Hereditary hemorrhagic telangiectasia
Encyclopedia
Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease and Osler-Weber-Rendu syndrome, is a genetic disorder
that leads to abnormal blood vessel formation in the skin
, mucous membrane
s, and often in organs such as the lung
s, liver
and brain
.
It may lead to nosebleeds, acute and chronic digestive tract bleeding
, and various problems due to the involvement of other organs. Treatment focuses on reducing bleeding from blood vessel lesions, and sometimes surgery
or other targeted interventions to remove arteriovenous malformation
s in organs. Chronic bleeding often requires iron supplements
and sometimes blood transfusion
s. HHT is transmitted in an autosomal dominant fashion, 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.
(small vascular malformations) may occur in the skin and mucosal linings of the nose and gastrointestinal tract. The most common problem is nosebleeds (epistaxis), which happen frequently from childhood and affect about 90–95% of people with HHT. Lesions on the skin and in the mouth bleed less often but may be considered cosmetically displeasing; they affect about 80%. The skin lesions characteristically occur on the lip
s, the nose
and the finger
s, and on the skin of the face in sun-exposed areas. They appear suddenly, with the number increasing over time.
A fifth are affected by symptomatic digestive tract lesions, although a higher number have lesions that are not causing symptoms. These lesions may bleed intermittently, which is rarely significant enough to be noticed (in the form of bloody vomiting
or black stool
), but eventually leads to depletion of iron
in the body, resulting in iron-deficiency anemia.
(AVM, larger vascular malformations) occur in larger organs, predominantly the lungs (50%), liver (30–70%) and the brain
(10%), with a very small proportion (<1%) having AVMs in the spinal cord
.
Vascular malformations in the lungs may cause a number of problems. The lungs normally "filter out" bacteria
and blood clots
from the bloodstream; AVMs bypass the capillary network of the lungs and allow these to migrate
to the brain, where bacteria may cause a brain abscess
and blood clots may lead to stroke
. HHT is the most common cause of lung AVMs: out of all people found to have lung AVMs, 70–80% are due to HHT. Bleeding from lung AVMs is relatively unusual, but may cause hemoptysis
(coughing up blood) or hemothorax
(blood accumulating in the chest cavity). Large vascular malformations in the lung allow oxygen-depleted blood from the right ventricle
to bypass the alveoli
, meaning that this blood does not have an opportunity absorb fresh oxygen. This may lead to breathlessness
. Large AVMs may lead to platypnea
, difficulty in breathing more marked when sitting up compared to lying down; this probably reflects changes in blood flow associated with positioning. Very large AVMs cause a marked inability to absorb oxygen, which may be noted by cyanosis
(bluish discoloration of the lips and skin), clubbing of the fingernails (often encountered in chronically low oxygen levels), and a humming noise
over the affected part of the lung detectable by stethoscope
.
The symptoms produced by AVMs in the liver depend on the type of abnormal connection that they form between blood vessels. If the connection is between arteries and vein
s, a large amount of blood bypasses the body's organs, for which the heart compensates by increasing the cardiac output
. Eventually congestive cardiac failure develops ("high-output cardiac failure"), with breathlessness and leg swelling among other problems. If the AVM creates a connection between the portal vein and the blood vessels of the liver, the result may be portal hypertension
(increased portal vein pressure), in which collateral blood vessels form in the esophagus
(esophageal varices
), which may bleed violently; furthermore, the increased pressure may give rise to fluid accumulation in the abdominal cavity (ascites
). If the flow in the AVM is in the other direction, portal venous blood flows directly into the veins rather than running through the liver; this may lead to hepatic encephalopathy
(confusion due to portal waste products irritating the brain). Rarely, the bile ducts are deprived of blood, leading to severe cholangitis (inflammation of the bile ducts). Liver AVMs are detectable in over 70% of people with HHT, but only 10% experience problems as a result.
In the brain, AVMs occasionally exert pressure, leading to headache
s. They may also increase the risk of seizure
s, as would any abnormal tissue in the brain. Finally, hemorrhage from an AVM may lead to intracerebral hemorrhage (bleeding into the brain), which causes any of the symptoms of stroke such as weakness in part of the body or difficulty speaking. If the bleeding occurs into the subarachnoid space
(subarachnoid hemorrhage
), there is usually a severe, sudden headache
and decreased level of consciousness and often weakness in part of the body.
in the large intestine
, which may bleed or transform into colorectal cancer
. A similarly small proportion experiences pulmonary hypertension
, a state in which the pressure in the lung arteries
is increased, exerting pressure on the right side of the heart
and causing peripheral edema
(swelling of the legs), fainting
and attacks of chest pain
. It has been observed that the risk of thrombosis
(particularly 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 a mild immunodeficiency
and are therefore at a slightly increased risk from infections.
HHT is a genetic disorder
by definition. It is inherited in an autosomal dominant manner, which means that an affected person carries one abnormal gene with a 50% chance of passing this gene to offspring. Those with HHT symptoms that have no relatives with the disease may have a new mutation. It seems that carrying two abnormal copies of the gene is not compatible with life, and hence no homozygotes have been described.
Five genetic types of HHT are recognized. Of these, three have been linked
to particular gene
s, while the two remaining have currently only been associated with a particular locus
. More than 80% of all cases of HHT are due to mutations in either ENG or ACVRL1. A total of over 600 different mutations is known. There is likely to be a predominance of either type in particular populations, but the data are conflicting. MADH4 mutations, which cause colonic polyposis in addition to HHT, comprise about 2% of disease-causing mutations. Apart from MADH4, it is not clear whether mutations in ENG and ACVRL1 lead to particular symptoms, although some reports suggest that ENG mutations are more likely to cause lung problems while ACVRL1 mutations may cause more liver problems, and pulmonary hypertension may be a particular problem in people with ACVRL1 mutations. People with exactly the same mutations may have different nature and severity of symptoms, suggesting that additional genes or other risk factors may determine the rate at which lesions develop; these have not yet been identified.
, the development of blood vessels out of existing ones. The development of a new blood vessels requires the activation and migration of various types of cell, chiefly endothelium
, smooth muscle
and pericyte
s. The exact mechanism by which the HHT mutations influence this process is not yet clear, and it is likely that they disrupt a balance between pro- and antiangiogenic signals in blood vessels. The wall of telangiectasias is unusually friable, which explains the tendency of these lesions to bleed.
All genes known so far to be linked to HHT code for proteins in the TGF-β signaling pathway
. This is a group of proteins that participates in signal transduction
of hormones of the transforming growth factor beta superfamily
(the transforming growth factor beta, bone morphogenetic protein
and growth differentiation factor
classes), specifically BMP9/GDF2
and BMP10
. The hormones do not enter the cell but link to receptors on the cell membrane; these then activate other proteins, eventually influencing cellular behavior in a number of ways such as cellular survival, proliferation (increasing in number) and differentiation (becoming more specialized). For the hormone signal to be adequately transduced, a combination of proteins is needed: two each of two types of serine/threonine-specific kinase type
membrane receptor
s and endoglin. When bound to the hormone, the type II receptor proteins phosphorylate
(transfer phosphate
) onto type I receptor proteins (of which Alk-1 is one), which in turn phosphorylate a complex of SMAD proteins
(chiefly SMAD1
, SMAD5
and SMAD8
). These bind to SMAD4 and migrate to the cell nucleus
where they act as transcription factors and participate in the transcription
of particular genes. In addition to the SMAD pathway, the membrane receptors also act on the MAPK pathway
, which has additional actions on the behavior of cells. Both Alk-1 and endoglin are expressed
predominantly in endothelium, perhaps explaining why HHT-causing mutations in these proteins lead predominantly to blood vessel problems. Both ENG and ACVRL1 mutations lead predominantly to underproduction of the related proteins, rather than misfunctioning of the proteins.
The skin and oral cavity telangiectasias are visually identifiable on physical examination
, and similarly the lesions in the nose may be seen on endoscopy
of the nasopharynx
or on laryngoscopy
. The severity of nosebleeds may be quantified objectively using a grid-like questionnaire in which the number of nosebleed episodes and their duration is recorded.
Digestive tract telangiectasias may be identified on esophagogastroduodenoscopy
(endoscopy of the esophagus, stomach and first part of the small intestine). This procedure will typically only be undertaken if there is anemia that is more marked than expected by the severity of nosebleeds, or if there is evidence of severe bleeding (vomiting blood, black stools). If the number of lesions seen on endoscopy is unexpectedly low, the remainder of the small intestine may be examined with capsule endoscopy
, in which the patient swallows a capsule-shaped device containing a miniature camera which transmits images of the digestive tract to a portable digital recorder.
of the organs most commonly affected by these lesions. Not all AVMs cause symptoms or are at risk of doing so, and hence there is a degree of variation between specialists as to whether such investigations would be performed, and by which modality; often, decisions on this issue are reached together with the patient.
