El síndrome de Heyde / Heyde syndrome / Síndrome de Heyde

Desde que Edward Heyde vislumbró en 1958 una misteriosa asociación entre estenosis aórtica y hemorragia digestiva han transcurrido seis décadas y se ha suscitado no poca controversia. En la época en que fue propuesta, el estatus técnico y metodológico de la ciencia médica y una interpretación sesgada de su idea original impidieron obtener un sustento estadístico y fisiopatológico que le otorgara un amplio reconocimiento como entidad clínica individual. Los avances en varias disciplinas permitieron demostrar que su frecuencia de presentación excede el efecto del azar, además de esclarecer con precisión y elegancia sus mecanismos fisiopatológicos. Su consolidación como síndrome nos revela una verdadera encrucijada entre la cardiología, la gastroenterología, la hematología y el laboratorio, especialidades involucradas tanto en su proceso de comprensión como en su manejo práctico en la actualidad. Sin embargo, a pesar de tener una incidencia no desdeñable y adquirir un papel central en la conducción clínica de la estenosis aórtica, esta entidad parece haber pasado de ser resistida a relativamente ignorada. Con el objetivo de contribuir a su visibilidad, la presente revisión ofrece un panorama integral sobre el tema, incluyendo una perspectiva histórica de los principales aportes en pos de su conocimiento y un abordaje en profundidad de sus mecanismos, las claves de su detección clínica y su impacto en el manejo de la estenosis aórtica y otras entidades con fisiopatología afín.

Since Edward Heyde perceived in 1958 a mysterious association between aortic stenosis and gastrointestinal bleeding, six decades have passed and no little controversy has arisen. At the time it was proposed, the technical and methodological status of medical science and a biased interpretation of his original idea prevented obtaining a statistical and pathophysiological support that would grant it wide recognition as and individual clinical entity. Advances in several disciplines allowed to demonstrate that its frequency of presentation exceeds the effect of chance, besides clarifying with precision and elegance its pathophysiological mechanisms. Its consolidation as a syndrome reveals a true crossroads between Cardiology, Gastroenterology, Hematology and Laboratory, specialties involved both in its understanding process and in its practical management today. However, despite having a not negligible incidence and acquiring a central role in the clinical conduction of aortic stenosis, this entity seems to have gone from being resisted to relatively ignored. With the objective of contributing to its visibility, this review offers a comprehensive overview of the subject, covering the main historical contributions to its knowledge and approaching in depth its mechanisms, the keys to its clinical detection and its impact on the management of aortic stenosis and other entities with related pathophysiology.

Desde que Edward Heyde imaginou em 1958 uma misteriosa associação entre estenose aórtica e hemorragia gastrointestinal, seis décadas se passaram e não houve pouca controvérsia. Na época em que foi levantada, o estado técnico e metodológico da ciência médica e uma interpretação tendenciosa de sua ideia original impediram a construção de um apoio estatístico e fisiopatológico que lhe concederia amplo reconhecimento como entidade clínica individual. Avanços em diversas disciplinas permitiram demonstrar que sua frequência de apresentação excede o efeito do acaso, além de esclarecer com precisão e elegância seus mecanismos fisiopatológicos. Sua consolidação como síndrome revela uma verdadeira encruzilhada entre Cardiologia, Gastroenterologia, Hematologia e Laboratório, especialidades envolvidas tanto em seu processo de compreensão quanto em sua gestão prática hoje. No entanto, apesar de ter uma incidência não desprezível e adquirir um papel central no manejo clínico da estenose aórtica, esta entidade parece ter passado de resistida para relativamente ignorada. Com o intuto de contribuir para sua visibilidade, esta revisão oferece um panorama abrangente do tema, revendo as principais contribuições históricas ao seu conhecimento e abordando em profundidade seus mecanismos, as chaves para sua detecção clínica e seu impacto na gestão da estenose aórtica e outras entidades com fisiopatologia relacionada.

Of aortic valve and bleeding: Heyde's syndrome.

