우유 소화효소가 없는 사람들 질병을 일으키는 기전

[문형철]

영향력지수 31점 논문

Gut. 2019 Nov; 68(11): 2080–2091.

Published online 2019 Aug 19. doi: 10.1136/gutjnl-2019-318404

PMCID: PMC6839734

PMID: 31427404

Update on lactose malabsorption and intolerance: pathogenesis, diagnosis and clinical management

Benjamin Misselwitz,1 Matthias Butter,2 Kristin Verbeke,3 and Mark R Fox2,4

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Abstract

Lactose is the main source of calories in milk, an essential nutriedigestion, patients with visceral hypersensitivity nt in infancy and a key part of the diet in populations that maintain the ability to digest this disaccharide in adulthood. Lactase deficiency (LD) is the failure to express the enzyme that hydrolyses lactose into galactose and glucose in the small intestine. The genetic mechanism of lactase persistence in adult Caucasians is mediated by a single C→T nucleotide polymorphism at the LCTbo −13’910 locus on chromosome-2. Lactose malabsorption (LM) refers to any cause of failure to digest and/or absorb lactose in the small intestine. This includes primary genetic and also secondary LD due to infection or other conditions that affect the mucosal integrity of the small bowel. Lactose intolerance (LI) is defined as the onset of abdominal symptoms such as abdominal pain, bloating and diarrhoea after lactose ingestion by an individual with LM. The likelihood of LI depends on the lactose dose, lactase expression‎ and the intestinal microbiome. Independent of lactose digestion, patients with visceral hypersensitivity associated with anxiety or the Irritable Bowel Syndrome (IBS) are at increased risk of the condition. Diagnostic investigations available to diagnose LM and LI include genetic, endoscopic and physiological tests. The association between self-reported LI, objective findings and clinical outcome of dietary intervention is variable. Treatment of LI can include low-lactose diet, lactase supplementation and, potentially, colonic adaptation by prebiotics. The clinical outcome of these treatments is modest, because lactose is just one of a number of poorly absorbed carbohydrates which can cause symptoms by similar mechanisms.

유당은 

우유의 주요 칼로리 공급원이며, 

필수 영양소인 소화불량, 

유아기 내장 과민증 환자,

 성인이 되어서도 이 당류를 소화할 수 있는 능력을 유지하는 인구의 식단에서 중요한 부분을 차지합니다. 

락타아제 결핍증(LD)은 

소장에서 유당을 갈락토스와 포도당으로 가수분해하는 효소가 발현되지 않는 것을 말합니다. 성인

 백인에서 

락타아제 지속성의 유전적 메커니즘은 

염색체 2번의 LCTbo -13'910좌위에서 단일 C→T 뉴클레오티드 다형성에 의해 매개됩니다. 

유당 흡수 장애(LM)는 

소장에서 유당을 소화 및/또는 흡수하지 못하는 모든 원인을 말합니다. 

여기에는 

일차적인 유전적 원인뿐만 아니라 

소장 점막의 완전성에 영향을 미치는 감염이나 

기타 질환으로 인한 

이차적인 유당불내증도 포함됩니다. 

유당불내증(LI)은 

유당불내증 환자가 유당을 섭취한 후 

복통, 복부 팽만감, 설사 등의 복부 증상이 나타나는 것으로 정의됩니다. 

LI의 가능성은 

유당 섭취량, 

락타아제 발현 및 장내 미생물 군집에 따라 달라집니다. 

유당 소화와는 무관하게 

불안 또는 과민성 대장 증후군(IBS)과 관련된 

내장 과민증 환자는 이 질환의 위험이 높습니다. 

LM 및 LI를 진단하기 위한 진단 검사에는 유전자 검사, 내시경 검사, 생리적 검사 등이 있습니다. 자가 보고된 LI, 객관적인 결과 및 식이 요법의 임상 결과 사이의 연관성은 다양합니다. LI의 치료에는 저유당 식단, 락타아제 보충제, 프리바이오틱스에 의한 대장 적응 등이 포함될 수 있습니다. 유당은 흡수가 잘 되지 않는 여러 탄수화물 중 하나에 불과하며 유사한 메커니즘으로 증상을 유발할 수 있기 때문에 이러한 치료의 임상 결과는 미미합니다.

Keywords: lactase, malabsorption, functional bowel disorder, diet, hydrogen breath tests

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Introduction

Lactose metabolism continuous to fascinate anthropologists, geneticists, physiologists and clinicians.1–3 Studying the mechanisms of lactose digestion and intolerance has provided insights not only into dietary causes of functional intestinal symptoms but also into human evolution and nutrition, culture and lifestyle (box 1). Recent evidence has demonstrated the impact of lactose digestion on the human microbiota and general health. Considering these issues has raised possible concerns of a dairy-free diet. This review will emphasise recent developments in the clinical diagnosis and management of this condition (box 2).

유당 대사는 

인류학자, 

유전학자, 

생리학자 및 

임상의를 끊임없이 매료시키고 있습니다.1-3 

유당 소화 및 과민증의 메커니즘을 연구하는 것은 

기능성 장 증상의 식이 원인뿐만 아니라 

인간의 진화와 영양, 

문화 및 생활 방식에 대한 통찰력을 제공했습니다(상자 1). 

최근의 증거에 따르면 

유당 소화가 

인체 미생물총과 전반적인 건강에 미치는 영향이 입증되었습니다. 

이러한 문제를 고려하면 

유제품 없는 식단에 대한 우려가 제기될 수 있습니다. 

이 리뷰에서는 이 질환의 임상 진단 및 관리에 대한 최근의 발전을 중점적으로 다룹니다(상자 2).

Box 1 Pathophysiology of lactose malabsorption

• Lactose malabsorption is typically caused by lactase downregulation after infancy due to lactase non-persistence which in Caucasians is mediated by the LCT −13’910:C/C genotype.

• Lactase non-persistence is the genetic wildtype and not a disease. Both lactase persistence and non-persistence are common phenotypes in healthy humans.

• The lactase genetic region is among the genetic regions strongest shaped by human evolution within the last 10 000 years, with lactase persistence providing a selective advantage of up to 4%–5% per generation.

• The LCT −13’910 is the region within the human genome with the strongest interaction with the intestinal microbiota. The LCT −13’910:C/C genotype is associated with higher Bifidobacteria levels on lactose consumption (bifidogenic effect).

• Genetic and physiological studies suggest higher bone mineral density and larger height in individuals with lactase persistence.

박스 1 유당 흡수 장애의 병태생리
유당 흡수 장애는 일반적으로 유아기 이후 락타아제 비지속성으로 인한 락타아제 하향 조절로 인해 발생하며, 백인의 경우 LCT -13'910:C/C 유전자형에 의해 매개됩니다.

락타아제 비지속성은 유전적 야생형이며 질병이 아닙니다. 락타아제 지속성과 비지속성 모두 건강한 사람에게서 흔히 볼 수 있는 표현형입니다.

락타아제 유전자 영역은 지난 1만 년 동안 인류 진화에 의해 가장 강하게 형성된 유전자 영역 중 하나이며, 락타아제 지속성은 세대당 최대 4~5%의 선택적 이점을 제공합니다.

LCT -13'910은 인간 게놈에서 장내 미생물과 가장 강력한 상호작용을 하는 영역입니다. LCT -13'910:C/C 유전자형은 유당 섭취 시 비피더스균 수치가 높아지는 것과 관련이 있습니다(비피도제닉 효과).

유전 및 생리학적 연구에 따르면 락타아제 지속성을 가진 사람의 골밀도가 높고 키가 더 큰 것으로 나타났습니다.

•  Clinical relevance of lactose intolerance

  • Lactose intolerance is defined as symptoms on lactose exposure in individuals with lactose malabsorption.

  • Most individuals with lactose malabsorption tolerate a dose of at least 12 g lactose (corresponding to 250 mL of milk) without problems. Larger doses may be tolerated if consumed with food or spread over a whole day.

  • Symptoms of lactose intolerance depend on the strength of the stimulus (ie, lactose dose) and the presence of visceral hypersensitivity, as observed in many patients with IBS.

  • Treatment options for lactose intolerance include a low-lactose diet, oral lactase enzyme replacement, prebiotics that produce bacterial lactase in the colon and, potentially, prebiotics that adapt the colonic microbiota.

  • Intolerance of low–moderate lactose doses often indicates the presence of IBS. Such individuals are sensitive to a range of poorly absorbed, fermentable foods (‘FODMAPs’). Effective dietary treatment in this group requires not a low-lactose but a low-FODMAP diet.