Lung AVMs may be suspected because of the abnormal appearance of the lungs on a chest X-ray, or hypoxia
(low oxygen levels) on pulse oximetry
or arterial blood gas
determination. Bubble contrast echocardiography (bubble echo) may be used as a screening tool to identify abnormal connections between the lung arteries
and veins
. This involves the injection of agitated saline
into a vein, followed by ultrasound-based imaging of the heart. Normally, the lungs remove small air bubbles from the circulation, and they are therefore only seen in the right atrium
and the right ventricle
. If an AVM is present, bubbles appear in the left atrium
and left ventricle
, usually 3–10 cardiac cycle
s after the right side; this is slower than in heart defects
, in which there are direct connections between the right and left side of the heart. A larger number of bubbles is more likely to indicate the presence of an AVM. Bubble echo is not a perfect screening tool as it can miss smaller AVMs and does not identify the site of AVMs. Often contrast
-enhanced computed tomography (CT angiography) is used to identify lung lesions; this modality has a sensitivity
of over 90%. It may be possible to omit contrast administration on modern CT scanners. Echocardiography is also used if there is a suspicion of pulmonary hypertension or high-output cardiac failure due to large liver lesions, sometimes followed by cardiac catheterization
to measure the pressures inside the various chambers of the heart.
Liver AVMs may be suspected because of abnormal liver function tests
in the blood, because the symptoms of heart failure develop, or because of jaundice
or other symptoms of liver dysfunction. The most reliable initial screening test is Doppler ultrasonography of the liver; this has a very high sensitivity for identifying vascular lesions in the liver. If necessary, contrast-enhanced CT may be used to further characterize AVMs. It is extremely common to find incidental nodules on liver scans, most commonly due to focal nodular hyperplasia
(FNH), as these are a hundredfold times more common in HHT compared to the general population. FNH is regarded as harmless. Generally, tumor marker
s and additional imaging modalities are used to differentiate between FNH and malignant tumors of the liver. Liver biopsy
is discouraged in people with HHT as the risk of hemorrhage from liver AVMs may be significant. Liver scans may be useful if someone is suspected of HHT, but does not meet the criteria (see below) unless liver lesions can be demonstrated.
Brain AVMs may be detected on computed tomography angiography
(CTA or CT angio) or magnetic resonance angiography
(MRA); CTA is better in showing the vessels themselves, and MRA provides more detail about the relationship between an AVM and surrounding brain tissue. In general, MRI is recommended. Various types of vascular malformations may be encountered: AVMs, micro-AVMs, telangiectasias and arteriovenous fistula
s. If surgery, embolization, or other treatment is contemplated (see below), cerebral angiography
may be required to get sufficient detail of the vessels. This procedure carries a small risk of stroke (0.5%) and is therefore limited to specific circumstances. Recent professional guidelines recommend that all children with suspected or definite HHT undergo a brain MRI early in life to identify AVMs that can cause major complications. Others suggest that screening for cerebral AVMs is probably unnecessary in those who are not experiencing any neurological symptoms, because most lesions discovered on screening scans would not require treatment, creating undesirable conundrums.
Genetic diagnosis in HHT is difficult, as mutations occur in numerous different locations in the linked genes, without particular mutations being highly frequent (as opposed to, for instance, the ΔF508 mutation in cystic fibrosis
). Sequence analysis
of the involved genes is therefore the most useful approach (sensitivity 75%), followed by additional testing to detect large deletions and duplications (additional 10%). Not all mutations in these genes have been linked with disease.
Mutations in the MADH4 gene is usually associated with juvenile polyposis, and detection of such a mutation would indicate a need to screen the patient and affected relatives for polyps and tumors of the large intestine.
criteria". If three or four are met, a patient has "definite HHT", while two gives "possible HHT":
Despite the designation "possible", someone with a visceral AVM and a family history but no nosebleeds or telangiectasias is still extremely likely to have HHT, because these AVMs are very uncommon in the general population. At the same time, the same cannot be said of nosebleeds and sparse telangiectasias, both of which occur in people without HHT, in the absence of AVMs. Someone's diagnostic status may change in the course of life, as young children may not yet exhibit all the symptoms; at age 16, thirteen percent are still indeterminate, while at age 60 the vast majority (99%) have a definite diagnostic classification. The children of established HHT patients may therefore be labeled as "possible HHT", as 50% may turn out to have HHT in the course of their life.
(it deals with the symptoms rather than the disease itself), as there is no therapy that stops the development of telangiectasias and AVMs directly. Furthermore, some treatments are applied to prevent the development of common complications. Chronic nosebleeds and digestive tract bleeding can both lead to anemia; if the bleeding itself cannot be completely stopped, the anemia requires treatment with iron supplements
. Those who cannot tolerate iron tablets or solutions may require administration of intravenous
iron sucrose, and blood transfusion
if the anemia is causing severe symptoms that warrant rapid improvement of the blood count.
Most treatments used in HHT have been described in adults, and the experience in treating children is more limited. Women with HHT who get pregnant
are at an increased risk of complications, and are observed closely, although the absolute risk is still low (1%).
Frequent nosebleeds can be prevented in part by keeping the nostrils moist, and by applying saline solution
, estrogen
-containing creams or tranexamic acid
; these have few side effects and may have a small degree of benefit. A number of additional modalities has been used to prevent recurrent bleeding if simple measures are unsuccessful. Medical therapies include oral tranexamic acid and estrogen; the evidence
for these is relatively limited, and estrogen is poorly tolerated by men and possibly carries risks of cancer and heart disease in women past the menopause. Nasal coagulation and cauterization
may reduce the bleeding from telangiectasias, and is recommended before surgery is considered; often, several sessions are needed. It may be possible to embolize
vascular lesions through interventional radiology
; this requires passing a catheter through a large artery and locating the maxillary artery under X-ray guidance
, followed by the injection into the vessel of particles that occlude the blood vessels. The benefit from the procedure tends to be short-lived, and it may be most appropriate in episodes of severe bleeding.
If other interventions have failed, several operations have been reported to provide benefit. One is septal dermoplasty or Saunders' procedure, in which skin is transplanted into the nostrils, and the other is Young's procedure, in which the nostrils are sealed off completely.
. Skin lesions in the fingertips may sometimes bleed and cause pain. Skin grafting
is occasionally needed to treat this problem.
With regards to digestive tract lesions, mild bleeding and mild resultant anemia is treated with iron supplementation, and no specific treatment is administered. There is limited data on hormone treatment and tranexamic acid to reduce bleeding and anemia. Severe anemia or episodes of severe bleeding are treated with endoscopic argon plasma coagulation
(APC) or laser treatment of any lesions identified; this may reduce the need for supportive treatment. The expected benefits are not such that repeated attempts at treating lesions are advocated. Sudden, very severe bleeding is unusual—if encountered, alternative causes (such as a peptic ulcer
) need to be considered—but embolization may be used in such instances.
), followed by advancing of a catheter through the right ventricle
and into the pulmonary artery
, after which radiocontrast
is injected to visualize the AVMs (pulmonary angiography
). Once the lesion has been identified, coils are deployed that obstruct the blood flow and allow the lesion to regress. In experienced hands, the procedure tends to be very effective and with limited side effects, but lesions may recur and further attempts may be required. CTA scans are repeated to monitor for recurrence. Surgical excision has now essentially been abandoned due to the success of embolotherapy.
Those with either definite pulmonary AVMs or an abnormal contrast echocardiogram with no clearly visible lesions are deemed to be at risk from brain emboli. They are therefore counselled to avoid scuba diving
, during which small air bubbles may form in the bloodsteam that may migrate to the brain and cause stroke. Similarly, antimicrobial prophylaxis is advised during procedures in which bacteria may enter the bloodstream, such as dental work
, and avoidance of air bubbles during intravenous therapy
.
s to reduce the circulating blood volume, restriction of salt and fluid intake, and antiarrhythmic agent
s in case of irregular heart beat
. This may be sufficient in treating the symptoms of swelling and breathlessness. If this treatment is not effective or leads to side effects or complications, the only remaining option is liver transplantation
. This is reserved for those with severe symptoms, as it carries a mortality
of about 10%, but leads to good results if successful. The exact point at which liver transplantion is to be offered is not yet completely established. Embolization treatment has been attempted, but leads to severe complications in a proportion of patients and is discouraged.
