# LACTOSE INTOLERANCE AND SMALL BOWEL BACTERIAL OVERGROWTH



## eric (Jul 8, 1999)

LACTOSE INTOLERANCE AND SMALL BOWEL BACTERIAL OVERGROWTH INIRRITABLE BOWEL SYNDROMESyed Thiwan, MDPostdoctoral Fellow, Instructor of MedicineINTRODUCTIONFunctional GI disorders are very common problems affecting the general population.They account for at least one-third of patient visits to a gastroenterologist and 12% ofvisits to a primary care physician(1, 2). Consequently, they are a significant burden onour nationï¿½s health care resources, but they also account for lost workdays. The directand indirect costs associated with these disorders are estimated to be at $8 billionannually(2). Next to dyspepsia, irritable bowel syndrome (IBS) is the most prevalentof all functional GI disorders. The prevalence of IBS varies depending on the criteriaused to define it, but it ranges from 4.3% to 21.8 % in most of the population-basedstudies(1). IBS is more prevalent among woman than men in most countries, at leastamong those who seek treatment for the disorder.IBS is defined as abdominal pain or discomfort in combination with any two of thefollowing three features: relief of abdominal pain or discomfort by defecation, onsetassociated with a change in stool frequency, or onset associated with a change instool form (consistency). These symptom-based criteria were developed by theRome II committee(1). This definition is based on a consensus of IBS experts. But, theoriginal Manning criteria for defining IBS were based on a study in which certainsymptoms predicted the diagnosis of IBS. Studies employing factor analysis (a type ofstatistical analysis) indicate that these symptoms constitute a naturally occurringcluster of symptoms, which identifies IBS as a distinct syndrome. This approach todiagnosis is somewhat different from the traditional approach in medicine, where adiagnosis is confirmed by various tests. However, the Manning model (i.e., symptomclusters) has been used for decades by the American Psychiatric Association andAmerican Rheumatologic Association(3).Since there is neither a specific biological marker nor a diagnostic test tocharacterize IBS, the pathophysiology of IBS has been a mystery to clinicians andinvestigators. Traditionally, physicians thought it was a motility disorder(abnormality of contraction and relaxation of intestinal muscles). The search for abetter understanding of IBS revolved around motility abnormalities until the laterpart of the last century. Since then, however, new phenomena -- such as visceralhypersensitivity (intestines have a low threshold for a stimulus such as balloondistension), altered gut immune function, autonomic nervous system dysfunction(part of the nervous system that controls our vital organs such as heart,gastrointestinal tract, etc.) and abnormal brain activation have been described. The(1)neurotransmitter Serotonin and itï¿½s receptor subtypes are believed to play key rolesin many of these processes. The model for IBS has evolved from being a purelyphysiological disorder into a biopsychosocial model in which physiological andpsychological factors interact to cause IBS. The approach to diagnosing IBS hasmoved from making a diagnosis by exclusion of any other disease, to making apositive diagnosis based on symptom-based criteria.Investigators have wondered whether IBS is a disorder with inherentpathophysiological abnormalities or whether some other diseases manifest withsimilar symptoms. This question has prompted investigators to search for specificconditions, such as lactose malabsorption or celiac disease and bacterial overgrowthin IBS patients. This article describes how lactose malabsorption and small bowelbacterial overgrowth play a role in IBS.LACTOSE MALABSORPTIONCarbohydrate malabsorption ï¿½ especially lactose and to a minor extent fructose ï¿½is an extremely common disorder with a high prevalence in many parts of the world.The prevalence in the United States is estimated to be at 7 to 20% in Caucasians, 80 to95% in Native Americans, 60 to 75% in Africans and African Americans, and 50%among Hispanics(4). Some Asian countries have a prevalence of lactose intolerance ashigh as 90%. It usually results from the loss of the enzyme lactase from the smallintestine after the age of 3-5 years. Apart from this ethnic distribution, there are casesof congenital deficiency transmitted as an autosomal recessive trait(5) and secondarycauses from mucosal diseases, such as viral gastroenteritis, Giardiasis, and others.Carbohydrate malabsorption also occurs in patients whose small intestinal mucosalabsorptive surface is damaged from other diseases, such as