An 80-year-old woman with severe aortic stenosis presented with relapsing enterorrhagia and severe anemia. A video capsule pan-endoscopy showed multiple sites of complex mucosal angiodysplasia in the jejunum. Direct hemostatic treatment of accessible angiodysplasia was done with argon plasma coagulation, and the patient was urgently referred for trans-catheter aortic valve replacement (TAVR). At follow-up 1 month and 3 months later, she was doing well with no further episodes of bleeding. Heyde's syndrome is referred to as the association of aortic stenosis, gastrointestinal angiodysplasia, bleeding, and anemia. It is an acquired type2A von Willebrand syndrome caused by the proteolysis and loss of the largest polymers of vWF due to the high shear forces generated through the stenotic aortic valve. The qualitative and quantitative vWF defects play a central role in the angiogenesis and development of gastrointestinal angiodysplasia The vWF abnormalities are closely associated with the hemodynamic severity of the aortic valve stenosis. Valve replacement is the pivotal strategy to achieve the long-term resolution of bleeding recurrences. TAVR is a valuable option particularly in high-risk patients for whom surgical valve replacement is not feasible.

Transcatheter aortic valve implantation in a patient with suspected hereditary von Willebrand disease and severe gastrointestinal bleeding - a case report.

INTRODUCTION: von Willebrand disease is the most common hereditary coagulopathy and is characterised by a deficiency in the quantity or quality of the von Willebrand factor. Heyde Syndrome, in contrast, is an acquired form of von Willebrand syndrome (AVWS) due to calcific aortic valve stenosis, characterised by gastrointestinal bleeding from angiodysplasia. CASE PRESENTATION: A 73-year-old patient presented with severe gastrointestinal bleeding and stated that she suffered from hereditary von Willebrand disease. Upon echocardiography, a severe aortic valve stenosis was found, and hence the suspicion of additional AVWS was raised. Since endoscopic interventions and conservative therapeutic approaches did not result in a cessation of the bleeding, transcatheter aortic valve implantation (TAVI) was performed to stop the additional shear stress on von Willebrand factor. This resulted in cessation of the bleeding. CONCLUSION: Retrospectively, this life-threatening gastrointestinal bleeding was a result of severe Heyde Syndrome, which could be alleviated by TAVI. Whether the patient had suffered from inherited von Willebrand disease in the past, remains uncertain. AVWS should be considered in patients with suspected inherited von Willebrand disease and concomitant severe aortic valve stenosis, since it constitutes a treatable cause of a potentially severe bleeding disorder.

An elderly man with gastric cancer, Saint's triad and Heyde's syndrome.

This case study describes a 71-year-old man with signet-ring cell gastric adenocarcinoma and malignant sigmoidal polyp; and typical features of Saint's triad and Heyde syndrome. He had digestive bleeding, two types of hernia, diverticulosis, arterial hypertension, malignant polyp, and antecedent of smoking, lung tuberculosis, and surgical correction of aortic valve stenosis. There is a hypothetical inverse relationship between herniosis and development of malignancy; however, the patient herein described presented gastric and sigmoidal cancers. Gastrointestinal malignancies are sometimes associated with paraneoplastic entities, isolated or manifested as syndromes, but neither Saint's triad or Heyde syndrome have been included. This patient persisted clinically stable during the preoperative period, but suddenly died; Trousseau's syndrome would be the most probable mechanism of sudden death in this setting. Case reports can stimulate further studies to get additional knowledge about unusual entities.

Clinical and In Vitro Evidence That Left Ventricular Assist Device-Induced von Willebrand Factor Degradation Alters Angiogenesis.

