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Malabsorption Syndrome Associated With Ulceration of the Stomach and Small Bowel Caused by Chronic Intestinal Ischemia in a Patient With Hyperhomocysteinemia

      We describe a 39-year-old woman with an 8-month history of abdominal pain, diarrhea, and weight loss. Clinical and laboratory evaluation indicated the presence of a malabsorption syndrome. Endoscopy revealed multiple gastric ulcerations and an abnormal “picture” of the duodenal mucosa. At duodenal biopsy, necrosis confined to the distal parts of the enteric villi and a polymorphonuclear leukocyte response were found. Further evaluation revealed intestinal ischemia as a result of mesenteric atherosele- rosis. After a revascularization procedure was performed, the symptoms disappeared. The macroscopic and microscopic picture of the bowel normalized. In our search for risk factors of atherosclerosis, we found a substantially increased basal plasma homocysteine concentration. This case suggests that hyper homocysteinemia may have a causal role in the development of symptomatic, premature atherosclerosis of the mes enteric circulation.
      Chronic intestinal ischemia, a rare clinical disorder, accounts for an estimated 1 in 12,000 surgical admissions.
      • Caldwell JH
      Intestinal angina.
      The classic features are postprandial abdominal pain, aversion to food, and weight loss.
      • Mikkelsen WP
      Intestinal angina: its surgical significance.
      • Shaw RS
      • Maynard III, EP
      Acute and chronic thrombosis of the mesenteric arteries associated with malabsorption: a report of two cases successfully treated by thromboendarter-ectomy.
      • Mikkelsen WP
      • Zaro Jr, JA
      Intestinal angina: report of a case with preoperative diagnosis and surgical relief.
      • Webb WR
      • Hardy JD
      Relief of abdominal angina by vascular graft.
      Other symptoms such as nausea, vomiting, constipation, or diarrhea may be found and occasionally dominate the clinical picture.
      • Marston A
      Chronic intestinal ischaemia.
      • Hunter GC
      • Guernsey JM
      Mesenteric ischemia.
      • Liberski SM
      • Koch KL
      • Atnip RG
      • Stern RM
      Ischémie gastroparesis: resolution after revascularization.
      • Hoogenberg K
      • Van Essen LH
      • Van den Dungen JJ
      • Limburg AJ
      • Boeve WJ
      • Kleibeuker JH
      Chronic mesenteric ischaemia: diagnostic challenges and treatment options.
      The diagnosis is difficult inasmuch as no specific diagnostic tests are available. Angiography generally reveals obstruction of at least two of the three splanchnic arteries
      • Caldwell JH
      Intestinal angina.
      • Rogers DM
      • Thompson JE
      • Garrett WV
      • Talkington CM
      • Patman RD
      Mesenteric vascular problems: a 26-year experience.
      • Marston A
      • Clarke JM
      • Garcia Garcia J
      • Miller AL
      Intestinal function and intestinal blood supply: a 20 year surgical study.
      but is inconclusive because all splanchnic arteries can be occluded without syrnptoms.
      • Chiene J
      Complete obliteration of the coeliac and mesenteric arteries: the viscera receiving their blood-supply through the extra-peritoneal system vessels.
      • Matz EM
      • Kahn PC
      Occlusion of celiac, superior mesenteric and inferior mesenteric arteries.
      Malabsorption syndrome resulting from chronic intestinal ischemia is a very rare clinical condition. II Herein we describe a woman who had malabsorption as a result of premature atherosclerosis of the mesenteric circulation, which was related to a substantial increase in the serum homocysteine level.

      REPORT OF CASE

      A 39-year-old premenopausal woman was admitted to our hospital for assessment of diarrhea, weight loss, and abdomi- nal pain. Her previous medical history was unremarkable. She had a 25-pack-year history of smoking. The symptoms of nausea, vomiting, and frequent passage of watery stools had begun 8 months earlier while she was vacationing in Portugal. She also noticed a “nagging” pain in her upper abdominal area; a few days later, the diarrhea decreased, but the pain continued. Bowel movements stabilized at about 4 times a day, with formation of semisolid stools. Her appetite was poor. After 2 weeks of vacation, she returned to the Netherlands and was examined by her primary-care physician. Antacid medication containing aluminum oxide and magnesium hydroxide was prescribed but did not relieve the pain. The pain varied during the day and did not seem to be related to food intake.
      Four months before admission of the patient, the diarrhea worsened, and Campylobacter jejuni was isolated from a stool specimen. Initiation of antibiotic treatment decreased stool frequency to a maximum of 10 times a day without passage of blood or mucus. The abdominal pain worsened. Repeated stool cultures were negative, and findings on a roentgenogram of the upper gastrointestinal tract with use of barium were reported as normaL The patient had lost a total of 17 kg of body weight.
