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Small intestinal bacterial overgrowth syndrome
GASTROENTEROLOGY
CLINICAL
1981;80:834-45
CONFERENCE
Small Intestinal Bacterial Overgrowth Syndrome JOHN G. BANWELL, Moderator PARTICIPANTS: LANE A. KISTLER, FREDRICK L. WEBER, Jr., ARTHUR DEBORAH E. POWELL
RALPH LIEBER,
A. GIANNELLA, and
Division of Gastroenterology, Department of Medicine, University of Kentucky College of Medicine, Lexington, Kentucky: and Veterans Administration Medical Center, Lexington, Kentucky
Introduction JOHN
G. BANWELL,
M.D.
The patient serving as a focus for our discussion had many symptoms and findings characteristic of the proliferation and overgrowth of a bacterial microflora in the small intestine. This syndrome has been recognized by several descriptive terms: blind-loop syndrome (BLS), small intestinal stasis syndrome, contaminated small bowel syndrome, and stagnant loop syndrome. Each emphasizes that alterations in intestinal structure or function permit the development of an abnormal small bowel flora which is the major pathophysiologic determinant of those clinical features which distinguish the syndrome (l-4). The classic syndrome is characterized by megaloblastic anemia due to vitamin B,, deficiency, and weight loss and diarrhea due to fat malabsorption. There are many causes for the syndrome. With each, there is some disruption or normal processes which prevent small intestinal bacterial overgrowth, such as intestinal motility, mucosal antibacterial defenses, and gastric acidity (5). The syndrome may occur at all ages but is primarily recognized in later life. It also may occur in a less florid manner when associated with or superimposed on other disorders of the gastrointestinal tract. Case Presentation LANE
A. KISTLER,
M.D,
A 55yr-old white male was admitted to the University of Kentucky Medical Center. He had felt Received September 22, 1980. Accepted December l5, 1980. Address requests for reprints to: John G. Banwell, M.D., Division of Gastroenterology, Department of Medicine, University of Kentucky College of Medicine, Lexington, Kentucky 40536. 0 1981 by the American Gastroenterological Association 0016-5085/81/040834-12$02.50
entirely well until 18 mo before admission when intermittent constipation developed. This was accompanied by abdominal bloating and occasional postprandial vomiting. The voluntary consumption of low-residue foods failed to control these symptoms. Diarrhea developed and progressed in severity until he was passing 12-24 watery brown stools/24-h period. He gradually lost weight from a normal 230 lbs. to 130 lbs. at the time of admission. His past medical history included an appendectomy in 1962 and a myocardial infarction in 1972. He complained of infrequent exertional chest pain readily relieved by nitroglycerin. At physical examination the patient appeared wasted with evident loss of subcutaneous tissue and skeletal muscle mass. Weight 59 kg (130 lbs.); height 154 cm. Vital signs were normal: there was no postural blood pressure change. The skin and mucus membranes were normal. There was no abdominal distension. Intestinal rushes were “audible across the room.” One examiner felt a right lower quadrant mass. There was no organomegaly. Rectal examination was normal; the stool was negative for occult blood. Mild lower extremity edema was present. Ophthalmoscopic, neurologic, and the remainder of the physical examination were normal. Laboratory studies revealed: hematocrit 35% hemoglobin 11.8 g/dl, WBC 8300 cells/ml; sodium 133 mEq/L; potassium 3.1 mEq/L; chloride 90 mEq/L; carbon dioxide 25 mEq/L; calcium 3.5 mEq/L; and phosphorus 3.0 mEq/L. Total proteins were 5.1 g/dl; albumin 1.9 g/dl; serum iron 70 pg/dl; and total iron binding capacity 105 pg/dl. Urinalysis, prothrombin time, BUN, glucose, SGOT, SGPT, LDH, alkaline phosphatase, and total bilirubin were normal. A
April 1981
BLIND-LOOP SYNDROME
Table 1A. Laboratory Data
Radiologic Findings ARTHUR
Results Investigative
procedure
Serum carotene (>40 ,ug/dl) D-xylose urinary excretion (>4.5g/5h) Fecal wet weight (~200 g/day) Fecal fat excretion (t7 g/day) Vitamin B1* absorption test (Schilling test) (>8% absorption) Vitamin B1* absorption test (with intrinsic factor) Wr-labeled albumin excretion (~0.7% fecal excretion/r? days)
835
On admission
After recovery
25 &dl 1.7g 870 g 30s 0.3%
72 pg/dl 4.4g 153 g 7.8 g 28%
1.1%
-
2.85%
-
Laboratory tests of (A) digestive and absorptive function, (B) jejunal bacterial flora, performed before and after surgical resection of an ileal carcinoid stricture in a patient with small bowel bacterial overgrowth syndrome.
screening test for urinary 5-HIAA excretion was negative. Laboratory tests evaluating small intestinal digestion and absorption are presented in Table 1A. The results of quantitative bacteriologic culture of small intestinal fluid are presented in Table 1B. These findings were consistent with a diagnosis of a small intestinal bacterial overgrowth syndrome. Radiologic investigation revealed a distal small bowel obstruction (vide infra). The patient underwent abdominal exploration. At operation, a 3 x 3cm obstructing tumor was detected in the distal ileum. Bowel loops proximal to the lesion appeared chronically dilated; the short segment of ileum distal to the obstruction and the colon were normal. A large lymph node at the base of the mesentery was biopsied and showed an undifferentiated tumor consistent with carcinoid. A small bowel resection with total excision of the tumor mass and end-to-side ileoileostomy was performed. Postoperative recovery was uneventful. All gastrointestinal symptoms resolved, and over the next few months the patient regained 54 lbs. in weight. He was subsequently admitted to UKMC for reevaluation. At this time he felt entirely well. He had no abdominal pain and complained of no features suggesting the carcinoid syndrome. Laboratory results showed a hematocrit of 50%; SGOT, SGPT, LDH, alkaline phosphatase, and total bilirubin were normal. A 24-h urinary 5-HIAA excretion was 6.6 mg (normal 2.2-10.0 mg). Total protein was 7.1 g/dl; albumin was 4.2 g/dl. Other laboratory data are presented in Table 1A and the results of small bowel culture are presented in Table 1B. A small bowel series and liver scan were normal.
LEIBER, M.D.
Anteroposterior films of the abdomen showed scattered, mildly dilated, small bowel loops associated with widespread air-fluid levels. A barium enema was normal, but barium refluxed into only a very short segment of terminal ileum. Upper gastrointestinal and small bowel series showed a normal stomach, and duodenum. Transit esophagus, through the small bowel was prolonged, and dilated small bowel loops extended to the distal ileum where a short, narrowed, small bowel segment was encountered on the 6-h films (Figure 1A and 1B). An impression of some loops converging towards this narrowing suggested that a partial volvulus might be present. An intravenous pylogram was normal. A chest x-ray was consistent with healed granulomatous disease. The finding of a partial lower small bowel obstruction might have been due to a variety of inflammatory or neoplastic causes, including an ileal carcinoid tumor. When small, intestinal carcinoids may present as sharply defined submucosal lesions which are difficult to detect on a routine small bowel examination. Later, most small bowel carcinoids grow eitraluminally, infiltrating the bowel wall, lymphatic channels, and eventually regional lymph nodes and mesentery. The local release of serotonin and other chemical agents may be responsible for the hypertrophic muscular thickening and the severe fibroblastic proliferation known to develop at this time. The radiographic findings are usually nonspecific and depend on the degree of desmoplastic response as well as on the size and location of the mesenteric tumor. A small bowel study at this time may show diffuse luminal narrowing, separation of intestinal loops and fixation and retraction producing localized abrupt angulation. Intraluminal growth with
Table
1B.
Bacteriologic
Data”
On admission
After recovery
Total aerobes Strep. fecalis Streptococci [other) Staph. Aureus Staph. Albus. E. coli Lactobocilli Serratia
8.1x 10R 6 XIOe 8 X 10’ 4 x 103 6 X104 8 X 10' 2 x lo8 0
6 X104 0 6 X10 8 Xl@ 2 x10' 0 0 2.6 X lo3
Total anaerobes Bifidobacteria Streptococci Bacterioides
1.4x 108 6 X 10’ 6 X lo7 8 X lo7
6.8x 104 5.4x 104 1.4x 104 0
0 Per milliliter jejunal aspirate.
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Figul pe 1. A. A 6-h film from a small bowel series shows marked dilatation of small bowel with the probable point of obstruction in the distal ileum. Some intestinal loops seem to converge towards a central point. B. Spot film of the distal ileum showing an area of narrowing with dilated bowel proximal to
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BLIND-LOOP SYNDROME
837
Figure 2. A. Distal ileum. The resected portion of ileum measured 155 cm. Arrow denotes area of constriction which is seen opened below (Figure ZB). Ileum proximal to this is dilated. B. Opened ileum at area of constriction (orrow). Note mass in this area. Dilated bowel is proximal to tumor mass. C. Photomicrograph of tumor showing sheets of cells with a prominent cribiform pattern characteristic of ileal carcinoid (H & E stain, x 100).D. Higher magnification photomicrograph of tumor showing regular cells with small nuclei and lack of nuclear atypia (H & E stain, X 400).
mucosal destruction leads to development of a short obstructive annular segment that may mimic primary adenocarcinoma or even inflammatory bowel disease (6). Pathologic
Findings
DEBORAH E. POWELL, M.D.
The segment of distal ileum with its attached mesentery measured 155 cm in length. Approxi-
mately 35 cm from the distal margin of resection, a firm, yellow-white, 3 x &cm tissue mass extended around one-half the circumference of the bowel. It constricted the wall and lumen in this area and extended into the mesentery (Figure 2). The small bowel proximal to the mass was significantly dilated, measuring 12 cm in circumference, as contrasted to the distal segment which measured 4 cm in circumference. Histologic sections of the mass showed a tumor composed of sheets and cords of
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uniform cells with central regular nuclei and a prominent focal cribiform pattern very characteristic of a carcinoid tumor. Many of the tumor nests were surrounded by dense fibrous tissue. Invasion of tumor cells into lymphatic or small vascular spaces was easily identified and 2 of 24 mesenteric lymph nodes contained metastatic tumor. Medium-sized arteries in the submucosa showed some intimal proliferation. A small-intestinal biopsy specimen showed a preserved villous pattern. An increased number of lymphocytes and plasma cells were observed within the lamina propria, but there were no alterations of the surface epithelium by light microscopy.
Diagnosis LANE
A. KISTLER,
M.D.
The blind-loop syndrome should be considered in any patient who has diarrhea, anemia, steatorrhea, and weight loss and should be especially suspected in any person with a known predisposition to this disorder as listed in Table 2. Once considered, the syndrome should be defined by procedures which (a) measure small-intestinal absorption (urinary D-xylose excretion, stool Sudan II stain, quantitative fecal fat collection, vitamin B,, absorption tests) and (b) detect significant small-intestinal bacterial overgrowth. Although tests for malabsorption are standard, clinically appropriate procedures for detecting bacterial overgrowth have been difficult to define. There are no simple specific screening tests available. Intestinal intubation and culture of aspirated intestinal fluid is the definitive procedure but requires careful collection, prompt handling, and aerobic and anaerobic culture (4). Diagnosis depends on the demonstration of abnormal concentrations (greater than 10” organisms/ml and usually greater than lOa organisms/ml) of both aerobic and anaerobic bacteria. Unfortunately, clinical laboratories are often ill-prepared for such thorough bacteriologic study of infrequent specimens. There is a need for procedures which allow a more simple approach to diagnosis. For this reason, indirect techniques have been proposed. Analysis of intestinal aspirates for the presence of deconjugated bile acids (7) and volatile fatty acids (8), and for their ability to deconjugate bile acids in vitro (7) has been suggested to avoid the problems of rigorous culture. However, these methods require intubation and moderately sophisticated biochemical methods for success and have not yet found widespread use in clinical practice. Noninvasive, indirect tests are appealing but have not yet achieved standard clinical use. These tests rely on specific properties of intestinal bacterial metabolism. They detect volatile bacterial metabolites
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of two types: “CO, released from deconjugated [“C]glycocholic acid or from [Ylxylose and hydrogen released by bacterial degradation of intestinal carbohydrates (9). Bile acid breath tests do not distinguish bacterial overgrowth from ileal mucosal disease and have a false-negative rate as high as 30% (10). The xylose breath test has promise (11) but will require further validation before being recommended for widespread use. Development of convenient techniques utilizing mass spectroscopy may permit more universal use of stable isotopes (‘“C) in these tests, eliminating the small radiation hazard to children and young adults (12). Breath hydrogen analysis by gas-liquid chtomatography may be clinically useful. Encouraging reports by Metz et al. using lactulose and glucose as test carbohydrates to induce hydrogen production by small intestinal bacteria are interesting (13). Further studies should be encouraged to both exclude false-positive results which occur when substrate enters the colon and false-negative results which occur when organisms associated with overgrowth are unable to generate hydrogen. Antibiotic administration as a diagnostic trial is not reliable but may, on rare occasion, be necessary in those who refuse or those who cannot have intestinal intubation.