Other liver-related complications (portal hypertension, esophageal varices, ascites, hepatic encephalopathy) are treated with the same modalities as used in cirrhosis
, although the use of transjugular intrahepatic portosystemic shunt
treatment is discouraged due to the lack of documented benefit.
s appears to matter less. In HHT, some lesions (high-flow arteriovenous fistulae) tend to cause more problems, and treatment is warranted. Other AVMs may regress over time without intervention. Various modalities are available, depending on the location of the AVM and its size: surgery, radiation-based treatment and embolization. Sometimes, multiple modalities are used on the same lesion.
Surgery (by craniotomy
, open brain surgery) may be offered based on the risks of treatment as determined by the Spetzler–Martin scale (grade 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 typically offered in those cases. Radiosurgery
(using targeted radiation therapy
such as by a gamma knife) may be used if the lesion is small but close to vital structures. Finally, embolization may be used on small lesions that have only a single feeding vessel.
Population studies from numerous areas in the world have shown that HHT occurs at roughly the same rate in almost all populations: somewhere around 1 in 5000. In some areas, it is much more common; for instance, in the French
region of Haut Jura
the rate is 1:2351 - twice as common as in other populations. This has been attributed to a founder effect
, in which a population descending from a small number of ancestors has a high rate of a particular genetic trait because one of these ancestors harbored this trait. In Haut Jura, this has been shown to be the result of a particular ACVRL1 mutation (named c.1112dupG or c.1112_1113insG). The highest rate of HHT is 1:1331, reported in Bonaire and Curaçao
, two islands in the Caribbean
belonging to the Netherlands Antilles
.
Most people with HHT have a normal lifespan. The skin lesions and nosebleeds tend to develop during childhood. AVMs are probably present from birth, but don't necessarily cause any symptoms. Frequent nosebleeds are the most common symptom and can significantly affect quality of life
.
(1836–1891) and followed by Benjamin Guy Babington
(1794–1866) and John Wickham Legg
(1843–1921), described the most common features of HHT, particularly the recurrent nosebleeds and the hereditary nature of the disease. The French physician Henri Jules Louis Marie Rendu (1844–1902) observed the skin and mucosal lesions, and distinguished the condition from hemophilia. The 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 digestive tract. The English physician Frederick Parkes Weber (1863–1962) reported further on the condition in 1907 with a series of cases. The term "hereditary hemorrhagic telangiectasia" was first used by the American physician Frederic M. Hanes (1883–1946) in a 1909 article on the condition.
The diagnosis of HHT remained a clinical one until the genetic defects that cause HHT were identified by a 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 now widely used Curaçao criteria. In 2006, a group of international experts met in Canada
and formulated an evidence-based
guideline, sponsored by the HHT Foundation International.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that leads to abnormal blood vessel formation in the skin
Human skin
The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals,...
, mucous membrane
Mucous membrane
The mucous membranes are linings of mostly endodermal origin, covered in epithelium, which are involved in absorption and secretion. They line cavities that are exposed to the external environment and internal organs...
s, and often in organs such as the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s, liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
.
It may lead to nosebleeds, acute and chronic digestive tract bleeding
Gastrointestinal bleeding
Gastrointestinal bleeding or gastrointestinal hemorrhage describes every form of hemorrhage in the gastrointestinal tract, from the pharynx to the rectum. It has diverse causes, and a medical history, as well as physical examination, generally distinguishes between the main forms...
, and various problems due to the involvement of other organs. Treatment focuses on reducing bleeding from blood vessel lesions, and sometimes surgery
Surgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
or other targeted interventions to remove arteriovenous malformation
Arteriovenous malformation
Arteriovenous malformation or AVM is an abnormal connection between veins and arteries, usually congenital. This pathology is widely known because of its occurrence in the central nervous system, but can appear in any location. An arteriovenous malformation is a vascular anomaly. It is a...
s in organs. Chronic bleeding often requires iron supplements
Iron supplements
Iron supplements are supplements that can be prescribed by a doctor for a medical reason. Iron can also be a dietary supplement, which can be purchased in supermarkets etc. These two categories should not be confused....
and sometimes blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
s. HHT is transmitted in an autosomal dominant fashion, and occurs in one in 5,000 people.
The disease carries the names of Sir William Osler
William Osler
Sir William Osler, 1st Baronet was a physician. He was one of the "Big Four" founding professors at Johns Hopkins Hospital as the first Professor of Medicine and founder of the Medical Service there. Sir William Osler, 1st Baronet (July 12, 1849 – December 29, 1919) was a physician. He was...
, Henri Jules Louis Marie Rendu
Henri Jules Louis Marie Rendu
Henri Jules Louis Marie Rendu was a French physician who was born in Paris. He was related to celebrated glaciologist Louis Rendu ....
and Frederick Parkes Weber
Frederick Parkes Weber
Frederick Parkes Weber was an English dermatologist who practiced medicine in London. His father, Sir Hermann David Weber was a personal physician to Queen Victoria....
, who described it in the late 19th and early 20th centuries.
Telangiectasias
TelangiectasiaTelangiectasia
Telangiectasias /tɛ.læn.dʒiː'ɛk.teɪ.ʃi:ə/ are small dilated blood vessels near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. They can develop anywhere on the body but are commonly seen on the face around the nose, cheeks, and chin...
(small vascular malformations) may occur in the skin and mucosal linings of the nose and gastrointestinal tract. The most common problem is nosebleeds (epistaxis), which happen frequently from childhood and affect about 90–95% of people with HHT. Lesions on the skin and in the mouth bleed less often but may be considered cosmetically displeasing; they affect about 80%. The skin lesions characteristically occur on the lip
Lip
Lips are a visible body part at the mouth of humans and many animals. Lips are soft, movable, and serve as the opening for food intake and in the articulation of sound and speech...
s, the nose
Human nose
The visible part of the human nose is the protruding part of the face that bears the nostrils. The shape of the nose is determined by the ethmoid bone and the nasal septum, which consists mostly of cartilage and which separates the nostrils...
and the finger
Finger
A finger is a limb of the human body and a type of digit, an organ of manipulation and sensation found in the hands of humans and other primates....
s, and on the skin of the face in sun-exposed areas. They appear suddenly, with the number increasing over time.
A fifth are affected by symptomatic digestive tract lesions, although a higher number have lesions that are not causing symptoms. These lesions may bleed intermittently, which is rarely significant enough to be noticed (in the form of bloody vomiting
Hematemesis
Hematemesis or haematemesis is the vomiting of blood. The source is generally the upper gastrointestinal tract. Patients can easily confuse it with hemoptysis , although the latter is more common.-Signs:...
or black stool
Melena
In medicine, melena or melaena refers to the black, "tarry" feces that are associated with gastrointestinal hemorrhage. The black color is caused by oxidation of the iron in hemoglobin during its passage through the ileum and colon.-Melena vs...
), but eventually leads to depletion of iron
Iron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
in the body, resulting in iron-deficiency anemia.
Arteriovenous malformation
Arteriovenous malformationArteriovenous malformation
Arteriovenous malformation or AVM is an abnormal connection between veins and arteries, usually congenital. This pathology is widely known because of its occurrence in the central nervous system, but can appear in any location. An arteriovenous malformation is a vascular anomaly. It is a...
(AVM, larger vascular malformations) occur in larger organs, predominantly the lungs (50%), liver (30–70%) and the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
(10%), with a very small proportion (<1%) having AVMs in the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
.
Vascular malformations in the lungs may cause a number of problems. The lungs normally "filter out" bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and blood clots
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...
from the bloodstream; AVMs bypass the capillary network of the lungs and allow these to migrate
Embolism
In medicine, an embolism is the event of lodging of an embolus into a narrow capillary vessel of an arterial bed which causes a blockage in a distant part of the body.Embolization is...
to the brain, where bacteria may cause a brain abscess
Brain abscess
Brain abscess is an abscess caused by inflammation and collection of infected material, coming from local or remote infectious sources, within the brain tissue...
and blood clots may lead to stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
. HHT is the most common cause of lung AVMs: out of all people found to have lung AVMs, 70–80% are due to HHT. Bleeding from lung AVMs is relatively unusual, but may cause hemoptysis
Hemoptysis
Hemoptysis or haemoptysis is the expectoration of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis is the expectoration (coughing up) of blood or of blood-stained sputum from the bronchi, larynx, trachea, or lungs Hemoptysis or haemoptysis ...
(coughing up blood) or hemothorax
Hemothorax
A hemothorax is a condition that results from blood accumulating in the pleural cavity.-Cause and presentation:Its cause is usually traumatic, from a blunt or penetrating injury to the thorax, resulting in a rupture of the serous membrane either lining the thorax or covering the lungs...
