Hereditary hemorrhagic telangiectasia (HHT), also known as Osler–Weber–Rendu disease and Osler–Weber–Rendu syndrome, is a rare autosomal dominant
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
that leads to abnormal blood vessel formation in the
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
,
mucous membrane
A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
s, and often in organs such as the
lung
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
s,
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
, and
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
.
[
It may lead to ]nosebleeds
A nosebleed, also known as epistaxis, is bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significant that low bloo ...
, 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
Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pat ...
or other targeted interventions to remove arteriovenous malformation
Arteriovenous malformation is an abnormal connection between arteries and veins, bypassing the capillary system. This vascular anomaly is widely known because of its occurrence in the central nervous system (usually cerebral AVM), but can appea ...
s in organs. Chronic bleeding often requires iron supplements
Iron supplements, also known as iron salts and iron pills, are a number of iron formulations used to treat and prevent iron deficiency including iron deficiency anemia. For prevention they are only recommended in those with poor absorption, h ...
and sometimes blood transfusion
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
s. HHT is transmitted in an autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
fashion, and occurs in one in 5,000–8,000 people in North America.[
The disease carries the names of Sir ]William Osler
Sir William Osler, 1st Baronet, (; July 12, 1849 – December 29, 1919) was a Canadian physician and one of the "Big Four" founding professors of Johns Hopkins Hospital. Osler created the first Residency (medicine), residency program for spec ...
, Henri Jules Louis Marie Rendu
Henri Jules Louis Marie Rendu (24 July 1844 – 16 April 1902) was a French physician born in Paris. He was related to glaciologist Louis Rendu (1789–1859).
He initially received an education in sciences at the school of agronomy in Rennes, a ...
, and Frederick Parkes Weber
Frederick Parkes Weber (8 May 1863 – 2 June 1962) was an English dermatologist and author who practiced medicine in London.
Background
Weber's father, Sir Hermann David Weber (1823–1918), was a personal physician to Queen Victoria.
...
, who described it in the late 19th and early 20th centuries.[
]
Signs and symptoms
Telangiectasias
Telangiectasia
Telangiectasias, also known as spider veins, are small dilated blood vessels that can occur near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. These dilated blood vessels can develop anywhere on ...
(small vascular malformations) may occur in the skin and mucosal linings of the nose and gastrointestinal tract. The most common problem is nosebleeds
A nosebleed, also known as epistaxis, is bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significant that low bloo ...
(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
The lips are the visible body part at the mouth of many animals, including humans. Lips are soft, movable, and serve as the opening for food intake and in the articulation of sound and speech. Human lips are a tactile sensory organ, and can be ...
s, the nose
A nose is a protuberance in vertebrates that houses the nostrils, or nares, which receive and expel air for respiration alongside the mouth. Behind the nose are the olfactory mucosa and the sinuses. Behind the nasal cavity, air next passes th ...
and the finger
A finger is a limb of the body and a type of digit, an organ of manipulation and sensation found in the hands of most of the Tetrapods, so also with humans and other primates. Most land vertebrates have five fingers ( Pentadactyly). Chambers ...
s, and on the skin of the face in sun-exposed areas. They appear suddenly, with the number increasing over time.[
About 20% are affected by symptomatic digestive tract lesions, although a higher percentage have lesions that do not cause symptoms. These lesions may bleed intermittently, which is rarely significant enough to be noticed (in the form of bloody vomiting or black stool), but can eventually lead to depletion of ]iron
Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...
in the body, resulting in iron-deficiency anemia
Iron-deficiency anemia is anemia caused by a iron deficiency, lack of iron. Anemia is defined as a decrease in the number of red blood cells or the amount of hemoglobin in the blood. When onset is slow, symptoms are often vague such as Fatigue (me ...
.[
]
Arteriovenous malformation
Arteriovenous malformation
Arteriovenous malformation is an abnormal connection between arteries and veins, bypassing the capillary system. This vascular anomaly is widely known because of its occurrence in the central nervous system (usually cerebral AVM), but can appea ...
s (AVMs, larger vascular malformations) occur in larger organs, predominantly the lungs ( pulmonary AVMs) (50%), liver (30–70%) and the brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
( cerebral AVMs, 10%), with a very small proportion (<1%) of AVMs in the spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the spi ...
