important role in the diagnosis of LM in diabetic patients without nephropathy, who cannot be subjected to a lactose overload, and even to explore the integrity of the intestinal mucus in patients with chemotherapy or coeliac disease; however, these potential uses will need to be confirmed in future studies.</p><p id="par0045" class="elsevierStylePara elsevierViewall">There is also a <span class="elsevierStyleItalic">symptom questionnaire</span> validated for the diagnosis of LI. It consists of 5 items (diarrhoea, abdominal pain, vomiting, intestinal noises and tympanites), which are assessed by means of an analogue visual scale of 10<span class="elsevierStyleHsp" style=""></span>cm (0 is the equivalent of the absence of symptoms and 10 is the maximum intensity of the symptoms). The global score of the questionnaire has a range of 0–50. A score of >7 is considered indicative of LI and ≤7 tolerant.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">17</span></a> In day-to-day clinical practice the absence of symptoms after the ingestion of 40–50<span class="elsevierStyleHsp" style=""></span>g of lactose allows the exclusion of LI due to the negative predictive high value.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">11</span></a> Sometimes, if symptoms appear, it is possible that it is a placebo effect, above all in patients without LM and in those with functional pathology or self-diagnosed with food intolerance or allergy.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> There are no specific symptoms that allow us to predict the presence of LNP, and the sensitivity and the specificity vary between 0% and 90% for symptoms such as bowel sounds, diarrhoea, tympanites and abdominal pain in different individual studies. In addition, the patient's perception of suffering from LI is unreliable, given that the sensitivity and specificity figures found oscillate between 30% and 70% and 25% and 87%, respectively.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">18</span></a> In a study recently-published by our group, we observed that the presence of diarrhoea after the overload of 50<span class="elsevierStyleHsp" style=""></span>g of lactose, independently of the intensity of the same, has a greater concordance with the genetic test than the LTT and the gaxilosa test. So much so that, when a patient suffers diarrhoea after an overload, they are 8 times more likely to have LNP than not.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In the current bibliography there is no clear consensus about which is the best diagnostic method for the detection of LM and LI, with very heterogeneous results from publications.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">20</span></a> It is likely that a strategy based on the combination and/or a sequential use of them is the ideal technique for the diagnosis of this disorder, but more research is needed to validate this. Therefore, the choice of one or another method depends on, among other factors, availability and cost. In any case, it is always preferable to use methods which provide more global information regarding the pathology, that is, that in addition to exploring the state of malabsorption are also capable of supporting the diagnosis of intolerance (LTT or HBTL together with symptom scales). A the same time, it is fundamentally important to know the limitations of all the existing processes and to have the capacity to be able to widen the necessary complementary explorations and studies in the case of clinical and analytical incongruence.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Domínguez-Jiménez JL, Fernández-Suárez A. Diagnóstico de la intolerancia a la lactosa. Med Clin (Barc). 2017;148:262–264.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0105" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Genetically defined adult-type hypolactasia and self-reported lactose intolerance as risk factors of osteoporosis in Finnish postmenopausal women" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "N. Enattah" 1 => "T. Pekkarinen" 2 => "M.J. Välimäki" 3 => "E. Löyttyniemi" 4 => "I. 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