Causes and Pathophysiology RALPH
A. GIANNELLA,
M.D.
The normal proximal small intestine is sparsely populated with bacteria, i.e., 103-10“ (lOOO10,000) bacteria per milliliter, with streptococci, staphylococci, diphtheroids, and fungi predominating. The concentration of organisms increases distally, and coliforms appear in the lower ileum. The concentration of organisms in the terminal ileum is approximately lo’-108/ml. On crossing the ileocecal valve, bacterial concentration increases to lo’-10” organisms per gram and strict anaerobes become the predominant species (14,15).
Table
2.
Disorders
Causing
Bacterial
Overgrowth
Structural
Surgical
loops-Bilroth II, entero-enter0 ileal bypass, continent Duodenal or jejunal diverticula Strictures-Crohn’s Disease, radiation Adhesions Tumors Gastrojejunocolic fistula Functional-Motility Disturbances Intestinal scleroderma Idiopathic pseudoobstruction Diabetic enteropathy Aged gut (?)
anastomosis, ileostomy enteritis
jejuno-
April 1981
A variety of mechanisms function to control and limit the bacterial population of the small intestine. The most important of these appears to be normal peristalsis by which the small intestine cleanses itself. Other factors controlling small intestinal flora include normal gastric acid secretion, bacterial growth inhibition by bile, luminal pH and oxidationreduction potential, and metabolic interactions between bacteria (14,15). These additional mechanisms are poorly understood and are of uncertain importance. A large number of anatomic and motor disorders of the small intestine are associated with bacterial overgrowth and the blind-loop syndrome. These are listed in Table 2. One should emphasize that these diverse conditions all share as a common feature the stasis of small bowel contents which allows bacterial overgrowth to occur (1,2,4,15). The bacterial flora in the small bowel of persons with bacterial overgrowth differs from normal in a number of ways. The concentration of organisms is usually much higher than normal, lo’-1O1* organisms/ml, and the flora is a complex mixture of large numbers of different bacteria. In general, the predominant flora are coliform organisms and strict anaerobes, such as bacteroides, clostridia, and bifidobacteria (X4,15). In some persons, bacterial overgrowth may be largely asymptomatic, while in others it may present with a variety of signs and symptoms. This diversity may be understood by recognizing that the consequences of small intestinal bacterial overgrowth require the presence of bacteria with particular metabolic properties in adequate concentrations at certain levels in the small bowel. For example, a complex flora of strict anaerabes and coliforms with the capacity to deconjugate bile salts and bind vitagreater than 10’ organmin B,,, in concentrations isms/ml and located in the proximal small intestine, is usually present when clinically significant malabsorption occurs. A flora lacking strict anaerobes or coliforms, or present in lesser numbers, or located in the distal small bowel rarely causes malabsorption (16,17). The usual clinical manifestations include anemia, malabsorption, weight loss, vitamin deficiencies, and diarrhea. Vitamin B,, absorption, as measured by the Schilling test, is abnormal and remains abnormal with added intrinsic factor. Serum folate levels are normal or high, the latter a consequence of folic acid elaboration by intestinal bacteria. Weight loss is common with the blind-loop syndrome and is usually accompanied by steatorrhea. Fecal fat loss averages lo-30 g/day but may occasionally be as high as 60-70 g/day. Steatorrhea is associated with malabsorption of fat soluble vitamins, and the resultant
BLIND-LOOP
SYNDROME
839
deficiency of vitamins A, D, and K may be manifest by night blindness, osteomalacia, and bleeding disorders. Hypoproteinemia is common, and occasionally weight loss, protein deficiency, and malnutrition may be so severe as to mimic the cachexia of malignancy (1,2). Steotorrhea. Normally, the bile salts found in the upper small bowel are the taurine and glycine conjugates of cholic, deoxycholic, and chenic acid. They function as detergents to incorporate the products of lipolysis, fatty acids, and monoglyceride into micelles which permit their absorption by the intestinal mucosa. Micelle formation occurs only in the presence of an adequate concentration of conjugated bile salts. In the blind-loop syndrome, bacteria resident in the proximal small bowel, particularly anaerobic bacteria, deconjugate bile salts to form free bile acids. Free bile acids are rarely demonstrated in the small intestine of normal persons but are frequently found in persons with bacterial overgrowth (17,18). Elimination of the deconjugating microflora is associated with the disappearance of these free bile acids. Bile salt deconjugation occurring in the proximal small intestine could interfere with normal fat absorption in two ways. Free bile acid concentrations could reach levels which are toxic to mucosal cells or the conjugated bile salt concentration could fall below the critical concentration essential for effective micelle formation. Ample evidence supports either mechanism. Neither alone can currently explain the fat malabsorption seen in all patients with the blind-loop syndrome. For a detailed discussion of the pathophysiology of steatorrhea in the blindloop syndrome, the interested reader is referred to several recent reviews (l-4). Mucosal Damage. Although bacterial alteration of bile salt metabolism is an important explanation for steatorrhea, it does not explain why some patients continue to have absorptive defects despite elimination of the abnormal flora and restoration of normal bile salt metabolism (4).Undoubtedly, there are other contributing factors. One might be that the small intestinal mucosa is morphologically and functionally damaged in the blind-loop syndrome (1921).Recent work has demonstrated light- and electron-microscopic abnormalities in both the clinical and experimental blind-loop syndromes (19-21). The lesion may be patchy in distribution and is characterized by blunting and broadening of villi and an increase in the number of mononuclear cells within the lamina propria. On rare occasion, the lesion can be severe and resemble that seen in gluten-sensitive enteropathy. A number of biochemical and functional abnormalities occur as a consequence of the mucosal
840
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injury. These include decreased brush-border enzyme activities (especially disaccharidases), decreased intracellular enzymes, defects in the mucosal uptake of sugars and amino acids, excessive enteric blood loss, and protein-losing enteropathy (4,20-22). The pathogenesis of this mucosal injury is uncertain. Usually free bile acids are considered responsible, but recent studies suggest that bacterially elaborated enzymes, such as proteases or glycosidases, may cause mucosal injury (23,24). Recovery of the morphologic and functional abnormalities usually occurs with suppression of bacterial overgrowth, but occasionally recovery is much delayed or even incomplete which may explain the incomplete clinical recovery seen in some patients (4). Vitamin B,, Malabsorption. Vitamin B,, deficiency in patients with bacterial overgrowth in a consequence of malabsorption of vitamin B,,. This is the result of disordered intraluminal physiology. Intrinsic factor (IF) is not altered, and ileal receptor sites and ileal absorptive function are normal. However, the intraluminal bacterial mass competes for available luminal B,, and makes it unavailable to the host (1,14,25). Many bacteria can bind free B,, with about the same affinity as IF. This bound vitamin temporarily remains available to recapture by IF since the B,, is bound to the bacterial cell surface. Prior binding of the vitamin to IF also decreases bacterial binding by some 20%-95% (26,27). Anaerobic bacteria seem especially able to compete for IFbound B,, and may do so by detaching the B,, from IF (4). However, once bacteria internalize the B,,, it is no longer available to IF or to the host. The bacteria then metabolize the B,, in part to physiologically inert derivatives which are excreted into the gut lumen and may interfere with both IF and ileal binding sites (28). Successful elimination of the bacterial overgrowth will restore vitamin B,, absorption to normal. Diarrhea. Diarrhea is a frequent complaint in the blind-loop syndrome and can occur even in the absence of significant steatorrhea. Unfortunately, this problem has been little studied,and the mechanisms responsible are uncertain. However, knowledge of other diarrhea1 disorders and of bacterial metabolism of unabsorbed substrates suggest that a variety of mechanisms contribute to the diarrhea. The disorder probably involves both the small and large intestine and is probably both a secretory and osmotic process. The bacterial production of intestinal secretogogues of various types is probably a major mechanism. For example, unabsorbed fat and bile salts pass into the colon and are modified there by bacteria to hydroxylated fatty acids and deconjugated bile acids, respectively, which stimulate colonic secretion of water and electrolytes (29). These same substances are probably also formed in the bacte-
Vol. 80, No. 4
rially contaminated small bowel and thus can also stimulate small intestine secretion (3). In addition, since small-intestinal disaccharidase activity is decreased and the small intestinal mucosa is morphologically and functionally abnormal, ingested sugars are incompletely digested and absorbed (3,4). These mono- and disaccharides are metabolized by bacteria to a variety of osmotically active small molecules which create an osmotic diarrhea. The role of bacterial “toxins” in the diarrhea1 process is uncertain, but the possibility of bacterial “toxins” contributing to the diarrhea1 process must be considered. Thus far, however, traditional bacterial exterotoxins of the cholera or E. coli type have not been found in the blind-loop syndrome.
Protein Malnutrition FREDRICK
L. WEBER,
JR., M.D.
