Superior mesenteric artery blood flow in celiac disease

Measurements of the hemodynamic parameters of the superior mesenteric artery were performed in 18 patients with celiac disease. Ten were studied at the time of diagnosis, when a small bowel biopsy showed a flat mucosa. The remaining eight patients
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  Digestive Diseases and Sciences, VoL 38, No. 7 (July 1993), pp. 1175-1182 Superior Mesenteric Artery Blood Flow in Celiac Disease DANIEL ALVAREZ, MD, HORACIO VAZQUEZ, MD, JULIO CESAR BAI, MD, RICARDO MASTAI, MD, DANIEL FLORES, MD, and LUIS BOERR, MD Measurements of the hemodynamic parameters of the superior mesenteric artery were performed in 18 patients with celiac disease. Ten were studied at the time of diagnosis, when a small bowel biopsy showed a flat mucosa. The remaining eight patients were studied after complete clinical and histological recovery induced by a gluten-free diet. Doppler ultrasound flowmetry was used to measure blood flow in physiological and fasting conditions and after a mixed liquid test meal (Ensure-Plus). The results were compared with those of healthy subjects (N = 7). Mean basal flow was 50% higher in untreated celiac disease patients than in healthy controls and patients with chronic pancreatitis (P = NS). Postprandial mesenteric blood flow was significantly increased (P < O. 002) and delayed in time (P < O. 005) in celiac disease as compared to controls. Successful treatment reduced the mesenteric blood flow in celiac disease to normal values. Our study demonstrates that pathophysiological changes in the small bowel mucosa during the active clinical phase of celiac disease induce an abnormal splanchnic circulation. KEY WORDS: splanchnic circulation; celiac disease; malabsorption; superior mesenteric artery blood flow; mucosal atrophy; Doppler. The digestive process elicits, among other physi- ological phenomena, an increase in the superior mesenteric artery blood flow (SMABF) (1-4). Moreover, it is known that postprandial hypere- mia is regulated by a variety of metabolic and neuroendocrine influences on the local vascula- ture (5-7). The morphological features in the small intestine of patients with celiac disease (CD) have been sub- jected to detailed investigation. However, regional vascularity and hemodynamics have received little attention (8, 9). The modified mucosal vascularity Manuscript received March 23, 1992; revised manuscript re- ceived July 24, 1992; accepted August 28, 1992. From the Small Bowel Section and Ecography Section, Clin- ical Department, Hospital Nacional de Gastroenterologia "Dr. Carlos Bonorino Udaondo," Liver Section, Instituto de Gastro- enterologia Dr. Jorge Perez Companc, Buenos Aires, Argentina. Address for reprint requests: Dr. Julio C. Bai, Uriburu 346, (1846) Adrogue, Buenos Aires, Argentina. demonstrated by Cooke and Holmes (8), consisting of a dense subepithelial capillar net with multiple arteriovenous shunts, suggests that the hemody- namics of intestinal vessels must be altered. In a recent study, we observed that postprandial intes- tinal blood flow in untreated CD patients, evaluated in the superior mesenteric artery by Doppler ultra- sound, was significantly increased and that the peak response to food was delayed in time with respect to normal subjects (10). The aim of this study was to record the superior mesenteric artery hemodynamics in groups of pa- tients with untreated and treated CD and in a small number of patients before and after successful treat- ment with a gluten-free diet. We also compared these findings with those observed in healthy con- trols and in patients with other forms of malabsorp- tion (non-CD). Digestive Diseases and Sciences, VoL 38, No. 7 (July 1993) 0163-2116/93/0700-1175507.00/0 9 1993 Plenum Publishing Corporation 1175  ALVAREZ ET AL TABLE 1. CLINICAL FEATURES OF PATIENTS ENROLLED IN THE STUDY* al-AT CI Serum Time of GFD Fecal fat clearance albumin Small bowel treatment Patient Age Gender (g/day) (ml/day) (g/dl) histologyt (months) i 24 F 3.8 3.8 