      On physical examination, the patient's blood pressure was 115/80 mm Hg, and her pulse was regular at a frequency of 94 beats/min. Her temperature was normal, She weighed 53 kg and was 168 em tall. A systolic bruit was detected in the abdomen, and on palpation of the upper abdominal area, tenderness was noted without severe rebound tenderness. Laboratory tests yielded an erythrocyte sedimentation rate of 43 mm in 1 hour, hemoglobin concentration of 13.5 g/dL, leukocyte count of 21 × 109/L, serum creatinine level of 0.66 mg/dL, and normal results for sodium, potassium, albumin, calcium, alkaline phosphatase, alanine aminotransferase, amylase, thiamine, folate, vitamin A, 25-hydroxycholecalciferol, and thyroid-stimulating hormone. The serum cholesterol level was 143 mg/dL. The D-xylose test results were abnormal. The mean stool fat content was 15 g in 24 hours (normal, less than 6), and the osmotic gap was increased at 248 mOsmol/L (normal, less than 100), indications of osmotic diarrhea and malabsorption. Fecal test results for occult blood were positive. Findings on the parasitologic examination were normal. Esophagogastroduodenoscopy disclosed multiple shallow ulcerations in the body and antrum of the stomach. The bulbar and postbulbar duodenal mucosa was unevenly covered with white adherent material, and multiple erosions were noted at both sites. Omeprazole (a proton pump inhibitor), 40 mg/day, was initiated. Examination of gastric biopsy specimens showed a chronic inflammatory response with few Helicobacter pylori organisms and nonspecific acute ulceration. Numerous fibrin thrombi were evident in the small vessels of the mucosa and submucosa. Postbulbar duodenal biopsy specimen showed necrosis of the distal parts of the villi and a cellular infiltration of polymorphonuclear leukocytes (Fig. 1 A). Endoscopic reexamination after 2 weeks of treatment with omeprazole showed no resolution of either the gastric or duodenal lesions. A small bowel enema examination disclosed an abnormally smooth outline of the jejunum for a considerable length (Fig. 2). A computed tomographic scan of the abdomen revealed extensive calcification of the ab- dominal aorta. Lateral aortography showed severe stenosis of the celiac trunk and superior mesenteric artery (Fig. 3). The inferior mesenteric artery was patent. Uncomplicated aortomesenteric and aortoceliac bypass was performed, and the symptoms disappeared.
      Figure thumbnail gr1
      Fig. 1A, Photomicrograph of postbulbar duodenal biopsy specimen, showing superficial necrosis and sloughing of mucosa with edema of lamina propria and infiltration of polymorphonuclear leukocytes. B, Two months after revascularization, findings are normal. (Hematoxylineosin; original magnification, × 10.)
      Figure thumbnail gr2
      Fig. 2Small bowel enema examination, showing abnormal smooth outline of proximaljejunum (arrows).
      Figure thumbnail gr3
      Fig. 3Lateral aortogram, showing severe stenosis at origins of celiac trunk and superior mesenteric arteries (arrows).
      Two months postoperatively, endoscopic findings were normal. A repeated biopsy of the stomach showed minimal chronic inflammatory changes, and the duodenal biopsy specimen was normal (Fig. 1 B). The patient gained 10 kg of body weight. Because the patient was young, possible occult risk factors for premature atherosclerosis were evaluated. The family history revealed that a brother had development of symptomatic peripheral atherosclerosis at age 34 years and had died at age 43 of a myocardial infarction. Examination of the lipid spectrum showed normal findings; however, the fasting total plasma homocysteine level was increased substantially-107 μmol/L (normal, 1.5 to 16.5). No concomitant deficiency of folic acid, pyridoxine, or cobalamin was detected, an indication of a hereditary variant of hyperhomocysteinemia.

      DISCUSSION

      Our patient had ischemic gastroenteritis with ulceration of the stomach, duodenum, and small bowel that resulted in malabsorption. Although H. pylori infection was detected, ischemia was the more likely cause of gastric and duodenal ulceration. This was supported by the absence of healing of the gastric and duodenal bulb lesions after 2 weeks of omeprazole treatment and the abundant presence of fibrin thrombi in the small vessels of gastric mucosa and submucosa, suggestive of vascular stasis. Moreover, duodenal erosions were located both bulbar and postbulbar, the latter site of which is unrelated to H. pylori infection. The diagnosis was delayed because symptoms were initially ascribed to episodes of bacterial enteritis. Intestinal ischemia was suspected after computed tomographic scanning revealed calci fications of the abdominal aorta. Angiography disclosed severe stenosis at the origins of the celiac and superior mesenteric arteries. A bypass operation resulted in rapid disappearance of symptoms and healing of stomach and small bowel lesions.
      Ulceration of the stomach and small intestine due to chronic intestinal ischemia has been previously reported.