  FODMAP, fermentable oligosaccharide, disaccharide and monosaccharide and polyols.

유당 불내증의 임상적 관련성
유당 불내증은 유당 흡수 장애가 있는 사람이 유당에 노출되었을 때 나타나는 증상으로 정의됩니다.

유당 흡수 장애가 있는 대부분의 사람은 최소 12g의 유당(우유 250mL에 해당)을 문제 없이 섭취할 수 있습니다. 음식과 함께 섭취하거나 하루 종일 섭취하면 더 많은 양을 견딜 수 있습니다.

유당 불내증의 증상은 자극의 강도(즉, 유당 용량)와 많은 과민성 대장 증후군 환자에서 관찰되는 내장 과민증의 존재 여부에 따라 달라집니다.

유당 불내증 치료 옵션으로는 저유당 식단, 경구용 락타아제 효소 대체제, 대장에서 박테리아 락타아제를 생성하는 프리바이오틱스, 잠재적으로 대장 미생물을 적응시키는 프리바이오틱스 등이 있습니다.

저-중등도 유당 불내증은 종종 과민성 대장 증후군(IBS)의 존재를 나타냅니다. 이러한 사람들은 흡수가 잘 되지 않는 다양한 발효 식품('FOD맵')에 민감합니다. 이 그룹의 효과적인 식이 치료를 위해서는 저유당이 아닌 저-FODMAP 식단이 필요합니다.

포드맵, 발효성 올리고당, 이당류, 단당류 및 폴리올.

Lactose is the main sugar in milk

Milk production by the mammary gland is a defining feature of mammals and lactose (‘milk sugar’; β-galactosyl-1,4 glucose) is the main source of carbohydrate in human milk and that of other mammals, except for sea lions and walruses which produce low volume, viscous and fatty lactose-free milk.4

Infants are uniquely adapted to lactose-based nutrition. In a randomised controlled study, infants fed with breast milk or lactose-based formula had higher levels of glucose and other nutrients (eg, amino acids) in the blood compared with infants with lactose-free formula.5 Lactose also seems to be the only monosaccharide or disaccharide that does not increase the risk of dental caries.6 In adults, dairy products account for approximately 14% of energy intake in Europe and North America. In recent years, the amount of milk consumed has slightly decreased in these regions. By contrast, in China and many developing countries, milk intake contributes only 4% to energy intake; however, consumption is increasing rapidly.3

Cow’s milk contains approximately 5 g lactose per 100 mL, equating to 12.5 g lactose in a typical serving size of 250 mL. Lactose is also present in cultured milk products such as yoghurt and cheese (the second-largest fermentation industry after alcohol).3 Yoghurt contains ≈50% of the lactose of unprocessed milk; whereas, cheese has low lactose content, especially if long-ripened products are consumed.3 Additionally, lactose powder is also a common additive in typical processed foods, enhancing the texture and flavour of sausages, gravy, margarines, bread, sauces, and many prepared meals (table 1).

유선에 의한 우유 생산은 

포유류의 특징이며 

유당('유당'; β-갈락토실-1,4 포도당)은 부피가 작고 점성이 있으며 

지방이 많은 유당이 없는 우유를 생산하는 바다사자와 바다코끼리를 제외한 

다른 포유류의 우유와 모유의 주요 탄수화물 공급원입니다.4

유아는 

유당 기반 영양에 독특하게 적응합니다. 

무작위 대조 연구에서 

모유 또는 유당 기반 분유를 먹은 유아는 

유당이 함유되지 않은 분유를 먹은 유아에 비해 

혈중 포도당 및 기타 영양소(예: 아미노산) 수치가 높았습니다.5 

또한 유당은 

충치 위험을 높이지 않는 

유일한 단당류 또는 이당류인 것으로 보입니다.6 

성인에서 유제품은 

유럽과 북미에서 에너지 섭취의 약 14%를 차지합니다. 

최근 몇 년 동안 이 지역에서는 

우유 소비량이 약간 감소했습니다. 

반면 중국과 많은 개발도상국에서는 우유 섭취량이 에너지 섭취량에서 차지하는 비중이 4%에 불과하지만 소비량은 빠르게 증가하고 있습니다.3

우유에는 

100mL당 약 5g의 유당이 함유되어 있으며, 

이는 일반적인 1회 제공량인 250mL의 경우 12.5g의 유당이 함유되어 있는 것과 같습니다. 

유당은 

요구르트와 치즈(알코올 다음으로 두 번째로 큰 발효 산업)와 같은 

배양유 제품에도 존재합니다.3 

요구르트는 

가공되지 않은 우유에 비해 

유당이 ≈50% 함유되어 있으며, 

치즈는 특히 오래 숙성된 제품을 섭취할 경우 유당 함량이 낮습니다.3 

또한 유당 분말은 

소시지, 그레이비, 마가린, 빵, 소스 및 

많은 조리 식품의 질감과 풍미를 향상시키는 

일반적인 가공 식품의 일반적인 첨가물입니다(표 1).

올리고당, 이당류 및 단당류와 폴리올.

Table 1

Lactose content in dairy products and foods (representative values are provided)

Food

Lactose content (g) per 100 g

Lactose content per typical serving (g)

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Lactose digestion and absorption

Digestion and absorption of lactose takes place in the small intestine (figure 1).7 8 Lactose is the main substrate of lactase-phlorizin hydrolase expressed on the brush border of villi with its highest expression‎ in the mid-jejunum. The enzyme spans the apical membrane of mature enterocytes and is made up of two identical extracellular 160 kDa polypeptide chains, as well as a short intracytoplasmic part. The alpha-glucosidase activity of this enzyme cleaves the milk sugar disaccharide into the monosaccharides glucose and galactose which are then actively transported into epithelial cells (enterocytes) by the sodium(+)/glucose (galactose) co-transporter (SGLT1). At higher concentrations, a second facilitative transporter (GLUT2) becomes involved.9 From the enterocytes, glucose moves into the surrounding capillaries by facilitated diffusion.

유당의 소화와 흡수는 소장에서 이루어집니다(그림 1).7 8 

유당은 

융모의 브러시 경계에서 발현되는 

락타아제-플로리진 가수분해효소의 주요 기질이며 

공장 중간에서 가장 많이 발현됩니다. 

이 효소는 성

숙한 장세포의 정단막에 걸쳐 있으며 

두 개의 동일한 세포 외 160kDa 폴리펩티드 사슬과 

짧은 세포질 내 부분으로 구성되어 있습니다. 

이 효소의 알파-글루코시다제 활성은 

유당 이당류를 

단당류인 포도당과 갈락토스로 분해한 다음 

나트륨(+)/포도당(갈락토스) 공동 수송체(SGLT1)에 의해 

상피 세포(장세포)로 활발히 운반합니다. 

농도가 높아지면 

두 번째 촉진 수송체(GLUT2)가 관여하게 됩니다.9 

장세포에서 포도당은 확산을 촉진하여 주변 모세혈관으로 이동합니다.

Figure 1

Physiology of lactose malabsorption. SCFA, short chain fatty acids.

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Lactase deficiency and lactose malabsorption

The terms relating to lactose metabolism are often mixed-up which may cause confusion (table 2). Lactase deficiency (LD) is the failure to express lactase at the brush border of the small intestine. Lactose malabsorption (LM) refers to any cause of failure to digest and/or absorb lactose in the small intestine. Lactose intolerance (LI) is the occurrence of symptoms such as abdominal pain, bloating or diarrhoea in LM patients after ingestion of lactose.

락타아제 결핍과 유당 흡수 장애

유당 대사와 관련된 용어는 종종 혼동되어 혼란을 야기할 수 있습니다(표 2). 

락타아제 결핍(LD)은 

소장의 브러시 경계에서 

락타아제가 발현되지 않는 것을 말합니다. 

유당 흡수 장애(LM)는 

소장에서 유당을 소화 및/또는 흡수하지 못하는 모든 원인을 말합니다. 

유당 불내증(LI)은 

유당 섭취 후 LM 환자에게 

복통, 복부 팽만감, 설사 등의 증상이 발생하는 것을 말합니다.

Table 2

Glossary with definitions related to lactase deficiency, lactose malabsorption and lactose intolerance

Concept

Definition

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Congenital lactase deficiency is a very rare paediatric condition that causes severe symptoms and failure to thrive in infants.10 The most common cause of LM in adolescents and adults is primary (genetic) lactase non-persistence (LNP). The activity of lactase in the small intestine reaches a peak at the time of birth but is reduced in most populations during childhood, a process which is thought to facilitate weaning. However, in some individuals, high activity of lactase persists, enabling consumption of large amounts of lactose also in adulthood. It should be emphasised that, worldwide, most individuals have LNP with phenotypic LD and LM (figure 2). Thus, LNP, LD and LM are not diseases but normal variants of human metabolism.11 Other causes of LM include secondary (acquired) LD, rapid small intestinal transit and small bowel bacterial overgrowth.

