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Gastrointestinal Bleeding, Aortic Stenosis, and the Hiding Culprit

      To the Editor:
      Management of gastrointestinal bleeding sometimes requires thinking beyond the gastrointestinal tract. A 57-year-old woman with a history of aortic stenosis was admitted with fatigue and light-headedness. Her history also included diabetes and hypertension.

      Assessment

      Examination revealed an asymptomatic woman with the following vital signs: pulse 61/min, blood pressure 94/50 mm Hg, respiratory rate 18/min, and oxygen saturation 100% (ambient air). Jugular venous pulse measured 12 cm, the cardiac impulse was diffuse, and auscultation revealed a 3/6 harsh systolic ejection murmur at the cardiac base that radiated to the carotid arteries; there were bibasilar crackles over the lower lung fields and 2+ edema below the knees. Rectal examination demonstrated melena and guaiac positive stool.
      Laboratory data revealed depressed serum hemoglobin of 4.5 gm and creatinine of 1.39 mg/dL. Platelet count, international normalized ratio, and liver function test results were normal. Transfusion of 2 U of packed red blood cells was administered, and the patient was admitted. During the hospitalization she required additional transfusions for persistent anemia. Esophagogastroduodenoscopy, colonoscopy, and capsule endoscopy failed to detect a source of hemorrhage. Transthoracic echocardiography revealed a left ventricular ejection fraction of 60% and severe aortic stenosis (valve area 0.88 cm2).

      Diagnosis

      The association between aortic stenosis and gastrointestinal hemorrhage was suggested by Heyde in 1958 in a letter to the New England Journal of Medicine.
      • Heyde E.C.
      Gastrointestinal bleeding aortic stenosis.
      It was subsequently recognized that gastrointestinal bleeding in this syndrome was related to submucosal angiodysplasia and loss of integrity of von Willebrand factor (vWF). Cessation of gastrointestinal hemorrhage after aortic valve replacement supported the role of aortic stenosis in the syndrome.
      • King R.M.
      • Pluth J.R.
      • Giuliani E.R.
      The association of unexpected unexplained gastrointestinal bleeding with calcific aortic stenosis.
      Von Willebrand factor plays a critical role in platelet adhesion and clot formation. Although it is referred to as a single unit, vWF comprises a system that includes a variety of essential enzymes. There are multiple von Willebrand defects (vWDs). The acquired vWD associated with aortic stenosis is designated type IIa. It is postulated that the turbulent flow across the stenotic valve induces traumatic conformational change to high molecular weight von Willebrand monomers, leaving them susceptible to cleavage.
      • Loscalzo J.
      From clinical observation to mechanism—Heyde's syndrome.
      High molecular weight monomers are considered important for maintaining hemostasis in areas of high sheer stress, such as arteriovenous malformations. Why patients with type IIa vWD are prone to develop angiodysplasia is not well understood. Among the methods for detection, the most reliable test is gel electrophoresis.
      • Michiels J.J.
      • Berneman Z.
      • Gadisseur A.
      • et al.
      Classification and characterization of hereditary types 2A, 2B, 2C, 2D, 2E, 2M, 2N, and 2U (unclassifiable) von Willebrand disease.

      Management

      The reported prevalence of aortic stenosis in patients with gastrointestinal angiodysplasia ranges from 0 to 41%, and this variable association has led some to question the existence of Heyde's syndrome.
      • Bhutani M.S.
      • Gupta S.C.
      • Markert R.J.
      • et al.
      A prospective controlled evaluation of endoscopic detection of angiodysplasia and its association with aortic valve disease.
      The strongest evidence in support of the association between aortic stenosis and gastrointestinal hemorrhage is the consistent alleviation of bleeding after aortic valve replacement.
      • Anderson R.P.
      • McGrath K.
      • Street A.
      Reversal of aortic stenosis, bleeding gastrointestinal angiodysplasia, and von Willebrand syndrome by aortic valve replacement.
      Our patient underwent aortic valve replacement, and during a follow-up interval of 4 months she has had no further evidence of gastrointestinal hemorrhage.
      Heyde's syndrome is a rare source of gastrointestinal hemorrhage that should be considered in patients with iron deficiency anemia and aortic stenosis. Advanced laboratory studies such as gel electrophoresis can help guide diagnosis, but clinical assessment is paramount.

      References

        • Heyde E.C.
        Gastrointestinal bleeding aortic stenosis.
        N Engl J Med. 1958; 259: 196
        • King R.M.
        • Pluth J.R.
        • Giuliani E.R.
        The association of unexpected unexplained gastrointestinal bleeding with calcific aortic stenosis.
        Ann Thorac Surg. 1987; 44: 514-516
        • Loscalzo J.
        From clinical observation to mechanism—Heyde's syndrome.
        N Engl J Med. 2012; 367: 1954-1956
        • Michiels J.J.
        • Berneman Z.
        • Gadisseur A.
        • et al.
        Classification and characterization of hereditary types 2A, 2B, 2C, 2D, 2E, 2M, 2N, and 2U (unclassifiable) von Willebrand disease.
        Clin Appl Thromb Hemost. 2006; 12: 397-420
        • Bhutani M.S.
        • Gupta S.C.
        • Markert R.J.
        • et al.
        A prospective controlled evaluation of endoscopic detection of angiodysplasia and its association with aortic valve disease.
        Gastrointest Endosc. 1995; 42: 328-402
        • Anderson R.P.
        • McGrath K.
        • Street A.
        Reversal of aortic stenosis, bleeding gastrointestinal angiodysplasia, and von Willebrand syndrome by aortic valve replacement.
        Lancet. 1996; 347: 689-690