Although less often appreciated than changes in fat and vitamin B,, absorption, alterations in the intestinal absorption of protein precursors frequently occur in patients with blind-loop syndrome (BLS). Hypoalbuminemia, as was seen in this patient, commonly occurs (4,31). Occasional BLS patients have severe protein deficiency and present with kwashiorkor, manifested by severe hypoalbuminemia, edema, abdominal distension, muscle wasting, and hair loss or change in hair color (3235). Various nutritional studies demonstrate that enteric flora can have a detrimental effect on nitrogen metabolism and growth, which can be reversed by antibiotic administration (36). In the BLS, reasons for protein and amino acid deficiency are complex and are not thoroughly understood. Evidence suggests that several different factors play a pathogenetic role. These include: (a) the catabolism of ingested protein by the gut flora, (b) increased enteric loss of endogenous protein because of mucosal defects, (c) increased catabolism of endogenous protein within the gut lumen, (d) diminished mucosal transport of dietary amino acids and peptides due to mucosal defects. Obviously, these various factors may have complex interrelationships. Protein synthesis is reduced in the BLS (31,34) and antibiotics reverse the defect (34). A depleted pool of essential amino acids may explain the reduced protein synthetic rates since patients with BLS and hypoalbuminemia have a reduction in many plasma essential amino acids and a reduction in the essential/ nonessential amino acid ratio (31,32,34) resulting in plasma aminograms very similar to those seen with kwashiorkor (37,38). However, one should note that plasma amino acid levels only variably reflect tissue levels in protein deficiency states, and there is no firm evidence to support a role for plasma amino
April 1981
BLIND-LOOP SYNDROME
841
acid concentrations in the regulation of protein synUnfortunately, nitrogen resulting from urea breakthesis (39). down would appear to be of little use in protein anaFecal nitrogen provides a crude index of the probolism. In 1 BLS patient studied by Varcoe et al. (35) tein wastage in the BLS. When measured, fecal nithe incorporation of urea nitrogen into albumin was trogen has been up to fivefold greater than normal in increased, but this accounted for only 0.8% of nitroprotein-depleted patients (33,40), but fecal nitrogen gen utilized for albumin synthesis or 0.4% of the niexcretion is not so striking in less severely affected trogen available from urea degradation. and experimental animals (43,44). In patients (41,42) Endogenous protein lost into the gut because of general, fecal nitrogen loss has not been as impresmucosal abnormalities is another cause of protein sive as has the degree of steatorrhea (44); however, malnutrition in the BLS. An increased fecal excreas discussed below, the magnitude of the nitrogen tion of endogenous protein is frequently seen in rats wastage in such patients may be reflected in the exwith BLS (50-52) but is rarely found in patients cretion of urinary nitrogen as well as fecal nitrogen. (53,54). Our patient, however, did have an increased Evidence suggests that the intraluminal metaboloss of endogenous protein based on the recovery of lism of amino acids by intestinal bacteria contribintravenously administered “‘C-labeled albumin in utes significantly to nitrogen loss and reduced prostool. Jeejeebhoy and Coghill felt that increased tein synthesis in these patients. Goldstein has fecal nitrogen losses seen in a patient with BLS estimated that the bacterial mass present in BLS paarose from endogenous protein since reducing diettients may require up to 5.25 g of nutrient per hour ary nitrogen intake to 0.9 mg/day did not reduce (45), although this is based on a doubling rate of 3/h fecal nitrogen excretion (4 g/day) (53). Increased which may exceed that which occurs in vivo (5). Uribacterial catabolism of endogenous protein which nary indican excretion in experimental animals and enters the gut lumen may further lead to the develpatients with BLS may account for 40% and 70%, reopment of protein depletion. Even in normal individspectively, of the bacterial metabolism of dietary uals, substantial amounts of protein may enter the tryptophan (46,47). Many other bacterial metabolites gut lumen. The quantity of protein which follows of amino acids, including tyrosine, phenylalanine, this route remains uncertain as do the relative lysine, arginine, and ornithine, have been identified amounts of such protein that are reabsorbed in a utiin the urine of BLS animals, although their quanlizable form or are catabolized by the gut flora (55). titative importance is smaller than is that of indican A further consideration is that mucosal abnormalities seen in the BLS may limit absorption of amino (46). acids and oligopeptides which have escaped intraHowever, excess bacterial metabolism of intraluminal metabolism by the small bowel flora. Reluminal amino acids can be expected to cause a variduced absorption of amino acids in rat intestine has ety of changes other than the appearance of specific amino acid metabolites in urine. Intraluminal amino been demonstrated in vitro (20)and in vivo (56,57). Furthermore, reduced levels of mucosal enterokiacids could also be incorporated into bacterial pronase have been observed in the intestinal lumen in tein, or could be metabolized and absorbed with rats with intestinal blind loops although this did not most of the nitrogen entering the body’s urea pool. result in a reduction in trypsin or amylase activities. Therefore, to obtain an adequate index of nitrogen wastage, it would be necessary to monitor urea synOf additional note is that protein malnutrition, once established in the BLS, may further aggravate thesis as well as fecal nitrogen and specific urinary malabsorption and bacterial overgrowth. In protein amino acid metabolites. A major portion of an inmalnutrition, malabsorption may result from both crease in urea synthesis would be reflected in urimucosal defects and pancreatic exocrine innary urea or total nitrogen. One BLS patient who sufficiency (47). Protein malnutrition due to a rehad approximately equal reductions in urinary and duced dietary nitrogen intake has also been associfecal nitrogen after antibiotic therapy demonstrated ated with small bowel overgrowth (59) and, hence, that nitrogen wastage may occur in both stool and in patients with BLS, protein depletion may serve to urine (40). perpetuate the presence of an abnormal small inAs expected, an increased urea synthetic rate has testinal flora. been found in patients with severe protein depletion caused by the BLS (34,48). These individuals have normal urea pools in contrast to patients with kwaTreatment shiorkor who have low plasma urea levels due to a JOHN G. BANWELL, M.D. reduced protein intake (49). The increased urea synCare for the patient with bacterial overgrowth thetic rate in the BLS has been associated with a may require several therapeutic approaches. These two- to threefold increase in the degradation rate of features in the management of the patient are deurea, a finding which has emphasized the catabolic potential of enteric bacteria in this disorder (34,48). scribed in Table 3.
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Management
Table 3.
NUTRITIONAL 1. Minerals
SUPPORT
(RDA)
Calcium 800-1200
mg
Phosphorus 800-1500
mg
Vitamins
(RDA)
Vitamin B, 25-50 mg Vitamin B, 5-10 mg Vitamin B, 20-50 mg
Vitamin lo-20 Vitamin lo-25 Vitamin 50 mg
B, mg B, mg C
Folic acid lmg Vitamin A lO,OOO-25,000 IU Vitamin D 4000-12,000
IU
Vitamin E 30-60 IU Vitamin
Available
preparations”
Calcium carbonat&O% calcium Tablets: 500 mg (200 mg calcium), 1.25 g (500 mg calcium) Calcium lactate-13% calcium Tablets: 325 mg (42.25 mg calcium), 650 mg (94.5 mg calcium) Calcium gluconate-6% calcium Syrup: 1.8 g (115 mg calcium/5 ml) Neutra-Phos Capsules: 250 mg phosphorus (7.125 mEq Na and K/capsule Powder: reconstituted (same as capsule/75 ml) Neutra-Phos-K Same preparations except potassium substituted for sodium Magnesium sulfate 50% solution: 202 mg magnesium/ml Zinc sulfate Capsules: 220 mg (50 mg zinc) Ferrous sulfate-20% iron Tablets: 300 mg (60 mg iron) Elixir: 200 mg (44 mg iron/5 ml) Ferrous gluconate-11.6% iron Tablets: 325 mg (38 mg iron) Elixir: 325 mg (38 mg iron/5 ml)
Magnesium 300-400 mg Zinc 50-150 mg Iron lo-18 mg
2.
of Bacterial Overgrowth
K
5mg
Vitamin B,, 100 pg i.m. monthly
Available
preparations”
Thiamine HCI Tablets: 5,10,25, 50 mg Elixir: 2.25 mg/5 ml Riboflavin Tablets: 5, 10 mg Niacin Tablets: 25, 50 mg Elixir: 50 mg per 5 ml Niacinamide (does not cause flushing) Tablets: 25, 50 mg Calcium pantothenate Tablets: 10 mg Pyridoxin HCI Tablets: 5, 10, 25 mg Ascorbic acid Tablets: 25, 50 mg Syrup: 20,100 mg/ml Folic acid Tablets: 0.1,0.4, 1 mg Vitamin A-water miscible Capsules: 10,000 and 25,000 IU Solution: 50,000 IU/ml Vitamin D Capsules: 25,000 and 50,000 IU Liquid: 8000 IU/ml Vitamin E-water miscible Capsules: 30 IU Solution: 50 IU/ml Menadiol sodium diphosphate (K4) Tablets: 5 mg Phytonadione (K,) Tablets: 5 mg Cyanocobalamin Injection: 30,100,1090 pg/ml
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843
Table 3. Management of Bacterial Overgrowth (continued) 3. Foodstuffs Fat: reduce dietary long-chain triglyceride to 30-40 g daily, supplement with medium-chain triglyceride, mg Protein Carbohydrate SPECIFIC THERAPY 1. Antibiotics
2. Fresh frozen plasma for persons with hypogammaglobulinemia 3. Agents which affect intestinal motility 4. Surgery SYMPTOMATIC THERAPY 1. Antidiarrhea agents
MCT oil: fractionated cocoanut oil consisting primarily of triglycerides of C,.C,, saturated fatty acids. One tbsp (15 ml) weighs 14 g and provides 115 cal. Portagen: powder provides 1.43 g fat (87% medium chain triglycerides), 1.05 g protein, 3.45 g carbohydrate, and 30 cal/fl. oz. Provide at least 1 g/kg body wt of high biologic value protein 250 g or more of palatable carbohydrate Tetracycline-250 mg q.i.d. for 14 days Ampicillin-250 mg q.i.d. for 14 days Chloramphenicol-500 mg q.i.d. for 14 days Metronidazole-750 mg t.i.d. for 14 days
Prostigmine-25 lndomethacin-25 See text
mg q.i.d. mg q.i.d.
Diphenoxylate (Lomotil)--one tablet up to six times daily Loperamide (Imodium)-one tablet t.i.d. Codeine sulfate30 or 60 mg up to q.i.d.
o There are no standard specific supplemental mineral-vitamin recommendations for persons with bacterial overgrowth. These recommendations seem reasonable for managing mild nutritional deficiencies. A variety of multivitamin-mineral preparations are available, providing 50%-150X of the RDA, for nutritional supplementation.
Patients with unusually severe diarrhea and acute dehydration should have fluid and electrolyte losses should be replaced intravenously. Minerals, water, and fat soluble vitamins should initially be replaced parenterally and later orally. Vitamin B,, deficiency should be treated by intramuscular cobalamin injection, 50 pg daily for 2 wk. Continued malabsorption of the vitamin will require regular monthly maintenance injections of 100 c(g (1,4). Folic acid deficiency will require 10 mg folic acid orally and then 1 mg daily. Acute bleeding phenomena due to vitamin K deficiency by 50 mg i.m. or i.v. Improvement in the patient’s nutritional status will require immediate attention. With severe malnutrition, intravenous hyperalimentation may be life saving and will allow for clinical improvement so that diagnostic studies and possible definitive surgery can be performed (68). There is insufficient experience with enteral alimentation in BLS. However, dietary supplementation is often sufficient to enhance caloric intake in mildly malnourished patients. An increased dietary intake can be achieved by providing increased calories (>2500 kcal) and protein (>80 g). Tolerance for fat in the diet will be reduced, and it should be restricted to 30-40 g/day. Medium-chain triglycerides may be used as dietary
energy supplements, if required, at tolerated levels of 30 g t.d.s. Dietary lactose may be poorly tolerated. Medical management should reduce, and, if possible, restore to normal the small intestinal bacterial flora (17,60,81). The choice of administered antibiotic is frequently empirical, because in the BLS, the flora is polymicrobial, and its sensitivity to any particular antibiotic is unknown. Many bacterial species with a variety of different antibiotic sensitivities are present, and the consequences of bacterial interreactions in this microflora are poorly understood. For example, one does not know whether all, several, or only one resident bacterial species requires elimination to achieve cure. Anaerobes are an important cause of the metabolic changes in BLS, but it is unknown whether they require specific treatment with an anaerobicidal antibiotic or whether antibiotic suppression of aerobic flora sufficiently alters the intestinal environment that continued anaerobic growth is impossible. Despite such limited understandings, several antibiotics have been found effective in clinical practice. These include: tetracycline (62), ampicillin (63), lincomycin (17,60), chloramphenicol (4), erythromycin (l), and metronidazole (4). Neomycin has been ineffective when used alone (60). Tetracycline, 250 mg four times daily for 10-14-
844
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GASTROENTEROLOGY
ET AL.
day courses has been most popular (6264). Diarrhea, steatorrhea, and vitamin B,, malabsorption are often corrected during treatment. Treated patients may remain well for prolonged periods, and, although recurrence is common when the underlying cause persists, they respond again to the same antibiotic treatment (1,4). Occasionally, prolonged treatment has been used successfully (1). If tetracycline is ineffective, chloramphenicol, clindamycin, and metronidazole, administered over a similar time interval, may be effective. Recurrent treatment failure requires intubation and culture to determine formally microbial sensitivity. Recolonization of the mucosa by different E. coli serotypes has been described in association with relapse (65). We have only limited understanding of those conditions which favor recolonization and properties of the flora which result in symptoms. The organism’s ability to utilize nutrients and cause mucosal damage are probably the most important, but identifying these characteristics is not yet possible with available clinical procedures. Infusion of fresh frozen plasma has been shown to cause short-term improvement in bowel function in a few patients with generalized hypoglobulinemia (66). Agents which enhance small-intestinal motor activity have been little used, but some favorable responses to prostigmin and indomethacin were recorded in patients with intestinal pseudoobstruction (67). As in the patient under discussion, surgical management may be curative (1,2,4). However, lesions amenable to surgical correction, such as intestinal strictures and fistulae, Bilroth II anastomoses and short segments involved by jejunal diverticuli, are only rarely found as a cause of BLS. Also, the general condition of patients already ill from other intestinal diseases, such as Crohn’s disease, or prior abdominal procedures may preclude further surgery * Generalized intestinal disorders, such as systemic sclerosis, jejunal diverticulosis, pseudoobstruction, and hypogammaglobulinemia, cannot be treated surgically. In such patients, dietary management can be invaluable, and symptomatic control of diarrhea, with loperamide or diphenoxylate, and abdominal pain with analgesics is useful. Some or all of these measures will allow an improved sense of well being and considerable control of symptoms in the majority of BLS patients, even when the underlying intestinal disorder cannot be cured.