.[
Vascular malformations in the lungs may cause a number of problems. The lungs normally "filter out" ]bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
and blood clots
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
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
Brain abscess (or cerebral abscess) is an abscess caused by inflammation and collection of infected material, coming from local (ear infection, dental abscess, infection of paranasal sinuses, infection of the mastoid air cells of the temporal bone ...
and blood clots may lead to stroke
A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
.[ 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 is the coughing up of blood or blood-stained mucus from the bronchi, larynx, trachea, or lungs. In other words, it is the airway bleeding. This can occur with lung cancer, infections such as tuberculosis, bronchitis, or pneumonia, and ...
(coughing up blood) or hemothorax
A hemothorax (derived from hemo- lood+ thorax hest plural ''hemothoraces'') is an accumulation of blood within the pleural cavity. The symptoms of a hemothorax may include chest pain and difficulty breathing, while the clinical signs may incl ...
(blood accumulating in the chest cavity).[ Large vascular malformations in the lung allow oxygen-depleted blood from the ]right ventricle
A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the uppe ...
to bypass the alveoli Alveolus (; pl. alveoli, adj. alveolar) is a general anatomical term for a concave cavity or pit.
Uses in anatomy and zoology
* Pulmonary alveolus, an air sac in the lungs
** Alveolar cell or pneumocyte
** Alveolar duct
** Alveolar macrophage
* ...
, meaning that this blood does not have an opportunity to absorb fresh oxygen. This may lead to breathlessness
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing dis ...
.[ Large AVMs may lead to ]platypnea
Platypnea or platypnoea is shortness of breath (dyspnea) that is relieved when lying down, and worsens when sitting or standing upright. It is the opposite of orthopnea. The condition was first described in 1949 and named in 1969.
A related cond ...
, difficulty in breathing that is 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 is the change of body tissue color to a bluish-purple hue as a result of having decreased amounts of oxygen bound to the hemoglobin in the red blood cells of the capillary bed. Body tissues that show cyanosis are usually in locations ...
(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
An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...
and vein
Veins are blood vessels in humans and most other animals 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 b ...
s, a large amount of blood bypasses the body's organs, for which the heart compensates by increasing the cardiac output
In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: t ...
. Eventually congestive cardiac failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, an ...
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
The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to the ...
(esophageal varices
Esophageal varices are extremely dilated sub-mucosal veins in the lower third of the esophagus. They are most often a consequence of portal hypertension, commonly due to cirrhosis. People with esophageal varices have a strong tendency to develop ...
), which may bleed violently; furthermore, the increased pressure may give rise to fluid accumulation in the abdominal cavity (ascites
Ascites is the abnormal build-up of fluid in the abdomen. Technically, it is more than 25 ml of fluid in the peritoneal cavity, although volumes greater than one liter may occur. Symptoms may include increased abdominal size, increased weight, ab ...
). 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 (HE) is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stages ...
(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 is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches.
Headaches can occur as a result ...
s. They may also increase the risk of seizure
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
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
In anatomy, the meninges (, ''singular:'' meninx ( or ), ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in th ...
( subarachnoid hemorrhage), there is usually a severe, sudden headache and decreased level of consciousness and often weakness in part of the body.[
]
Other problems
A very small proportion (those affected by ''SMAD4'' (MADH4) mutations, see below) have multiple benign polyps in the large intestine
The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being r ...
, which may bleed or transform into colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
. 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
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
and causing peripheral edema
Peripheral edema is edema (accumulation of fluid causing swelling) in tissues perfused by the peripheral vascular system, usually in the lower limbs. In the most dependent parts of the body (those hanging distally), it may be called dependent ede ...
(swelling of the legs), fainting
Syncope, commonly known as fainting, or passing out, is a loss of consciousness and muscle strength characterized by a fast onset, short duration, and spontaneous recovery. It is caused by a decrease in blood flow to the brain, typically from ...
and attacks of chest pain
Chest pain is pain or discomfort in the chest, typically the front of the chest. It may be described as sharp, dull, pressure, heaviness or squeezing. Associated symptoms may include pain in the shoulder, arm, upper abdomen, or jaw, along with n ...