(blood accumulating in the chest cavity). Large vascular malformations in the lung allow oxygen-depleted blood from the right ventricle
Right ventricle
The right ventricle is one of four chambers in the human heart. It receives deoxygenated blood from the right atrium via the tricuspid valve, and pumps it into the pulmonary artery via the pulmonary valve and pulmonary trunk....
to bypass the alveoli
Pulmonary alveolus
An alveolus is an anatomical structure that has the form of a hollow cavity. Found in the lung parenchyma, the pulmonary alveoli are the dead ends of the respiratory tree, which outcrop from either alveolar sacs or alveolar ducts, which are both sites of gas exchange with the blood as well...
, meaning that this blood does not have an opportunity absorb fresh oxygen. This may lead to breathlessness
Dyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...
. Large AVMs may lead to platypnea
Platypnea
In medicine, platypnea refers to shortness of breath that is relieved when lying down, and worsens when sitting or standing up. It is the opposite of orthopnea...
, difficulty in breathing more marked when sitting up compared to lying down; this probably reflects changes in blood flow associated with positioning. Very large AVMs cause a marked inability to absorb oxygen, which may be noted by cyanosis
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
(bluish discoloration of the lips and skin), clubbing of the fingernails (often encountered in chronically low oxygen levels), and a humming noise
Bruit
Bruit is the term for the unusual sound that blood makes when it rushes past an obstruction in an artery when the sound is auscultated with the bell portion of a stethoscope.The term "bruit" simply refers to the sound...
over the affected part of the lung detectable by stethoscope
Stethoscope
The stethoscope is an acoustic medical device for auscultation, or listening to the internal sounds of an animal body. It is often used to listen to lung and heart sounds. It is also used to listen to intestines and blood flow in arteries and veins...
.
The symptoms produced by AVMs in the liver depend on the type of abnormal connection that they form between blood vessels. If the connection is between arteries and vein
Vein
In the circulatory system, veins are blood vessels that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated blood to the heart...
s, a large amount of blood bypasses the body's organs, for which the heart compensates by increasing the cardiac output
Cardiac output
Cardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...
. Eventually congestive cardiac failure develops ("high-output cardiac failure"), with breathlessness and leg swelling among other problems. If the AVM creates a connection between the portal vein and the blood vessels of the liver, the result may be portal hypertension
Portal hypertension
In medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...
(increased portal vein pressure), in which collateral blood vessels form in the esophagus
Esophagus
The esophagus is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. During swallowing, food passes from the mouth through the pharynx into the esophagus and travels via peristalsis to the stomach...
(esophageal varices
Esophageal varices
In medicine , esophageal varices are extremely dilated sub-mucosal veins in the lower esophagus...
), which may bleed violently; furthermore, the increased pressure may give rise to fluid accumulation in the abdominal cavity (ascites
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
). If the flow in the AVM is in the other direction, portal venous blood flows directly into the veins rather than running through the liver; this may lead to hepatic encephalopathy
Hepatic encephalopathy
Hepatic encephalopathy is the occurrence of confusion, altered level of consciousness and coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum...
(confusion due to portal waste products irritating the brain). Rarely, the bile ducts are deprived of blood, leading to severe cholangitis (inflammation of the bile ducts). Liver AVMs are detectable in over 70% of people with HHT, but only 10% experience problems as a result.
In the brain, AVMs occasionally exert pressure, leading to headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s. They may also increase the risk of seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, as would any abnormal tissue in the brain. Finally, hemorrhage from an AVM may lead to intracerebral hemorrhage (bleeding into the brain), which causes any of the symptoms of stroke such as weakness in part of the body or difficulty speaking. If the bleeding occurs into the subarachnoid space
Subarachnoid space
In the central nervous system, the subarachnoid cavity is the interval between the arachnoid membrane and pia mater....
(subarachnoid hemorrhage
Subarachnoid hemorrhage
A subarachnoid hemorrhage , or subarachnoid haemorrhage in British English, is bleeding into the subarachnoid space—the area between the arachnoid membrane and the pia mater surrounding the brain...
), there is usually a severe, sudden headache
Thunderclap headache
A thunderclap headache is a headache that is severe and sudden-onset. It is defined as a severe headache that takes seconds to minutes to reach maximum intensity. It can be indicative of a number of medical problems, most importantly subarachnoid hemorrhage, which can be potentially life-threatening...
and decreased level of consciousness and often weakness in part of the body.
Other problems
A very small proportion (those affected by SMAD4 mutations, see below) have multiple benign polypsJuvenile polyposis syndrome
Juvenile polyposis syndrome is a syndrome characterized by the appearance of multiple polyps in the gastrointestinal tract, usually in a child, adolescent or young adult. Polyps refers to a growth arising from the lumen of the colon or stomach...
in the large intestine
Colon (anatomy)
The colon is the last part of the digestive system in most vertebrates; it extracts water and salt from solid wastes before they are eliminated from the body, and is the site in which flora-aided fermentation of unabsorbed material occurs. Unlike the small intestine, the colon does not play a...
, which may bleed or transform into colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
. A similarly small proportion experiences pulmonary hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...
, a state in which the pressure in the lung arteries
Pulmonary artery pressure
Pulmonary artery pressure is a measure of the blood pressure found in the pulmonary artery. Mean pulmonary arterial pressure is normally 9 - 18 mmHg.It is usually higher than the pulmonary wedge pressure....
is increased, exerting pressure on the right side of the heart
Right ventricle
The right ventricle is one of four chambers in the human heart. It receives deoxygenated blood from the right atrium via the tricuspid valve, and pumps it into the pulmonary artery via the pulmonary valve and pulmonary trunk....
and causing peripheral edema
Peripheral edema
Peripheral edema is the swelling of tissues, usually in the lower limbs, due to the accumulation of fluids.The condition is commonly associated with aging, but can be caused by many other conditions, including congestive heart failure, trauma, alcoholism, altitude sickness, pregnancy,...
(swelling of the legs), fainting
Syncope
In phonology, syncope is the loss of one or more sounds from the interior of a word; especially, the loss of an unstressed vowel. It is found bothin Synchronic analysis of languages and Diachronics .-Found synchronically:...
and attacks of chest pain
Chest pain
Chest pain may be a symptom of a number of serious conditions and is generally considered a medical emergency. Even though it may be determined that the pain is non-cardiac in origin, this is often a diagnosis of exclusion made after ruling out more serious causes of the pain.-Differential...
. It has been observed that the risk of thrombosis
Thrombosis
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss...
(particularly venous thrombosis
Venous thrombosis
A venous thrombosis is a blood clot that forms within a vein. A venous thrombosis is a blood clot that forms within a vein. A venous thrombosis is a blood clot that forms within a vein. (Thrombosis is a medical term for blood clotting (Haemostasis) occurring in the wrong place, i.e...
, in the form of deep vein thrombosis
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
or pulmonary embolism
Pulmonary embolism
Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...
) may be increased. There is a suspicion that those with HHT may have a mild immunodeficiency
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
and are therefore at a slightly increased risk from infections.
Genetics
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
by definition. It is inherited in an autosomal dominant manner, which means that an affected person carries one abnormal gene with a 50% chance of passing this gene to offspring. Those with HHT symptoms that have no relatives with the disease may have a new mutation. It seems that carrying two abnormal copies of the gene is not compatible with life, and hence no homozygotes have been described.