      • Liberski SM
      • Koch KL
      • Atnip RG
      • Stern RM
      Ischémie gastroparesis: resolution after revascularization.
      • Hoogenberg K
      • Van Essen LH
      • Van den Dungen JJ
      • Limburg AJ
      • Boeve WJ
      • Kleibeuker JH
      Chronic mesenteric ischaemia: diagnostic challenges and treatment options.
      • Garisch JA
      • Marks IN
      Mesenteric ischemia-a diagnostic triad?.
      • Force T
      • MacDonald D
      • Eade OE
      • Doane C
      • Krawitt EL
      Ischémie gastritis and duodenitis.
      • Allende HD
      • Ona FV
      Celiac artery and superior mesenteric artery insufficiency: unusual cause of erosive gastroduo-denitis.
      • Talansky AL
      • Katz S
      • Naidich J
      Aphthous ulcers in ischémie gastroenterocolitis: a case report.
      • Cherry RD
      • Jabbari M
      • Goresky CA
      • Herba M
      • Reich D
      • Blundell PE
      Chronic mesenteric vascular insufficiency with gastric ulcération.
      • Hojgaard L
      • Krag E
      Chronic ischémie gastritis reversed after revascularization operation.
      In addition, abnormalities in motility
      • Liberski SM
      • Koch KL
      • Atnip RG
      • Stern RM
      Ischémie gastroparesis: resolution after revascularization.
      and absorption
      • Shaw RS
      • Maynard III, EP
      Acute and chronic thrombosis of the mesenteric arteries associated with malabsorption: a report of two cases successfully treated by thromboendarter-ectomy.
      • Webb WR
      • Hardy JD
      Relief of abdominal angina by vascular graft.
      • Hoogenberg K
      • Van Essen LH
      • Van den Dungen JJ
      • Limburg AJ
      • Boeve WJ
      • Kleibeuker JH
      Chronic mesenteric ischaemia: diagnostic challenges and treatment options.
      • Marston A
      • Clarke JM
      • Garcia Garcia J
      • Miller AL
      Intestinal function and intestinal blood supply: a 20 year surgical study.
      • Dardik H
      • Seidenberg B
      • Parker JG
      • Hurwitt ES
      Intestinal angina with malabsorption treated by elective revascularization.
      • Watt JK
      • Watson WC
      • Haase S
      Chronic intestinal ischaemia.
      • Nerstrom B
      • Worning H
      Chronic intestinal ischemia with severe steatorrhea treated by reconstruction of the superior mesenteric artery.
      • Tilson MD
      • Stansel HC
      Abdominal angina: intestinal absorption eight years after successful mesenteric revascularization.
      have been noted. In patients with abnormal angina, disturbance of absorption, however, is rare.
      • Marston A
      • Clarke JM
      • Garcia Garcia J
      • Miller AL
      Intestinal function and intestinal blood supply: a 20 year surgical study.
      The malabsorption in our patient was explained by the morphologic changes in the small bowel. Abnormalities detected on small bowel biopsy due to chronic ischemia have been previously described, including nonspecific inflammatory changes and villous atrophy.
      • Force T
      • MacDonald D
      • Eade OE
      • Doane C
      • Krawitt EL
      Ischémie gastritis and duodenitis.
      • Watt JK
      • Watson WC
      • Haase S
      Chronic intestinal ischaemia.
      • Nerstrom B
      • Worning H
      Chronic intestinal ischemia with severe steatorrhea treated by reconstruction of the superior mesenteric artery.
      Remarkably, most major textbooks of gastroenterology and internal medicine still do not mention chronic ischemia as a possible cause of abnormal findings on small bowel biopsy.
      • Powell OW
      Approach to the patient with diarrhea.
      • Surawicz CM
      Morphology of the small intestine in health and disease.
      • Greenberger NJ
      • Isselbacher KJ
      Disorders of absorption.
      • Toskes PP
      Malabsorption.
      Thus, this sequela of chronic intestinal ischemia is not recognized universally.
      The cause of chronic intestinal ischemia is generally narrowing of the proximal part of the splanchnic arteries due to atherosclerosis.
      • Marston A
      • Clarke JM
      • Garcia Garcia J
      • Miller AL
      Intestinal function and intestinal blood supply: a 20 year surgical study.
      Uncommon causes are vasculitis, radiation-induced vasculopathy, fibromuscular dysplasia, fibri- noid necrosis of the vascular wall after aortic surgical treatment of coarctation, and a controversial syndrome termed the “celiac band syndrome.”
      • Hunter GC
      • Guernsey JM
      Mesenteric ischemia.
      • Marston A
      • Clarke JM
      • Garcia Garcia J
      • Miller AL
      Intestinal function and intestinal blood supply: a 20 year surgical study.