. It has been observed that the risk of thrombosis
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
(particularly venous thrombosis
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
, in the form of deep vein thrombosis
Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...
or pulmonary embolism
Pulmonary embolism (PE) is a blockage of an pulmonary artery, artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include dyspnea, shortness of breath, chest pain p ...
) 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.[
]
Genetics
HHT is a genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
with an autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
inheritance pattern. Those with HHT symptoms that have no relatives with the disease may have a new mutation. Homozygosity appears to be fatal in utero.[
Five genetic types of HHT are recognized. Of these, three have been linked to particular ]gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s, while the two remaining have currently only been associated with a particular locus
Locus (plural loci) is Latin for "place". It may refer to:
Entertainment
* Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front
* ''Locus'' (magazine), science fiction and fantasy magazine
** ''Locus Award' ...
. More than 80% of all cases of HHT are due to mutations in either ''ENG'' or ''ACVRL1''. A total of over 600 different mutations are 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.][
]
Pathophysiology
Telangiectasias and arteriovenous malformations in HHT are thought to arise because of changes in angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
, the development of blood vessels out of existing ones. The development of a new blood vessel requires the activation and migration of various types of cells, chiefly endothelium
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
, smooth muscle
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
and pericyte
Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood ca ...
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
Friability ( ), the condition of being friable, describes the tendency of a solid substance to break into smaller pieces under duress or contact, especially by rubbing. The opposite of friable is indurate.
Substances that are designated hazardous, ...
, 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
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
of hormones of the transforming growth factor beta superfamily
The transforming growth factor beta (TGF-β) superfamily is a large group of structurally related cell regulatory proteins that was named after its first member, TGF-β1, originally described in 1983. They interact with TGF-beta receptors.
Ma ...
(the transforming growth factor beta
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
, bone morphogenetic protein and growth differentiation factor Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in development.
Types
Several members of this subfamily have been described, and name ...
classes), specifically BMP9/GDF2 and BMP10
Bone morphogenetic protein 10 (BMP10) 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 inv ...
. 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
Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...
s and endoglin. When bound to the hormone, the type II receptor proteins phosphorylate
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...
(transfer phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phospho ...
) onto type I receptor proteins (of which Alk-1 is one), which in turn phosphorylate a complex of SMAD proteins (chiefly SMAD1
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
SMAD1 belongs to the SMAD, a family of proteins similar to the gene products of the ...
, SMAD5 and SMAD8). These bind to SMAD4 and migrate to the cell nucleus
The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
where they act as transcription factors
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...
and participate in the transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
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.][
]
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
The skin and oral cavity telangiectasias are visually identifiable on physical examination
In a physical examination, medical examination, or clinical examination, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally consists of a series of questions about the patien ...
, and similarly the lesions in the nose may be seen on endoscopy
An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are insert ...
of the nasopharynx
The pharynx (plural: pharynges) is the part of the throat behind the mouth and nasal cavity, and above the oesophagus and trachea (the tubes going down to the stomach and the lungs). It is found in vertebrates and invertebrates, though its struct ...
or on laryngoscopy
Laryngoscopy () is endoscopy of the larynx, a part of the throat. It is a medical procedure that is used to obtain a view, for example, of the vocal folds and the glottis. Laryngoscopy may be performed to facilitate tracheal intubation during ...
. 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 (EGD) or oesophagogastroduodenoscopy (OGD), also called by various other names, is a diagnostic endoscopic procedure that visualizes the upper part of the gastrointestinal tract down to the duodenum. It is considered ...
(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 is a medical procedure used to record internal images of the gastrointestinal tract for use in disease diagnosis. Newer developments are also able to take biopsies and release medication at specific locations of the entire g ...
, 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 imaging
Medical imaging is the technique and process of imaging the interior of a body for clinical analysis and medical intervention, as well as visual representation of the function of some organs or tissues (physiology). Medical imaging seeks to rev ...
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
A chest radiograph, called a chest X-ray (CXR), or chest film, is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures. Chest radiographs are the most common film taken in med ...