Background Gastrointestinal bleeding from angiodysplasia is a major problem in continuous-flow left ventricular assist device (LVAD) patients. LVAD shear stress causes pathologic degradation of VWF (von Willebrand factor). A mechanistic relationship between VWF degradation and angiodysplasia has not been explored. We tested 2 novel hypotheses: (1) clinical hypothesis: VWF fragments are elevated in LVAD patients that develop angiodysplasia and (2) in vitro hypothesis: VWF fragments generated during LVAD support alter angiogenesis, which may contribute to angiodysplasia. Methods and Results Clinical study: Paired blood samples were collected from continuous-flow LVAD patients (n=35). VWF was quantified with immunoblotting. In vitro experiments: (1) To investigate whether LVAD support alters angiogenesis, human endothelial cells were cultured with LVAD patient plasma (n=11). To investigate mechanism, endothelial cells were cultured with VWF fragments produced by exposing human VWF and ADAMTS-13 (VWF protease) to LVAD-like shear stress (175 dyne/cm2, n=8). Clinical study results: in all patients (n=35, mean support 666±430 days), LVAD support degraded high-molecular-weight VWF multimers ( P<0.0001) into low-molecular-weight VWF multimers ( P<0.0001) and VWF fragments ( P<0.0001). In patients with gastrointestinal bleeding from angiodysplasia (n=7), VWF fragments were elevated ( P=0.02) versus nonbleeders. In contrast, in patients with gastrointestinal bleeding without angiodysplasia, VWF fragments were not elevated versus nonbleeders ( P=0.96). In vitro experiments results: LVAD patient plasma caused abnormal angiogenesis with reduced tubule length ( P=0.04) and migration ( P=0.05). Similarly, endothelial cells grown with VWF degradation fragments exhibited reduced tubule length ( P<0.001) and migration ( P=0.01). Conclusions LVAD patients who bled from angiodysplasia had higher levels of VWF fragments than nonbleeders and gastrointestinal bleeders without angiodysplasia. VWF fragments caused abnormal angiogenesis in vitro. These findings suggest that VWF fragments may be a mechanistic link between LVAD support, abnormal angiogenesis, angiodysplasia, and gastrointestinal bleeding.

Digoxin Is Associated With a Decreased Incidence of Angiodysplasia-Related Gastrointestinal Bleeding in Patients With Continuous-Flow Left Ventricular Assist Devices.

BACKGROUND: Gastrointestinal bleeding (GIB) is one of the principal adverse events affecting patients with continuous-flow left ventricular assist devices (CF-LVADs). Despite the early recognition that GIB is commonly because of gastrointestinal angiodysplasia (GIAD), the exact pathophysiology of this process remains elusive. It has been postulated that the abnormal hemodynamic profile in CF-LVAD patients may activate the angiogenesis signaling cascade via the HIF (hypoxia-inducible factor)-1α/angiopoietin-2 pathway leading to formation of GIADs. Digoxin is a potent inhibitor of HIF-1α synthesis, and we hypothesized that its use reduces the incidence of GIAD and GIB in patients with CF-LVAD. METHODS AND RESULTS: Charts of all adult patients implanted with CF-LVAD between February 2006 and February 2017 were reviewed with particular emphasis on occurrence and cause of GIB. Fifty-four of 199 patients (27%) experienced a GIB. Overall frequency of GIB was lower in the 64 patients receiving digoxin compared with the 135 patients not receiving digoxin (16% versus 33%, P=0.01). Multivariable-adjusted Cox regression analysis confirmed that digoxin use was independently associated with a reduced risk for overall GIB (hazard ratio, 0.49; 95% CI, 0.24-0.98; P=0.045). GIBs were then categorized as non-GIAD, GIAD, or likely GIAD. Although the incidence of non-GIAD was similar in both groups (11% versus 7%, P=0.41), the frequency of GIAD/likely GIAD bleeding was significantly reduced in the digoxin group (5% versus 25%, P=0.0003). Multivariable-adjusted analysis confirmed that digoxin use was independently associated with a reduced risk for GIAD/likely GIAD bleeding (hazard ratio, 0.18; 95% CI, 0.06-0.6; P=0.005). However, digoxin use was not associated with reduced risk for non-GIAD GIB (hazard ratio, 1.54; 95% CI, 0.58-4.08; P=0.39). CONCLUSIONS: Use of digoxin was associated with a significant reduction in GIAD-related GIB in patients with CF-LVAD.

An elderly man with gastric cancer, Saint's triad and Heyde's syndrome / Un anciano con cáncer gástrico, tríada de Saint y síndrome de Heyde

This case study describes a 71-year-old man with signet-ring cell gastric adenocarcinoma and malignant sigmoidal polyp; and typical features of Saint's triad and Heyde syndrome. He had digestive bleeding, two types of hernia, diverticulosis, arterial hypertension, malignant polyp, and antecedent of smoking, lung tuberculosis, and surgical correction of aortic valve stenosis. There is a hypothetical inverse relationship between herniosis and development of malignancy; however, the patient herein described presented gastric and sigmoidal cancers. Gastrointestinal malignancies are sometimes associated with paraneoplastic entities, isolated or manifested as syndromes, but neither Saint's triad or Heyde syndrome have been included. This patient persisted clinically stable during the preoperative period, but suddenly died; Trousseau's syndrome would be the most probable mechanism of sudden death in this setting. Case reports can stimulate further studies to get additional knowledge about unusual entities.