3.5 IV a 2 25 F 4.0 1.7 4.1 IV 3 34 F 19.0 69.0 4.0 IV b 4 19 F 7.7 62.5 3.5 III e 5 22 M 5.5 2~2 4.3 IV 6 25 F 18.0 28.0 3.7 IV 7 47 F 39.8 129.6 2.4 III 8 41 F 24.9 25.1 3.9 IV d 9 40 F 18.8 146.0 3.6 IV 10 46 F 25.5 39.7 3.8 IV 11 42 F 4.6 2.2 4.5 I 32 12 35 F 5.3 12.0 4.0 I 42 13 17 F 3.4 10.2 3.7 I 26 14 34 F 3.5 2.9 3.9 I 10 15 25 F 2.9 4.3 4.1 I 14a 16 35 F 6.9 4.6 4.1 II 12b 17 20 F 3.2 11.9 3.8 II 11c 18 41 F 6.5 14.8 4.1 II 6d 19 64 M 76.6 82.0 3.8 I 20 30 M 25.4 172.0 2.8 I 21 56 F 15.2 8.8 3.9 I 22 48 M 22.3 12.0 3.8 I *Patients 1-10 are untreated celiac disease patients; patients 11-18 are gluten-free diet-treated patients, a, b, c, d indicate the four celiac patients that were studied before and after treatment. Patients 19 and 20: Crohn's disease; patients 21 and 22: chronic pancreatitis. GFD, Gluten-free diet. tHistology: degree of mucosal atrophy (I through IV). MATERIALS AND METHODS Patients. Eighteen patients with celiac disease (17 women and 1 man; mean age 32 years; range 19-47) were examined with a duplex scanner for SMABF. Ten pa- tients were evaluated at the time of diagnostic duodenal biopsy (untreated group); all biopsies showed severe mu- cosal atrophy (grade III/IV). Eight patients were evalu: ated at least six months after beginning a gluten-free diet (mean 33 months, range 6-180) when a duodenal biopsy showed a normal or almost normal mucosa and the clin- ical and biochemical features had improved (treated group). Four patients of the untreated group were reex- amined when treated. Four patients with fat malabsorp- tion due to chronic pancreatitis (N = 2) and extensive small bowel Crohn's disease (N = 2) were evaluated as a disease control group. Clinical data of patients and dis- ease controls evaluated at the time of the study are shown in Table 1. Seven subjects from the staff of the Hospital Nacional de Gastroenterologia were included as a healthy controls. Patients and controls were matched by sex and age. Neither the healthy volunteers nor the patients were taking any vasoactive medication. The protocol was approved by the Clinical Research Committee of the Hospital Nacional de Gastroenterologia in April 1990. Patients gave their consent to participate in the study after receiving a full explanation of its purposes and the risk involved. Procedure. Blood flow was measured by a duplex scan- ner (Aloka SSD-630, HGR 23), comprising a real=time, two-dimensional ultrasonic scanner and an associated 3.5-MHz pulsed Doppler flowmeter. After a precise B-mode ultrasound visualization of superior mesenteric artery, a sampling marker was set in the middle of the lumen along the beam axis and a second marker was positioned parallel to the direction of blood flow. Care was taken to maintain the angle formed by the ultrasonic beam and blood flow direction below 60 ~ since the accu- racy of the measurements decreases with greater angles. Every measurement was performed repeatedly, until a reproducible spectrum pattern of blood flow was ob- tained. Measurements were carried out during expiration. The cross-sectional diameter of the superior mesenteric artery was measured at the beginning of each examination and was calculated on the basis of the inner diameter, assuming a circular shape. Peak systolic velocity was the maximum flow velocity recorded during each cardiac cycle. Mean velocity was a computer-derived value de- termined by integrating the area under each individual velocity waveform. End-diastolic velocity was recorded just before the next systolic upstroke, and it correlated with the resistance of the organ to blood flow. Superior mesenteric artery blood flow was calculated according to the following formula: SMABF = 3.14 x 1/4 (diameter 2) x mean velocity Investigators were blinded to the clinical status of pa- tients. Studies were performed early in the morning (8 AM) after an overnight fast. After a rest period of 20 min in a supine position, Doppler ultrasound of the superior mesenteric artery was carried out at the end of the rest period (basal) and at 10, 20, 30, 45, 