Five genetic types of HHT are recognized. Of these, three have been linked
Genetic linkage
Genetic linkage is the tendency of certain loci or alleles to be inherited together. Genetic loci that are physically close to one another on the same chromosome tend to stay together during meiosis, and are thus genetically linked.-Background:...
to particular gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, while the two remaining have currently only been associated with a particular locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
. More than 80% of all cases of HHT are due to mutations in either ENG or ACVRL1. A total of over 600 different mutations is known. There is likely to be a predominance of either type in particular populations, but the data are conflicting. MADH4 mutations, which cause colonic polyposis in addition to HHT, comprise about 2% of disease-causing mutations. Apart from MADH4, it is not clear whether mutations in ENG and ACVRL1 lead to particular symptoms, although some reports suggest that ENG mutations are more likely to cause lung problems while ACVRL1 mutations may cause more liver problems, and pulmonary hypertension may be a particular problem in people with ACVRL1 mutations. People with exactly the same mutations may have different nature and severity of symptoms, suggesting that additional genes or other risk factors may determine the rate at which lesions develop; these have not yet been identified.
| Name | OMIM | Gene | Locus | Description |
|---|---|---|---|---|
| HHT1 | ENG Endoglin Endoglin is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex.The protein consists of a homodimer of 180 kDA with disulfide links.... |
9q34.1 | ENG codes for endoglin, a receptor Receptor (biochemistry) In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism... of TGF-β1 TGF beta 1 Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis... (transforming growth factor beta 1) and TGF-β3 TGF beta 3 Transforming growth factor beta 3 is a type of protein, known as a cytokine, which is involved in cell differentiation, embryogenesis and development... ; the genetic linkage was identified in 1994. A high proportion of frameshift mutation Frameshift mutation A frameshift mutation is a genetic mutation caused by indels of a number of nucleotides that is not evenly divisible by three from a DNA sequence... s has been observed. Practically all mutations occur in the extracellular part of the protein (the part that sits on the surface of the cell Cell membrane The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell... ). |
|
| HHT2 | ACVRL1 ACVRL1 Serine/threonine-protein kinase receptor R3 is an enzyme that in humans is encoded by the ACVRL1 gene.ACVRL1 is a receptor in the TGF beta signaling pathway.It is also known as "activin receptor-like kinase 1", or "ALK1".-Further reading:... |
12q11-q14 | ACVRL1 codes for Alk-1 (activin receptor-like kinase 1), a TGF-β1 receptor; genetic linkage was identified in 1996. | |
| HHT3 | Unknown | 5q31 | Function unknown, linkage identified in 2005. | |
| HHT4 | Unknown | 7p14. | Function unknown, linkage identified in 2006. | |
| JPHT | MADH4 Mothers against decapentaplegic homolog 4 SMAD family member 4, also known as SMAD4, is a protein that in humans is encoded by the SMAD4 gene.SMAD4 is a 552-amino acid protein involved in cell signaling. It belongs to the Darfwin family of proteins that modulate members of the TGFβ protein superfamily... |
18q21.1 | MADH4 codes for SMAD4, an intracellular signalling protein for the TGF superfamily receptors. Mutations in this gene cause HHT and juvenile polyposis. Linkage was identified in 2004. Mutations mostly in exons 8–11, often de novo (newly acquired, not inherited). |
Pathophysiology
Telangiectasias and arteriovenous malformations in HHT are thought to arise because of changes in angiogenesisAngiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, the development of blood vessels out of existing ones. The development of a new blood vessels requires the activation and migration of various types of cell, chiefly endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
and pericyte
Pericyte
A pericyte is a type of cell found in the central nervous system. These cells play an integral role in the maintenance of the blood brain barrier as well as several other homeostatic and hemostatic functions of the brain. Pericytes are also a key component of the neurovascular unit, which also...
s. The exact mechanism by which the HHT mutations influence this process is not yet clear, and it is likely that they disrupt a balance between pro- and antiangiogenic signals in blood vessels. The wall of telangiectasias is unusually friable, which explains the tendency of these lesions to bleed.
All genes known so far to be linked to HHT code for proteins in the TGF-β signaling pathway
TGF beta signaling pathway
The Transforming growth factor beta signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. In spite of the wide range of cellular...
. This is a group of proteins that participates in signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
of hormones of the transforming growth factor beta superfamily
Transforming growth factor beta superfamily
The transforming growth factor beta superfamily is a large family of structurally related cell regulatory proteins that was named after its first member, TGF-β1, originally described in 1983....
(the transforming growth factor beta, bone morphogenetic protein
Bone morphogenetic protein
Bone morphogenetic proteins are a group of growth factors also known as cytokines and as metabologens . Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue...
and growth differentiation factor
Growth differentiation factor
Growth differentiation factors are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in development.-Types:...
classes), specifically BMP9/GDF2
GDF2
Growth differentiation factor 2 also known as bone morphogenetic protein -9 is a protein that in humans is encoded by the GDF2 gene...
and BMP10
Bone morphogenetic protein 10
Bone morphogenetic protein 10 is a protein that in humans is encoded by the BMP10 gene.BMP10 is a polypeptide belonging to the TGF-β superfamily of proteins. It is a novel protein that, unlike most other BMP's, is likely to be involved in the tabeculation of the heart. Bone morphogenetic proteins...
. The hormones do not enter the cell but link to receptors on the cell membrane; these then activate other proteins, eventually influencing cellular behavior in a number of ways such as cellular survival, proliferation (increasing in number) and differentiation (becoming more specialized). For the hormone signal to be adequately transduced, a combination of proteins is needed: two each of two types of serine/threonine-specific kinase type
Serine/threonine-specific protein kinase
Serine/threonine protein kinases phosphorylate the OH group of serine or threonine .At least 125 of the 500+ human protein kinases are serine/threonine kinases .-Regulation:...
membrane receptor
Membrane receptor
Cell surface receptors are specialized integral membrane proteins that take part in communication between the cell and the outside world...
s and endoglin. When bound to the hormone, the type II receptor proteins phosphorylate
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
(transfer phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
) onto type I receptor proteins (of which Alk-1 is one), which in turn phosphorylate a complex of SMAD proteins
SMAD (protein)
SMADs are intracellular proteins that transduce extracellular signals from transforming growth factor beta ligands to the nucleus where they activate downstream TGF-β gene transcription....
(chiefly SMAD1
Mothers against decapentaplegic homolog 1
Mothers against decapentaplegic homolog 1 also known as SMAD family member 1 or SMAD1 is a protein that in humans is encoded by the SMAD1 gene.-Nomenclature:...
, SMAD5
Mothers against decapentaplegic homolog 5
Mothers against decapentaplegic homolog 5 also known as SMAD5 is a protein that in humans is encoded by the SAMD5 gene.SMAD5, as its name describes, is a homolog of the Drosophila gene: "Mothers against decapentaplegic". It belongs to the SMAD family of proteins, which belong to the TGFβ...
and SMAD8
Mothers against decapentaplegic homolog 9
Mothers against decapentaplegic homolog 9 also known as SMAD9, SMAD8, and MADH6 is a protein that in humans is enocoded by the SMAD9 gene....
). These bind to SMAD4 and migrate to the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
where they act as transcription factors and participate in the transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of particular genes. In addition to the SMAD pathway, the membrane receptors also act on the MAPK pathway
MAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
, which has additional actions on the behavior of cells. Both Alk-1 and endoglin are expressed
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
predominantly in endothelium, perhaps explaining why HHT-causing mutations in these proteins lead predominantly to blood vessel problems. Both ENG and ACVRL1 mutations lead predominantly to underproduction of the related proteins, rather than misfunctioning of the proteins.
Diagnosis
Diagnostic tests may be conducted for various reasons. Firstly, some tests are needed to confirm or refute the diagnosis. Secondly, some are needed to identify any potential complications.Telangiectasias
Physical examination
Physical examination or clinical examination is the process by which a doctor investigates the body of a patient for signs of disease. It generally follows the taking of the medical history — an account of the symptoms as experienced by the patient...
, and similarly the lesions in the nose may be seen on endoscopy
Endoscopy
Endoscopy means looking inside and typically refers to looking inside the body for medical reasons using an endoscope , an instrument used to examine the interior of a hollow organ or cavity of the body. Unlike most other medical imaging devices, endoscopes are inserted directly into the organ...
of the nasopharynx
Nasopharynx
The nasopharynx is the uppermost part of the pharynx. It extends from the base of the skull to the upper surface of the soft palate; it differs from the oral and laryngeal parts of the pharynx in that its cavity always remains patent .-Lateral:On its lateral wall is the pharyngeal ostium of the...
or on laryngoscopy
Laryngoscope
Laryngoscopy is a medical procedure that is used to obtain a view of the vocal folds and the glottis. Laryngoscopy may be performed to facilitate tracheal intubation during general anesthesia or cardiopulmonary resuscitation or for procedures on the larynx or other parts of the upper...
. The severity of nosebleeds may be quantified objectively using a grid-like questionnaire in which the number of nosebleed episodes and their duration is recorded.
Digestive tract telangiectasias may be identified on esophagogastroduodenoscopy
Esophagogastroduodenoscopy
For other expansions of the initialism "OGD", see the disambiguation page.In medicine , esophagogastroduodenoscopy is a diagnostic endoscopic procedure that visualizes the upper part of the gastrointestinal tract up to the duodenum...