Este estudio de caso describe un hombre de 71 años de edad, con adenocarcinoma gástrico con células en anillo de sello y un pólipo maligno sigmoideo; y características típicas de la tríada de Saint y del síndrome de Heyde. Tuvo una hemorragia digestiva, dos tipos de hernias, divertículos, hipertensión arterial, y pólipo maligno; con antecedente de tabaquismo, tuberculosis pulmonar, y corrección quirúrgica de estenosis de la válvula aórtica. Hay una hipotética relación inversa entre hernioses y el desarrollo de malignidades; sin embargo, el paciente que se describe en el presente documento presentó cánceres gástrico y sigmoideo. Neoplasias gastrointestinales se asocian a veces con entidades para neoplásicas aisladas o manifiestan síndromes, pero ni la tríada de Saint ni el síndrome de Heyde se ha incluido. Este paciente persistió clínicamente estable durante el período preoperatorio, pero de repente murió; síndrome de Trousseau sería el mecanismo más probable de muerte súbita en esta situación. Los informes de casos pueden estimular más estudios para obtener un conocimiento adicional sobre esas entidades inusuales.

Histopathology of Calciphylaxis: Cohort Study With Clinical Correlations.

Calciphylaxis is a rare, painful, and life-threatening condition with a high mortality rate. Although the etiology of calciphylaxis is not well understood, it has been proposed that calcium deposition within and around subcutaneous vessels restricts blood flow chronically, thereby predisposing the patient to acute pannicular and dermal thrombosis. Given increasing recognition of the role of hypercoagulability in calciphylaxis, this retrospective cohort study sought to evaluate the presence of thromboses and dermal angioplasia in calciphylaxis. Moreover, we aimed to validate previous observations about the histopathology of calciphylaxis compared with skin biopsies from patients with end-stage renal disease but without calciphylaxis. After a meticulous clinical chart review, we assessed the corresponding skin biopsies for the presence of vessel calcification, thromboses, and dermal angioplasia in skin biopsies from patients with calciphylaxis (n = 57) and compared with those from patients with end-stage renal disease but without calciphylaxis (n = 26). Histopathologic findings were correlated with clinical features such as chronic kidney disease, diabetes, or associated malignancy. Our results validated a prior observation that calciphylaxis was significantly more likely to show calcification of dermal vessels and diffuse dermal thrombi. This study reports the frequent finding of dermal angioplasia, a potential marker of chronic low-grade ischemia, as another frequent microscopic finding in calciphylaxis. Among cases of calciphylaxis, histopathologic changes in patients with chronic kidney disease were indistinguishable from those in patients without chronic kidney disease, thereby implying a final common pathogenic pathway in both uremic and nonuremic calciphylaxis. In future, larger, prospective studies may be useful in validating these findings.

Continuous-Flow LVAD Support Causes a Distinct Form of Intestinal Angiodysplasia.

RATIONALE: The objective of this autopsy study was to determine whether gastrointestinal angiodysplasia develops during continuous-flow left ventricular assist device (LVAD) support. OBJECTIVE: LVAD support causes pathologic degradation of von Willebrand factor (vWF) and bleeding from gastrointestinal angiodysplasia at an alarming rate. It has been speculated that LVAD support itself may cause angiodysplasia. The relationship to abnormal vWF metabolism is unknown. We tested the hypothesis that abnormal gastrointestinal vascularity develops during continuous-flow LVAD support. METHODS AND RESULTS: Small bowel was obtained from deceased humans, cows, and sheep supported with a continuous-flow LVAD (n=9 LVAD, n=11 control). Transmural sections of jejunum were stained with fluorescein isothiocyanate-conjugated isolectin-B4 for endothelium to demarcate vascular structures and quantify intestinal vascularity. Paired plasma samples were obtained from humans before LVAD implantation and during LVAD support (n=41). vWF multimers and degradation fragments were quantified with agarose and polyacrylamide gel electrophoresis and immunoblotting. Abnormal vascular architecture was observed in the submucosa of the jejunum of human patients, cows, and sheep supported with a continuous-flow LVAD. Intestinal vascularity was significantly higher after LVAD support versus controls (5.2±1.0% versus 2.1±0.4%, P=0.004). LVAD support caused significant degradation of high-molecular-weight vWF multimers (-9±1%, P<0.0001) and accumulation of low-molecular-weight vWF multimers (+40±5%, P<0.0001) and vWF degradation fragments (+53±6%, P<0.0001). CONCLUSIONS: Abnormal intestinal vascular architecture and LVAD-associated vWF degradation were consistent findings in multiple species supported with a continuous-flow LVAD. These are the first direct evidence that LVAD support causes gastrointestinal angiodysplasia. Pathologic vWF metabolism may be a mechanistic link between LVAD support, abnormal angiogenesis, gastrointestinal angiodysplasia, and bleeding.