60, 75, and 90 min after the ingestion of a test meal (Ensure-Plus, Ross 1176 Digestive Diseases and Sciences, Vol. 38, No. 7 (July 1993)  SPLANCHNIC HEMODYNAMIC IN CELIAC DISEASE D cm/s big 1. Superior mesenteric artery waveform in fasting state in healthy controls (A) and in untreated patients (B), and at the peak hyperemic effect after ingestion of a mixed test meal in control subjects (C) and untreated patients (D). RF: reverse flow; PSV: peak systolic velocity; EDV: end diastolic velocity. Note the scale of velocity (cm/sec). Laboratories; volume 240 ml, composition: protein 13.0 g, fat 12.6 g, and carbohydrates 43.7 g per 100 ml). We also measured hemodynamic parameters at the right fem- ora/ artery. In addition, we monitored arterial pressure at the left forearm and arterial pulse at the radial artery. Measurements were performed in triplicate for each study. Interobserver variation between two experienced operators in our laboratory was <6%. Intraobserver vari- ation evaluated in five healthy control subjects in three different determinations was <3%. Statistics. Results are expressed as mean _+ standard error (X +-- SEM). Differences among curves were evalu- ated with ANOVA test, and a Bonferroni t correction test was used for independent samples. Differences in the time of the peak effect of SMABF were evaluated by the Mann-Whitney rank sum test and Kruskal-Wallis test. Area under the SMABF curves in the four patients stud- ied at the time of diagnosis and after treatment, calculated with a computer-assisted program, was assumed to be the complete flow in the superior mesenteric artery during the complete period of the study (90 min). RESULTS The configuration of the superior mesenteric ar- tery velocity waveform obtained in fasting state and after feeding in untreated CD patients was different from that of controls and treated patients (Figure 1). Peak systolic velocity and end-diastolic velocity were increased in untreated celiac patients both in the fasting state and after ingestion of the mixed test meal. Fasting Blood Flow Parameters. As shown in Fig- ures 2, 5, and 6, the superior mesenteric artery blood flow in fasting conditions was increased in untreated patients with celiac disease (618 __ 98.1 ml/min) in relation to control subjects (413 __ 54.3) and treated patients (447 _ 53.4). However, these differences were not significant. Fasting peak sys- tolic velocity was similar in untreated patients (128 + 14.9 cm/sec), control subjects (105 _+ 8.3; P = NS), and gluten-free diet-treated patients (123 ___ 6.6). However, fasting end-diastolic velocity in un- treated celiacs (21 --- 3.2 cm/sec) was significantly higher than in healthy controls (17 +__ 1.5; P < 0.05) and treated patients (17 --- 1.0; P < 0.02). Patients with chronic pancreatitis had hemody- namic parameters similar to those of healthy con- Digestive Diseases and Sciences, Vol. 38, No. 7 (July 1993) 1177  ALVAREZ ET AL 111100-:- 1 leO0, ~- 1400 ~- llO0"T- .- E looom aoo t I,L i 400 "5- II 00 -~ i oi T ~ q- -T ~.s t~ ..-., ........ -- ......... i ..................... i~ ........... --- '~ < = = ........ 2 I i ~ i I Baseline 10 20 30 45 60 75 90 Time l rnin ] Fig 2. Flow in the superior mesenteric artery in basal condition and after a mixed test meal (Ensure Plus) !n healthy controls (.. A-.), untreated celiac disease (--II--), and gluten-free diet-treated patients (--e--); X _+ SEM. Untreated patients are significantly different from treated patients and hea!thy persons (P < 0.002). trois. On the other hand, patients with extensive small bowel Crohn's disease presented with a very high blood flow in the fasting state (mean blood flow: 1343 ml/min; mean peak systolic velocity: 180 cm/sec; mean end-diastolic velocity 28 cm/sec) with a small postprandial response. Superior Mesenterie Artery Blood Flow After Food Ingestion. As shown in Figure 2, the SMABF after test meal was significantly higher in untreated pa- tients than it was in controls and patients treated with gluten-free diet (P < 0.002). Figure 3 shows the percentage increase