      • Ripley HR
      • Levin SM
      Abdominal angina associated with fibromuscular hyperplasia of the celiac and superior mesenteric arteries.
      In our patient, atherosclerosis was diagnosed as the cause of mesenteric vascular insufficiency. The basal plasma homocysteine concentration was substantially increased.
      In recent years, hyperhomocysteinemia has been recognized as a major risk factor for the development of symptomatic, premature atherosclerosis.
      • Ueland PM
      • Refsum H
      • Brattström L
      Plasma homocysteine and cardiovascular disease.
      • Boers GH
      Hyperhomocysteinaemia: a newly recognized risk factor for vascular disease.
      • Stampfer MJ
      • Malinow MR
      • Willett WC
      • Newcomer LM
      • Upson B
      • Ullmann D
      • et al.
      A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians.
      • Boers GH
      • Smals AG
      • Trijbels FJ
      • Fowler B
      • Bakkeren JA
      • Schoonderwaldt HC
      • et al.
      Heterozygosity for homocystin-uria in premature peripheral and cerebral occlusive arterial disease.
      • Clarke R
      • Daly L
      • Robinson K
      • Naughten E
      • Cahalane S
      • Fowler B
      • et al.
      Hyperhomocysteinemia: an independent risk factor for vascular disease.
      Mutations in the genes of cystathionine synthase and 5,10-methylenetetrahydrofolate reductase (Fig. 4) that lead to a deficiency of these enzymes have been shown to be responsible.
      • Clarke R
      • Daly L
      • Robinson K
      • Naughten E
      • Cahalane S
      • Fowler B
      • et al.
      Hyperhomocysteinemia: an independent risk factor for vascular disease.
      • Kang SS
      • Wong PW
      • Bock HG
      • Horwitz A
      • Grix A
      Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reducíase mutations.
      • Ueland PM
      • Refsum H
      Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy.
      Deficiencies of other enzymes that function in homocysteine metabolism (Fig. 4) may be involved but have not yet been established. Plasma homocysteine concentration is also determined by external factors. Folic acid, vitamin B12 or vitamin B6 deficiency, and chronic renal failure increase the concentration.
      • Ueland PM
      • Refsum H
      Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy.
      In addition, gender, premenopausal or postmenopausal state, and age are known influential factors.
      Figure thumbnail gr4
      Fig. 4Enzymes and cofactors involved in homocysteine metabolism in humans. 1 = cystathionine synthase; 2 = γ-cystathionase; 3 = N5-methyltetrahydrofolate-homocysteine methyltransferase; 4 = 5,10-methylenetetrahydrofolate reductase; 5 = betaine-homocysteine methyltransferase. (From Boers.
      • Boers GH
      Hyperhomocysteinaemia: a newly recognized risk factor for vascular disease.
      By permission.)
      The pathogenesis of premature atherosclerosis in hyperhomocysteinemia is unknown; various hypotheses have been proposed.
      • Ueland PM
      • Refsum H
      • Brattström L
      Plasma homocysteine and cardiovascular disease.
      Currently, data are limited on hyperhomocysteinemia and symptomatic, premature atherosclerosis of the mesenteric circulation. Boers and associates
      • Boers GH
      • Smals AG
      • Trijbels FJ
      • Fowler B
      • Bakkeren JA
      • Schoonderwaldt HC
      • et al.
      Heterozygosity for homocystin-uria in premature peripheral and cerebral occlusive arterial disease.
      described a 48-year-old woman who had abdominal angina and hyperhomocysteinemia, defined as a pathologic increase of the serum homocysteine level after methionine loading. Postmortem studies have shown a correlation between the severity of atherosclerosis in the coronary and cerebral vascular beds and the severity of atherosclerosis in the mesenteric arteries.
      • Reiner L
      • Jimenez FA
      • Rodriguez FL
      Atherosclerosis in the mesenteric circulation: observations and correlations with aortic and coronary atherosclerosis.
      Therefore, hyperhomocysteinemia is likely to be a risk factor for symptomatic, premature atherosclerosis of the mesenteric circulation. Our patient's history strongly suggests that this is indeed true. Because the plasma homocysteine level can often be decreased by administration of pyridoxine, folic acid, and betaine,
      • Brattström L
      • Israelsson B
      • Norrving B
      • Bergqvist D
      • Thörne J
      • Hultberg B
      • et al.
      Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease: effects of pyridoxine and folie acid treatment.
      • Franken DG
      • Boers GH
      • Blom HJ
      • Trijbels FJ
      • Kloppenborg PW
      Treatment of mild hyperhomocysteinemia in vascular disease patients.
      screening for hyperhomocysteinemia in young patients with abdominal angina seems appropriate. Whether a reduction in the plasma homocysteine level will decrease future ischemic vascular events remains to be proved.

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