Acquired Von Willebrand Syndrome In Aortic Stenosis: Case Report And Review.

We present a case of a 61 year old man who presented with a 3 week history of easy bruising and ecchymoses in both thighs and right arm without significant trauma. Physical exam was remarkable for oozing gums, diminished second heart sound, a systolic ejection murmur at the aortic position with radiation to carotids, and delayed pulses. Laboratories were remarkable for iron deficiency anemia. Echocardiogram was consistent with severe aortic stenosis. Colonoscopy revealed several arteriovenous malformations throughout the colon. There is an association between severe aortic stenosis and gastrointestinal bleeding. The pathogenesis of Heyde's Syndrome involves iron deficiency anemia due to acquired von Willebrand factor (vWF) deficiency and ultimately gastrointestinal angiodysplasia. Correct diagnosis and management warrants a multidisciplinary approach.

Use of polymethylmethacrylate in treatment of arteriovenous angiodysplasia with bone lesions.

Arteriovenous dysplasia is rather uncommon disease, quite often leading to severe complications even in young age. Involvement of the osseous apparatus into the pathological process is frequently associated with the problem of amputation of the affected limb. Therefore, salvage of the extremity while removing arteriovenous shunt and trophic impairments is an extremely important clinical task. In the presented herein clinical case report, a female patient with arteriovenous angiodysplasia of the lower limb with the tibial bone involved into the pathological process underwent repeated stagewise embolisations, failing however to achieve complete liquidation of the arteriovenous reflux. In this connection, after removal of angiomatous tissues, requiring also excochleation of the damaged portions of the bone, in order to reinforce the axis of the tibial bone the intramedullary canal of the latter was filled with polymethylmethacrylate (PMMA). Expansion of the spectrum of auxiliary methods, besides the most frequently performed in such patients embolisations of afferent arteries and removal of angiomatous tissues would make it possible to increase radical nature of interventions with salvage of the supporting function of limbs.

Prevalence, variability, and outcomes in portal hypertensive colopathy: a study in patients with cirrhosis and paired controls.

BACKGROUND: Management of portal hypertensive colopathy (PHC) has been challenged by controversial results in its prevalence and clinical relevance. OBJECTIVE: To describe the PHC prevalence and to evaluate the variability in diagnosis, the relation to severity of liver disease, and the incidence of severe outcomes. DESIGN: Cross-sectional study. SETTING: Endoscopic unit of a tertiary-care academic center in Rio de Janeiro, Brazil. PATIENTS: Patients with cirrhosis with portal hypertension and controls paired for age and sex. INTERVENTIONS: All patients were submitted to standard and image-enhanced colonoscopies, which were recorded in a coded video file and analyzed twice by a blinded endoscopist. MAIN OUTCOME MEASUREMENTS: The prevalence of PHC. RESULTS: A total of 51 patients with cirrhosis (55% male, mean age 59 years) and 51 healthy controls (43% male, mean age 61 years) were included. The top ranking colonoscopic findings were angiodysplasia-like lesions, nonspecific vascular pattern, red spots, and colorectal varices, all significantly more frequent in patients with cirrhosis compared with controls. PHC prevalence was 71% in patients with cirrhosis. For PHC, interobserver and intraobserver agreement (k values [standard error]) were 0.68 (0.09) and 0.63 (0.10), respectively. Intraobserver agreement for colonoscopic findings was satisfactory. PHC was not related to more severe liver disease or liver stiffness. Only 5 patients developed severe outcomes during follow-up. LIMITATIONS: The exclusion of patients with cirrhosis without esophageal varices and the absence of an interobserver agreement analysis by double-blinded endoscopists. CONCLUSION: PHC was highly prevalent in patients with cirrhosis, and its diagnostic agreement was satisfactory. PHC is not associated with relevant severe outcomes in a 12-month follow-up.

