hereditary hemorrhagic telangiectasia ( HHT ), also known as Osler-Weber-Rendu disease and Osler-Weber-Rendu syndrome , is a rare autosomal dominant genetic disorder that leads to the formation of abnormal blood vessels in the skin, mucous membranes, and often in organs such as the lungs, liver, and brain.
This can cause nosebleeds, acute and chronic gastrointestinal bleeding, and various problems due to the involvement of other organs. Treatment focuses on reducing bleeding from vascular lesions, and sometimes other operations or interventions targeted to eliminate arterial malformations in organs. Chronic bleeding often requires iron supplements and sometimes blood transfusions. HHT is transmitted predominantly autosomal, and occurs in one in 5,000 people.
The disease carries the names of Sir William Osler, Henri Jules Louis Marie Rendu, and Frederick Parkes Weber, who described it in the late 19th and early 20th centuries.
Video Hereditary hemorrhagic telangiectasia
Signs and symptoms
Telangiectasias
Telangiectasia (small vascular malformations) can occur in the skin and nasal mucosal lining and gastrointestinal tract. The most common problem is nosebleeds (epistaxis), which often occur since childhood and affects about 90-95% of people with HHT. Lesions on the skin and in the mouth are more rarely bloody but can be considered unpleasant cosmetics; they affect about 80%. Skin lesions typically occur on the lips, nose and fingers, and on facial skin in sun-exposed areas. They appear suddenly, with an increasing amount over time.
Approximately 20% are affected by symptomatic gastrointestinal lesions, although higher percentages have non-symptomatic lesions. These lesions may bleed intermittently, which are rarely significant enough to be noticed (in the form of bloody vomit or black stool), but may eventually lead to iron depletion in the body, resulting in iron deficiency anemia.
Open arterial malformations
Open arterial malformations (AVM, larger vascular malformations) occur in larger organs, especially the lungs (50%), liver (30-70%) and brain (cerebral AVMs, 10%), with a very small proportion (& lt; 1%) has AVM in the spinal cord.
Vascular malformations in the lungs can cause a number of problems. The lungs usually "filter" bacteria and blood clots from the bloodstream; AVM cuts the lung capillary tissue and allows it to migrate to the brain, where bacteria can cause brain abscesses and blood clots can cause strokes. HHT is the most common cause of pulmonary AVMs: of all people found to have pulmonary AVMs, 70-80% are caused by HHT. Bleeding from lung AVMs is relatively unusual, but can cause hemoptysis (coughing up blood) or hemotoraks (blood accumulates in the chest cavity). Major vascular malformations in the lungs allow oxygen-deficient blood from the right ventricle to cut the alveoli, meaning that this blood does not have a chance to absorb fresh oxygen. This can cause shortness of breath. A large AVM can cause platypnea, more prominent breathing difficulties when sitting compared to lying down; this may reflect changes in blood flow associated with positioning. Very large AVMs cause a noticeable inability to absorb oxygen, which can be recorded with cyanosis (bluish discoloration of the lips and skin), fingernails (often found in chronic low oxygen levels), and humming sounds in the lung- lung detectable by stethoscope.
The symptoms produced by AVM in the liver depend on the type of abnormal connection they form between the blood vessels. If the connection is between an artery and a vein, a large amount of blood passes through the body's organs, which the heart compensates by increasing the heart's output. Eventually congestive heart failure develops ("high-output heart failure"), with shortness of breath and swollen legs among other problems. If AVM creates a connection between the portal vein and the liver vein, the result may be portal hypertension (increased portal venous pressure), in which the collateral vessels are formed in the esophagus (esophageal varices), which can bleed out loudly; Furthermore, increased pressure may cause fluid accumulation in the abdominal cavity (ascites). If the flow in the AVM is in the other direction, portal vein blood flows directly into the vein rather than through the liver; this can lead to liver encephalopathy (confusion as portal waste products disrupt the brain). Rarely, the bile duct loses blood, causing severe cholangitis (inflammation of the bile ducts). Liver AVMs are detected in more than 70% of people with HHT, but only 10% have problems as a result.