(endoscopy of the esophagus, stomach and first part of the small intestine). This procedure will typically only be undertaken if there is anemia that is more marked than expected by the severity of nosebleeds, or if there is evidence of severe bleeding (vomiting blood, black stools). If the number of lesions seen on endoscopy is unexpectedly low, the remainder of the small intestine may be examined with capsule endoscopy
Capsule endoscopy
Capsule endoscopy is a way to record images of the digestive tract for use in medicine. The capsule is the size and shape of a pill and contains a tiny camera. After a patient swallows the capsule, it takes pictures of the inside of the gastrointestinal tract...
, in which the patient swallows a capsule-shaped device containing a miniature camera which transmits images of the digestive tract to a portable digital recorder.
Arteriovenous malformations
Identification of AVMs requires detailed medical imagingMedical imaging
Medical imaging is the technique and process used to create images of the human body for clinical purposes or medical science...
of the organs most commonly affected by these lesions. Not all AVMs cause symptoms or are at risk of doing so, and hence there is a degree of variation between specialists as to whether such investigations would be performed, and by which modality; often, decisions on this issue are reached together with the patient.
Lung AVMs may be suspected because of the abnormal appearance of the lungs on a chest X-ray, or hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
(low oxygen levels) on pulse oximetry
Pulse oximetry
Pulse oximetry is a non-invasive method allowing the monitoring of the oxygenation of a patient's hemoglobin.A sensor is placed on a thin part of the patient's body, usually a fingertip or earlobe, or in the case of an infant, across a foot....
or arterial blood gas
Arterial blood gas
An arterial blood gas is a blood test that is performed using blood from an artery. It involves puncturing an artery with a thin needle and syringe and drawing a small volume of blood. The most common puncture site is the radial artery at the wrist, but sometimes the femoral artery in the groin or...
determination. Bubble contrast echocardiography (bubble echo) may be used as a screening tool to identify abnormal connections between the lung arteries
Pulmonary artery
The pulmonary arteries carry deoxygenated blood from the heart to the lungs. They are the only arteries that carry deoxygenated blood....
and veins
Pulmonary vein
The pulmonary veins are large blood vessels that carry blood from the lungs to the left atrium of the heart. In humans there are four pulmonary veins, two from each lung...
. This involves the injection of agitated saline
Saline (medicine)
In medicine, saline is a general term referring to a sterile solution of sodium chloride in water but is only sterile when it is to be placed intravenously, otherwise, a saline solution is a salt water solution...
into a vein, followed by ultrasound-based imaging of the heart. Normally, the lungs remove small air bubbles from the circulation, and they are therefore only seen in the right atrium
Right atrium
The right atrium is one of four chambers in the hearts of mammals and archosaurs...
and the right ventricle
Right ventricle
The right ventricle is one of four chambers in the human heart. It receives deoxygenated blood from the right atrium via the tricuspid valve, and pumps it into the pulmonary artery via the pulmonary valve and pulmonary trunk....
. If an AVM is present, bubbles appear in the left atrium
Left atrium
The left atrium is one of the four chambers in the human heart. It receives oxygenated blood from the pulmonary veins, and pumps it into the left ventricle, via the mitral valve.-Foramen ovale:...
and left ventricle
Left ventricle
The left ventricle is one of four chambers in the human heart. It receives oxygenated blood from the left atrium via the mitral valve, and pumps it into the aorta via the aortic valve.-Shape:...
, usually 3–10 cardiac cycle
Cardiac cycle
The cardiac cycle is a term referring to all or any of the events related to the flow or blood pressure that occurs from the beginning of one heartbeat to the beginning of the next. The frequency of the cardiac cycle is described by the heart rate. Each beat of the heart involves five major stages...
s after the right side; this is slower than in heart defects
Congenital heart defect
A congenital heart defect is a defect in the structure of the heart and great vessels which is present at birth. Many types of heart defects exist, most of which either obstruct blood flow in the heart or vessels near it, or cause blood to flow through the heart in an abnormal pattern. Other...
, in which there are direct connections between the right and left side of the heart. A larger number of bubbles is more likely to indicate the presence of an AVM. Bubble echo is not a perfect screening tool as it can miss smaller AVMs and does not identify the site of AVMs. Often contrast
Radiocontrast
Radiocontrast agents are a type of medical contrast medium used to improve the visibility of internal bodily structures in an X-ray based imaging techniques such as computed tomography or radiography...
-enhanced computed tomography (CT angiography) is used to identify lung lesions; this modality has a sensitivity
Sensitivity and specificity
Sensitivity and specificity are statistical measures of the performance of a binary classification test, also known in statistics as classification function. Sensitivity measures the proportion of actual positives which are correctly identified as such Sensitivity and specificity are statistical...
of over 90%. It may be possible to omit contrast administration on modern CT scanners. Echocardiography is also used if there is a suspicion of pulmonary hypertension or high-output cardiac failure due to large liver lesions, sometimes followed by cardiac catheterization
Cardiac catheterization
Cardiac catheterization is the insertion of a catheter into a chamber or vessel of the heart. This is done for both investigational and interventional purposes...
to measure the pressures inside the various chambers of the heart.
Liver AVMs may be suspected because of abnormal liver function tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
in the blood, because the symptoms of heart failure develop, or because of jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
or other symptoms of liver dysfunction. The most reliable initial screening test is Doppler ultrasonography of the liver; this has a very high sensitivity for identifying vascular lesions in the liver. If necessary, contrast-enhanced CT may be used to further characterize AVMs. It is extremely common to find incidental nodules on liver scans, most commonly due to focal nodular hyperplasia
Focal nodular hyperplasia
Focal nodular hyperplasia is a benign tumour of the liver , which is the second most prevalent tumour of the liver . It is usually asymptomatic, rarely grows or bleeds, and has no malignant potential...
(FNH), as these are a hundredfold times more common in HHT compared to the general population. FNH is regarded as harmless. Generally, tumor marker
Tumor marker
A tumor marker is a substance found in the blood, urine, or body tissues that can be elevated in cancer, among other tissue types. There are many different tumor markers, each indicative of a particular disease process, and they are used in oncology to help detect the presence of cancer...
s and additional imaging modalities are used to differentiate between FNH and malignant tumors of the liver. Liver biopsy
Liver biopsy
Liver biopsy is the biopsy from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.-History:...
is discouraged in people with HHT as the risk of hemorrhage from liver AVMs may be significant. Liver scans may be useful if someone is suspected of HHT, but does not meet the criteria (see below) unless liver lesions can be demonstrated.
Brain AVMs may be detected on computed tomography angiography
Computed tomography angiography
Computed tomography angiography is a computed tomography technique used to visualize arterial and venous vessels throughout the body. This ranges from arteries serving the brain to those bringing blood to the lungs, kidneys, arms and legs.-Technique:...
(CTA or CT angio) or magnetic resonance angiography
Magnetic Resonance Angiography
Magnetic resonance angiography is a group of techniques based on Magnetic Resonance Imaging to image blood vessels. Magnetic resonance angiography is used to generate images of the arteries in order to evaluate them for stenosis , occlusion or aneurysms...
(MRA); CTA is better in showing the vessels themselves, and MRA provides more detail about the relationship between an AVM and surrounding brain tissue. In general, MRI is recommended. Various types of vascular malformations may be encountered: AVMs, micro-AVMs, telangiectasias and arteriovenous fistula
Fistula
In medicine, a fistula is an abnormal connection or passageway between two epithelium-lined organs or vessels that normally do not connect. It is generally a disease condition, but a fistula may be surgically created for therapeutic reasons.-Locations:Fistulas can develop in various parts of the...
s. If surgery, embolization, or other treatment is contemplated (see below), cerebral angiography
Cerebral angiography
Cerebral angiography is a form of angiography which provides images of blood vessels in and around the brain, thereby allowing detection of abnormalities such as arteriovenous malformations and aneurysms....
may be required to get sufficient detail of the vessels. This procedure carries a small risk of stroke (0.5%) and is therefore limited to specific circumstances. Recent professional guidelines recommend that all children with suspected or definite HHT undergo a brain MRI early in life to identify AVMs that can cause major complications. Others suggest that screening for cerebral AVMs is probably unnecessary in those who are not experiencing any neurological symptoms, because most lesions discovered on screening scans would not require treatment, creating undesirable conundrums.