, or hypoxia (low oxygen levels) on pulse oximetry
Pulse oximetry is a noninvasive method for monitoring a person's oxygen saturation. Peripheral oxygen saturation (SpO2) readings are typically within 2% accuracy (within 4% accuracy in 95% of cases) of the more accurate (and invasive) reading of ...
or arterial blood gas
An arterial blood gas (ABG) test, or arterial blood gas analysis (ABGA) measures the amounts of arterial gases, such as oxygen and carbon dioxide. An ABG test requires that a small volume of blood be drawn from the radial artery with a syringe an ...
determination. Bubble contrast echocardiography (bubble echo) may be used as a screening tool to identify abnormal connections between the lung arteries
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...
and veins
Veins are blood vessels in humans and most other animals 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 b ...
. 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
The atrium ( la, ātrium, , entry hall) is one of two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular valves.
There are two at ...
and the right ventricle
A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the uppe ...
. If an AVM is present, bubbles appear in the left atrium
The atrium ( la, ātrium, , entry hall) is one of two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular valves.
There are two atr ...
and left ventricle
A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the upper ...
, usually 3–10 cardiac cycle
The cardiac cycle is the performance of the human heart from the beginning of one heartbeat to the beginning of the next. It consists of two periods: one during which the heart muscle relaxes and refills with blood, called diastole, following ...
s after the right side; this is slower than in heart defects
A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
, 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
Cardiac catheterization (heart cath) is the insertion of a catheter into a chamber or vessel of the heart. This is done both for diagnostic and interventional purposes.
A common example of cardiac catheterization is coronary catheterization that ...
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 (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin ti ...
in the blood, because the symptoms of heart failure develop, or because of jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
or other symptoms of liver dysfunction. The most reliable initial screening test is Doppler ultrasonography
Doppler ultrasonography is medical ultrasonography that employs the Doppler effect to perform imaging of the movement of tissues and body fluids (usually blood), and their relative velocity to the probe. By calculating the frequency shift of ...
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 (FNH) is a benign tumor of the liver ( hepatic tumor), which is the second most prevalent tumor of the liver (the first is hepatic hemangioma). It is usually asymptomatic, rarely grows or bleeds, and has no malignant pot ...
(FNH), as these are a hundredfold times more common in HHT compared to the general population. FNH is regarded as harmless. Generally, tumor marker
A tumor marker is a biomarker found in blood, urine, or body tissues that can be elevated by the presence of one or more types of cancer. There are many different tumor markers, each indicative of a particular disease process, and they are used in ...
s and additional imaging modalities are used to differentiate between FNH and malignant tumors of the liver. Liver biopsy
Liver biopsy is the biopsy (removal of a small sample of tissue) 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.
Medica ...
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 (also called CT angiography or CTA) is a computed tomography technique used for angiography—the visualization of arteries and veins—throughout the human body. Using contrast injected into the blood vessels, ...
(CTA or CT angio) or magnetic resonance angiography
Magnetic resonance angiography (MRA) is a group of techniques based on magnetic resonance imaging (MRI) to image blood vessels. Magnetic resonance angiography is used to generate images of arteries (and less commonly veins) in order to evaluate ...
(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
A fistula (plural: fistulas or fistulae ; from Latin ''fistula'', "tube, pipe") in anatomy is an abnormal connection between two hollow spaces (technically, two epithelialized surfaces), such as blood vessels, intestines, or other hollow or ...
s.[ If surgery, embolization, or other treatment is contemplated (see below), ]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.
It was pioneered in 1927 by the Portugues ...
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
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene.
Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wit ...
mutation in cystic fibrosis
Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...
). Sequence analysis
In bioinformatics, sequence analysis is 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 alig ...
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 can be made depending on the presence of four criteria, known as the "Curaçao
Curaçao ( ; ; pap, Kòrsou, ), officially the Country of Curaçao ( nl, Land Curaçao; pap, Pais Kòrsou), is a Lesser Antilles island country in the southern Caribbean Sea and the Dutch Caribbean region, about north of the Venezuela coast ...
criteria". If three or four are met, a patient has "definite HHT", while two gives "possible HHT":
# Spontaneous recurrent epistaxis
A nosebleed, also known as epistaxis, is bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significant that low bl ...