In the brain, AVM occasionally exerts pressure, which causes headaches. They can also increase the risk of seizures, as do abnormal tissue in the brain. Finally, bleeding from the AVM can cause intracerebral hemorrhage (bleeding to the brain), which causes one of the symptoms of a stroke such as weakness in the body or difficulty speaking. If bleeding occurs to the subarachnoid space (subarachnoid hemorrhage), there is usually a severe, sudden and severe headache of consciousness and often weakness in the body.
Other issues
A very small proportion (which is affected by the mutations SMAD4 (MADH4), see below) has many benign polyps in the colon, which can bleed or turn into colorectal cancer. A similarly small proportion develops pulmonary hypertension, a condition in which pressure in the pulmonary artery increases, puts pressure on the right side of the heart and causes peripheral edema (swelling of the feet), fainting and chest pain attacks. It has been observed that the risk of thrombosis (especially venous thrombosis, in the form of deep vein thrombosis or pulmonary embolism) may be increased. There is a suspicion that those with HHT may have mild immunodeficiency and therefore at slightly increased risk of infection.
Maps Hereditary hemorrhagic telangiectasia
Genetics
HHT is a genetic disorder with an autosomal dominant inheritance pattern. Those with symptoms of HHT who have no family with this disease may have a new mutation. Homozygosity seems to be fatal in the womb.
Five types of HHT genetic are recognized. Of these, three have been associated with a particular gene, while the remaining two are currently only associated with a particular locus. More than 80% of all cases of HHT are caused by mutations in either ENG or ACVRL1 . A total of more than 600 different mutations are known. There is likely to be dominance of any type in a particular population, but the data are conflicting. MADH4 mutations, which cause colon polyposis other than HHT, comprise about 2% of disease-causing mutations. Apart from MADH4 , it is unclear whether the mutations in ENG and ACVRL1 lead to certain symptoms, although some reports indicate that ENG mutations are more likely to cause lung problems while mutations ACVRL1 may cause more liver problems, and pulmonary hypertension may be a particular problem in people with ACVRL1 mutations. People with the same mutation may have different symptoms and severity of symptoms, suggesting that additional genes or other risk factors may determine the rate at which the lesions develop; this has not been identified.
Pathophysiology
Telangiectasis and arteriovenous malformations in HHT are thought to arise because of changes in angiogenesis, the development of blood vessels from existing ones. The development of new blood vessels requires the activation and migration of different types of cells, especially endothelium, smooth muscle and pericytes. The exact mechanism by which the HHT mutation affects this process is unclear, and they may disrupt the balance between pro and antiangiogenic signals in the blood vessels. The wall of telangiectasis is extremely fragile, which explains the tendency of this bloody lesion.
All the genes known so far are related to the HHT codes for proteins in TGF-? signaling pathways. This is a group of proteins that participate in hormonal signal transduction of growth factor beta superfamily transformation (growth factor of beta transformation, bone morphogenetic protein and growth differentiation factor), especially BMP9/GDF2 and BMP10. Hormones do not enter the cell but connect to the receptors on the cell membrane; this then activates other proteins, ultimately affecting cellular behavior in a number of ways such as cell survival, proliferation (multiplication) and differentiation (becoming more specific). In order for the hormone signal to be adequately transduced, a combination of proteins is required: two of each of the two types of specific serine/thermonine type kinase-specific membrane receptors and endoglins. When bound to hormones, the type II receptor proteins phosphorylate (phosphate transfer) to the type I receptor protein (which is Alk-1 is one), which in turn phosphorylates the SMAD protein complex (mainly SMAD1, SMAD5 and SMAD8). It binds SMAD4 and migrates to the cell nucleus where they act as transcription factors and participate in the transcription of certain genes. In addition to the SMAD line, membrane receptors also act on the MAPK pathway, which has additional action on cell behavior. Both Alk-1 and endoglin are expressed predominantly on the endothelium, perhaps explaining why the mutations causing HHT in these proteins primarily lead to blood vessel problems. Mutations of ENG and ACVRL1 mostly lead to a corresponding protein deficiency, rather than a protein function error.
Diagnosis
Diagnostic tests can be performed for various reasons. First, some tests are needed to confirm or disprove the diagnosis. Secondly, some are needed to identify any potential complications.