선천성 락타아제 결핍증은 

영아에게 심각한 증상과 성장 장애를 일으키는 

매우 드문 소아 질환입니다.10 

청소년과 성인에서 LM의 가장 흔한 원인은 

원발성(유전적) 락타아제 비지속성(LNP)입니다. 

소장에서의 락타아제 활동은 

출생 시 최고조에 달하지만 

대부분의 인구에서 어린 시절에 감소하며, 

이 과정은 이유식을 용이하게 하는 것으로 여겨집니다. 

그러나 일부 사람의 경우 

락타아제의 높은 활성이 지속되어 

성인이 되어서도 다량의 유당을 섭취할 수 있습니다. 

전 세계적으로 대부분의 개인이 표현형 LD 및 LM을 가진 LNP를 가지고 있다는 점을 강조해야 합니다(그림 2). 

따라서 

LNP, LD 및 LM은 질병이 아니라 

인체 대사의 정상적인 변형입니다.11 

LM의 다른 원인으로는 

이차성(후천성) LD, 

빠른 소장 통과 및 

소장 박테리아 과증식 등이 있습니다.

Figure 2

Worldwide preval‎ence of lactose malabsorption. Online supplement 1 breaks down the the evidence base in terms of the investigative modality used to acquire the epidemiological information (eg, genetic test and breath test). Online supplement 2 provides the complete reference list.

Supplementary data

gutjnl-2019-318404supp001.pdf

Supplementary data

gutjnl-2019-318404supp002.pdf

In case of LM (primary or secondary), undigested lactose comes into contact with the intestinal microbiota. Bacterial fermentation of lactose results in production of gasses including hydrogen (H2), carbon dioxide (CO2), methane (CH4) and short chain fatty acids (SCFA) that have effects on GI function (figure 1).

LM(1차 또는 2차)의 경우, 

소화되지 않은 유당이 

장내 미생물과 접촉합니다. 

유당이 박테리아에 의해 발효되면 

수소(H2), 

이산화탄소(CO2), 

메탄(CH4), 

단쇄지방산(SCFA) 등의 가스가 생성되어 

위장 기능에 영향을 줍니다(그림 1). (후천성) 

LD, 빠른 소장 통과, 소장 세균 과증식이 발생합니다(후천성)

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Lactose intolerance

Lactose malabsorption (LM) is a necessary precondition for lactose intolerance (LI). However, the two must not be confused and the causes of symptoms must be considered separately. Many individuals with LM have no symptoms after ingestion of a standard serving of dairy products (table 1) whereas others develop symptoms (‘intolerance’) such as abdominal pain, borborygmi (rumbling tummy) and bloating after lactose intake (figure 1). The onset of these symptoms is strongly correlated to the appearance of hydrogen gas during breath tests12. Further, undigested lactose in the small intestine lead to osmotic trapping of water and the osmotic load in the colon is increased about eightfold by fermentation of lactose to SCFA.13 14 Diarrhoea will result if the respective load of lactose exceeds the capacity of the colonic microbiota for fermentation or the SCFA load exceeds the colon capacity for resorption.15

The likelihood of developing symptoms after lactose ingestion is multifactorial (figure 3). Extrinsic factors include the amount of lactose ingested and whether dairy products are ingested with other foods that affect intestinal transit and the rate of lactose delivery to the colon. Intrinsic factors include expression‎ of lactase at the brush border of the small intestine, history of GI disorders or abdominal surgery and the composition of the intestinal microbiome. When incubated in vitro with lactose, faecal samples from lactose-intolerant subjects mediated faster and higher production of SCFA than samples from lactose-tolerant subjects.16 17 However, an impact of SCFA on symptoms has not been directly demonstrated in humans. Further, in the anaerobic environment of the intestinal tract, generation of reducing equivalents result in rapid hydrogen production, and in several clinical studies, the amount of gas production correlated with the presence and severity of intestinal symptoms.18 19 Other patient factors not directly related to lactose digestion are also associated with LI. These include the presence of anxiety disorders, high levels of psychosocial stress and the presence of functional GI disorders such as IBS (figures 3 and 4).

유당 흡수 장애(LM)는 

유당 불내증(LI)의 필수 전제 조건입니다. 

그러나 

이 두 가지를 혼동해서는 안 되며 

증상의 원인을 별도로 고려해야 합니다. 

유당불내증 환자 중 상당수는 

유제품 표준 섭취량(표 1)을 섭취한 후에도 증상이 나타나지 않는 반면, 

유당 섭취 후 복통, 보르보리미(배가 울렁거림), 복부 팽만감 등의 

증상('불내성')이 나타나는 사람도 있습니다(그림 1). 

이러한 증상의 시작은 

호흡 테스트 중 수소 가스의 출현과 밀접한 관련이 있습니다12. 

또한 소장에서 소화되지 않은 유당은 

삼투압에 의해 수분을 가두게 되고 

유당이 SCFA로 발효되면 

대장의 삼투압 부하가 약 8배 증가합니다.13 14 

유당의 각각의 부하가 

대장 미생물의 발효 능력을 초과하거나 

SCFA 부하가 대장 흡수 능력을 초과하면 

설사를 유발합니다.15

유당 섭취 후 

증상이 나타날 가능성은 

여러 가지 요인이 복합적으로 작용합니다(그림 3). 

외적 요인으로는 

섭취한 유당의 양, 

유제품을 장 통과에 영향을 미치는 다른 음식과 함께 섭취했는지 여부, 

유당이 결장으로 전달되는 속도 등이 있습니다. 

내재적 요인으로는 

소장 브러시 경계부에서의 락타아제 발현, 

위장 장애 또는 

복부 수술 병력, 

장내 미생물군 구성 등이 있습니다. 

유당과 함께 시험관 내에서 배양했을 때, 

유당 불내성 피험자의 분변 샘플은 

유당 내성 피험자의 샘플보다 

더 빠르고 더 높은 SCFA 생성을 매개했습니다.16 17 

그러나 

SCFA가 증상에 미치는 영향은 

사람에게서 직접적으로 입증되지 않았습니다. 

또한 장의 혐기성 환경에서 

환원 등가물의 생성은 

빠른 수소 생성을 초래하며, 

여러 임상 연구에서 가스 생성량은 

장 증상의 유무 및 심각도와 상관관계가 있는 것으로 나타났습니다.18 19 

유당 소화와 직접 관련이 없는 다른 환자 요인도 LI와 관련이 있습니다. 

여기에는 

불안 장애의 존재, 

높은 수준의 심리사회적 스트레스, 

IBS와 같은 기능성 위장 장애가 포함됩니다(그림 3 및 4).

Figure 3

Schematic model of the pathogenesis of lactose intolerance symptoms. In a given population, a fraction of individuals will have digestive dysfunction resulting in lactose malabsorption. Within this population, individuals with anxiety disorders or GI disease that increase visceral sensitivity are more susceptible to the lactose challenge. In this model, the risk of developing symptoms increases with lactose dose, severity of digestive dysfunction (lactose malabsorption) and visceral sensitivity. This model of disease is not restricted to lactose but is likely to be shared by other FODMAPs, fermentable oligosaccharides, disaccharides and monosaccharides and polyols.

유당 불내증 증상의 발병 기전에 대한 개략적인 모델. 

특정 인구에서 일부 사람들은 

소화 기능 장애로 인해 

유당 흡수 장애를 겪게 됩니다. 

이 집단 내에서 

내장 민감성을 증가시키는 불안 장애 또는 

위장 질환이 있는 개인은 

유당 과민증에 더 취약합니다. 

이 모델에서는 

유당 섭취량, 

소화 기능 장애(유당 흡수 장애)의 심각도 및 

내장 민감도에 따라 증상 발생 위험이 증가합니다. 

이 질병 모델은 유당에 국한된 것이 아니라 다른 FOD맵, 발효성 올리고당, 이당류, 단당류 및 폴리올에 의해 공유될 가능성이 높습니다.

Figure 4

Mechanistic model of lactose digestion in patients with lactase persistence and lactase deficiency illustrating the relationship between lactose malabsorption, visceral sensitivity and symptoms.