Genetic testing
Genetic tests are available for the ENG, ACVRL1 and MADH4 mutations. Testing is not always needed for diagnosis, because the symptoms are sufficient to distinguish the disease from other diagnoses. There are situations in which testing can be particularly useful. Firstly, children and young adults with a parent with definite HHT may have limited symptoms, yet be at risk from some of the complications mentioned above; if the mutation is known in the affected parent, absence of this mutation in the child would prevent the need for screening tests. Furthermore, genetic testing may confirm the diagnosis in those with limited symptoms who otherwise would have been labeled "possible HHT" (see below).Genetic diagnosis in HHT is difficult, as mutations occur in numerous different locations in the linked genes, without particular mutations being highly frequent (as opposed to, for instance, the ΔF508 mutation in cystic fibrosis
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
). Sequence analysis
Sequence analysis
In bioinformatics, the term sequence analysis refers to the process of subjecting a DNA, RNA or peptide sequence to any of a wide range of analytical methods to understand its features, function, structure, or evolution. Methodologies used include sequence alignment, searches against biological...
of the involved genes is therefore the most useful approach (sensitivity 75%), followed by additional testing to detect large deletions and duplications (additional 10%). Not all mutations in these genes have been linked with disease.
Mutations in the MADH4 gene is usually associated with juvenile polyposis, and detection of such a mutation would indicate a need to screen the patient and affected relatives for polyps and tumors of the large intestine.
Criteria
The diagnosis of made depending on the presence of four criteria, known as the "CuraçaoCuraçao
Curaçao is an island in the southern Caribbean Sea, off the Venezuelan coast. The Country of Curaçao , which includes the main island plus the small, uninhabited island of Klein Curaçao , is a constituent country of the Kingdom of the Netherlands...
criteria". If three or four are met, a patient has "definite HHT", while two gives "possible HHT":
- Spontaneous recurrent epistaxis
- Multiple telangiectasias in typical locations (see above)
- Proven visceral AVM (lung, liver, brain, spine)
- First-degree family member with HHT
Despite the designation "possible", someone with a visceral AVM and a family history but no nosebleeds or telangiectasias is still extremely likely to have HHT, because these AVMs are very uncommon in the general population. At the same time, the same cannot be said of nosebleeds and sparse telangiectasias, both of which occur in people without HHT, in the absence of AVMs. Someone's diagnostic status may change in the course of life, as young children may not yet exhibit all the symptoms; at age 16, thirteen percent are still indeterminate, while at age 60 the vast majority (99%) have a definite diagnostic classification. The children of established HHT patients may therefore be labeled as "possible HHT", as 50% may turn out to have HHT in the course of their life.
Treatment
Treatment of HHT is symptomaticSymptomatic treatment
Symptomatic treatment is any medical therapy of a disease that only affects its symptoms, not its cause, i.e., its etiology. It is usually aimed at reducing the signs and symptoms for the comfort and well-being of the patient, but it also may be useful in reducing organic consequences and sequelae...
(it deals with the symptoms rather than the disease itself), as there is no therapy that stops the development of telangiectasias and AVMs directly. Furthermore, some treatments are applied to prevent the development of common complications. Chronic nosebleeds and digestive tract bleeding can both lead to anemia; if the bleeding itself cannot be completely stopped, the anemia requires treatment with iron supplements
Iron supplements
Iron supplements are supplements that can be prescribed by a doctor for a medical reason. Iron can also be a dietary supplement, which can be purchased in supermarkets etc. These two categories should not be confused....
. Those who cannot tolerate iron tablets or solutions may require administration of intravenous
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
iron sucrose, and blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
if the anemia is causing severe symptoms that warrant rapid improvement of the blood count.
Most treatments used in HHT have been described in adults, and the experience in treating children is more limited. Women with HHT who get pregnant
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
are at an increased risk of complications, and are observed closely, although the absolute risk is still low (1%).
Nosebleeds
An acute nosebleed may be managed with a variety of measures, such as packing of the nasal cavity with absorbent swabs or gels. Removal of the packs after the bleeding may lead to reopening of the fragile vessels, and therefore lubricated or atraumatic packing is recommended. Some patients may wish to learn packing themselves to deal with nosebleeds without having to resort to medical help.Frequent nosebleeds can be prevented in part by keeping the nostrils moist, and by applying saline solution
Saline (medicine)
In medicine, saline is a general term referring to a sterile solution of sodium chloride in water but is only sterile when it is to be placed intravenously, otherwise, a saline solution is a salt water solution...
, estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
-containing creams or tranexamic acid
Tranexamic acid
Tranexamic acid is a drug used to treat or prevent excessive blood loss during surgery and in certain other conditions...
; these have few side effects and may have a small degree of benefit. A number of additional modalities has been used to prevent recurrent bleeding if simple measures are unsuccessful. Medical therapies include oral tranexamic acid and estrogen; the evidence
Evidence-based medicine
Evidence-based medicine or evidence-based practice aims to apply the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of evidence of the risks and benefits of treatments and diagnostic tests...
for these is relatively limited, and estrogen is poorly tolerated by men and possibly carries risks of cancer and heart disease in women past the menopause. Nasal coagulation and cauterization
Cauterization
The medical practice or technique of cauterization is the burning of part of a body to remove or close off a part of it in a process called cautery, which destroys some tissue, in an attempt to mitigate damage, remove an undesired growth, or minimize other potential medical harmful possibilities...
may reduce the bleeding from telangiectasias, and is recommended before surgery is considered; often, several sessions are needed. It may be possible to embolize
Embolization
Embolization is a non-surgical, minimally-invasive procedure performed by an interventional radiologist and interventional neuroradiologists. It involves the selective occlusion of blood vessels by purposely introducing emboli.-Therapeutic applications:...
vascular lesions through interventional radiology
Interventional radiology
Interventional radiology is a specialty of radiology, in which image-guided procedures are used to diagnose and treat a multitude of diseases across all body systems...
; this requires passing a catheter through a large artery and locating the maxillary artery under X-ray guidance
Fluoroscopy
Fluoroscopy is an imaging technique commonly used by physicians to obtain real-time moving images of the internal structures of a patient through the use of a fluoroscope. In its simplest form, a fluoroscope consists of an X-ray source and fluorescent screen between which a patient is placed...
, followed by the injection into the vessel of particles that occlude the blood vessels. The benefit from the procedure tends to be short-lived, and it may be most appropriate in episodes of severe bleeding.
If other interventions have failed, several operations have been reported to provide benefit. One is septal dermoplasty or Saunders' procedure, in which skin is transplanted into the nostrils, and the other is Young's procedure, in which the nostrils are sealed off completely.
Skin and digestive tract
The skin lesions of HHT can be disfiguring, and may respond to treatment with long-pulsed Nd:YAG laserNd:YAG laser
Nd:YAG is a crystal that is used as a lasing medium for solid-state lasers. The dopant, triply ionized neodymium, typically replaces yttrium in the crystal structure of the yttrium aluminium garnet , since they are of similar size...
. Skin lesions in the fingertips may sometimes bleed and cause pain. Skin grafting
Skin grafting
Skin grafting is a type of graft surgery involving the transplantation of skin. The transplanted tissue is called a skin graft.Skin grafting is often used to treat:*Extensive wounding or trauma*Burns...
is occasionally needed to treat this problem.
With regards to digestive tract lesions, mild bleeding and mild resultant anemia is treated with iron supplementation, and no specific treatment is administered. There is limited data on hormone treatment and tranexamic acid to reduce bleeding and anemia. Severe anemia or episodes of severe bleeding are treated with endoscopic argon plasma coagulation
Argon plasma coagulation
Argon plasma coagulation or APC is a medical endoscopic procedure used primarily to control bleeding from certain lesions in the gastrointestinal tract, and also sometimes to debulk tumours in the case of patients for whom surgery is not recommended...
(APC) or laser treatment of any lesions identified; this may reduce the need for supportive treatment. The expected benefits are not such that repeated attempts at treating lesions are advocated. Sudden, very severe bleeding is unusual—if encountered, alternative causes (such as a peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
) need to be considered—but embolization may be used in such instances.
Lung AVMs
Lung lesions, once identified, are usually treated to prevent episodes of bleeding and more importantly embolism to the brain. This is particularly done in lesions with a feeding blood vessel of 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 detachable metal coils. The procedure involves puncture of a large vein (usually under a general anestheticGeneral anaesthetic
A general anaesthetic is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthesia provider to induce or maintain general anaesthesia to facilitate surgery...
), followed by advancing of a catheter through the right ventricle
Cardiac catheterization
Cardiac catheterization is the insertion of a catheter into a chamber or vessel of the heart. This is done for both investigational and interventional purposes...
and into the pulmonary artery
Pulmonary artery
The pulmonary arteries carry deoxygenated blood from the heart to the lungs. They are the only arteries that carry deoxygenated blood....
, after which radiocontrast
Radiocontrast
Radiocontrast agents are a type of medical contrast medium used to improve the visibility of internal bodily structures in an X-ray based imaging techniques such as computed tomography or radiography...
is injected to visualize the AVMs (pulmonary angiography
Pulmonary angiography
Pulmonary angiography is a cardiological medical procedure. Pulmonary blood vessels are x-rayed to detect arteriovenous malformations....
