Heyde's syndrome

With time
Didn't play the corresponding interactive case or want to try it again? Click here to do so.

Diagnosis and reasoning

This elderly man has presented following the passage of blood per-rectum. His only known comorbidity is asymptomatic moderate aortic stenosis. He was stable on admission and did not develop re-bleeding afterward. Investigations show a picture suggestive of iron-deficiency anemia. The above combination of findings is suggestive of a colonic source of bleeding; the presence of iron deficiency anemia is particularly ominous, indicating that subclinical bleeding may have been going on for some time now. A colorectal malignancy is a serious consideration here. Colonoscopy is an essential next step. This however, reveals angiodysplasia of the right colon. Note that angiodysplasia are a complication of aging, and are not uncommon in the elderly. While the source of bleeding has now been found, his evaluation should not stop here. Importantly, the combination of aortic stenosis with bleeding angiodysplasia should prompt consideration of Heyde's syndrome. In this condition, acquired von Willebrand factor (vWF) deficiency due to the aortic stenosis predisposes to angiodysplasial bleeding. Von Willebrand factor testing should follow. Here, the combination of low ristocetin cofactor (RCO) activity, reduced ristocetin induced platelet aggregation, normal vWF antigen levels (VWA), normal factor VIII levels, and a RCO/VWA ratio <0.5 suggests at type IIA vWF disease; this is compatible with the acquired vWF deficiency seen in Heyde's syndrome, clinching the diagnosis. Coagulation studies should also be performed as a baseline; the normal results seen here are not unusual, as clotting factor levels may remain normal in acquired vWF deficiency. Note that there is no clear rationale for upper gastrointestinal (GI) endoscopy; an upper GI source of bleeding would have resulted in malena. Laser coagulation of the angiodysplasia should be considered in light of the hemorrhage. As he is clinically stable, with only minimally reduced hemoglobin levels, blood transfusion is not indicated. The acquired vWF deficiency seen here is generally not responsive to treatments used in congenital vWF deficiency, e.g., desmopressin. While aortic valve replacement (AVR) will both improve the coagulation abnormalities and possibly result in complete resolution of symptoms, it is a high-risk intervention. Note also that patients with asymptomatic (i.e. no cardiac symptoms) aortic stenosis have a survival rate similar to that of the general population. Given the above points, the risks of AVR outweigh the benefits in this hemodynamically stable patient with moderate bleeding.


Discussion

Heyde syndrome refers to the triad of aortic stenosis, acquired von Willebrand syndrome, and bleeding from gastrointestinal (GI) angiodysplasia; this was first described by Edward Heyde in 1958. Both aortic stenosis and angiodysplasia can occur due to age-related degenerative processes, and are both common in the elderly. Because of this, there was doubt for many years as to whether Heyde’s syndrome was mere correlation, rather than causation. Warkentin et al. provided a plausible explanation in 1992: acquired von Willebrand factor (vWF) deficiency. VWF, a key component of the hemostatic process, circulates as high molecular weight protein multimers. These multimers are cleaved into monomers at sites of vascular injury where there is a high-velocity blood flow; this subsequently enables platelets to adhere to those sites. In patients with aortic stenosis, blood passing through the stenotic valve is exposed to high shear stress; it is postulated that this predisposes to vWF multimer cleavage. The resulting active monomers are degraded by the enzyme ADAMTS13 as part of the normal homeostatic process. The ultimate outcome is vWF deficiency, impaired clotting, and therefore, increased risk of angiodysplasial bleeding. Other factors that may be implicated in the pathogenesis of Heyde syndrome include mucosal ischemia, cholesterol embolization, acquired platelet dysfunction and inflammatory reactions. The presentation is usually related to the GI bleeding. Patients may present acutely with overt bleeding, or more indolently, with signs and symptoms of anemia. Signs and symptoms of left ventricular outflow tract obstruction may also be present, or unmasked by the bleeding. The initial workup should aim to exclude more common causes of GI bleeding, including gastric or duodenal ulcers, malignancies, diverticular disease, and inflammatory bowel disease. Most angiodysplasia occur in the right colon and cecum, and are detected upon lower GI endoscopy. Where bleeding angiodysplasia are detected in conjunction with aortic stenosis, Heyde syndrome should always be considered; demonstration of WF deficiency will clinch the diagnosis. Unfortunately, there is no single assay that can diagnose vWF deficiency with complete confidence; ranked in order of sensitivity, the potential tests are: gel electrophoresis, PFA-100 closure time, vWF ristocetin cofactor activity, and vWF antigen levels. The range of treatment options includes medical management, endoscopic interventions, colonic surgery, and aortic valve replacement (AVR). The acquired vWF deficiency seen in Heyde syndrome is generally not responsive to the treatments used in von Willebrand disease, e.g., octreotide, desmopressin, or factor VIII/vWF supplementation. Some experts suggest the use of estrogen–progesterone preparations, although their mechanism of action is unknown. Thalidomide has been shown to reduce the incidence of severe bleeding. Local endoscopic interventions, e.g., electrocoagulation,laser photocoagulation or sclerotherapy, can be used to treat the GI bleeding. Severe bleeding may necessitate emergency bowel resection. Recurrent severe GI bleeding, particularly if medical and endoscopic treatment has failed, is a strong indication for AVR. This improves the coagulation abnormality, and may also result in long-term resolution of symptoms. Note that oral anticoagulation following placement of a mechanical valve predisposes to rebleeding; a bioprosthesis is preferred, especially if the patient is elderly.