Products of lactose fermentation may also trigger extra-intestinal symptoms. A recent review of results from >2000 patients with a clinical diagnosis of functional GI disorders, reported a high frequency of neurological symptoms such as tiredness and headache after lactose or fructose ingestion.20 However, it is uncertain whether the occurrence of neurological symptoms was caused by LM, because these patients have a high preval‎ence of nonspecific somatic complaints21, there was no placebo control, no statistical relationship between H2 production and symptoms was present and no mechanistic explanation was provided.20

락타아제 지속성 및 락타아제 결핍 환자의 유당 소화에 대한 메커니즘 모델로 유당 흡수 장애, 내장 민감성 및 증상 간의 관계를 설명합니다.

유당 발효 산물은 장외 증상도 유발할 수 있습니다. 최근 기능성 위장 장애로 임상 진단을 받은 2000명 이상의 환자를 대상으로 한 연구 결과에 따르면 유당 또는 과당 섭취 후 피로, 두통과 같은 신경학적 증상이 높은 빈도로 보고되었습니다.20 그러나 이러한 환자들은 비특이적 신체 증상의 유병률이 높고21, 위약 대조군이 없었으며 H2 생산과 증상 간의 통계적 관계가 없었고 기계적인 설명이 제공되지 않았으므로 신경학적 증상 발생이 LM으로 인한 것인지 확실하지 않습니다.20

Epidemiology

A recent meta-analysis estimated the preval‎ence of LM worldwide at 68% with higher rates reported for genetic tests than hydrogen breath tests (HBTs).22 LM is lowest in Nordic countries (<5% in Denmark) and highest in Korean and Han Chinese populations (approaches 100%). Large variations in LM are seen on a regional level (figure 2),22 reflecting the underlying genetic heritage and preval‎ence of primary LD in these populations. Testing for LI is more complex and would require standardised hydrogen breath testing in large, carefully selected populations and, for this reason, the preval‎ence of LI is unknown.

최근 메타 분석에 따르면 

전 세계 LM 유병률은 68%로 추정되며, 

수소 호흡 검사(HBT)보다 유전자 검사에서 더 높은 비율이 보고되었습니다.22 

LM은 북유럽 국가에서 가장 낮고(덴마크의 경우 5% 미만) 

한국 및 한족 인구에서 가장 높습니다(100%에 근접). 

LM은 지역별로 큰 편차를 보이는데(그림 2),22 

이는 해당 인구의 근본적인 유전적 유산과 

원발성 LD의 유병률을 반영합니다. 

LI 검사는 더 복잡하고 신중하게 선택된 대규모 집단에서 표준화된 수소 호흡 검사가 필요하며, 이러한 이유로 LI의 유병률은 알려져 있지 않습니다.

Genetics

In the Caucasian population, lactase persistence (LP) is due to a gain-of-function mutation 13.9 kb upstream of the lactase gene (LCT-13’910:C→T, ‘‘T’ for tolerance’) on chromosome 2. This single nucleotide polymorphism (SNP) is far upstream of the protein forming unit within the intron of an unrelated gene (figure 5A).23 This mutation creates a new binding site for the transcription factor that promotes persistent lactase expression‎ after infancy.24

백인 집단에서 락타아제 지속성(LP)은 

염색체 2번의 락타아제 유전자 상류 13.9 kb에 있는 

기능 이득 돌연변이(LCT-13'910:C→T, ''T''는 내성을 의미함)에 기인합니다. 

이 단일염기다형성(SNP)은 관련 없는 유전자의 인트론 내 단백질 형성 단위의 훨씬 상류에 있습니다(그림 5A).23 이 돌연변이는 유아기 이후 지속적인 락타아제 발현을 촉진하는 전사인자의 새로운 결합 부위를 생성합니다.24

Figure 5

Genetics of lactose malabsorption. (A) Organisation of the lactase genetic locus on chromosome 2. The positions of the lactase gene (LCT) and the neighbouring genes aspartyl-tRNA synthetase (DARS), minichromosome maintenance complex component 6 (MCM6) and UBX domain-containing protein 4 (UBXN4) are indicated. Polymorphisms relevant for lactose malabsorption are located within intron 13 of the MCM6 gene, upstream of the lactase gene. (B) Differential levels of methylation of intron 13 of MCM6 and the LCT gene in individuals with genetic lactose malabsorption (LCT −13910:C/C), lactose tolerance (LCT −13910:T/T) and the clinically silent, physiologically intermediate genotype LCT −13910:C/T. Hypermethylation (red colour) results in genetic silencing of the respective gene. (Source: From Labrie et al 26).

Genetic LP is considered a dominant genotype, and only individuals with two LCT-13’910:C alleles should be considered to have LNP. However, heterozygotes with LCT-13’910:CT genotype may have higher H2 levels in the HBT than LCT-13’910:TT individuals.25 This intermediate phenotype might be relevant during nutritional challenges or intestinal diseases. By contrast, epigenetic regulation of the lactase gene appears to be critical. Methylation patterns in the region of the LCT-13’910:C/T polymorphism in small intestinal enterocytes strongly differ dependent on the genotype, from >80% modification with the LNP genotype to 20% with the LP genotype (figure 5B). It has also been shown that LCT promotor methylation is low after birth but increases in childhood in the presence of LCT-13’910:C but not LCT-13’910:T.26 Thus, LNP is a good example of a condition in which DNA sequence variations set the stage for age-dependent methylation which later results in a clinical phenotype, a mechanism that might be applicable also to complex diseases.27

The LCT-13’910:T SNP associated with LP in Europe and many near Asian regions resides on the same haplotype, indicating rapid spread of a single mutation.28 The mutation appears in prehistoric skeletons for the first time approximately 10 500 years ago in Anatolia with spread to Europe and Northern Africa over time in line with domestication of animals. In Africa and the Middle East, different mutations in the same genetic region are responsible for LP1 29 (table 3), indicating convergent evolution.

유전적 LP는 우성 유전자형으로 간주되며, LCT-13'910:C 대립유전자를 2개 보유한 개인만 LNP를 가진 것으로 간주해야 합니다. 그러나 LCT-13'910:CT 유전자형을 가진 이형 접합체는 LCT-13'910:TT 개인보다 HBT에서 H2 수치가 더 높을 수 있습니다.25 이 중간 표현형은 영양 문제나 장 질환과 관련이 있을 수 있습니다. 이와 대조적으로 락타아제 유전자의 후성유전학적 조절은 매우 중요한 것으로 보입니다. 소장 장세포에서 LCT-13'910:C/T 다형성 영역의 메틸화 패턴은 유전자형에 따라 크게 달라지는데, LNP 유전자형에서는 80% 이상 변형되는 반면 LP 유전자형에서는 20%까지 변형됩니다(그림 5B). 또한 LCT 프로모터 메틸화는 출생 후 낮지만 LCT-13'910:C가 있지만 LCT-13'910:T가 없는 경우 어린 시절에 증가하는 것으로 나타났습니다.26 따라서 LNP는 DNA 서열 변이가 연령에 따른 메틸화의 단계를 설정하여 나중에 임상 표현형을 초래하는 상태의 좋은 예이며 복잡한 질병에도 적용될 수 있는 메커니즘입니다.27

유럽과 많은 아시아 인근 지역에서 LP와 관련된 LCT-13'910:T SNP는 동일한 일배 체형에 존재하며 단일 돌연변이의 빠른 확산을 나타냅니다.28 이 돌연변이는 약 10 500 년 전 아나톨리아에서 처음으로 선사 시대 골격에 나타나고 동물의 가축화에 따라 유럽과 북부 아프리카로 시간이 지남에 따라 확산되었습니다. 아프리카와 중동에서는 동일한 유전자 영

Table 3

Genetic variations affecting lactase persistence and LM1

Mutation associated with lactase persistence

Geographic region

SNP

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*This mutation is in strong linkage disequilibrium with the LCT −22’018-A mutation. Mechanistic evidence indicates that the −13’910 mutation is responsible for lactase persistence.

LM,  lactose malabsorption;  SNP,  single nucleotide polymorphism.

Source: Adapted from Segurel and Bon 1

There is convincing genetic evidence for a strong selection pressure for LP. In a whole genome analysis of skeletons originating between 6500 and 300 BC, the LCT-13’910:T allele showed increasing preval‎ence over time.30 LP provided an advantage of up to 4%–5% per generation, which is one of the largest selection pressures observed for any gene in recent human evolution and is in the same order of magnitude as resistance genes for malaria (4%–9%), skin pigmentation in Europeans (3%) and genes associated with hypoxia response in Tibetan populations at high altitude.1

The ability to digest lactose after infancy made milk a source of nutrition (calories, protein) and clean water accessible to adults. This is likely to have been critical in periods of famine. However, why LP increased fitness to such a high degree is unclear since many individuals with LM can consume 250 mL of milk without developing symptoms, and processing of milk to yoghurt, cheese or butter decreases the advantage of LP further.31 Further, the ‘cost’ of LNP with generally mild abdominal symptoms seems modest and individuals with LNP may even benefit from milk consumption due to prebiotic activity of lactose on the colonic microbiota.1 Increased intake of vitamin D from milk could also provide a selective advantage, especially in Northern Europe with a high risk of vitamin D deficiency due to low ultraviolet exposure.3 32

Taken together, impressive selection pressure took place at the lactase genetic locus after the uptake of pastoralist farming, favouring LP in many regions worldwide; however, the specific advantage of milk consumption that increased survival and whether these are present only during times of dietary or health stress or continuously remain unclear.