# 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 symptomatic
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...
(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, also known as iron salts and iron pills, are a number of iron formulations used to treat and prevent iron deficiency including iron deficiency anemia. For prevention they are only recommended in those with poor absorption, h ...
. Those who cannot tolerate iron tablets or solutions may require administration of intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
iron, and blood transfusion
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
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 is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occur ...
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 (also known as saline solution) is a mixture of sodium chloride (salt) and water. It has a number of uses in medicine including cleaning wounds, removal and storage of contact lenses, and help with dry eyes. By injection into a vein it ...
, estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
-containing creams or tranexamic acid
Tranexamic acid (TXA) is a medication used to treat or prevent excessive blood loss from major trauma, postpartum bleeding, surgery, tooth removal, nosebleeds, and heavy menstruation. It is also used for hereditary angioedema. It is taken eit ...
; 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 for a proposition is what supports this proposition. It is usually understood as an indication that the supported proposition is true. What role evidence plays and how it is conceived varies from field to field.
In epistemology, evidenc ...
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 (or cauterisation, or cautery) is a medical practice or technique of burning a part of a body to remove or close off a part of it. It destroys some tissue in an attempt to mitigate bleeding and damage, remove an undesired growth, o ...
may reduce the bleeding from telangiectasias, and is recommended before surgery is considered. However, it is highly recommended to use the least heat and time to prevent septal perforations and excessive trauma to the nasal mucosa that are already susceptible to bleeding. Sclerotherapy is another option to manage the bleeding. This process involves injecting a small amount of an aerated irritant (detergent such as sodium tetradecyl sulfate) directly into the telangiectasias. The detergent causes the vessel to collapse and harden, resulting in scar tissue residue. This is the same procedure used to treat varicose veins and similar disorders.
It may be possible to embolize
An embolism is the lodging of an embolus, a blockage-causing piece of material, inside a blood vessel. The embolus may be a blood clot (thrombus), a fat globule (fat embolism), a bubble of air or other gas (gas embolism), amniotic fluid (amnio ...
vascular lesions through interventional radiology
Interventional radiology (IR) is a medical specialty that performs various minimally-invasive procedures using medical imaging guidance, such as x-ray fluoroscopy, computed tomography, magnetic resonance imaging, or ultrasound. IR performs bo ...
; this requires passing a catheter through a large artery and locating the maxillary artery
The maxillary artery supplies deep structures of the face. It branches from the external carotid artery just deep to the neck of the mandible.
Structure
The maxillary artery, the larger of the two terminal branches of the external carotid 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.][
To more effectively minimize recurrence and severity of epistaxis, other options may be used in conjunction with therapies listed above. Intravenously administered anti-VEGF substances such as bevacizumab (brand name Avastin), pazopinab and thalidomide or its derivatives interfere with the production of new blood vessels that are weak and therefore prone to bleeding. Due to the past experiences with prescribing thalidomide to pregnant women to alleviate symptoms of nausea and the terrible birth defects that followed, thalidomide is a last resort therapy. Additionally, thalidomide can cause neuropathy. Though this can be mitigated by tinkering with dosages and prescribing its derivatives such as lenolidomide and pomalidomide, many doctors prefer alternative VEGF inhibitors. Bevacizumab has been shown to significantly reduce the severity of epistaxis without side effects.
If other interventions 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 laser.[ Skin lesions in the fingertips may sometimes bleed and cause pain. ]Skin grafting
Skin grafting, a type of graft surgery, involves the transplantation of skin. The transplanted tissue is called a skin graft.
Surgeons may use skin grafting to treat:
* extensive wounding or trauma
* burns
* areas of extensive skin loss d ...
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 (APC) is a medical endoscopic procedure used to control bleeding from certain lesions in the gastrointestinal tract. It is administered during esophagogastroduodenoscopy or colonoscopy.
Medical use
APC involves the use ...
(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 disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines i ...
) 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 or plugs. The procedure involves puncture of a large vein (usually under a general anesthetic
General anaesthetics (or anesthetics, see spelling differences) are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma ...