Crohnï¿½s disease, Celiacdisease, or small bowel resection. The usual symptoms are diarrhea, abdominal pain,bloating, and flatulence. Occasionally, it can present with vomiting and nausea. InAfrican Americans and Asians, the onset of symptoms is usually in early childhood,whereas among Caucasians it seems to occur later in childhood or adolescence.Lactose malabsorption is usually diagnosed by a lactose breath-hydrogen test wherethe confirmatory test is an assay of the enzyme lactase in small bowel mucosal biopsysamples. Lactose intolerance is diagnosed by a positive lactose breath test in thepresence of symptoms upon ingestion of lactose. Treatment usually entails restrictingor avoiding milk and dairy products and using commercially available lactasesupplements.ROLE OF LACTOSE INTOLERANCE IN IBSIS IT LACTOSE INTOLERANCE THAT CAUSES SYMPTOMS IN IBS PATIENTS?Studies have reported conflicting findings. Bohmer et al(6) reported a higherincidence of clinically unrecognized lactose malabsorption in IBS patients, althoughthere was no difference in symptoms between the groups with both negative andpositive breath tests. However, the symptom score improved in the lactose-restrictedgroup after six weeks. Another group(7) reported 40% and 35% prevalence of lactosemalabsorption by breath test and by lactase assay in jejunal biopsies respectively inIBS patients.Hamm et al(8) evaluated the utility of a battery of tests in a large number of patientswith IBS who met the Rome I criteria for at least six months; they found an incidenceof 23% of lactose malabsorption, which is similar to the incidence in the generalpopulation (25%). This is in marked contrast to the finding of Rana et al (9) whoreported an increased incidence of lactose malabsorption in IBS-diarrhea patients.Tolliver et al(10) found evidence of lactose malabsorption in 25.8% of 196 IBS patients,but only 48% of them were aware of this association. As they did not describe theethnic background of this population, an ethnic group with a higher prevalence oflactose malabsorption could explain this relatively higher incidence. Another studyby the same author(11) suggested that 29% of IBS patients had lactose malabsorption,but only 49% of them were aware of the association. After a mean period of 41months, although 87.2% reported avoiding lactose foods, there was no difference inIBS symptom severity between IBS patients with and without lactose malabsorption.While Cierna et al(12) found lactose intolerance in 24.3% of children with abdominalpain, Webster et al(13) found lactose malabsorption in 24% of children with recurrentabdominal pain (a condition that is the pediatric counterpart, or childrenï¿½s equivalentof IBS). Neither the prevalence nor the perception of symptoms in relation to lactosewas different in children with or without lactose malabsorption. However, thosechildren with malabsorption reported some improvement with a lactose-restricteddiet.In a group of referral patients, lactose related symptoms were equal in both lactosemalabsorbers (30%) and absorbers (36%), and the majority of them were unaware ofthe connection between dairy products and symptoms(14). One study showed thatmaking patients aware of their inability to absorb lactose led to a greater willingnessto participate in their care by changing their dietary intake; however, it did notchange the clinical outcome at all.Although the research literature is still inconclusive with respect to whether lactosemalabsorption is a cause or an exacerbating factor in IBS, it is the opinion of thisauthor that lactose malabsorption is a different disorder, which may mimic thesymptoms of IBS and lead to misdiagnosis, or lactose malabsorption may occur as acomorbid condition.OTHER CARBOHYDRATE MALABSORPTIONApart from lactose malabsorption, both the general population as well as IBS patientsreport intolerance to various other sugars as well. A study by Fernandez-Banares etal(15) addressed this issue by testing for lactose, fructose, sorbitol, sucrose andfructose plus sorbitol in both IBS patients and healthy controls. While there was ahigh degree (>90%) of sugar malabsorption of at least one sugar among bothpatients and controls, IBS patients had more symptoms with lactose and fructose plussorbitol along with increased H2 production. Restriction of offending sugars in thesepatients resulted in improvement in 40% of the patients. A recent study by Choi etal(16) showed a prevalence of 73% of fructose intolerance in a referral population(patients referred to a major hospital or a center) with unexplained abdominalsymptoms, which presumably included IBS patients. It is important to