LP에 대한 강력한 선택 압력에 대한 설득력 있는 유전적 증거가 있습니다. 

기원전 6500년에서 300년 사이의 골격에 대한 

전체 게놈 분석에서 LCT-13'910:T 대립 유전자는 

시간이 지남에 따라 유병률이 증가하는 것으로 나타났습니다.30 

LP는 세대당 최대 4~5%의 이점을 제공했는데, 이는 최근 인류 진화에서 관찰된 유전자 중 가장 큰 선택 압력이며 말라리아 저항 유전자(4%-9%), 유럽인의 피부 색소 침착(3%), 고산지대 티벳인의 저산소 반응과 관련된 유전자들과 같은 규모에 속하는 것입니다.1

유아기 이후 유당을 소화할 수 있게 되면서 

우유는 성인에게 영양(칼로리, 단백질)과 

깨끗한 물을 공급하는 원천이 되었습니다. 

이는 기근이 발생했을 때 

매우 중요했을 것입니다. 

그러나 

LM을 가진 많은 사람들이 

증상 없이 250mL의 우유를 섭취할 수 있고 

우유를 요구르트, 치즈 또는 버터로 가공하면 

LP의 이점이 더욱 감소하기 때문에 L

P가 왜 그렇게 높은 수준으로 체력을 증가시켰는지는 불분명합니다.31 

또한, 일반적으로 경미한 복부 증상을 보이는 LNP의 '비용'은 크지 않은 것으로 보이며, 대장 미생물총에서 유당의 프리바이오틱스 활동으로 인해 LNP가 있는 개인은 우유 섭취로 혜택을 볼 수도 있습니다.1 특히 자외선 노출이 적어 비타민 D 결핍 위험이 높은 북유럽에서는 우유를 통한 비타민 D 섭취 증가도 선택적 이점을 제공할 수 있습니다.3 32

종합하면, 

목축 농업이 도입된 후 

락타아제 유전자 좌위에서 인상적인 선택 압력이 발생하여 전 세계 많은 지역에서 LP를 선호하게 되었지만, 생존율을 높이는 우유 섭취의 구체적인 이점과 이것이 식이 또는 건강 스트레스가 있을 때만 나타나는지 아니면 지속적으로 나타나는지는 아직 명확하지 않습니다.

Go to:

Secondary lactose malabsorption

Secondary LM refers to the development of LM in individuals who are potentially able to digest lactose (ie, LP individuals).33 34 Lactase is situated at the tip of intestinal villi and thus vulnerable to intestinal injury, especially since new immature enterocytes are lactase deficient.6 As a consequence, secondary LM can complicate GI conditions including infectious gastroenteritis, IBD, coeliac disease and systemic sclerosis (SSc).

The incidence of secondary LM, which is often transitory, caused by infectious gastroenteritis is increased and can be clinically relevant,35 especially in infants for whom milk is the staple food. In a paediatric study (mean age 12 months) with 126 patients with rotavirus infection and 62 controls with rotavirus negative diarrhoea, LM was more frequent in the former group (60% vs 49%, p=0.002).36 Similarly, in adult patients with chronic diarrhoea after kidney transplantation, those with norovirus colonisation had a much higher risk for LM than a control group (100% vs 12.5%).37 A systematic review concluded that exclusion of lactose would reduce the duration of acute diarrhoea in children by up to a day and reduce ‘treatment failure’ (RR: 0.5, 95% CI: 0.4 to 0.7), variously described in studies as requirement for unscheduled intravenous fluid injection or persistent stool weight >30 g/ kg after 3 days.38

Similar but more persistent results are seen in IBD. In a meta-analysis, the overall OR for LM in patients with IBD was 1.6 (95% CI: 1.0 to 2.6, p=0.048), being highest in Crohn’s disease (CD) affecting the small bowel.39 In line with this observation, a paediatric study showed reduced lactase expression‎ in CD patients with the risk of LD correlated with villous atrophy.39 40 High preval‎ence of secondary LM has also been reported in other conditions that affect the mucosal integrity or function of the small bowel. Patients with a new diagnosis of coeliac disease often have a positive lactose HBT; however, many recover the ability to digest lactose after 6–12 months on a gluten-free diet.41Patients with SSc also have a high preval‎ence of LM on breath testing, a finding that is associated with more advanced disease.42 Secondary LD may complicate environmental enteric dysfunction (EED), a condition that affects mainly children in an environment with low resources, poor hygiene and poor nutrition. EED is characterised by intestinal atrophy and dysbiosis associated with enzyme deficiencies, malabsorption and malnutrition.43

이차성 유당 흡수 장애

이차성 LM은 

잠재적으로 유당을 소화할 수 있는 개인(즉, LP 개인)에서 

LM이 발생하는 것을 말합니다.33 34 

락타아제는 

장 융모의 끝에 위치하므로 장 손상에 취약하며, 

특히 새로운 미성숙 장세포는 락타아제가 결핍되어 있기 때문입니다.6 

결과적으로 이차성 LM은 

감염성 위장염, 

IBD, 

체강 질병 및 전신 경화증(SSc) 등의 GI 상태를 복잡하게 만들 수 있습니다.

감염성 위장염으로 인한 

이차성 LM의 발생률은 일시적인 경우가 많으며,35 

특히 우유를 주식으로 하는 유아의 경우 

임상적으로 관련이 있을 수 있습니다. 

로타바이러스 감염 환자 126명과 로타바이러스 음성 설사를 보인 대조군 62명을 대상으로 한 소아 연구(평균 연령 12개월)에서 LM은 전자의 그룹에서 더 자주 발생했습니다(60% 대 49%, p=0.002).36 마찬가지로, 신장 이식 후 만성 설사를 보인 성인 환자에서 노로바이러스 군집화가 있는 환자는 대조군보다 LM 위험이 훨씬 높았습니다(100% 대 12. 5%).37 체계적 문헌고찰에 따르면 유당을 배제하면 어린이의 급성 설사 기간이 최대 하루까지 줄어들고 '치료 실패'(RR: 0.5, 95% CI: 0.4~0.7)가 감소하는 것으로 나타났는데, 연구에서는 예정되지 않은 정맥 수액 주사 또는 3일 후에도 대변 무게가 30g/kg 이상 지속되는 것으로 다양하게 설명했습니다.38

IBD에서도 비슷하지만 더 지속적인 결과가 나타납니다. 한 메타 분석에서 IBD 환자의 LM에 대한 전체 OR은 1.6(95% CI: 1.0~2.6, p=0.048)으로 소장에 영향을 미치는 크론병(CD)에서 가장 높았습니다.39 이러한 관찰과 일치하는 소아 연구에서도 CD 환자의 락타아제 발현 감소와 융모 위축증의 위험이 상관관계를 보였습니다.39 40 소장의 점막 완전성 또는 기능에 영향을 미치는 다른 질환에서도 이차성 LM의 높은 유병률이 보고되고 있습니다. 새로 체강 질환을 진단받은 환자는 종종 유당 HBT 양성 반응을 보이지만, 글루텐이 없는 식단으로 6~12개월이 지나면 유당 소화 능력이 회복되는 경우가 많습니다.41 또한 호흡 검사에서 LM 유병률이 높으며, 이는 더 진행된 질환과 관련이 있습니다.42 이차성 LD는 주로 자원이 부족하고 위생 및 영양이 열악한 환경에서 어린이에게 영향을 미치는 질환인 환경 장 기능 장애(EED)를 복잡하게 만들 수 있습니다. EED는 효소 결핍, 흡수 장애 및 영양실조와 관련된 장 위축 및 장내 미생물 이상증상이 특징입니다.43

Lactose malabsorption and the microbiota

The human body harbours approximately 40 trillion bacteria with approximately 99% of the microbiome contained within in the human colon. Fermentation of lactose by saccharolytic (‘sugar digesting’) bacteria in individuals with LM can cause abdominal symptoms (figures 1 and 4). However, this process also has benefits. SCFA and other products of fermentation are required for colonic health and liberate additional calories from otherwise indigestible carbohydrates. Moreover, the intestinal microbiota adapts to facilitate intake of dairy products. As a result, although lactase expression‎ is not upregulated by lactose ingestion, regular consumption of lactose appears to reduce breath hydrogen excretion and reduced lactose intolerant symptoms.44 Both in vitro and in vivo studies demonstrate increases in Bifidobacteria and/or Lactobacilli that are considered to be healthy components of the microbiome.45 46 In a large study of healthy Japanese, the abundance of Bifidobacteria correlated positively with dietary dairy intake.47 As this population is 90%–100% LNP, this could reflect the effect of regular lactose intake on the microbiota; however, the reverse cannot be excluded.