), followed by advancing of a catheter through the right ventricle and into the pulmonary artery
A pulmonary artery is an artery in the pulmonary circulation that carries deoxygenated blood from the right side of the heart to the lungs. The largest pulmonary artery is the ''main pulmonary artery'' or ''pulmonary trunk'' from the heart, and t ...
, after which radiocontrast
Radiocontrast agents are substances used to enhance the visibility of internal structures in X-ray-based imaging techniques such as computed tomography (contrast CT), projectional radiography, and fluoroscopy. Radiocontrast agents are typically io ...
is injected to visualize the AVMs (pulmonary angiography
Pulmonary angiography (or pulmonary arteriography,conventional pulmonary angiography, selective pulmonary angiography) is a medical fluoroscopic procedure used to visualize the pulmonary arteries and much less frequently, the pulmonary veins. It ...
). 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 is a mode of underwater diving whereby divers use breathing equipment that is completely independent of a surface air supply. The name "scuba", an acronym for "Self-Contained Underwater Breathing Apparatus", was coined by Chris ...
, during which small air bubbles may form in the bloodstream that may migrate to the brain and cause stroke. Similarly, antimicrobial prophylaxis
An antimicrobial is an agent that kills microorganisms or stops their growth. Antimicrobial medicines can be grouped according to the microorganisms they act primarily against. For example, antibiotics are used against bacteria, and antifungals ar ...
is advised during procedures in which bacteria may enter the bloodstream, such as dental work, and avoidance of air bubbles during intravenous therapy
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutri ...
.[
]
Liver AVMs
Given that liver AVMs generally cause high-output cardiac failure, the emphasis is on treating this with diuretic
A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...
s to reduce the circulating blood volume, restriction of salt and fluid intake, and antiarrhythmic agent
Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms ( tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular ta ...
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
Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...
, although the use of transjugular intrahepatic portosystemic shunt
Transjugular intrahepatic portosystemic shunt (TIPS or TIPSS) is an artificial channel within the liver that establishes communication between the inflow portal vein and the outflow hepatic vein. It is used to treat portal hypertension (which is ...
treatment is discouraged due to the lack of documented benefit.[
]
Brain AVMs
The decision to treat brain arteriovenous malformations
Arteriovenous malformation is an abnormal connection between arteries and veins, bypassing the capillary system. This vascular anomaly is widely known because of its occurrence in the central nervous system (usually cerebral AVM), but can app ...
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 aneurysm
An aneurysm is an outward bulging, likened to a bubble or balloon, caused by a localized, abnormal, weak spot on a blood vessel wall. Aneurysms may be a result of a hereditary condition or an acquired disease. Aneurysms can also be a nidus (s ...
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
A craniotomy is a surgical operation in which a bone flap is temporarily removed from the skull to access the brain. Craniotomies are often critical operations, performed on patients who are suffering from brain lesions, such as tumors, blood clot ...
, 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
Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radia ...
such as by a gamma knife
Radiosurgery is surgery using radiation, that is, the destruction of precisely selected areas of tissue using ionizing radiation rather than excision with a blade. Like other forms of radiation therapy (also called radiotherapy), it is usually u ...
) 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.[
]
Experimental treatments
Several anti-angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
drugs approved for other conditions, such as cancer, have been investigated in small clinical trials. The anti-VEGF
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...
antibody bevacizumab, for instance, has been used off-label
Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although ...
in several studies. In a large clinical trial, bevacizumab infusion was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis in treated HHT patients. Thalidomide
Thalidomide, sold under the brand names Contergan and Thalomid among others, is a medication used to treat a number of cancers (including multiple myeloma), graft-versus-host disease, and a number of skin conditions including complications of ...
, another anti-angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
drug, was also reported to have beneficial effects in HHT patients. Thalidomide treatment was found to induce vessel maturation in an experimental mouse model of HHT and to reduce the severity and frequency of nosebleeds in the majority of a small group of HHT patients. The blood hemoglobin levels of these treated patients rose as a result of reduced hemorrhage and enhanced blood vessel stabilization.
Epidemiology
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 Jura Mountains ( , , , ; french: Massif du Jura; german: Juragebirge; it, Massiccio del Giura, rm, Montagnas da Jura) are a Montane ecosystem, sub-alpine mountain range a short distance north of the Western Alps and mainly demarcate a long ...
the rate is 1:2351 - twice as common as in other populations. This has been attributed to a 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 ...