keep in mindthat fructose is poorly absorbed by virtually everyone, which is the reason it is usedas an artificial sweetener. It is not possible to conclude whether IBS patients absorbfructose more poorly than healthy individuals, but it is clear that high levels ofconsumption of any poorly-absorbed sugar can cause symptoms similar to IBS andthat limiting consumption may result in symptom improvement.POSTINFECTIOUS IBSPostinfectious IBS, originally described about three decades ago, has resurfacedagain in the recent years. Lactose malabsorption is touted as a possible etiology forpost-infectious IBS, because transient lactose intolerance has been known to happenin children after rotavirus infections. However, this is not the case with adult bacterialgastroenteritis in which postinfectious IBS usually develops and correlates with theseverity of gastroenteritis. This was shown by a recent study by Parry et al(17) fromNorthern England that showed no lactose intolerance in post-infectious IBS. Gwee etal(18) also reported lactose malabsorption was not an important factor in postinfectiousIBS, while psychological factors appeared to be more important in thepathogenesis.IS IT IBS THAT CAUSES SYMPTOMS IN PATIENTS WITH LACTOSEMALABSORPTION?Similarity of symptoms between lactose intolerance and IBS can not only confuse thepatient but can also fool the doctor. A study by Vesa et al(19) found that IBS is just asprevalent (15%) in lactose maldigesters as in lactose digesters. This study provides auseful insight into how IBS could interact with lactose enzyme deficiencies in theproduction of symptoms. In this study, among 427 patients who participated, 24%were lactose maldigesters based on a lactose tolerance test with ethanol. Among themaldigesters, 70% reported symptoms associated with dairy products containing20g of lactose or less, compared with 21% of the lactose digesters. However, amongthe 28.3% of patients who reported they got symptoms when they drank milk, only51.2% were maldigesters by objective testing, and 8.9% of the patients who reportedthat they could drink milk were found to be lactose maldigesters.Although a logistic regression (a type of statistical analysis) showed that lactosemaldigestion (objectively measured) was the primary factor (ten fold) in explainingself-reported symptoms of lactose intolerance, the presence of IBS was anindependent risk factor that increased the likelihood of reporting symptoms almostfive fold. Because of the visceral hypersensitivity that exists in the IBS population,these patients may report more symptoms in response to lactose containing milk thanhealthy controls even if they were not lactose maldigesters. Of the IBS patients, morewere women and more reported lactose intolerance (60%), while the percentage oflactose maldigesters was similar (24%) between IBS and non-IBS patients.Interestingly, patients who claim to be sensitive to lactose could tolerate moderateamounts of lactose without any symptoms but, at the same time, some lactoseintolerant patients report symptoms even after taking lactose-free milk. Some authorshave tried explaining this phenomenon by invoking a diagnosis of underlying IBS inthese patients. Johnson et al(20) reported that 77% of 22 African-American patientswith lactose maldigestion and intolerance were able to tolerate at least 12g or moreof lactose in milk (equivalent of 8 oz. or one cup of milk) if it was ingested ingradually increasing amounts. Another study by the same group of investigators(21)found that among 164 African Americans who claimed intolerance to one cup of milk,50% were lactose maldigesters and intolerant, 8% were maldigesters but tolerant,15% were digesters but intolerant, and 27% were digesters and tolerant. This studyclassically describes the heterogeneity (diversity) of this population with lactoseintolerance. Furthermore, one-third (33%) of 45 subjects from the lactose intolerantand maldigesting group in this study reported symptoms to both milk with reducedamounts of lactose and milk containing a normal amount of lactose.IS IT BOTH IBS AND LACTOSE INTOLERANCE?An Italian group of investigators(22) followed a cohort of IBS patients with lactosemalabsorption on a long-term lactose-free diet and found that among the people whowere compliant with the dietary regimen, 43.6% reported resolution of symptomswhile 39.1% reported that symptoms were somewhat reduced. Symptomatic lactosebreath test strongly suggested a favorable response to diet but did not predictwhether it would eliminate or reduce the symptoms. In this study, the prevalence oflactose malabsorption was 68.2%, which is consistent with