Recent data point to interactions between human genes and the microbiota. In association studies between human genetic variations and the microbiota, to date, the association most consistently described is that between the LCT-13’910:C/T SNP and the abundance of Bifidobacterium.48–50 Such interactions might have practical implications because SCFAs produced by microbial fermentation of lactose are involved in immune regulation,51 glucose and lipid homeostasis,52 colonocyte differentiation53 with implications for homeostasis and gut-brain modulation.54 Taken together, some experts suggest that LNP subjects may have ‘more to gain than to lose’ by consumption of small amounts of lactose-containing foods.55

인체에는 

약 40조 마리의 박테리아가 서식하고 있으며, 

이 중 약 99%가 대장에 포함되어 있습니다. 

LM을 가진 사람의 당분 분해('당 소화') 박테리아에 의한 

유당 발효는 복부 증상을 유발할 수 있습니다(그림 1과 4). 

그러나 이 과정에는 이점도 있습니다. 

SCFA 및 기타 발효 산물은 

대장 건강에 필요하며 

소화가 잘 되지 않는 탄수화물에서 

추가 칼로리를 방출합니다. 

또한 장내 미생물 총은 

유제품 섭취를 용이하게 하도록 적응합니다. 

결과적으로 

유당 섭취에 의해 락타아제 발현이 상향 조절되지는 않지만, 

유당을 규칙적으로 섭취하면 호흡 수소 배설이 감소하고 

유당 불내성 증상이 감소하는 것으로 보입니다.44 

시험관 및 생체 내 연구 모두에서 마이크로바이옴의 건강한 구성 요소로 간주되는 비피도박테리아와 락토바실리가 증가하는 것으로 나타났습니다.45 46 건강한 일본인을 대상으로 한 대규모 연구에서 비피더스균의 풍부함은 식이 유제품 섭취와 양의 상관관계가 있는 것으로 나타났습니다.47 이 집단은 90~100% LNP이므로 규칙적인 유당 섭취가 미생물군에 미치는 영향을 반영할 수 있지만 그 반대일 가능성도 배제할 수 없습니다.

최근의 데이터는 인간 유전자와 미생물총 사이의 상호작용을 지적합니다. 현재까지 인간 유전자 변이와 미생물총 간의 연관성 연구에서 가장 일관되게 설명된 것은 LCT-13'910:C/T SNP와 비피도박테리움의 풍부함 사이의 연관성입니다.48 -50 이러한 상호작용은 유당의 미생물 발효에 의해 생성되는 SCFA가 면역 조절,51 포도당 및 지질 항상성,52 결장 세포 분화53 및 항상성 및 장-뇌 조절에 관여하기 때문에 실질적인 의미를 가질 수 있습니다.54 종합하면, 일부 전문가들은 LNP 대상자가 소량의 유당 함유 식품을 섭취함으로써 '잃는 것보다 얻는 것이 더 클 수 있다'고 제안합니다.55

Lactose intolerance and IBS

The relationship of LI and IBS has been extensively studied in a South Chinese population with near 100% LNP on genetic testing. A double-blinded, randomised, cross-over comparison of lactose tolerance at 10, 20 and 40 g lactose was performed in IBS patients with diarrhoea (IBS-D) and healthy controls.56 There was a very strong correlation between the appearance of hydrogen gas in the breath and reports of bloating, pain and other symptoms in patients with lactose intolerance. However, the correlation between the amount of hydrogen gas in the breath and the severity of symptoms was much weaker. Consistent with preliminary findings in a European population,57 a key observation was that the risk of symptoms and the severity of symptoms were greatly increased in IBS patients, especially at the low to moderate doses found in the normal diet. It is well known that many patients with functional GI disorders have psychological comorbidity and are hypersensitive to dietary and physical stimuli that affect the digestive tract. 21 58 Further work demonstrated that anxiety, visceral hypersensitivity (defined by rectal barostat) and high levels of gas production on breath tests all increased the severity of abdominal symptoms after ingestion of 20 g lactose.19 Moreover, mucosal biopsies from the ileum and colon showed increased numbers of mast cells and intraepithelial lymphocytes in lactose-sensitive patients and showed that the release of inflammatory cytokines (eg, tumour necrosis factor) after lactose intake was higher in this group than controls.59

These observations are similar to those in post-infective IBS58 and provide insight into the pathophysiological basis not only of food intolerance but, more generally, functional GI symptoms. IBS is a heterogenous condition; however, symptoms related to intake of food items with poorly absorbed, fermentable carbohydrates such as lactose are reported by up to 70% of patients with this diagnosis.60–62 Patients with LI and IBS complain of similar symptoms, have high rates of psychological comorbidity and markers of an activated innate mucosal immune system. Moreover, both respond to similar dietary interventions (see below). Together, this evidence suggests a common pathological basis in which a susceptible individual with a sensitive (‘irritable’) bowel develops symptoms when exposed even to a modest stimulus, such as low–moderate doses of lactose (figure 3).33

LI와 IBS의 관계는 유전자 검사에서 거의 100%에 가까운 LNP를 가진 중국 남부 인구에서 광범위하게 연구되었습니다. 설사를 동반한 유당불내증 환자(IBS-D)와 건강한 대조군을 대상으로 10, 20, 40g의 유당에 대한 이중 맹검, 무작위 교차 비교를 실시했습니다.56 유당불내증 환자의 호흡 중 수소 가스의 출현과 팽만감, 통증 및 기타 증상 보고 사이에는 매우 강한 상관관계가 있었습니다. 그러나 호흡 내 수소 가스의 양과 증상의 심각성 사이의 상관관계는 훨씬 약했습니다. 유럽인을 대상으로 한 예비 연구 결과와 일관되게,57 주요 관찰 결과는 IBS 환자, 특히 정상 식단에서 발견되는 저용량에서 중등도 용량에서 증상 위험과 증상의 심각성이 크게 증가한다는 것이었습니다. 기능성 위장 장애를 가진 많은 환자가 심리적 동반 질환을 가지고 있으며 소화관에 영향을 미치는 식이 및 물리적 자극에 과민 반응을 보인다는 것은 잘 알려져 있습니다. 21 58 추가 연구에 따르면 불안, 내장 과민증(직장 바로스타트로 정의), 호흡 검사에서 높은 수준의 가스 생성은 모두 유당 20g 섭취 후 복부 증상의 심각성을 증가시키는 것으로 나타났습니다.19 또한 회장과 결장의 점막 생검 결과 유당 민감성 환자에서 비만 세포와 상피 내 림프구 수가 증가했으며, 유당 섭취 후 염증성 사이토카인(예: 종양 괴사인자)의 방출이 대조군보다 더 높은 것으로 나타났습니다.59

이러한 관찰은 감염 후 IBS58에서 관찰된 것과 유사하며 음식 과민증뿐만 아니라 더 일반적으로 기능성 위장 증상의 병태생리학적 근거에 대한 통찰력을 제공합니다. IBS는 이질적인 질환이지만, 유당과 같이 흡수가 잘 되지 않는 발효성 탄수화물이 함유된 식품 섭취와 관련된 증상이 이 진단을 받은 환자의 최대 70%에서 보고됩니다.60-62 LI와 IBS 환자는 유사한 증상을 호소하고 심리적 동반 질환의 비율이 높으며 활성화된 선천성 점막 면역 체계의 마커를 가지고 있습니다. 또한, 두 질환 모두 유사한 식이 요법에 반응합니다(아래 참조). 이러한 증거를 종합하면, 민감한('과민성') 대장을 가진 취약한 개인이 저-중등도의 유당과 같은 가벼운 자극에도 노출될 때 증상이 나타나는 공통의 병리학적인 근거가 제시됩니다(그림 3).33