, 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
Bonaire (; , ; pap, Boneiru, , almost pronounced ) is a Dutch island in the Leeward Antilles in the Caribbean Sea. Its capital is the port of Kralendijk, on the west ( leeward) coast of the island. Aruba, Bonaire and Curaçao form the ABC i ...
and Curaçao
Curaçao ( ; ; pap, Kòrsou, ), officially the Country of Curaçao ( nl, Land Curaçao; pap, Pais Kòrsou), is a Lesser Antilles island country in the southern Caribbean Sea and the Dutch Caribbean region, about north of the Venezuela coast ...
, two islands in the Caribbean
The Caribbean (, ) ( es, El Caribe; french: la Caraïbe; ht, Karayib; nl, De Caraïben) is a region of the Americas that consists of the Caribbean Sea, its islands (some surrounded by the Caribbean Sea and some bordering both the Caribbean Se ...
belonging to the Netherlands Antilles
nl, In vrijheid verenigd"Unified by freedom"
, national_anthem =
, common_languages = Dutch English Papiamento
, demonym = Netherlands Antillean
, capital = Willemstad
, year_start = 1954
, year_end = 2010
, date_start = 15 December
, ...
.[
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 (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
.[
]
History
Several 19th century English physicians, starting with Henry Gawen Sutton (1836–1891) and followed by Benjamin Guy Babington
Benjamin Guy Babington (5 March 1794 – 8 April 1866) was an English physician and epidemiologist.
Life
He was born on 5 March 1794, the son of the physician and mineralogist William Babington (1756–1833) and his wife, Martha Elizabeth (née ...
(1794–1866) and John Wickham Legg
John Wickham Legg (28 December 1843 – 28 October 1921) was an English physician and a writer on theological subjects, especially ecclesiology and liturgy.
Life and career
He was the third son of the printer and bookseller George Legg, and ...
(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
Haemophilia, or hemophilia (), is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, ...
. The Canadian-born Sir William Osler
Sir William Osler, 1st Baronet, (; July 12, 1849 – December 29, 1919) was a Canadian physician and one of the "Big Four" founding professors of Johns Hopkins Hospital. Osler created the first residency program for specialty training of phys ...
(1849–1919), then at Johns Hopkins Hospital
The Johns Hopkins Hospital (JHH) is the teaching hospital and biomedical research facility of the Johns Hopkins School of Medicine, located in Baltimore, Maryland, U.S. It was founded in 1889 using money from a bequest of over $7 million (1873 mo ...
and later at Oxford University
Oxford () is a city in England. It is the county town and only city of Oxfordshire. In 2020, its population was estimated at 151,584. It is north-west of London, south-east of Birmingham and north-east of Bristol. The city is home to the ...
, made further contributions with a 1901 report in which he described characteristic lesions in the digestive tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans a ...
. 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 is a 957-acute care bed academic tertiary care facility located in Durham, North Carolina. Established in 1930, it is the flagship teaching hospital for the Duke University Health System, a network of physicians and hos ...
, in 1994 and 1996 respectively.[ In 2000, the international scientific advisory committee of cureHHT formerly called the HHT Foundation International published the now widely used Curaçao criteria.][ In 2006, a group of international experts met in ]Canada
Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...
and formulated an evidence-based
Evidence-based practice (EBP) is the idea that occupational practices ought to be based on scientific evidence. While seemingly obviously desirable, the proposal has been controversial, with some arguing that results may not specialize to indiv ...
guideline
A guideline is a statement by which to determine a course of action. A guideline aims to streamline particular processes according to a set routine or sound practice. Guidelines may be issued by and used by any organization (governmental or pri ...
, sponsored by cureHHT.[ This guideline has since been updated in 2020 and can be foun]
here
References
{{Good article
Diseases of arteries, arterioles and capillaries
Vascular-related cutaneous conditions
Respiratory diseases
Neurological disorders
Autosomal dominant disorders
Cell surface receptor deficiencies
Syndromes affecting the nervous system
Syndromes affecting the lung
Syndromes affecting the gastrointestinal tract