incidence in the generalpopulation of Italy.Bolin et al(23) reported the prevalence of IBS and lactose malabsorption in 28% and40%, respectively, of 100 patients with chronic diarrhea and this indicates overlap ofboth conditions in at least some proportion of patients with chronic diarrhea.A double blind, crossover intervention trial was carried out in lactose intolerant IBSpatients in Mexico, where the prevalence of lactose malabsorption is high.Exogenous lactase supplementation was compared to placebo for three months. Thisstudy showed that GI symptoms persisted in spite of lactase treatment(24). Althoughpresence of IBS could explain the persistence of symptoms in these patients, it isdifficult to draw a conclusion from this study that lactase supplementation did nothave an effect on the symptoms at all. It is possible that small sample size and lack ofmonitoring for adherence to lactase supplements contributed to this finding of a lackof effect of lactase supplementation on GI symptoms in this study.SMALL BOWEL BACTERIAL OVERGROWTH (SBBO)Small bowel bacterial overgrowth is characterized by the presence of an abnormallyhigh number of bacteria in the upper gastrointestinal tract accompanied by poorabsorption of certain nutritional elements. It commonly occurs in patients withpredisposing conditions that are associated with abnormal GI passage due tomechanical factors (e.g. surgically defunctionalized loops of intestine, surgical loss ofthe ileocecal valve, partial bowel obstruction, and diverticuli) or abnormal motilitysecondary to a systemic disorder such as diabetes, scleroderma, or changes ingastric acid (post-gastrectomy). The usual symptoms are diarrhea, steatorrhea(greasy stools from poor absorption of fat), weight loss, bloating, and anemia.The definitive test for SBBO is to suction fluid from the small intestine (jejunum) andculture it to see which bacteria grow. However, this is an invasive procedure andpotentially misses some cases of bacterial overgrowth if it is restricted to the end ofthe small intestine. Consequently, SBBO is usually diagnosed by a breath test. Theclinical efficacy committee of the American College of Physicians has approved aone-gram 14C-D-xylose breath test for this indication. Treatment is usually a trial ofantibiotics, such as ciprofloxacin and metronidazole.ROLE OF SBBO IN IBSA study by Galatola et al(25) in 1991 showed that 29% of IBS patients without diarrhea(probably the constipation group), and 56% of those with diarrhea of obscure originhad an abnormal 1g-14C Xylose breath test. The authors concluded that thediagnostic value of this test for identifying causes of diarrhea is low, because it doesnot separate patients with diarrhea predominant IBS from IBS patients withoutdiarrhea.Almost a decade later, Pimental et al(26) reported a prevalence of SBBO of almost 80%among IBS patients. This was the first study to show such an association, and thisauthor suggested that SBBO is the cause for most cases of IBS. He believed SBBOcould account for the higher frequency of abnormal breath test in patients withobscure diarrhea in the Galatola study. In either case, this would be consistent withthe relatively poor association between diarrhea and an abnormal breath test. Thisstudy provoked a lot of criticism within the scientific community. There might havebeen a selection bias, since all of the patients included in the study had beenreferred for a lactulose breath test, presumably because the physicians who orderedthis breath test had some suspicion regarding SBBO in these patients. The mostserious concern is the possibility that the peak in breath H2 following lactuloseingestion was due to entry of the lactulose into the bacteria-rich colon, rather thandigestion of the lactulose by bacteria in the lowest part of the small intestine. Thiswould lead to the erroneous conclusion that the patient had SBBO, and it mightexplain the unusually high proportion of abnormal tests in this study compared to theexperience of other investigators. The investigators tried to avoid this mistake byrequiring that the patient show two distinct peaks in breath H2, presuming that thefirst would reflect bacterial digestion of lactulose in the small intestine and thesecond would reflect entry of the lactulose into the colon. However, this judgment isdifficult and error prone.Methane levels were not measured, undermining the sensitivity of the test. (Methaneis produced by bacteria that are present normally in the colon or that are presentabnormally in small intestine in certain conditions; they cleave carbohydrate andrelease H2 and methane.) Since constipation is an unlikely