Take home messages

  1. Heyde's syndrome refers to the triad of triad of aortic stenosis, acquired von Willebrand syndrome, and recurrent bleeding from gastrointestinal (GI) angiodysplasia.
  2. Most angiodysplasia occur in the right colon and cecum and can be detected upon lower GI endoscopy.
  3. Aortic valve replacement (AVR) often resolves the coagulation abnormality and may even cause complete resolution of symptoms; however, this needs to be balanced against the risk of complications.

Insightful, fun cases to improve your diagnostic skills

Use your detective skills, strengthen fundamentals faster, and access a wealth of knowledge.

  1. BAUMGARTNER H.. Aortic stenosis: medical and surgical management. Heart [online] 2005 November, 91(11):1483-1488 [viewed 10 September 2017] Available from: doi:10.1136/hrt.2004.056176
  2. HUDZIK B, WILCZEK K, GASIOR M. Heyde syndrome: gastrointestinal bleeding and aortic stenosis CMAJ [online] 2016 Feb 2, 188(2):135-138 [viewed 20 April 2019] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732965
  3. JOHNSON-WIMBLEY TERRI D., GRAHAM DAVID Y.. Diagnosis and management of iron deficiency anemia in the 21st century. Therapeutic Advances in Gastroenterology [online] December, 4(3):177-184 [viewed 10 September 2017] Available from: doi:10.1177/1756283X11398736
  4. LOSCALZO JOSEPH. From Clinical Observation to Mechanism — Heyde's Syndrome. N Engl J Med [online] 2012 November, 367(20):1954-1956 [viewed 10 September 2017] Available from: doi:10.1056/NEJMcibr1205363
  5. MAGANTI KAMESWARI, RIGOLIN VERA H., SARANO MAURICE ENRIQUEZ, BONOW ROBERT O.. Valvular Heart Disease: Diagnosis and Management. Mayo Clinic Proceedings [online] 2010 May, 85(5):483-500 [viewed 10 September 2017] Available from: doi:10.4065/mcp.2009.0706
  6. MASSYN M. W., KHAN S. A.. Heyde syndrome: a common diagnosis in older patients with severe aortic stenosis. Age and Ageing [online] 2008 October, 38(3):267-270 [viewed 10 September 2017] Available from: doi:10.1093/ageing/afp019
  7. ZHU AMY, KANESHIRO MARC, KAUNITZ JONATHAN D.. Evaluation and Treatment of Iron Deficiency Anemia: A Gastroenterological Perspective. Dig Dis Sci [online] December, 55(3):548-559 [viewed 10 September 2017] Available from: doi:10.1007/s10620-009-1108-6