). Once the lesion has been identified, coils are deployed that obstruct the blood flow and allow the lesion to regress. In experienced hands, the procedure tends to be very effective and with limited side effects, but lesions may recur and further attempts may be required. CTA scans are repeated to monitor for recurrence. Surgical excision has now essentially been abandoned due to the success of embolotherapy.
Those with either definite pulmonary AVMs or an abnormal contrast echocardiogram with no clearly visible lesions are deemed to be at risk from brain emboli. They are therefore counselled to avoid scuba diving
Scuba diving
Scuba diving is a form of underwater diving in which a diver uses a scuba set to breathe underwater....
, during which small air bubbles may form in the bloodsteam that may migrate to the brain and cause stroke. Similarly, antimicrobial prophylaxis is advised during procedures in which bacteria may enter the bloodstream, such as dental work
Dentistry
Dentistry is the branch of medicine that is involved in the study, diagnosis, prevention, and treatment of diseases, disorders and conditions of the oral cavity, maxillofacial area and the adjacent and associated structures and their impact on the human body. Dentistry is widely considered...
, and avoidance of air bubbles during intravenous therapy
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
.
Liver AVMs
Given that liver AVMs generally cause high-output cardiac failure, the emphasis is on treating this with diureticDiuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
s to reduce the circulating blood volume, restriction of salt and fluid intake, and antiarrhythmic agent
Antiarrhythmic agent
Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart , such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation....
s in case of irregular heart beat
Cardiac dysrhythmia
Cardiac dysrhythmia is any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.Some arrhythmias are life-threatening medical emergencies that can result in cardiac...
. This may be sufficient in treating the symptoms of swelling and breathlessness. If this treatment is not effective or leads to side effects or complications, the only remaining option is liver transplantation
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
. This is reserved for those with severe symptoms, as it carries a mortality
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...
of about 10%, but leads to good results if successful. The exact point at which liver transplantion is to be offered is not yet completely established. Embolization treatment has been attempted, but leads to severe complications in a proportion of patients and is discouraged.
Other liver-related complications (portal hypertension, esophageal varices, ascites, hepatic encephalopathy) are treated with the same modalities as used in cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, although the use of transjugular intrahepatic portosystemic shunt
Transjugular intrahepatic portosystemic shunt
A Transjugular Intrahepatic Portosystemic Shunt is an artificial channel within the liver that establishes communication between the inflow portal vein and the outflow hepatic vein...
treatment is discouraged due to the lack of documented benefit.
Brain AVMs
The decision to treat brain AVMs depends on the symptoms that they cause (such as seizures or headaches). The bleeding risk is predicted by previous episodes of hemorrhage, and whether on the CTA or MRA scan the AVM appears to be deep seated or have deep venous drainage. Size of the AVM and the presence of aneurysmAneurysm
An aneurysm or aneurism is a localized, blood-filled balloon-like bulge in the wall of a blood vessel. Aneurysms can commonly occur in arteries at the base of the brain and an aortic aneurysm occurs in the main artery carrying blood from the left ventricle of the heart...
s appears to matter less. In HHT, some lesions (high-flow arteriovenous fistulae) tend to cause more problems, and treatment is warranted. Other AVMs may regress over time without intervention. Various modalities are available, depending on the location of the AVM and its size: surgery, radiation-based treatment and embolization. Sometimes, multiple modalities are used on the same lesion.
Surgery (by craniotomy
Craniotomy
A craniotomy is a surgical operation in which a bone flap is temporarily removed from the skull to access the brain. Craniotomies are often a critical operation performed on patients recording, brain imaging, and for neurological manipulations such as electrical stimulation and chemical...
, open brain surgery) may be offered based on the risks of treatment as determined by the Spetzler–Martin scale (grade 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 typically offered in those cases. Radiosurgery
Radiosurgery
Radiosurgery is a medical procedure that allows non-invasive treatment of benign and malignant tumors. It is also known as stereotactic radiotherapy, when used to target lesions in the brain, and stereotactic body radiotherapy when used to target lesions in the body...
(using targeted radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
such as by a gamma knife) may be used if the lesion is small but close to vital structures. Finally, embolization may be used on small lesions that have only a single feeding vessel.
Epidemiology
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
region of Haut Jura
Jura mountains
The Jura Mountains are a small mountain range located north of the Alps, separating the Rhine and Rhone rivers and forming part of the watershed of each...
the rate is 1:2351 - twice as common as in other populations. This has been attributed to a founder effect
Founder effect
In population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, using existing theoretical work by those such as Sewall...
, in which a population descending from a small number of ancestors has a high rate of a particular genetic trait because one of these ancestors harbored this trait. In Haut Jura, this has been shown to be the result of a particular ACVRL1 mutation (named c.1112dupG or c.1112_1113insG). The highest rate of HHT is 1:1331, reported in Bonaire and Curaçao
Curaçao
Curaçao is an island in the southern Caribbean Sea, off the Venezuelan coast. The Country of Curaçao , which includes the main island plus the small, uninhabited island of Klein Curaçao , is a constituent country of the Kingdom of the Netherlands...
, two islands in the Caribbean
Caribbean Sea
The Caribbean Sea is a sea of the Atlantic Ocean located in the tropics of the Western hemisphere. It is bounded by Mexico and Central America to the west and southwest, to the north by the Greater Antilles, and to the east by the Lesser Antilles....
belonging to the Netherlands Antilles
Netherlands Antilles
The Netherlands Antilles , also referred to informally as the Dutch Antilles, was an autonomous Caribbean country within the Kingdom of the Netherlands, consisting of two groups of islands in the Lesser Antilles: Aruba, Bonaire and Curaçao , in Leeward Antilles just off the Venezuelan coast; and Sint...
.
Most people with HHT have a normal lifespan. The skin lesions and nosebleeds tend to develop during childhood. AVMs are probably present from birth, but don't necessarily cause any symptoms. Frequent nosebleeds are the most common symptom and can significantly affect quality of life
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
.
History
Several 19th century English physicians, starting with Henry Gawen SuttonHenry Gawen Sutton
Henry Gawen Sutton was an English physician. He was born in Middlesbrough and obtained his medical training at Middlesbrough but qualified at University College London and practised in London for the rest of his life, initially as a general practitioner but later, after gaining membership of the...
(1836–1891) and followed by Benjamin Guy Babington
Benjamin Guy Babington
Benjamin Guy Babington was an English physician and epidemiologist.He was born on 5 March 1794, the son of the physician and mineralogist William Babington and his wife, Martha Elizabeth Babington....
(1794–1866) and John Wickham Legg
John Wickham Legg
John Wickham Legg was the third son of the printer and bookseller George Legg, and was born at Alverstoke near Portsmouth in Hampshire, England, on 28 December 1843...
(1843–1921), described the most common features of HHT, particularly the recurrent nosebleeds and the hereditary nature of the disease. The French physician Henri Jules Louis Marie Rendu (1844–1902) observed the skin and mucosal lesions, and distinguished the condition from hemophilia. The Canadian-born Sir William Osler (1849–1919), then at Johns Hopkins Hospital
Johns Hopkins Hospital
The Johns Hopkins Hospital is the teaching hospital and biomedical research facility of Johns Hopkins University School of Medicine, located in Baltimore, Maryland . It was founded using money from a bequest by philanthropist Johns Hopkins...
and later at Oxford University, made further contributions with a 1901 report in which he described characteristic lesions in the digestive tract. The English physician Frederick Parkes Weber (1863–1962) reported further on the condition in 1907 with a series of cases. The term "hereditary hemorrhagic telangiectasia" was first used by the American physician Frederic M. Hanes (1883–1946) in a 1909 article on the condition.
The diagnosis of HHT remained a clinical one until the genetic defects that cause HHT were identified by a research group at Duke University Medical Center
Duke University Hospital
Duke University Medical Center is a 924-bed academic tertiary care facility located in Durham, North Carolina. Since its establishment in 1930, the hospital has grown from a small regional hospital to an academic medical center...
, in 1994 and 1996 respectively. In 2000, the international scientific advisory committee of HHT Foundation International published the now widely used Curaçao criteria. In 2006, a group of international experts met in Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...
and formulated an evidence-based
Evidence-based medicine
Evidence-based medicine or evidence-based practice aims to apply the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of evidence of the risks and benefits of treatments and diagnostic tests...
guideline, sponsored by the HHT Foundation International.
External links
- HHT Foundation International
- HHT mutation database (ENG and ACVRL1)