Lactose intolerance and quality of life

Like other functional GI disorders, LI is not a trivial condition but has a negative impact on quality of life and nutrition. Anxiety increases the risk of symptoms (‘intolerance’) after lactose ingestion, but the fear that food will trigger bloating, pain and diarrhoea is also a cause of anxiety. Indeed, in studies, not only patients with LI but also those with self-diagnosed LI who do not have the condition describe a lower quality of life than individuals without concerns about food intolerance.61 62 This anxiety generalises to other foods, and patients with LI often describe intolerance to a range of products, especially those known to cause bloating (eg, legumes and dried fruit).62 As a result, individuals might adopt a restrictive diet that could impact on health in a variety of ways.60 62 63 In severe cases, this form of behaviour is termed avoidant/restrictive food intake disorder by DSM-5, a form of eating disorder that is associated with weight loss but not with body dysmorphia.64

유당 불내증과 삶의 질

다른 기능성 위장 장애와 마찬가지로 LI는 사소한 질환은 아니지만 삶의 질과 영양에 부정적인 영향을 미칩니다. 불안은 유당 섭취 후 증상('불내성')의 위험을 증가시키지만, 음식이 팽만감, 통증 및 설사를 유발할 것이라는 두려움도 불안의 원인입니다. 실제로 연구에 따르면, LI 환자뿐만 아니라 자가 진단을 받은 LI 환자 중 증상이 없는 사람들도 음식 과민증에 대한 우려가 없는 사람보다 삶의 질이 낮다고 답했습니다.61 62 이러한 불안은 다른 음식으로 일반화되며, LI 환자는 종종 다양한 제품, 특히 복부 팽만감을 유발하는 것으로 알려진 제품(예: 콩류 및 말린 과일)에 대한 불내성을 설명합니다.62 결과적으로 개인은 다양한 방식으로 건강에 영향을 미칠 수 있는 제한적인 식단을 채택할 수 있습니다.60 62 63 심한 경우, 이러한 형태의 행동은 체중 감소와 관련이 있지만 신체 이상과는 관련이 없는 섭식 장애의 한 형태인 DSM-5에서 회피/제한적 음식 섭취 장애로 분류합니다.64

Testing for lactose malabsorption and intolerance

Five tests of lactose digestion are available, each of which investigates different aspects of the process and has specific advantages and disadvantages (table 4).

Table 4

Brief characterisation of the diagnostic tests available for lactose malabsorption

Hydrogen breath test

Lactose tolerance test

Duodenal lactase activity

Serum gaxilose or urine galactose test

Genetic test

Open in a separate window

LD, lactase deficiency; LI, lactose intolerance; LM, lactose malabsorption; LNP, lactase non-persistence; SIBO, small intestinal bacterial overgrowth.

Genetic tests apply real-time PCR or sequencing on DNA extracted from a venous blood or buccal swab sample and are most appropriate in epidemiological studies. In Caucasians, LP is nearly uniformly mediated by the LCT-13910:C/T polymorphism, and genetic testing can detect genetic LNP. However, the genetic situation is more complex in patients with African or Asian heritage (table 3) and genetic tests are currently not advocated in these populations for clinical purposes. Importantly, secondary LM will not be detected by genetic tests.

Tests for lactase enzymatic activities on intestinal biopsies will detect primary and secondary LM. While an endoscopy with sedation is not indicated for this purpose, this test can be performed if endoscopy is indicated for other reasons. It should be noted that lactase activity is patchy and more than a single biopsy may be required for optimal test accuracy.65

The lactose HBT measures the excretion of hydrogen in expiratory air after an oral challenge with a standard dose of lactose. As hydrogen is not produced by mammalian enzymes, its presence indicates contact of the sugar with bacteria indicating LM, although small intestinal bacterial overgrowth cannot be excluded. In clinical practice, an intermediate lactose dosage of 20–25 g may be optimal.56 66 Smaller amounts of lactose lack sensitivity for LM. Larger amounts used in epidemiological studies (eg, 40–50 g, figure 6) induce symptoms even in healthy individuals with LM that tolerate the amount of lactose present in normal diets (see below).56 A baseline H2 value <20 ppm is a requirement for a reliable test and an increase ≥20 ppm within 3 hours is diagnostic of LM.66 Reducing observation time impairs sensitivity; however, only four measurements (0, 90, 120, 180 min) are required for valid results.67 An H2-non-producing microbiota can lead to false-negative HBT. In some of these individuals, methanogenic bacteria (eg, Methanobrevibacter smithii) convert hydrogen to methane (CH4) in a 4:1 ratio resulting in lower H2 excretion and a lower fraction of positive tests.66 Simultaneous assessment of methane can partially overcome this limitation. Therefore, even though the increase in CH4 is often low (<20 ppm) and not correlated to symptoms, combined H2/CH4-measurements are recommended by some authors.66 68 A more reliable approach involves the use of 13C-lactose with simultaneous breath measurements of 13CO2 as a marker of lactose digestion and H2 as a marker of LM (figure 7); however, this technique is not available outside specialist centers.69

Figure 6

Symptoms in individuals with lactose malabsorption depend on lactose dose and visceral hypersensitivity. A population of Chinese individuals (100% primary lactase non-persistence) including HV with no history of abdominal symptoms and individuals with IBS-D was tested three times with different lactose dosages (10, 20 and  40 g) in a blinded fashion. The likelihood of a clinically positive HBT was higher in individuals with IBS-D for the low and the intermediate lactose dose. HBT,  hydrogen breath test; HV, healthy volunteers; IBS-D, diarrhoea-predominant  irritable bowel syndrome.  (Source: Adapted from Yang et al.56)

Figure 7

Results of a hydrogen breath test of an individual with lactose intolerance with simultaneous assessment symptoms and H2 levels, indicating lactose fermentation by the microbiota. An H2 increase by ≥20 ppm over baseline indicates lactose malabsorption. When 13C-labelled lactose is administered, 13CO2 levels indicate absorption and metabolisation of 13C-labelled lactose by the subject. Patient reports of abdominal symptoms subsequent to increases in these markers is diagnostic of lactose intolerance.

The lactose tolerance test measures glucose in plasma at different times (e.g. 0, 30, 60, 120 min) after ingestion of 50 g lactose. Although the test does not require complex or expensive equipment, its invasive nature (multiple blood samples) limits its utility. Use of capillary blood measurements with portable glucose metres makes the test less invasive but does not offer the same diagnostic accuracy as measurements in venous blood.70

The gaxilose test involves the administration of the lactase substrate gaxilose (4-galactosylxylose) with measurement of D-xylose in urine or blood. Conceptually, gaxilose measurements are ideal for assessment of intestinal lactase since activity over the entire small intestine is measured.71 In a manufacturer-sponsored trial, the diagnostic accuracy of gaxilose tests (0.93) was higher than HBT (0.85) or lactose tolerance tests (0.79) in comparison to duodenal biopsies.71 However, this was not confirmed in an independent study when the genetic test (LCT-13’910:C/T) was used as reference.72

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Testing for lactose intolerance

The major limitation of the genetic, enzymatic and gaxilose tests is that LM is common in healthy individuals, and a positive test does not confirm‎ that symptoms are caused by this condition. For this reason, in our practice, HBT is the method of choice because reasonably reliable information about digestive function and patient symptoms are obtained.

The diagnosis of LI requires appropriate testing of symptoms using validated questionnaires designed for the purpose.73 A National Institute of Health consensus conference defined LI as ‘the onset of GI symptoms following a blinded, single-dose challenge of ingested lactose by an individual with LM, which are not observed when the person ingests an indistinguishable placebo’,74 thus supporting the case for blinded testing of symptoms. Although rarely performed outside clinical studies, blinded testing might be useful since in clinical practice, the correlation between self-reported symptoms of LI and objective findings on tests for lactose digestion is low.62 Indeed, among individuals referred for HBT, about half of those with normal lactose digestion report abdominal discomfort after an unblinded lactose challenge.69 Further, intolerance to dairy products is reported by 20% of all individuals75 and up to 70% of IBS patients in European populations with low rates of genetic LNP.60

A ‘blinded multiple dose challenge’ would provide clarity not only regarding lactose digestion but also identify the amount of lactose that individuals could ‘safely’ consume (figure 6).56 Moreover, in subjects with known LNP, these could be performed at patients’ homes with a negative control, low and intermediate lactose challenge (eg, 12.5 and 25 g, corresponding to 250 and 500 mL milk, respectively).34 This could help educate patients because, in real life, it is self-reported intolerance and not the objective results of testing that best predicts food choices.62 However, to the best of our knowledge, blinded home-based testing has not been tested in routine clinical practice. The need for a well-accepted, practical and cost-effective investigation of food intolerance that predicts the outcome of dietary therapy is a key clinical challenge in functional GI disorders. The ability to predict the outcome of dietary therapy would be the measure for an appropriate symptom assessment.