Telangiectasias
Telangiectasis of the skin cavity and oral cavity are visually identifiable on physical examination, and so the nasal lesions can be seen in nasopharyngeal or laryngoscopy endoscopy. The severity of the nosebleed can be quantified objectively using a questionnaire such as a grid in which the number of nosebleed episodes and their duration are recorded.
Gastrointestinal telangiectasis can be identified in esophagogastroduodenoscopy (esophageal endoscopy, stomach and first part of the small intestine). This procedure will usually only be done if there is anemia more marked than predicted by the severity of the nosebleed, or if there is evidence of severe bleeding (vomiting blood, black stool). If the number of lesions seen at the endoscope is suddenly low, the rest of the small intestine may be examined with capsule endoscopy, in which the patient ingests a capsule-shaped device containing a miniature camera that transmits a digestive tract image to a portable digital. recorder.
Open arterial malformations
Identification of AVMs requires detailed medical imaging of the organ most frequently affected by this lesion. Not all AVMs cause symptoms or are at risk of doing so, and therefore there is a degree of variation between specialists as to whether such an inquiry will be conducted, and with what modalities; Often, decisions on this issue are accomplished along with the patient.
Lung AVMs can be suspected due to the appearance of abnormal lungs in chest X-ray, or hypoxia (low oxygen levels) in pulse oximetry or arterial blood gas determination. The echocardiography contrast bubble (echo bubble) can be used as a screening tool to identify abnormal connections between pulmonary and venous arteries. This involves injection of saline into the vein, followed by ultrasound-based heart imaging. Usually, the lungs secrete small air bubbles from the circulation, and therefore only seen in the right atrium and right ventricle. If AVM is present, bubbles appear in the left atrium and left ventricle, usually 3-10 heart cycles after the right side; this is slower than the heart defect, where there is a direct relationship between the right and left side of the heart. The larger number of bubbles is more likely to indicate the presence of AVM. The echo bubble is not a perfect screening tool as it can lose a smaller AVM and does not identify the AVM site. Often contrast-enhanced computed tomography (CT angiography) is used to identify lung lesions; This modality has a sensitivity of over 90%. It is possible to eliminate contrast administration on modern CT scanners. Echocardiography is also used if there is suspicion of pulmonary hypertension or high heart failure due to large liver lesions, sometimes followed by cardiac catheterization to measure pressure within the various chambers of the heart.
Liver AVMs may be suspected for abnormal liver function tests in the blood, as symptoms of heart failure develop, or due to jaundice or other symptoms of liver dysfunction. The most reliable initial screening test is liver Doppler ultrasound; this has a very high sensitivity to identify vascular lesions in the liver. If necessary, enhanced contrast CT may be used to further characterize the AVM. It is common to find incidental nodules in liver scans, most often due to focal nodular hyperplasia (FNH), since this is a hundredfold more common in HHT than in the general population. FNH is considered harmless. Generally, tumor markers and additional imaging modalities are used to distinguish between FNH and liver malignant tumors. Liver biopsy is not recommended in people with HHT because the risk of hemorrhage from a liver AVM may be significant. Liver scanning may be useful if a person is suspected of HHT, but does not meet the criteria (see below) unless a liver lesion can be demonstrated.
Brain AVMs can be detected in computed tomography angiography (CTA or CT angio) or magnetic resonance angiography (MRA); CTA is better at showing the vessels themselves, and the MRA provides more detail about the relationship between AVM and surrounding brain tissue. In general, MRI is recommended. Various types of vascular malformations can be found: AVM, micro-AVM, telangiectasia and arteriovenous fistulas. If surgery, embolization, or other medications are contemplated (see below), cerebral angiography may be necessary to obtain sufficient detail of the blood vessels. This procedure carries a small risk of stroke (0.5%) and is therefore limited to certain circumstances. The latest professional guidelines recommend that all children with HHT suspected or inevitably undergo brain MRI early in life to identify an AVM that can cause major complications. Others suggest that screening for cerebral AVM may not be necessary in those without neurological symptoms, as most lesions found in screening scans do not require treatment, creating undesirable puzzles.