References 1. Donaldson RM. Small Med 1970;16:191-212.
bowsel bacterial
overgrowth.
Adv
Int
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2. Tabaqchali S. The pathophysiological role of small intestinal bacterial flora. Stand J Gastroent Suppl 1970:6:139-63. 3. Gracey M. The contaminated small bowel syndrome: pathogenesis, diagnosis and treatment. Am J Clin Nutr 1979;32:23443. 4. King CE. Toskes PP. Small intestine bacterial overgrowth. Gastroenterology 1979;76:1035-55. 5. Savage DC. Microbial ecology of the gastrointestinal tract. Ann Rev Microbial 1977;31:107-33. 6. Balthazar EJ. Carcinoid tumors of the alimentary tract-radiographic diagnosis. Gastrointest Radio1 1978;3:47-56. 7. Egger G, Kessler JI. Clinical experience with a simple test for the detection of bacterial deconjugation of bile salts and the site and extent of bacterial overgrowth in the small intestine. Gastroenterology 1973;64:545-51. 8. Chernov AJ, Doe WF, Gompertz D. Intrajejunal volatile fatty acids in the stagnant loop syndrome. Gut 1972;13:103-6. 9. Hepner G. Breath tests in gastroenterology. Adv Intern Med 1978:23:25-45. 10. Lauterburg BH, Newcomer AD, Hoffman AF. Clinical value of the bile acid breath test. Evaluation of the Mayo Clinic experience. Mayo Clin Proc 1978;53:227-33. 11. King CE, Toskes PP, Spivey JC, et al. Detection of small intestine bacterial overgrowth by means of a ‘%-n-xylose breath test. Gastroenterology 1979;77:75-82 12. Solomons NW, Schoeller DA, Wagonfeld JB, et al. Application of a stable isotope (‘“C) labelled glycocholate breath test to diagnose bacterial overgrowth and ileal dysfunction. J Lab Clin Med 1977;90:405-11. 13. Metz G, Gassull MA, Drasar BS, et al. Breath hydrogen test for small intestinal bacterial colonization. Lancet 1976;1:6689. 14. Donaldson RM Jr. Role of indigenous enterir: bacteria in intestinal function and disease. In: Handbook of physiology, section 6, alimentary canal, Washington, DC: American Physiological Society, 19682807-37. 15. Gorbach SL. Intestinal microflora. Gastroenterology 1971; 60:1110-29. 16. Hamilton JD, Dyer NH, Dawson AM, et al. Assessment and significance of bacterial overgrowth in the small bowel. Q J Med 1970;39:265-85. 17. Gorbach SL, Tabaqchali S. Bacteria. bile and the small bowel. Gut 1969;10:963-72.
18. Northfield TC, Drasar BS. Wright JT. Value of small iritestinal bile acid analysis in the diagnosis of the stagnant loop syndrome. Gut 1973;14:341-7. 19. Ament ME, Shimoda SS, Saunders DR, et al. Pathogenesis of steatorrhea in three cases of small intestinal stasis syndrome. Gastroenterology 1972;63:728-47. 20. Giannella RA, Rout WR. Toskes PP. Jejunal brush border injury and impaired sugar and amino acid uptake in the blind loop syndrome. Gastroenterology 1974;67:965-74. 21. Toskes PP, Giannella RA, Jervis HR, et al. Small intestinal mucosal injury in the experimental blind loop syndrome: light and electron-microscopic and histochemical studies. Gastroenterology 1975;68:1193-1203. 22. Giannella RA, Toskes PP. Gastrointestinal bleeding and iron absorption in the experimental blind loop syndrome. Am J Clin Nutr 1976;29:754-7. 23. Jonas A, Flannagan PR, Forstner GG. Pathogenesis of mucosal injury in the blind loop syndrome: brush border enzyme activity and glycoprotein degradation. J Clin Invest 1977:60:1321-30. 24. Jonas A, Krishnan C, Forstner GG. Pathogenesis of mucosal injury in the blind loop syndrome: release of disaccharidases from brush border membranes by extracts of bacteria obtained from intestinal blind loops in rats. Gastroenterology 1978;75:791-5.
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25. Donaldson RM Jr. Malabsorption of COW-labelled cyanocobalamin in rats with intestinal diverticula. I. Evaluation of possible mechanisms. Gastroenterology 1962;43:271-80. 26. Giannella RA, Broitman SA, Zamcheck N. Vitamin B,, uptake by intestinal microorganisms: mechanism and relevance to syndromes of intestinal bacterial overgrowth. J Clin Invest 1971;50:1100-7. 27. Giannella RA, Broitman SA, Zamcheck N. Competition between bacteria and intrinsic factor for vitamin B,z: implications for vitamin B,, malabsorption in intestinal bacterial overgrowth. Gastroenterology 1972;62:255-60. 28. Brandt LJ, Bernstein LH, Wagle A. Production of vitamin B,, analogues in patients with small bowel bacterial overgrowth. Ann Intern Med 1977;67:546-51. 29. Phillips SF. Diarrhea: a current view of the pathophysiology. Gastroenterology 1972;63:495-518. 30. Klipstein FA, Engert RF, Short HB. Enterotoxigenicity of colonizing coliform bacteria in tropical sprue and blind loop syndrome. Lancet 1978; 11:342-4. 31. Yap SH, Hafkenscheid JCM, van Tongeren JHM, et al. Rate of synthesis of albumin in relation to serum levels of essential amino acids in patients with bacterial overgrowth in the small bowel. Eur J Clin Invest 1974;4:279-84. 32. Neale G, Antcliff AC, Welbourn RD, et al. Protein malnutrition after partial gastrectomy. Q J Med 1967;36:469-94. 33. Krikler DM, Schrire V. Kwashiorkor in an adult due to an intestinal blind loop. Lancet 1958;1:510-11. 34. Jones EA, Craigie A, Tavill AS, et al. Protein metabolism in the intestinal stagnant loop syndrome. Gut 1968;9:466-9. 35. Varcoe R, Halliday D, Tavill AS. Utilization of urea nitrogen for albumin synthesis in the stagnant loop syndrome. Gut 1974;15:898-902. 36. Rosenberg IH, Solomons NW. The potential for antidiarrheal and nutrient-sparing effects of oral antibiotic use in children: a position paper. Am J Clin Nutr 1978;31:2202-7. 37. Whitehead RG. Rapid determination of some plasma aminoacids in subclinical kwashiorkor. Lancet 1964;1:250-2. 38. Holt LE, Snyderman SE, Norton PM, et al. The plasma aminogram in kwashiorkor. Lancet 1963;11:1343-8. 39. Waterlow JC. The effects of nutrition and hormones on protein turnover in muscle. In: Protein turnover in mammalian tissues and in the whole body. Amsterdam: North-Holland Publishing Company 1978:625-95. 40. Jeejeebhoy KN. Endogenous protein loss into the bowel as a cause of hypoalbuminaemia. In: Munro HN, ed. The role of the gastrointestinal tract in protein metabolism. Philadelphia: FA Davis Company, 1964:357-83. 41. Badenoch J, Bedford PD, Evans JR. Massive diverticulosis of the small intestine with steatorrhea and megaloblastic anemia. Q J Med 1955;24:321-30. 42. Doig A, Girdwood RH. The absorption of folic acid and labelled cyanocobalamin in intestinal malabsorption. Q J Med 1960;29:333-74. 43. Donaldson RM Jr. Role of enteric microorganisms in malabsorption. Fed Proc 1967;26:1426-31. 44. Nygaard K. Nutrition and absorption after resections and bypass operations on the small intestines in rats. Acta Chir Schand 1968;134:63-77. 45. Goldstein F. Mechanisms of malabsorption and malnutrition in the blind loop syndrome. Gastroenterology 1971;61:780-4. 46. Miller B, Mitchinson R, Tabagchali S, et al. The effects of ex-
BLIND-LOOP SYNDROME
845
cessive bacterial proliferation on protein metabolism in rats with self-filling jejunal sacs. Eur J Clin Invest 1971;2:23-31. 47. Neale G. Protein malnutrition. In: Fourth Symposium in Advanced Medicine. London: Pitman Medical, 1968:260-72. 46. Jones EA, Smallwood RA, Craigie A, et al. The enterohepatic circulation of urea nitrogen. Gut 1969;37:825-36. 49. Schwartz IL, Thayson JH, Dole VP. Evidence that urea is excreted in human sweat by a passive process. Fed Proc 1952;11:142. 50. Nygaard K, Rootwelt K. Intestinal protein loss in rats with blind segments on the small bowel. Gastroenterology 1968;54:52-5. 51. Neale G, Gompertz D, Schonsby H, et al. The metabolic and nutritional consequences of bacterial overgrowth in the small intestine. Am J Clin Nutr 1972;25:1409-17. 52. Curtis KJ, Prinzont R, Kim YS. Protein digestion and absorption in the blind loop syndrome. Dig Dis Sci 1979;24:929-33. 53. Jeejeebhoy KN, Coghill NF. The measurement of gastrointestinal protein loss by a new method. Gut 196X2:123-30. 54. King C, Lorenz E, Toskes P. The pathogenesis of decreased serum protein levels in the blind loop syndrome: evaluation including a newly developed ‘%amino acid breath test (abstr). Gastroenterology 1976;70:901. 55. Fauconneau G, Michel MC. The role of the gastrointestinal tract in the regulation of protein metabolism. In: Munro HN, ed. Mammalian protein metabolism. New York.: Academic Press, Volume IV 1970: 239-66. 56. Baraona E, Palma R, Navia E, et al. The role of unconjugated bile salts in the malabsorption of glucose and tyrosine by everted sacs of jejunum of rats with the blind loop syndrome. Acta Physiol Lat Amer 1968;18:291-7. 57. Giannella RA. Intestinal transport abnormalities in the experimental blind loop syndrome. Clin Res 1979;27:683. 58. Rutgeerts L, Mainguet P, Tytgat G, et al. Enterokinase in contaminated small bowel syndrome. Digestion 1974;10:249-54. 59. Gorbach SL, Banwell JG, Jacobs B, et al. Tropical sprue and malnutrition in West Bengal. I. Intestinal microflora and absorption. Am J Clin Nutr 1970;23:1545-58. 60. Joiner KA, Gorbach SL. Antimicrobial therapy of digestive diseases. Clin Gastroenterol 1979;8:3-35. 61. Polter DE, Boyle JD, Miller LG, Finegold SM. Anaerobic bacteria as cause of the blind loop syndrome. Gastroenterology 1968;54:1148-54. 62. Kahn IJ, Jeffries GH, Sleisenger MH. Malabsorption in intestinal scleroderma: correction by antibiotics. N Engl J Med 1966;274:1339-44. 63. Goldstein F, Wirts W, Kowlessar OD. Diabetic diarrhea and steatorrhea. Ann Intern Med 1970;72:215-18. 64. Goldstein F, Wirts CW, Kramer S. The relationship of afferent loop stasis and bacterial flora to the production of postgastrectomy steatorrhea. Gastroenterology 1961;40:47-54. 65. Tabaqchali S, Howard A, Teoh-Chan CH, et al. Escherichio coli serotypes throughout the gastrointestinal tract of patients with intestinal disorders. Gut 1977;18:351-8. 66. Hersh T, Floch MH, Binder HJ, et al. Disturbance of the jejunal and colonic bacterial flora in immunoglobulin deficiencies. Am J Clin Nutr 1970;23:1595-601. 67. Anuras S, Crane SA, Faulk DL, et al. Intestinal pseudo-obstruction. Gastroenterology 1978;74:1318-24. 68. Berenson MM, Bowers JH. Supplemental nutrition and digestive disease. Clin Gastroenterol 1979;8(1):141-59.