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Therapeutic options

Therapy of lactose intolerance aims to improve patient symptoms and to avoid risk for undernutrition or malnutrition in the long term (figure 8). A diet low in lactose is typically recommended and this is supported by common sense and clinical evidence.56 However, in contrast to the management of sprue or food allergies, a strict lactose-free diet is not required since patients with LI often tolerate up to 250 mL milk (12 g lactose) without symptoms and more when consumed with food.31

Figure 8

Management of lactose malabsorption and lactose intolerance. FODMAPs, fermentable oligosaccharides, disaccharides and monosaccharides and polyols.

Improved lactose tolerance by manipulating the colonic microbiota could also be achieved by ingestion of prebiotics.44 A randomised placebo-controlled study in 85 LI patients reported that regular ingestion of short-chain galacto-oligosaccharides (GOS, RP-G28) tended to reduce H2 production and improve abdominal pain during lactose HBT. After 1 month, 30% of GOS-treated patients versus 6% of placebo-treated patients considered themselves lactose tolerant.76 Microbiological workup revealed a transient increase in lactose fermenting Bifidobacterium spp. on GOS treatment and a negative correlation between Bifidobacterium levels and abdominal pain, and re-introduction of milk prompted a further shift in bacterial composition, including an increase in the genus Roseburia.77

Lactose-free dairy products in which lactase is added to milk are widely available and considered safe, although allergic reactions have been reported.78 Lactase treatment of milk products also reduces crystallisation of lactose, increasing sweetness and fermentation for production of yoghurt.79 However, residual side proteolytic activity of lactase can degenerate casein and impair taste, especially after long storage.80

Lactase supplementation by tablets improves both lactose digestion (reduced H2 production) and symptoms81 82 although the effects are modest (eg, 18% with overall reduction of symptoms82). An alternative approach is to ingest probiotics such as Lactobacillus spp., Bifidobacterium longum or Bifidobacterium animalis that produce lactase in the gut. A recent systematic review of this treatment option confirmed an overall positive effect; however, the effect size was not consistently better than lactase supplementation and study quality was poor.83

In many clinical studies, only a minority of patients with LI on HBT report satisfactory improvement in symptoms after treatment to reduce intake of dairy products or supplement lactase. Moreover, it remains unclear, to what extent the therapy itself and conditioning of patient expectations contribute to outcome. Lack of improvement can also be due to the presence of functional bowel disorders, which are present in many patients referred for investigation. These patients are sensitive to various nutrients, mechanical and chemical stimuli and, therefore, rarely respond to restriction of dairy products alone.84

IBS patients develop symptoms after ingestion of a range of poorly absorbed, fermentable carbohydrates (fermentable oligosaccharides, disaccharides and monosaccharides and polyols (FODMAPs)) that includes but is not restricted to lactose even in LM patients.85 A low-FODMAP diet improves abdominal symptoms in 50%–80% of IBS patients.86 87 This dietary therapy requires commitment from the patient and is best delivered by professional dietician. Identification of factors predicting dietary outcome would improve compliance and cost-effectiveness of this intervention; however, in a large clinical study neither clinical presentation nor HBT results (high dose lactose 50 g or fructose 35 g) predicted response to the low-FODMAP diet.87 The response to an intermediate dose of a representative, non-absorbable FODMAP (eg, lactulose 20 g) that rarely c symptoms in health, but often induces bloating, abdominal pain and diarrhea in FGID patients may improve the ability of HBT to identify individuals that respond to this dietary intervention. Alternatively, bioassays to identify saccharolytic bacteria and/or fermentation capacity in faecal samples might be developed that predict outcome of lactose (or FODMAP) restriction in patients.88

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Long-term complications of lactose intolerance

Considering the objective effects of genetic LD on intestinal microbiota and recent human evolution (see above), LM and LI are likely to have a relevant impact on nutrition. Dairy products are valuable sources of protein, calcium and vitamin D.89 However, these nutrients can also be acquired from other food sources.

The relationship between lactose tolerance and height has been demonstrated, although some of this effect could be explained by population stratification.90 Daily milk consumption of 245 mL is associated with increased body height (0.39 cm, 95% CI: 0.29 to 0.48).90 Similarly, milk intake and LP have been linked with higher body mass index (BMI) in some studies.91

Effects of nutrition on health are difficult to address in interventional studies due to need for long-term follow-up, costs and limited compliance in patients. However, since LM in Caucasians is a monogenic condition (LCT −13’910C genotype), this question can be addressed by applying a Mendelian randomisation approach that limits confounding by social, environmental or behavioural factors. A recent study using this methodology confirmed higher milk consumption in individuals with genetic LP and this was associated with vitamin D levels which were 2.3-fold (OR: 1.6–3.4) lower in individuals with LCT-13’910:CC and 1.5-fold lower in LCT-13’910:CT compared with LCT-13’910:TT.92 Vitamin D is important for bone mineralisation and a separate meta-analysis showed a higher bone mineral density and a lower risk of fractures for TT versus CT/CC (OR: 0.81, 95% CI: 0.7 to 0.94, p=0.005).93 However, this finding was not confirmed in a European study that applied a similar study design.91

Results regarding other effects of milk consumption such as cardiovascular health and cancer are controversial.94 In a large Swedish study, individuals with high consumption of non-fermented milk and other dairy products had a higher all-cause mortality (HR: 1.32, 95% CI: 1.18 to 1.48); however, these results were not robust in the subgroup for which a Mendelian randomisation study could be performed.95 Some of these findings might be explained by an effect of LP on BMI (see above). In any case, these conflicting results are not surprising considering the complexity of the diet with regards to availability of lactose-free milk, intake of calcium, vitamin D, saturated fats, cholesterol, proteins and calories. Moreover, other genetic markers for lipid metabolism and polymorphisms of the vitamin D receptor might also impact on health.94 Additional studies with new approaches accounting for multiple nutrients and multiple genetic markers are needed to clarify the relationship of milk consumption, LM and long-term outcomes.

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Outlook

Primary genetic LP and non-persistence are common in healthy humans; however, ingestion of milk by individuals with LD leads to LM and, in susceptible patients, to symptoms of lactose intolerance. Diagnosis is based on detection either of the genetic mutation, loss of lactase activity in the enteric mucosa or evidence of malabsorption by breath tests. However, the association between self-reported LI, objective findings of tests and clinical outcome of dietary intervention is variable. Recent studies have provided important new insight into the complex relationship between LD, LM and symptom generation. This work has shed light on the important issue of food intolerance as a cause of symptoms in IBS and other functional GI disorders.

The development of a well-accepted, practical and cost-effective investigation of food intolerance that predicts the outcome of dietary therapy is one of the biggest clinical challenges in the field of functional GI disorders. Understanding the biological mechanism for food intolerance will help clinicians make a definitive diagnosis and guide rational dietary and medical management. Ongoing studies will provide high-quality evidence to document the clinical outcome, cost-effectiveness and long-term effects of these strategies.

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Acknowledgments

The authors would like to thank Professor Ning Dai, President of the school of medicine, Zhejiang University City College, and her team at the Sir Run Run Shaw Hospital in Hangzhou for their excellent work on the Sino–Swiss trials into the mechanism of lactose intolerance that inform key sections of this review referred to in this article. We thank also Dr Lars Fadnes of the Department of Global Public Health and Primary Care, University of Bergen, attached to Haukeland University Hospital. The figures and supplemental file were prepared by Lars Fadnes for this publication. His work collating epidemiological studies of lactose malabsorption and intolerance is presented in figure 2 and supplemental files.

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Footnotes

Contributors: MB and BM performed the literature search, collated the information and produced the first draft of the manuscript. KV and MRF contributed additional material and edited the publication. All authors discussed and revised the draft and approved the final version of the manuscript.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests: MF has received research funding from Nestlé International for studies of lactose digestion and tolerance.

Provenance and peer review: Commissioned; externally peer reviewed.

Collaborators: Professor Ning Dai, Department of Gastroenterology, Zhejiang University School of Medicine, Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China, 310016; E-mail: 2267454962@qq.com. Dr Lars Fadnes, Department of Global Public Health and Primary Care, University of Bergen and Bergen Addiction Research Group, Department of Addiction Medicine, Haukeland University Hospital, Post box 7804, 5020 Bergen, Norway (Web: http://www.uib.no/en/persons/Lars.Thore.Fadnes) E-mail: Lars.Fadnes@uib.no

Patient consent for publication: Not required.

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