symptom of SBBO, thishypothesis of SBBO as the cause of IBS does not explain the IBS-constipation subtype.These were some of the other concerns of this study.A second study by the same author(27) tried to address some of these criticisms bydoing a double blind, randomized, placebo controlled study with antibiotictreatment. In this study, there was once again a high prevalence of 84% of abnormallactulose breath tests in a random sample of IBS patients (not patients who had beenreferred for testing because they had symptoms of SBBO). Methane levels weremeasured and a high methane excretion was correlated with IBS-constipation type.Successful treatment with neomycin resulted in improvement of the symptoms ofabdominal pain, constipation, and diarrhea, but only 20% of the study population haderadication of the bacterial overgrowth. These authors have postulated that theabnormal lactulose breath test may be either due to SBBO or due to relativelyexcessive enteric flora that is present in IBS patients, which may not be clinicallyadequate to call it SBBO.One of the inherent problems of the lactulose breath test is its low reproducibility,which certainly could have accounted for at least some of this treatment effect.Pimental and his colleagues tried to explain the constipation subtype by invoking arole for methane. But this could simply have been an association due to theconversion of H2 into methane in patients with constipation, as the colonic bacteriahas had more time to convert H2 to methane. Corazza et al(28) have tried to explainthe low H2 production and high methane excretion in constipated individuals asbeing due to poor fecal mixing which results in trapping of H2 in feces producing ahigh fecal H2 tension and rapid H2 consumption. This may result in higher excretionof methane, since most of the methane in the large intestine is derived from H2.Bond(29) and Flourie (30) have shown that methane-producing bacteria are mostlylocated in the left colon. Therefore, in patients with constipation, bubbles of methanecould be trapped in feces and released from the left colon into the blood stream.These findings need to be reproduced in other centers. If confirmed, this would leadto major changes in the basic understanding of SBBO traditionally thought to occuronly in predisposed patients due to abnormal motility or mechanical factors such asblind loop, partial intestinal obstruction or achlorhydria (lack of acid in stomach) andit would change our understanding and management of IBS. One way to confirmthese findings would be to repeat the study with a better test such as the 1g-14cXylose breath test, which has better sensitivity and specificity, along with transitmeasurement. Over all, the jury is still out as to whether SBBO could explain thesymptoms of IBS.CONCLUSIONThe degree and nature of symptoms of even the completely lactose intolerant patientare very variable. In addition, patients with partial lactase deficiency will havevariable symptom presentation. It is interesting to note that most of the studiesquoted a prevalence of lactose malabsorption in IBS patients that is similar to theprevalence in the general population. Moreover, neither the controlled double blindtreatment trial with lactase supplements nor the long-term lactose-free diet had anymeaningful effect on the outcome of IBS patients. This points to the conclusion thatboth of these conditions are widely prevalent and naturally coexist, which explains alot of the discrepancy noted in the studies.Most experts agree that lactose malabsorption and IBS can coexist, since both ofthem are very common disorders; the presence of one does not rule out thepossibility of the other. So, it makes sense to ask about the history of lactoseintolerance in all patients with IBS, and it is worth a try to put those with intoleranceon a trial of lactose-free diet. It is reasonable to continue them on that diet if theyshow at least a partial positive response. Clinicians should also remember to askpatients about their diets to identify those whose symptoms are due to excessconsumption of artificial sweeteners that are poorly absorbed.In terms of small bowel bacterial overgrowth, more data are needed to understandthe possible association between SBBO and IBS. Future studies should confirm thediagnosis of SBBO by a definitive test, such as jejunal fluid culture, preferably with atransit study or radiological studies to look for predisposing conditions in IBS. Longtermfollow up of these patients is also needed, since these patientsï¿½ symptoms areknown to wax and wane over time.References:1. 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