Clinical features and endoscopic findings in patients with actively bleeding colonic angiodysplasia.

Colonic angiodysplasia (AGD) is an important cause of lower gastrointestinal bleeding. However, most episodes of bleeding from colonic AGD stop spontaneously. To date, few data are available regarding the endoscopic findings of bleeding colonic AGD. In order to clarify the clinical features and endoscopic findings of actively bleeding colonic AGD, we conducted a retrospective study of patients treated with colonoscopy at our hospital. From November 2006 to March 2013 inclusive, 32,586 colonoscopies were performed at this hospital, among which 13 patients with bleeding colonic AGD were enrolled in the current study. The mean age was 84 years (range: 69-90 years). All patients had chronic heart disease and were currently using anticoagulant and/or antiplatelet drugs. Sites of bleeding AGD were localized in the left colon in two patients (15 %) and in the right colon in the remaining patients (85 %). A total of 77 % of the lesions (10/13) were 1-2 mm in size and two lesions were 4 mm in size; only one lesion was larger than 5 mm. Endoscopic treatment resulted in a therapeutic success rate of 100 %, and no recurrence of bleeding was observed in 85 % of the patients (11/13) after treatment. During the study period, two patients presented with bleeding from residual AGD and underwent endoscopic treatment. In the present study, most sites of bleeding colonic AGD were very small, termed "micro-angiodysplasia", and targeted endoscopic treatment for actively bleeding AGD was found to be effective and safe. It is essential that physicians consider the potential for actively bleeding colonic AGD, especially "micro-angiodysplasia", when performing colonoscopy in elderly patients with a history of cardiovascular disease and/or treatment with anticoagulant or antiplatelet therapy.

Lower gastrointestinal bleeding.

This article examines causes of occult, moderate and severe lower gastrointestinal (GI) bleeding. The difference in the workup of stable vs unstable patients is stressed. Treatment options ranging from minimally invasive techniques to open surgery are explored.

Heyde syndrome in a 71-year-old man who underwent chest radiotherapy at young age.

We report the case of a 71-year-old man with diagnosis of aortic valve stenosis for ten years, who came to hospital because of breathlessness during the previous two months and recent low intestinal hemorrhage. On admission, laboratory tests and upper gastrointestinal endoscopy and colonoscopy revealed anemia and bleeding cecal angiodysplasia. The echocardiography study showed a severe aortic stenosis. Classical Heyde syndrome is described as the association of aortic stenosis, bleeding gastrointestinal angiodysplasia and secondary anemia. The antecedent of mediastinal radiotherapy for treatment of Hodgkin's disease during his youth, and eventual late cardiac adverse effects that may include aortic or mitral valve disturbances are highlighted. Electrocoagulation with argonium was performed on the sites of active bleeding during the colonoscopy. In sequence, surgical replacement by bioprothesis was done on the aortic valve. The patient remains asymptomatic, under long-term outpatient surveillance, with normal control evaluations. The aim of this case study is to emphasize difficulties related to diagnosis, and to highlight the role of endoscopy and imaging studies to confirm a hypothesis of this underestimated condition.

[Lymphedema: anatomy, physiology and pathophysiology of lymphedema, definition and classification of lymphedema and lymphatic vascular malformations]. / Das Lymphödem - Anatomie, Physiologie und Pathophysiologie des Lymphödems, Definition und Klassifizierung des Lymphödems und lymphatischer Gefäßmalformationen.

Lymphedema is a chronic disease associated with a congenital or acquired disorder of the lymphatic vessels or lymph nodes. Untreated lymphedema can lead to complications and disability. Clinical Lymphology deals not only with lymphedema of the extremities but also of the head, the genitals and the internal organs (lymphostatic enteropathy, chylaskos, chylothorax, chylopericard etc). Symptoms of this disorder are often misdiagnosed or not recognized. Ignorance and trivialization of lymphedema causes insufficient treatment, which then is not carried out to the extent as it is possible today by scientific findings. Even today delayed or not optimal treatment causes a long ordeal for many patients.The fact that lymphedema for those affected is a major psychological and social burden, which is limiting the quality of life, has also often been unregarded. The knowledge of anatomy, physiology and pathophysiology as well as the knowledge of causes are necessary for diagnosis, so that early treatment can be initiated.