Genetic testing
Genetic tests are available for ENG , ACVRL1 and MADH4 mutations. Testing is not always necessary for diagnosis, because the symptoms are sufficient to differentiate the disease from other diagnoses. There are situations where testing can be very useful. First, children and young adults with parents with HHT may inevitably have limited symptoms, but are at risk from some of the above-mentioned complications; if the mutation is known to the affected parent, the absence of mutations in the child will prevent the need for a screening test. Furthermore, genetic testing may confirm the diagnosis in those with limited symptoms that would otherwise be labeled "probable HHT" (see below).
The genetic diagnosis of HHT is difficult, since mutations occur in many different locations of the associated genes, with no particular mutations very often (as opposed to, for example, F508 mutations in cystic fibrosis). Analysis of the sequence of genes involved was the most useful approach (75% sensitivity), followed by additional testing to detect large deletion and duplication (an additional 10%). Not all mutations in this gene are associated with the disease.
Mutations in the MADH4 gene are usually associated with adolescent polyposis, and detection of these mutations will indicate the need to screen affected patients and relatives for polyps and tumors of the colon.
Criteria
Diagnosis may be made depending on the presence of four criteria, known as "CuraÃÆ'§ao criteria". If three or four are fulfilled, the patient has a "definite HHT", while the two give "the possibility of HHT":
- Epistaxis repeats spontaneously
- Some telangiectases in typical locations (see above)
- Proven AVM visceral (lung, liver, brain, spine)
- First level family members with HHT
Despite the "possible" title, a person with visceral AVC and family history but no nosebleeds or telangiectases is still very likely to have HHT, since AVM is very rare in the general population. At the same time, the same can not be said of nosebleeds and rare telangiectasis, both of which occur in people without HHT, in the absence of AVM. A person's diagnostic status may change in the course of life, as young children may not show all symptoms; at age 16, thirteen percent still can not be determined, while at the age of 60 most (99%) have definite diagnostic classifications. Children from established HHT patients can be labeled as "possible HHT", as 50% may actually have HHT in their course of life.
Treatment
HHT treatment is symptomatic (associated with symptoms rather than the disease itself), as there is no treatment that stops the development of telangiectasis and AVM directly. Furthermore, some treatments are applied to prevent the development of common complications. Chronic nosebleeds and gastrointestinal bleeding may cause anemia; if the bleeding itself can not be completely stopped, anemia requires treatment with iron supplements. Those who can not tolerate tablets or iron solutions may require intravenous iron delivery, and blood transfusions if anemia causes severe symptoms requiring rapid repair of blood counts.
Most of the treatments used in HHT have been described in adults, and experience in caring for children is more limited. Women with pregnant HHT are at increased risk of complications, and are closely observed, although the absolute risk is still low (1%).
Nosebleeds
Acute nosebleeds can be managed in various sizes, such as packing the nasal cavity with swabs or absorbent gel. Removal of packets after bleeding may lead to reopening of fragile vessels, and hence packaging or atraumatic packing is recommended. Some patients may want to learn packing to handle nosebleeds without having to use medical help.
Often nosebleeds can be partially prevented by keeping the nostrils moist, and by applying salt solutions, creams containing estrogen or tranexamic acid; this has some side effects and may have little benefit. A number of additional modalities have been used to prevent recurrent bleeding if simple actions fail. Medical therapy includes oral and estrogen tranexamic acid; evidence for this is relatively limited, and estrogen is poorly tolerated by men and may carry the risk of cancer and heart disease in women through menopause. Nasal coagulation and cauterization can reduce bleeding from telangiectasis, and is recommended before surgery is considered. However, it is advisable to use the least amount of heat and time to prevent excessive perforation of the septum and trauma to the nasal mucosa that is susceptible to bleeding. Sclerotherapy is another option for managing bleeding. This process involves injecting a small amount of aeration irritation (detergents such as sodium tetradecyl sulfate) directly into telangiectasis. Detergents cause the vessels to collapse and harden, resulting in scarring residue. This is the same procedure used to treat varicose veins and similar disorders.