of post- prandial blood flow over fasting values in untreated and treated patients and in healthy control subjects. Relative changes are not different but the most significant change is the delayed peak effect in the CD patients. Mean time for hyperemia to reach peak of SMABF in untreated patients was 61.5 __ 4.6 min (range 45-90), in healthy controls it was 39.3 _ 3.9 (range 20-45) (P < 0.005), and in gluten-free diet- treated patients 40.6 -+ 7.0 (range 20-75) (P > 0.05) (Figure 4). Figures 5 and 6 show the curves of peak systolic velocity and end,diastolic velocity after feeding in the groups studied. End-diastolic velocity was sig- 1178 nificantly increased at 60 and 75 min in untreated celiac patients (P < 0.05). Total blood flow through the mesenteric artery during the study period (90 rain) was measured by the area under the curves in the four patients stud- ied when untreated and after successful treatment. At diagnosis, blood flow was 81,212 -_+ 12,172 ml, whereas it was 46,847 _+ 5783 (P < 0.05) after treatment (Figure 7). Other Hemodynamic Parameters. Mean systolic blood pressure during the rest period before the ingestion of the test meal did not show any statisti- cal difference among groups. Mean diastolic blood pressure of untreated patients (59.4 -+ 4.1 mm Hg) was significantly reduced with respect to controls (71.2 _+ 2.3; P < 0.05), but there was no difference with respect to treated patients (62.5 _+ 2.5; P = NS). Femoral artery blood and blood pressure moni- tored during the entire study did not show any significant changes. DISCUSSION Superior mesenteric artery blood flow has been subjected to detailed investigation in attempts to Digestive Diseases and Sciences, VoL 38, No. 7 (Jury 1993)  SPLANCHNIC HEMODYNAMIC IN CELIAC DISEASE 'oo T Io 1 9 ?0+ @ ~ iio- e. ~ so- ~ 40- J" .......... -,k i ,~ \ :m / / "\\ i // / / \ ... ",~'-.. ,,- 2" i i Bllellne 10 20 30 45 60 7S gO Time [ Mlnutem ] Fig 3. Percentage of increase of superior mesenteric artery blood flow above the basal flow after a test meal in control subjects. (. 9 9 9 ) and untreated (--II--) and gluten-free diet-treated pa- tients (--e--). There was a similar increase in flow but a delayed peak effect in untreated patients. understand its physiological control (2-7). Recent advances have made it possible to measure visceral blood flow noninvasively (6, 11, 17). Current belief is that postprandial hyperemia is limited to the or- gans involved in the digestion and absorption of food (5). Furthermore, blood flow seems to increase almost exclusively in those parts of the small intes- tine in contact with chyme (14). However, little information exists on SMABF and intestinal dis- eases (15, 16). Thus, celiac disease, a condition where the morphologic and pathophysiological changes of the small bowel mucosa are well identi- fied, constitutes an interesting model to explore the hemodynamics of celiac disease. Data from the present study clearly show that SMABF in CD is abnormal in several ways. Fasting blood flow was significantly increased during the phase of active disease, and the peak response of the postprandial hyperemia was significantly de- layed with respect to control subjects. We also observed that successful treatment with a gluten- free diet reduced the hemodynamic abnormalities of active celiac disease. No postprandial changes in femoral artery flow and blood pressure were ob- served during postprandial hyperemia in the supe- rior mesenteric artery. Moreover, since patients with pancreatic steatorrhea had normal hemody- namics, we conclude that steatorrhea was not a g w ,m o too T t I I I I go t t t 70"~ I O0 T SO 4o T I I so --i- t I i io.'-- i I I 1o-I- i oi UNTREATED p < 0 05 p < 0,005 t TREATED CONTROL8 Fig 4o Mean peak hyperemic effect in the different groups studied. The effect was significantly delayed in untreated patients compared to treated patients (P < 0.05) and control subjects (P < 0.005). Digestive Diseases and Sciences, Vol. 38, No. 7 (July 1993) 1179
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