CLINICAL
1981;80:834-45
CONFERENCE
Small Intestinal Bacterial Overgrowth Syndrome JOHN G. BANWELL, Moderator PARTICIPANTS: LANE A. KISTLER, FREDRICK L. WEBER, Jr., ARTHUR DEBORAH E. POWELL
RALPH LIEBER,
A. GIANNELLA, and
Division of Gastroenterology, Department of Medicine, University of Kentucky College of Medicine, Lexington, Kentucky: and Veterans Administration Medical Center, Lexington, Kentucky
Introduction JOHN
G. BANWELL,
M.D.
The patient serving as a focus for our discussion had many symptoms and findings characteristic of the proliferation and overgrowth of a bacterial microflora in the small intestine. This syndrome has been recognized by several descriptive terms: blind-loop syndrome (BLS), small intestinal stasis syndrome, contaminated small bowel syndrome, and stagnant loop syndrome. Each emphasizes that alterations in intestinal structure or function permit the development of an abnormal small bowel flora which is the major pathophysiologic determinant of those clinical features which distinguish the syndrome (l-4). The classic syndrome is characterized by megaloblastic anemia due to vitamin B,, deficiency, and weight loss and diarrhea due to fat malabsorption. There are many causes for the syndrome. With each, there is some disruption or normal processes which prevent small intestinal bacterial overgrowth, such as intestinal motility, mucosal antibacterial defenses, and gastric acidity (5). The syndrome may occur at all ages but is primarily recognized in later life. It also may occur in a less florid manner when associated with or superimposed on other disorders of the gastrointestinal tract. Case Presentation LANE
A. KISTLER,
M.D,
A 55yr-old white male was admitted to the University of Kentucky Medical Center. He had felt Received September 22, 1980. Accepted December l5, 1980. Address requests for reprints to: John G. Banwell, M.D., Division of Gastroenterology, Department of Medicine, University of Kentucky College of Medicine, Lexington, Kentucky 40536. 0 1981 by the American Gastroenterological Association 0016-5085/81/040834-12$02.50
entirely well until 18 mo before admission when intermittent constipation developed. This was accompanied by abdominal bloating and occasional postprandial vomiting. The voluntary consumption of low-residue foods failed to control these symptoms. Diarrhea developed and progressed in severity until he was passing 12-24 watery brown stools/24-h period. He gradually lost weight from a normal 230 lbs. to 130 lbs. at the time of admission. His past medical history included an appendectomy in 1962 and a myocardial infarction in 1972. He complained of infrequent exertional chest pain readily relieved by nitroglycerin. At physical examination the patient appeared wasted with evident loss of subcutaneous tissue and skeletal muscle mass. Weight 59 kg (130 lbs.); height 154 cm. Vital signs were normal: there was no postural blood pressure change. The skin and mucus membranes were normal. There was no abdominal distension. Intestinal rushes were “audible across the room.” One examiner felt a right lower quadrant mass. There was no organomegaly. Rectal examination was normal; the stool was negative for occult blood. Mild lower extremity edema was present. Ophthalmoscopic, neurologic, and the remainder of the physical examination were normal. Laboratory studies revealed: hematocrit 35% hemoglobin 11.8 g/dl, WBC 8300 cells/ml; sodium 133 mEq/L; potassium 3.1 mEq/L; chloride 90 mEq/L; carbon dioxide 25 mEq/L; calcium 3.5 mEq/L; and phosphorus 3.0 mEq/L. Total proteins were 5.1 g/dl; albumin 1.9 g/dl; serum iron 70 pg/dl; and total iron binding capacity 105 pg/dl. Urinalysis, prothrombin time, BUN, glucose, SGOT, SGPT, LDH, alkaline phosphatase, and total bilirubin were normal. A
April 1981
BLIND-LOOP SYNDROME
Table 1A. Laboratory Data
Radiologic Findings ARTHUR
Results Investigative
procedure
Serum carotene (>40 ,ug/dl) D-xylose urinary excretion (>4.5g/5h) Fecal wet weight (~200 g/day) Fecal fat excretion (t7 g/day) Vitamin B1* absorption test (Schilling test) (>8% absorption) Vitamin B1* absorption test (with intrinsic factor) Wr-labeled albumin excretion (~0.7% fecal excretion/r? days)
835
On admission
After recovery
25 &dl 1.7g 870 g 30s 0.3%
72 pg/dl 4.4g 153 g 7.8 g 28%
1.1%
-
2.85%
-
Laboratory tests of (A) digestive and absorptive function, (B) jejunal bacterial flora, performed before and after surgical resection of an ileal carcinoid stricture in a patient with small bowel bacterial overgrowth syndrome.
screening test for urinary 5-HIAA excretion was negative. Laboratory tests evaluating small intestinal digestion and absorption are presented in Table 1A. The results of quantitative bacteriologic culture of small intestinal fluid are presented in Table 1B. These findings were consistent with a diagnosis of a small intestinal bacterial overgrowth syndrome. Radiologic investigation revealed a distal small bowel obstruction (vide infra). The patient underwent abdominal exploration. At operation, a 3 x 3cm obstructing tumor was detected in the distal ileum. Bowel loops proximal to the lesion appeared chronically dilated; the short segment of ileum distal to the obstruction and the colon were normal. A large lymph node at the base of the mesentery was biopsied and showed an undifferentiated tumor consistent with carcinoid. A small bowel resection with total excision of the tumor mass and end-to-side ileoileostomy was performed. Postoperative recovery was uneventful. All gastrointestinal symptoms resolved, and over the next few months the patient regained 54 lbs. in weight. He was subsequently admitted to UKMC for reevaluation. At this time he felt entirely well. He had no abdominal pain and complained of no features suggesting the carcinoid syndrome. Laboratory results showed a hematocrit of 50%; SGOT, SGPT, LDH, alkaline phosphatase, and total bilirubin were normal. A 24-h urinary 5-HIAA excretion was 6.6 mg (normal 2.2-10.0 mg). Total protein was 7.1 g/dl; albumin was 4.2 g/dl. Other laboratory data are presented in Table 1A and the results of small bowel culture are presented in Table 1B. A small bowel series and liver scan were normal.
LEIBER, M.D.
Anteroposterior films of the abdomen showed scattered, mildly dilated, small bowel loops associated with widespread air-fluid levels. A barium enema was normal, but barium refluxed into only a very short segment of terminal ileum. Upper gastrointestinal and small bowel series showed a normal stomach, and duodenum. Transit esophagus, through the small bowel was prolonged, and dilated small bowel loops extended to the distal ileum where a short, narrowed, small bowel segment was encountered on the 6-h films (Figure 1A and 1B). An impression of some loops converging towards this narrowing suggested that a partial volvulus might be present. An intravenous pylogram was normal. A chest x-ray was consistent with healed granulomatous disease. The finding of a partial lower small bowel obstruction might have been due to a variety of inflammatory or neoplastic causes, including an ileal carcinoid tumor. When small, intestinal carcinoids may present as sharply defined submucosal lesions which are difficult to detect on a routine small bowel examination. Later, most small bowel carcinoids grow eitraluminally, infiltrating the bowel wall, lymphatic channels, and eventually regional lymph nodes and mesentery. The local release of serotonin and other chemical agents may be responsible for the hypertrophic muscular thickening and the severe fibroblastic proliferation known to develop at this time. The radiographic findings are usually nonspecific and depend on the degree of desmoplastic response as well as on the size and location of the mesenteric tumor. A small bowel study at this time may show diffuse luminal narrowing, separation of intestinal loops and fixation and retraction producing localized abrupt angulation. Intraluminal growth with
Table
1B.
Bacteriologic
Data”
On admission
After recovery
Total aerobes Strep. fecalis Streptococci [other) Staph. Aureus Staph. Albus. E. coli Lactobocilli Serratia
8.1x 10R 6 XIOe 8 X 10’ 4 x 103 6 X104 8 X 10' 2 x lo8 0
6 X104 0 6 X10 8 Xl@ 2 x10' 0 0 2.6 X lo3
Total anaerobes Bifidobacteria Streptococci Bacterioides
1.4x 108 6 X 10’ 6 X lo7 8 X lo7
6.8x 104 5.4x 104 1.4x 104 0
0 Per milliliter jejunal aspirate.
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ET AL.
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Vol. 80, No. 4
Figul pe 1. A. A 6-h film from a small bowel series shows marked dilatation of small bowel with the probable point of obstruction in the distal ileum. Some intestinal loops seem to converge towards a central point. B. Spot film of the distal ileum showing an area of narrowing with dilated bowel proximal to
April 1981
BLIND-LOOP SYNDROME
837
Figure 2. A. Distal ileum. The resected portion of ileum measured 155 cm. Arrow denotes area of constriction which is seen opened below (Figure ZB). Ileum proximal to this is dilated. B. Opened ileum at area of constriction (orrow). Note mass in this area. Dilated bowel is proximal to tumor mass. C. Photomicrograph of tumor showing sheets of cells with a prominent cribiform pattern characteristic of ileal carcinoid (H & E stain, x 100).D. Higher magnification photomicrograph of tumor showing regular cells with small nuclei and lack of nuclear atypia (H & E stain, X 400).
mucosal destruction leads to development of a short obstructive annular segment that may mimic primary adenocarcinoma or even inflammatory bowel disease (6). Pathologic
Findings
DEBORAH E. POWELL, M.D.
The segment of distal ileum with its attached mesentery measured 155 cm in length. Approxi-
mately 35 cm from the distal margin of resection, a firm, yellow-white, 3 x &cm tissue mass extended around one-half the circumference of the bowel. It constricted the wall and lumen in this area and extended into the mesentery (Figure 2). The small bowel proximal to the mass was significantly dilated, measuring 12 cm in circumference, as contrasted to the distal segment which measured 4 cm in circumference. Histologic sections of the mass showed a tumor composed of sheets and cords of
838
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CASTROENTEROLOGY
ET AL.
uniform cells with central regular nuclei and a prominent focal cribiform pattern very characteristic of a carcinoid tumor. Many of the tumor nests were surrounded by dense fibrous tissue. Invasion of tumor cells into lymphatic or small vascular spaces was easily identified and 2 of 24 mesenteric lymph nodes contained metastatic tumor. Medium-sized arteries in the submucosa showed some intimal proliferation. A small-intestinal biopsy specimen showed a preserved villous pattern. An increased number of lymphocytes and plasma cells were observed within the lamina propria, but there were no alterations of the surface epithelium by light microscopy.
Diagnosis LANE
A. KISTLER,
M.D.