It is possible to shed vascular lesions through radiological intervention; this requires passing the catheter through a large artery and finding the maxillary artery under the guidance of X-rays, followed by injection into the vein of the particles clogging the blood vessels. The benefits of this procedure tend to be short-lived, and probably most appropriate in severe bleeding episodes.
To more effectively minimize epistaxis recurrence and severity, other options may be used in conjunction with the therapies listed above. The intravenously administered anti-VEGF elements such as bevacizumab (brand name Avastin), pazopinab and thalidomide or its derivatives interfere with the production of new weak blood vessels and are therefore susceptible to bleeding. Due to past experience with prescribing thalidomide for pregnant women to reduce the symptoms of nausea and horrific birth defects that followed, thalidomide was the last therapy. In addition, thalidomide can cause neuropathy. Although this can be reduced by tampering with doses and prescribing derivatives such as lenolidomide and pomalidomide, many doctors prefer alternative VEGF inhibitors. Bevacizumab has been shown to significantly reduce the severity of epistaxis without side effects.
If other interventions fail, some operations have been reported to be beneficial. One is dermoplasty septum or Saunders' procedure, in which the skin is transplanted into the nostrils, and the other is Young's procedure, where the nostrils are completely covered.
Skin and digestive tract
HHT skin lesions can be damaging, and may respond to treatment with long-pulsed Nd: YAG lasers. Skin lesions at the fingertips sometimes bleed and cause pain. Skin grafting is sometimes necessary to treat this problem.
With regard to gastrointestinal lesions, mild bleeding and mild anemia are produced treated with iron supplementation, and no specific treatment is given. There is limited data on the treatment of hormones and tranexamic acid to reduce bleeding and anemia. Severe anemia or severe bleeding episodes are treated with endoscopic argon plasma coagulation (APC) or laser treatment of any identified lesions; this may reduce the need for supportive care. The expected benefit is unlike repeated attempts to treat the recommended lesions. Sudden hemorrhage, very severe is unusual - if found, alternative causes (such as peptic ulcer) need to be considered - but embolization may be used in such cases.
Lung AVMs
Lung lesions, once identified, are usually treated to prevent more important episodes of bleeding and embolism into the brain. This is mainly done on lesions with blood vessels eating 3 mm or larger, as these are the most likely to cause long-term complications unless treated. The most effective current therapy is embolization with a removable metal roll. This procedure involves a large venous puncture (usually under general anesthesia), followed by progressing the catheter through the right ventricle and into the pulmonary artery, after which radiocontras are injected to visualize the AVM (pulmonary angiography). Once the lesion has been identified, the coils are deployed that block the blood flow and allow the lesion to retreat. In experienced hands, the procedure tends to be very effective and with limited side effects, but the lesions may recur and further efforts may be required. The CTA scan is repeated to monitor recurrence. Surgical excision has now been abandoned due to the success of embolotherapy.
Those who have certain lung AVMs or an abnormal contrast echocardiogram without lesions clearly appear to be considered at risk from brain embolism. Therefore they are advised to avoid scuba diving, where small air bubbles can form in bloodsteam that can migrate to the brain and cause stroke. Similarly, antimicrobial prophylaxis is recommended during procedures in which bacteria can enter the bloodstream, such as dental work, and avoid air bubbles during intravenous therapy.
AVM Heart
Given that liver AVM commonly causes high heart failure, the emphasis is to treat this with diuretics to reduce circulating blood volume, limit salt and fluid intake, and antiarrhythmic agents if the heart is irregular. This may be enough to treat symptoms of swelling and shortness of breath. If this treatment is ineffective or leads to side effects or complications, the only remaining option is a liver transplant. It is reserved for those with severe symptoms, because it carries about 10% mortality, but leads to good results if successful. The exact point at which liver transplants are offered is not yet fully established. Treatment of embolization has been tried, but leads to severe complications in some patients and is not recommended.
Other liver-related complications (portal hypertension, esophageal varices, ascites, hepatic encephalopathy) are treated with the same modalities as those used in cirrhosis, although transjugular use of intrahepatic portosystemic shunt treatment is not recommended because of the lack of documented benefits.