The blind-loop syndrome should be considered in any patient who has diarrhea, anemia, steatorrhea, and weight loss and should be especially suspected in any person with a known predisposition to this disorder as listed in Table 2. Once considered, the syndrome should be defined by procedures which (a) measure small-intestinal absorption (urinary D-xylose excretion, stool Sudan II stain, quantitative fecal fat collection, vitamin B,, absorption tests) and (b) detect significant small-intestinal bacterial overgrowth. Although tests for malabsorption are standard, clinically appropriate procedures for detecting bacterial overgrowth have been difficult to define. There are no simple specific screening tests available. Intestinal intubation and culture of aspirated intestinal fluid is the definitive procedure but requires careful collection, prompt handling, and aerobic and anaerobic culture (4). Diagnosis depends on the demonstration of abnormal concentrations (greater than 10” organisms/ml and usually greater than lOa organisms/ml) of both aerobic and anaerobic bacteria. Unfortunately, clinical laboratories are often ill-prepared for such thorough bacteriologic study of infrequent specimens. There is a need for procedures which allow a more simple approach to diagnosis. For this reason, indirect techniques have been proposed. Analysis of intestinal aspirates for the presence of deconjugated bile acids (7) and volatile fatty acids (8), and for their ability to deconjugate bile acids in vitro (7) has been suggested to avoid the problems of rigorous culture. However, these methods require intubation and moderately sophisticated biochemical methods for success and have not yet found widespread use in clinical practice. Noninvasive, indirect tests are appealing but have not yet achieved standard clinical use. These tests rely on specific properties of intestinal bacterial metabolism. They detect volatile bacterial metabolites
Vol. 80, No. 4
of two types: “CO, released from deconjugated [“C]glycocholic acid or from [Ylxylose and hydrogen released by bacterial degradation of intestinal carbohydrates (9). Bile acid breath tests do not distinguish bacterial overgrowth from ileal mucosal disease and have a false-negative rate as high as 30% (10). The xylose breath test has promise (11) but will require further validation before being recommended for widespread use. Development of convenient techniques utilizing mass spectroscopy may permit more universal use of stable isotopes (‘“C) in these tests, eliminating the small radiation hazard to children and young adults (12). Breath hydrogen analysis by gas-liquid chtomatography may be clinically useful. Encouraging reports by Metz et al. using lactulose and glucose as test carbohydrates to induce hydrogen production by small intestinal bacteria are interesting (13). Further studies should be encouraged to both exclude false-positive results which occur when substrate enters the colon and false-negative results which occur when organisms associated with overgrowth are unable to generate hydrogen. Antibiotic administration as a diagnostic trial is not reliable but may, on rare occasion, be necessary in those who refuse or those who cannot have intestinal intubation.
Causes and Pathophysiology RALPH
A. GIANNELLA,
M.D.
The normal proximal small intestine is sparsely populated with bacteria, i.e., 103-10“ (lOOO10,000) bacteria per milliliter, with streptococci, staphylococci, diphtheroids, and fungi predominating. The concentration of organisms increases distally, and coliforms appear in the lower ileum. The concentration of organisms in the terminal ileum is approximately lo’-108/ml. On crossing the ileocecal valve, bacterial concentration increases to lo’-10” organisms per gram and strict anaerobes become the predominant species (14,15).
Table
2.
Disorders
Causing
Bacterial
Overgrowth
Structural
Surgical
loops-Bilroth II, entero-enter0 ileal bypass, continent Duodenal or jejunal diverticula Strictures-Crohn’s Disease, radiation Adhesions Tumors Gastrojejunocolic fistula Functional-Motility Disturbances Intestinal scleroderma Idiopathic pseudoobstruction Diabetic enteropathy Aged gut (?)
anastomosis, ileostomy enteritis
jejuno-
April 1981
A variety of mechanisms function to control and limit the bacterial population of the small intestine. The most important of these appears to be normal peristalsis by which the small intestine cleanses itself. Other factors controlling small intestinal flora include normal gastric acid secretion, bacterial growth inhibition by bile, luminal pH and oxidationreduction potential, and metabolic interactions between bacteria (14,15). These additional mechanisms are poorly understood and are of uncertain importance. A large number of anatomic and motor disorders of the small intestine are associated with bacterial overgrowth and the blind-loop syndrome. These are listed in Table 2. One should emphasize that these diverse conditions all share as a common feature the stasis of small bowel contents which allows bacterial overgrowth to occur (1,2,4,15). The bacterial flora in the small bowel of persons with bacterial overgrowth differs from normal in a number of ways. The concentration of organisms is usually much higher than normal, lo’-1O1* organisms/ml, and the flora is a complex mixture of large numbers of different bacteria. In general, the predominant flora are coliform organisms and strict anaerobes, such as bacteroides, clostridia, and bifidobacteria (X4,15). In some persons, bacterial overgrowth may be largely asymptomatic, while in others it may present with a variety of signs and symptoms. This diversity may be understood by recognizing that the consequences of small intestinal bacterial overgrowth require the presence of bacteria with particular metabolic properties in adequate concentrations at certain levels in the small bowel. For example, a complex flora of strict anaerabes and coliforms with the capacity to deconjugate bile salts and bind vitagreater than 10’ organmin B,,, in concentrations isms/ml and located in the proximal small intestine, is usually present when clinically significant malabsorption occurs. A flora lacking strict anaerobes or coliforms, or present in lesser numbers, or located in the distal small bowel rarely causes malabsorption (16,17). The usual clinical manifestations include anemia, malabsorption, weight loss, vitamin deficiencies, and diarrhea. Vitamin B,, absorption, as measured by the Schilling test, is abnormal and remains abnormal with added intrinsic factor. Serum folate levels are normal or high, the latter a consequence of folic acid elaboration by intestinal bacteria. Weight loss is common with the blind-loop syndrome and is usually accompanied by steatorrhea. Fecal fat loss averages lo-30 g/day but may occasionally be as high as 60-70 g/day. Steatorrhea is associated with malabsorption of fat soluble vitamins, and the resultant
BLIND-LOOP
SYNDROME
839
deficiency of vitamins A, D, and K may be manifest by night blindness, osteomalacia, and bleeding disorders. Hypoproteinemia is common, and occasionally weight loss, protein deficiency, and malnutrition may be so severe as to mimic the cachexia of malignancy (1,2). Steotorrhea. Normally, the bile salts found in the upper small bowel are the taurine and glycine conjugates of cholic, deoxycholic, and chenic acid. They function as detergents to incorporate the products of lipolysis, fatty acids, and monoglyceride into micelles which permit their absorption by the intestinal mucosa. Micelle formation occurs only in the presence of an adequate concentration of conjugated bile salts. In the blind-loop syndrome, bacteria resident in the proximal small bowel, particularly anaerobic bacteria, deconjugate bile salts to form free bile acids. Free bile acids are rarely demonstrated in the small intestine of normal persons but are frequently found in persons with bacterial overgrowth (17,18). Elimination of the deconjugating microflora is associated with the disappearance of these free bile acids. Bile salt deconjugation occurring in the proximal small intestine could interfere with normal fat absorption in two ways. Free bile acid concentrations could reach levels which are toxic to mucosal cells or the conjugated bile salt concentration could fall below the critical concentration essential for effective micelle formation. Ample evidence supports either mechanism. Neither alone can currently explain the fat malabsorption seen in all patients with the blind-loop syndrome. For a detailed discussion of the pathophysiology of steatorrhea in the blindloop syndrome, the interested reader is referred to several recent reviews (l-4). Mucosal Damage. Although bacterial alteration of bile salt metabolism is an important explanation for steatorrhea, it does not explain why some patients continue to have absorptive defects despite elimination of the abnormal flora and restoration of normal bile salt metabolism (4).Undoubtedly, there are other contributing factors. One might be that the small intestinal mucosa is morphologically and functionally damaged in the blind-loop syndrome (1921).Recent work has demonstrated light- and electron-microscopic abnormalities in both the clinical and experimental blind-loop syndromes (19-21). The lesion may be patchy in distribution and is characterized by blunting and broadening of villi and an increase in the number of mononuclear cells within the lamina propria. On rare occasion, the lesion can be severe and resemble that seen in gluten-sensitive enteropathy. A number of biochemical and functional abnormalities occur as a consequence of the mucosal
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injury. These include decreased brush-border enzyme activities (especially disaccharidases), decreased intracellular enzymes, defects in the mucosal uptake of sugars and amino acids, excessive enteric blood loss, and protein-losing enteropathy (4,20-22). The pathogenesis of this mucosal injury is uncertain. Usually free bile acids are considered responsible, but recent studies suggest that bacterially elaborated enzymes, such as proteases or glycosidases, may cause mucosal injury (23,24). Recovery of the morphologic and functional abnormalities usually occurs with suppression of bacterial overgrowth, but occasionally recovery is much delayed or even incomplete which may explain the incomplete clinical recovery seen in some patients (4). Vitamin B,, Malabsorption. Vitamin B,, deficiency in patients with bacterial overgrowth in a consequence of malabsorption of vitamin B,,. This is the result of disordered intraluminal physiology. Intrinsic factor (IF) is not altered, and ileal receptor sites and ileal absorptive function are normal. However, the intraluminal bacterial mass competes for available luminal B,, and makes it unavailable to the host (1,14,25). Many bacteria can bind free B,, with about the same affinity as IF. This bound vitamin temporarily remains available to recapture by IF since the B,, is bound to the bacterial cell surface. Prior binding of the vitamin to IF also decreases bacterial binding by some 20%-95% (26,27). Anaerobic bacteria seem especially able to compete for IFbound B,, and may do so by detaching the B,, from IF (4). However, once bacteria internalize the B,,, it is no longer available to IF or to the host. The bacteria then metabolize the B,, in part to physiologically inert derivatives which are excreted into the gut lumen and may interfere with both IF and ileal binding sites (28). Successful elimination of the bacterial overgrowth will restore vitamin B,, absorption to normal. Diarrhea. Diarrhea is a frequent complaint in the blind-loop syndrome and can occur even in the absence of significant steatorrhea. Unfortunately, this problem has been little studied,and the mechanisms responsible are uncertain. However, knowledge of other diarrhea1 disorders and of bacterial metabolism of unabsorbed substrates suggest that a variety of mechanisms contribute to the diarrhea. The disorder probably involves both the small and large intestine and is probably both a secretory and osmotic process. The bacterial production of intestinal secretogogues of various types is probably a major mechanism. For example, unabsorbed fat and bile salts pass into the colon and are modified there by bacteria to hydroxylated fatty acids and deconjugated bile acids, respectively, which stimulate colonic secretion of water and electrolytes (29). These same substances are probably also formed in the bacte-
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rially contaminated small bowel and thus can also stimulate small intestine secretion (3). In addition, since small-intestinal disaccharidase activity is decreased and the small intestinal mucosa is morphologically and functionally abnormal, ingested sugars are incompletely digested and absorbed (3,4). These mono- and disaccharides are metabolized by bacteria to a variety of osmotically active small molecules which create an osmotic diarrhea. The role of bacterial “toxins” in the diarrhea1 process is uncertain, but the possibility of bacterial “toxins” contributing to the diarrhea1 process must be considered. Thus far, however, traditional bacterial exterotoxins of the cholera or E. coli type have not been found in the blind-loop syndrome.
Protein Malnutrition FREDRICK
L. WEBER,
JR., M.D.
Although less often appreciated than changes in fat and vitamin B,, absorption, alterations in the intestinal absorption of protein precursors frequently occur in patients with blind-loop syndrome (BLS). Hypoalbuminemia, as was seen in this patient, commonly occurs (4,31). Occasional BLS patients have severe protein deficiency and present with kwashiorkor, manifested by severe hypoalbuminemia, edema, abdominal distension, muscle wasting, and hair loss or change in hair color (3235). Various nutritional studies demonstrate that enteric flora can have a detrimental effect on nitrogen metabolism and growth, which can be reversed by antibiotic administration (36). In the BLS, reasons for protein and amino acid deficiency are complex and are not thoroughly understood. Evidence suggests that several different factors play a pathogenetic role. These include: (a) the catabolism of ingested protein by the gut flora, (b) increased enteric loss of endogenous protein because of mucosal defects, (c) increased catabolism of endogenous protein within the gut lumen, (d) diminished mucosal transport of dietary amino acids and peptides due to mucosal defects. Obviously, these various factors may have complex interrelationships. Protein synthesis is reduced in the BLS (31,34) and antibiotics reverse the defect (34). A depleted pool of essential amino acids may explain the reduced protein synthetic rates since patients with BLS and hypoalbuminemia have a reduction in many plasma essential amino acids and a reduction in the essential/ nonessential amino acid ratio (31,32,34) resulting in plasma aminograms very similar to those seen with kwashiorkor (37,38). However, one should note that plasma amino acid levels only variably reflect tissue levels in protein deficiency states, and there is no firm evidence to support a role for plasma amino
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acid concentrations in the regulation of protein synUnfortunately, nitrogen resulting from urea breakthesis (39). down would appear to be of little use in protein anaFecal nitrogen provides a crude index of the probolism. In 1 BLS patient studied by Varcoe et al. (35) tein wastage in the BLS. When measured, fecal nithe incorporation of urea nitrogen into albumin was trogen has been up to fivefold greater than normal in increased, but this accounted for only 0.8% of nitroprotein-depleted patients (33,40), but fecal nitrogen gen utilized for albumin synthesis or 0.4% of the niexcretion is not so striking in less severely affected trogen available from urea degradation. and experimental animals (43,44). In patients (41,42) Endogenous protein lost into the gut because of general, fecal nitrogen loss has not been as impresmucosal abnormalities is another cause of protein sive as has the degree of steatorrhea (44); however, malnutrition in the BLS. An increased fecal excreas discussed below, the magnitude of the nitrogen tion of endogenous protein is frequently seen in rats wastage in such patients may be reflected in the exwith BLS (50-52) but is rarely found in patients cretion of urinary nitrogen as well as fecal nitrogen. (53,54). Our patient, however, did have an increased Evidence suggests that the intraluminal metaboloss of endogenous protein based on the recovery of lism of amino acids by intestinal bacteria contribintravenously administered “‘C-labeled albumin in utes significantly to nitrogen loss and reduced prostool. Jeejeebhoy and Coghill felt that increased tein synthesis in these patients. Goldstein has fecal nitrogen losses seen in a patient with BLS estimated that the bacterial mass present in BLS paarose from endogenous protein since reducing diettients may require up to 5.25 g of nutrient per hour ary nitrogen intake to 0.9 mg/day did not reduce (45), although this is based on a doubling rate of 3/h fecal nitrogen excretion (4 g/day) (53). Increased which may exceed that which occurs in vivo (5). Uribacterial catabolism of endogenous protein which nary indican excretion in experimental animals and enters the gut lumen may further lead to the develpatients with BLS may account for 40% and 70%, reopment of protein depletion. Even in normal individspectively, of the bacterial metabolism of dietary uals, substantial amounts of protein may enter the tryptophan (46,47). Many other bacterial metabolites gut lumen. The quantity of protein which follows of amino acids, including tyrosine, phenylalanine, this route remains uncertain as do the relative lysine, arginine, and ornithine, have been identified amounts of such protein that are reabsorbed in a utiin the urine of BLS animals, although their quanlizable form or are catabolized by the gut flora (55). titative importance is smaller than is that of indican A further consideration is that mucosal abnormalities seen in the BLS may limit absorption of amino (46). acids and oligopeptides which have escaped intraHowever, excess bacterial metabolism of intraluminal metabolism by the small bowel flora. Reluminal amino acids can be expected to cause a variduced absorption of amino acids in rat intestine has ety of changes other than the appearance of specific amino acid metabolites in urine. Intraluminal amino been demonstrated in vitro (20)and in vivo (56,57). Furthermore, reduced levels of mucosal enterokiacids could also be incorporated into bacterial pronase have been observed in the intestinal lumen in tein, or could be metabolized and absorbed with rats with intestinal blind loops although this did not most of the nitrogen entering the body’s urea pool. result in a reduction in trypsin or amylase activities. Therefore, to obtain an adequate index of nitrogen wastage, it would be necessary to monitor urea synOf additional note is that protein malnutrition, once established in the BLS, may further aggravate thesis as well as fecal nitrogen and specific urinary malabsorption and bacterial overgrowth. In protein amino acid metabolites. A major portion of an inmalnutrition, malabsorption may result from both crease in urea synthesis would be reflected in urimucosal defects and pancreatic exocrine innary urea or total nitrogen. One BLS patient who sufficiency (47). Protein malnutrition due to a rehad approximately equal reductions in urinary and duced dietary nitrogen intake has also been associfecal nitrogen after antibiotic therapy demonstrated ated with small bowel overgrowth (59) and, hence, that nitrogen wastage may occur in both stool and in patients with BLS, protein depletion may serve to urine (40). perpetuate the presence of an abnormal small inAs expected, an increased urea synthetic rate has testinal flora. been found in patients with severe protein depletion caused by the BLS (34,48). These individuals have normal urea pools in contrast to patients with kwaTreatment shiorkor who have low plasma urea levels due to a JOHN G. BANWELL, M.D. reduced protein intake (49). The increased urea synCare for the patient with bacterial overgrowth thetic rate in the BLS has been associated with a may require several therapeutic approaches. These two- to threefold increase in the degradation rate of features in the management of the patient are deurea, a finding which has emphasized the catabolic potential of enteric bacteria in this disorder (34,48). scribed in Table 3.
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Management
Table 3.
NUTRITIONAL 1. Minerals
SUPPORT
(RDA)
Calcium 800-1200
mg
Phosphorus 800-1500
mg
Vitamins
(RDA)
Vitamin B, 25-50 mg Vitamin B, 5-10 mg Vitamin B, 20-50 mg
Vitamin lo-20 Vitamin lo-25 Vitamin 50 mg
B, mg B, mg C
Folic acid lmg Vitamin A lO,OOO-25,000 IU Vitamin D 4000-12,000
IU
Vitamin E 30-60 IU Vitamin
Available
preparations”
Calcium carbonat&O% calcium Tablets: 500 mg (200 mg calcium), 1.25 g (500 mg calcium) Calcium lactate-13% calcium Tablets: 325 mg (42.25 mg calcium), 650 mg (94.5 mg calcium) Calcium gluconate-6% calcium Syrup: 1.8 g (115 mg calcium/5 ml) Neutra-Phos Capsules: 250 mg phosphorus (7.125 mEq Na and K/capsule Powder: reconstituted (same as capsule/75 ml) Neutra-Phos-K Same preparations except potassium substituted for sodium Magnesium sulfate 50% solution: 202 mg magnesium/ml Zinc sulfate Capsules: 220 mg (50 mg zinc) Ferrous sulfate-20% iron Tablets: 300 mg (60 mg iron) Elixir: 200 mg (44 mg iron/5 ml) Ferrous gluconate-11.6% iron Tablets: 325 mg (38 mg iron) Elixir: 325 mg (38 mg iron/5 ml)
Magnesium 300-400 mg Zinc 50-150 mg Iron lo-18 mg
2.
of Bacterial Overgrowth
K
5mg
Vitamin B,, 100 pg i.m. monthly
Available
preparations”
Thiamine HCI Tablets: 5,10,25, 50 mg Elixir: 2.25 mg/5 ml Riboflavin Tablets: 5, 10 mg Niacin Tablets: 25, 50 mg Elixir: 50 mg per 5 ml Niacinamide (does not cause flushing) Tablets: 25, 50 mg Calcium pantothenate Tablets: 10 mg Pyridoxin HCI Tablets: 5, 10, 25 mg Ascorbic acid Tablets: 25, 50 mg Syrup: 20,100 mg/ml Folic acid Tablets: 0.1,0.4, 1 mg Vitamin A-water miscible Capsules: 10,000 and 25,000 IU Solution: 50,000 IU/ml Vitamin D Capsules: 25,000 and 50,000 IU Liquid: 8000 IU/ml Vitamin E-water miscible Capsules: 30 IU Solution: 50 IU/ml Menadiol sodium diphosphate (K4) Tablets: 5 mg Phytonadione (K,) Tablets: 5 mg Cyanocobalamin Injection: 30,100,1090 pg/ml
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Table 3. Management of Bacterial Overgrowth (continued) 3. Foodstuffs Fat: reduce dietary long-chain triglyceride to 30-40 g daily, supplement with medium-chain triglyceride, mg Protein Carbohydrate SPECIFIC THERAPY 1. Antibiotics
2. Fresh frozen plasma for persons with hypogammaglobulinemia 3. Agents which affect intestinal motility 4. Surgery SYMPTOMATIC THERAPY 1. Antidiarrhea agents
MCT oil: fractionated cocoanut oil consisting primarily of triglycerides of C,.C,, saturated fatty acids. One tbsp (15 ml) weighs 14 g and provides 115 cal. Portagen: powder provides 1.43 g fat (87% medium chain triglycerides), 1.05 g protein, 3.45 g carbohydrate, and 30 cal/fl. oz. Provide at least 1 g/kg body wt of high biologic value protein 250 g or more of palatable carbohydrate Tetracycline-250 mg q.i.d. for 14 days Ampicillin-250 mg q.i.d. for 14 days Chloramphenicol-500 mg q.i.d. for 14 days Metronidazole-750 mg t.i.d. for 14 days
Prostigmine-25 lndomethacin-25 See text
mg q.i.d. mg q.i.d.
Diphenoxylate (Lomotil)--one tablet up to six times daily Loperamide (Imodium)-one tablet t.i.d. Codeine sulfate30 or 60 mg up to q.i.d.
o There are no standard specific supplemental mineral-vitamin recommendations for persons with bacterial overgrowth. These recommendations seem reasonable for managing mild nutritional deficiencies. A variety of multivitamin-mineral preparations are available, providing 50%-150X of the RDA, for nutritional supplementation.
Patients with unusually severe diarrhea and acute dehydration should have fluid and electrolyte losses should be replaced intravenously. Minerals, water, and fat soluble vitamins should initially be replaced parenterally and later orally. Vitamin B,, deficiency should be treated by intramuscular cobalamin injection, 50 pg daily for 2 wk. Continued malabsorption of the vitamin will require regular monthly maintenance injections of 100 c(g (1,4). Folic acid deficiency will require 10 mg folic acid orally and then 1 mg daily. Acute bleeding phenomena due to vitamin K deficiency by 50 mg i.m. or i.v. Improvement in the patient’s nutritional status will require immediate attention. With severe malnutrition, intravenous hyperalimentation may be life saving and will allow for clinical improvement so that diagnostic studies and possible definitive surgery can be performed (68). There is insufficient experience with enteral alimentation in BLS. However, dietary supplementation is often sufficient to enhance caloric intake in mildly malnourished patients. An increased dietary intake can be achieved by providing increased calories (>2500 kcal) and protein (>80 g). Tolerance for fat in the diet will be reduced, and it should be restricted to 30-40 g/day. Medium-chain triglycerides may be used as dietary
energy supplements, if required, at tolerated levels of 30 g t.d.s. Dietary lactose may be poorly tolerated. Medical management should reduce, and, if possible, restore to normal the small intestinal bacterial flora (17,60,81). The choice of administered antibiotic is frequently empirical, because in the BLS, the flora is polymicrobial, and its sensitivity to any particular antibiotic is unknown. Many bacterial species with a variety of different antibiotic sensitivities are present, and the consequences of bacterial interreactions in this microflora are poorly understood. For example, one does not know whether all, several, or only one resident bacterial species requires elimination to achieve cure. Anaerobes are an important cause of the metabolic changes in BLS, but it is unknown whether they require specific treatment with an anaerobicidal antibiotic or whether antibiotic suppression of aerobic flora sufficiently alters the intestinal environment that continued anaerobic growth is impossible. Despite such limited understandings, several antibiotics have been found effective in clinical practice. These include: tetracycline (62), ampicillin (63), lincomycin (17,60), chloramphenicol (4), erythromycin (l), and metronidazole (4). Neomycin has been ineffective when used alone (60). Tetracycline, 250 mg four times daily for 10-14-
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day courses has been most popular (6264). Diarrhea, steatorrhea, and vitamin B,, malabsorption are often corrected during treatment. Treated patients may remain well for prolonged periods, and, although recurrence is common when the underlying cause persists, they respond again to the same antibiotic treatment (1,4). Occasionally, prolonged treatment has been used successfully (1). If tetracycline is ineffective, chloramphenicol, clindamycin, and metronidazole, administered over a similar time interval, may be effective. Recurrent treatment failure requires intubation and culture to determine formally microbial sensitivity. Recolonization of the mucosa by different E. coli serotypes has been described in association with relapse (65). We have only limited understanding of those conditions which favor recolonization and properties of the flora which result in symptoms. The organism’s ability to utilize nutrients and cause mucosal damage are probably the most important, but identifying these characteristics is not yet possible with available clinical procedures. Infusion of fresh frozen plasma has been shown to cause short-term improvement in bowel function in a few patients with generalized hypoglobulinemia (66). Agents which enhance small-intestinal motor activity have been little used, but some favorable responses to prostigmin and indomethacin were recorded in patients with intestinal pseudoobstruction (67). As in the patient under discussion, surgical management may be curative (1,2,4). However, lesions amenable to surgical correction, such as intestinal strictures and fistulae, Bilroth II anastomoses and short segments involved by jejunal diverticuli, are only rarely found as a cause of BLS. Also, the general condition of patients already ill from other intestinal diseases, such as Crohn’s disease, or prior abdominal procedures may preclude further surgery * Generalized intestinal disorders, such as systemic sclerosis, jejunal diverticulosis, pseudoobstruction, and hypogammaglobulinemia, cannot be treated surgically. In such patients, dietary management can be invaluable, and symptomatic control of diarrhea, with loperamide or diphenoxylate, and abdominal pain with analgesics is useful. Some or all of these measures will allow an improved sense of well being and considerable control of symptoms in the majority of BLS patients, even when the underlying intestinal disorder cannot be cured.