Brain AVMs
The decision to treat brain arteriovenous malformations depends on the symptoms it causes (such as seizures or headaches). The risk of bleeding is predicted by previous bleeding episodes, and whether on CTA or MRA AVM scans seem to sit in or have deep vein drainage. The size of the AVM and the presence of aneurysms appear to be less important. In HHT, some lesions (high flow arteriovenous fistula) tend to cause more problems, and treatment is justified. Other AVMs may withdraw from time to time without intervention. Various modalities are available, depending on the AVM location and size: operation, radiation-based care and embolization. Sometimes, various modalities are used in the same lesions.
Surgery (with craniotomy, open brain surgery) can be offered based on the treatment risks determined by the Spetzler-Martin scale (class I-V); this score is higher in larger lesions that are close to important brain structures and have deep venous drainage. High-grade lesions (IV and V) have an unacceptably high risk and surgery is not usually offered in such cases. Radiosurgery (using targeted radiation therapy such as by a gamma blade) can be used if the lesion is small but close to the vital structure. Finally, embolization can be used in small lesions that have only one feeding container.
Experimental treatment
Some anti-angiogenesis drugs approved for other conditions, such as cancer, have been investigated in small clinical trials. Anti-VEGF antivod bevacizumab, for example, has been used off-label in several studies. In the largest study conducted so far, infusion of bevacizumab was associated with decreased cardiac output and reduced duration and number of epistaxis episodes in treated HHT patients. Thalidomide, another anti-angiogenesis drug, is also reported to have beneficial effects on HHT patients. Thalidomide treatment was found to induce vascular maturation in the HHT trial model and to reduce the severity and frequency of nosebleeds in the majority of small groups of HHT patients. The blood hemoglobin levels of treated patients are increased as a result of reduced bleeding and increased blood vessel stabilization.
Epidemiology
Population studies from different regions of the world have shown that HHT occurs at almost the same rate in almost all populations: somewhere around 1 in 5000. In some areas, it is much more common; for example, in the French territory of Haut Jura, the charge is 1: 2351 - twice as common as other populations. This has been attributed to the founder effect, in which the population descends from a small number of ancestors having a high degree of certain genetic properties because one of these ancestors harbored this trait. In Haut Jura, this has been proven to be the result of certain ACVRL1 mutations (named c.1112dupG or c.1112_1113insG). The highest HHT level is 1: 1331, reported in Bonaire and CuraÃÆ'§ao, two islands in the Caribbean belonging to the Netherlands Antilles.
Most people with HHT have a normal age. Skin lesions and nosebleeds tend to develop during childhood. AVM may be present at birth, but it does not always cause any symptoms. Often nosebleeds are the most common symptoms and can significantly affect quality of life.
History
Some 19th-century British physicians, beginning with Henry Gawen Sutton (1836-1891) and followed by Benjamin Guy Babington (1794-1866) and John Wickham Legg (1843-1921), described the most common features of HHT, especially nosebleeds repetitive and hereditary nature of the disease. French physician Henri Jules Louis Marie Rendu (1844-1902) studied skin and mucosal lesions, and distinguished the condition of hemophilia. Canadian-born Sir William Osler (1849-1919), then at Johns Hopkins Hospital and later at Oxford University, made further contributions with a 1901 report in which he described characteristic lesions in the gastrointestinal tract. British physician Frederick Parkes Weber (1863-1962) reported more on the condition in 1907 with a series of cases. The term "hereditary hemorrhagic telangiectasia" was first used by American physician Frederic M. Hanes (1883-1946) in a 1909 article on his condition.
The diagnosis of HHT remained clinical until the genetic defect that caused HHT was identified by the research group at Duke University Medical Center, in 1994 and 1996 respectively. In 2000, the international scientific advisory committee of HHT Foundation International published the criteria of CuraÃÆ'§ao which are now widely used. In 2006, a group of international experts met in Canada and formulated evidence-based guidelines, sponsored by HHT Foundation International.
References
External links
- Cure HHT
- What is HHT? FAQ
- HHT Diagnosis and Treatment
- HHT Research
- Cure HHT Resource Library
- North American HHT Center of Excellence
- International Treatment Center
- HHT mutation database ( ENG and ACVRL1 ) at the University of Utah
Source of the article : Wikipedia
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