References 1. Donaldson RM. Small Med 1970;16:191-212.
bowsel bacterial
overgrowth.
Adv
Int
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2. Tabaqchali S. The pathophysiological role of small intestinal bacterial flora. Stand J Gastroent Suppl 1970:6:139-63. 3. Gracey M. The contaminated small bowel syndrome: pathogenesis, diagnosis and treatment. Am J Clin Nutr 1979;32:23443. 4. King CE. Toskes PP. Small intestine bacterial overgrowth. Gastroenterology 1979;76:1035-55. 5. Savage DC. Microbial ecology of the gastrointestinal tract. Ann Rev Microbial 1977;31:107-33. 6. Balthazar EJ. Carcinoid tumors of the alimentary tract-radiographic diagnosis. Gastrointest Radio1 1978;3:47-56. 7. Egger G, Kessler JI. Clinical experience with a simple test for the detection of bacterial deconjugation of bile salts and the site and extent of bacterial overgrowth in the small intestine. Gastroenterology 1973;64:545-51. 8. Chernov AJ, Doe WF, Gompertz D. Intrajejunal volatile fatty acids in the stagnant loop syndrome. Gut 1972;13:103-6. 9. Hepner G. Breath tests in gastroenterology. Adv Intern Med 1978:23:25-45. 10. Lauterburg BH, Newcomer AD, Hoffman AF. Clinical value of the bile acid breath test. Evaluation of the Mayo Clinic experience. Mayo Clin Proc 1978;53:227-33. 11. King CE, Toskes PP, Spivey JC, et al. Detection of small intestine bacterial overgrowth by means of a ‘%-n-xylose breath test. Gastroenterology 1979;77:75-82 12. Solomons NW, Schoeller DA, Wagonfeld JB, et al. Application of a stable isotope (‘“C) labelled glycocholate breath test to diagnose bacterial overgrowth and ileal dysfunction. J Lab Clin Med 1977;90:405-11. 13. Metz G, Gassull MA, Drasar BS, et al. Breath hydrogen test for small intestinal bacterial colonization. Lancet 1976;1:6689. 14. Donaldson RM Jr. Role of indigenous enterir: bacteria in intestinal function and disease. In: Handbook of physiology, section 6, alimentary canal, Washington, DC: American Physiological Society, 19682807-37. 15. Gorbach SL. Intestinal microflora. Gastroenterology 1971; 60:1110-29. 16. Hamilton JD, Dyer NH, Dawson AM, et al. Assessment and significance of bacterial overgrowth in the small bowel. Q J Med 1970;39:265-85. 17. Gorbach SL, Tabaqchali S. Bacteria. bile and the small bowel. Gut 1969;10:963-72.
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25. Donaldson RM Jr. Malabsorption of COW-labelled cyanocobalamin in rats with intestinal diverticula. I. Evaluation of possible mechanisms. Gastroenterology 1962;43:271-80. 26. Giannella RA, Broitman SA, Zamcheck N. Vitamin B,, uptake by intestinal microorganisms: mechanism and relevance to syndromes of intestinal bacterial overgrowth. J Clin Invest 1971;50:1100-7. 27. Giannella RA, Broitman SA, Zamcheck N. Competition between bacteria and intrinsic factor for vitamin B,z: implications for vitamin B,, malabsorption in intestinal bacterial overgrowth. Gastroenterology 1972;62:255-60. 28. Brandt LJ, Bernstein LH, Wagle A. Production of vitamin B,, analogues in patients with small bowel bacterial overgrowth. Ann Intern Med 1977;67:546-51. 29. Phillips SF. Diarrhea: a current view of the pathophysiology. Gastroenterology 1972;63:495-518. 30. Klipstein FA, Engert RF, Short HB. Enterotoxigenicity of colonizing coliform bacteria in tropical sprue and blind loop syndrome. Lancet 1978; 11:342-4. 31. Yap SH, Hafkenscheid JCM, van Tongeren JHM, et al. Rate of synthesis of albumin in relation to serum levels of essential amino acids in patients with bacterial overgrowth in the small bowel. Eur J Clin Invest 1974;4:279-84. 32. Neale G, Antcliff AC, Welbourn RD, et al. Protein malnutrition after partial gastrectomy. Q J Med 1967;36:469-94. 33. Krikler DM, Schrire V. Kwashiorkor in an adult due to an intestinal blind loop. Lancet 1958;1:510-11. 34. Jones EA, Craigie A, Tavill AS, et al. Protein metabolism in the intestinal stagnant loop syndrome. Gut 1968;9:466-9. 35. Varcoe R, Halliday D, Tavill AS. Utilization of urea nitrogen for albumin synthesis in the stagnant loop syndrome. Gut 1974;15:898-902. 36. Rosenberg IH, Solomons NW. The potential for antidiarrheal and nutrient-sparing effects of oral antibiotic use in children: a position paper. Am J Clin Nutr 1978;31:2202-7. 37. Whitehead RG. Rapid determination of some plasma aminoacids in subclinical kwashiorkor. Lancet 1964;1:250-2. 38. Holt LE, Snyderman SE, Norton PM, et al. The plasma aminogram in kwashiorkor. Lancet 1963;11:1343-8. 39. Waterlow JC. The effects of nutrition and hormones on protein turnover in muscle. In: Protein turnover in mammalian tissues and in the whole body. Amsterdam: North-Holland Publishing Company 1978:625-95. 40. Jeejeebhoy KN. Endogenous protein loss into the bowel as a cause of hypoalbuminaemia. In: Munro HN, ed. The role of the gastrointestinal tract in protein metabolism. Philadelphia: FA Davis Company, 1964:357-83. 41. Badenoch J, Bedford PD, Evans JR. Massive diverticulosis of the small intestine with steatorrhea and megaloblastic anemia. Q J Med 1955;24:321-30. 42. Doig A, Girdwood RH. The absorption of folic acid and labelled cyanocobalamin in intestinal malabsorption. Q J Med 1960;29:333-74. 43. Donaldson RM Jr. Role of enteric microorganisms in malabsorption. Fed Proc 1967;26:1426-31. 44. Nygaard K. Nutrition and absorption after resections and bypass operations on the small intestines in rats. Acta Chir Schand 1968;134:63-77. 45. Goldstein F. Mechanisms of malabsorption and malnutrition in the blind loop syndrome. Gastroenterology 1971;61:780-4. 46. Miller B, Mitchinson R, Tabagchali S, et al. The effects of ex-
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cessive bacterial proliferation on protein metabolism in rats with self-filling jejunal sacs. Eur J Clin Invest 1971;2:23-31. 47. Neale G. Protein malnutrition. In: Fourth Symposium in Advanced Medicine. London: Pitman Medical, 1968:260-72. 46. Jones EA, Smallwood RA, Craigie A, et al. The enterohepatic circulation of urea nitrogen. Gut 1969;37:825-36. 49. Schwartz IL, Thayson JH, Dole VP. Evidence that urea is excreted in human sweat by a passive process. Fed Proc 1952;11:142. 50. Nygaard K, Rootwelt K. Intestinal protein loss in rats with blind segments on the small bowel. Gastroenterology 1968;54:52-5. 51. Neale G, Gompertz D, Schonsby H, et al. The metabolic and nutritional consequences of bacterial overgrowth in the small intestine. Am J Clin Nutr 1972;25:1409-17. 52. Curtis KJ, Prinzont R, Kim YS. Protein digestion and absorption in the blind loop syndrome. Dig Dis Sci 1979;24:929-33. 53. Jeejeebhoy KN, Coghill NF. The measurement of gastrointestinal protein loss by a new method. Gut 196X2:123-30. 54. King C, Lorenz E, Toskes P. The pathogenesis of decreased serum protein levels in the blind loop syndrome: evaluation including a newly developed ‘%amino acid breath test (abstr). Gastroenterology 1976;70:901. 55. Fauconneau G, Michel MC. The role of the gastrointestinal tract in the regulation of protein metabolism. In: Munro HN, ed. Mammalian protein metabolism. New York.: Academic Press, Volume IV 1970: 239-66. 56. Baraona E, Palma R, Navia E, et al. The role of unconjugated bile salts in the malabsorption of glucose and tyrosine by everted sacs of jejunum of rats with the blind loop syndrome. Acta Physiol Lat Amer 1968;18:291-7. 57. Giannella RA. Intestinal transport abnormalities in the experimental blind loop syndrome. Clin Res 1979;27:683. 58. Rutgeerts L, Mainguet P, Tytgat G, et al. Enterokinase in contaminated small bowel syndrome. Digestion 1974;10:249-54. 59. Gorbach SL, Banwell JG, Jacobs B, et al. Tropical sprue and malnutrition in West Bengal. I. Intestinal microflora and absorption. Am J Clin Nutr 1970;23:1545-58. 60. Joiner KA, Gorbach SL. Antimicrobial therapy of digestive diseases. Clin Gastroenterol 1979;8:3-35. 61. Polter DE, Boyle JD, Miller LG, Finegold SM. Anaerobic bacteria as cause of the blind loop syndrome. Gastroenterology 1968;54:1148-54. 62. Kahn IJ, Jeffries GH, Sleisenger MH. Malabsorption in intestinal scleroderma: correction by antibiotics. N Engl J Med 1966;274:1339-44. 63. Goldstein F, Wirts W, Kowlessar OD. Diabetic diarrhea and steatorrhea. Ann Intern Med 1970;72:215-18. 64. Goldstein F, Wirts CW, Kramer S. The relationship of afferent loop stasis and bacterial flora to the production of postgastrectomy steatorrhea. Gastroenterology 1961;40:47-54. 65. Tabaqchali S, Howard A, Teoh-Chan CH, et al. Escherichio coli serotypes throughout the gastrointestinal tract of patients with intestinal disorders. Gut 1977;18:351-8. 66. Hersh T, Floch MH, Binder HJ, et al. Disturbance of the jejunal and colonic bacterial flora in immunoglobulin deficiencies. Am J Clin Nutr 1970;23:1595-601. 67. Anuras S, Crane SA, Faulk DL, et al. Intestinal pseudo-obstruction. Gastroenterology 1978;74:1318-24. 68. Berenson MM, Bowers JH. Supplemental nutrition and digestive disease. Clin Gastroenterol 1979;8(1):141-59.