excerpted from
chapter 3 of Pulmonary
Hypertension: A Patient's Survival Guide - Third Edition
|
(WHO World Symposium on PAH Venice 2003)
[This material appeared in a larger context
in an article by Dr.
Lewis Rubin in the July 2004 Journal
of the American College of Cardiology. Used with
special permission.]
1. Pulmonary Arterial Hypertension (PAH)
1.1 Idiopathic (IPAH)
1.2 Familial (FPAH)
1.3 Associated with (APAH):
1.3.1 Collagen Vascular Disease
1.3.2 Congenital systemic to
pulmonary shunts **
1.3.3 Portal hypertension
1.3.4 HIV infection
1.3.5 Drugs & toxins
1.3.6 Other (Thyroid disorders,
Glycogen Storage Disease, Gaucher's Disease, Hereditary
Hemorrhagic Telangiectasia, Hemoglobinopathies, Myeloproliferative
Disorders, Splenectomy)
1.4 Associated with significant venous
or capillary involvement
1.4.1 Pulmonary veno-occlusive
disease (PVO)
1.4.2 Pulmonary capillary hemangiomatosis
(PCH)
1.5 Persistent pulmonary hypertension
of the Newborn
2 Pulmonary Venous Hypertension
2.1 Left-sided atrial or ventricular
heart disease
2.2 Left-sided valvular heart disease
3. Pulmonary Hypertension associated with
hypoxemia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Sleep-disordered breathing
3.4 Alveolar hypoventilation disorders
3.5 Chronic exposire to high altitude
3.6 Developmental abnormalities
4. Pulmonary Hypertension due to chronic thrombotic
and/or embolic disease
4.1 Thromboembolic obstruction of proximal
pulmonary arteries
4.2 Thromboembolic obstruction of distal
pulmonary arteries
4.3 Non-thrombotic pulmonary embolism
(tumor, parasites, foreign material)
5. Miscellaneous
Sarcoidosis, Histiocytosis X, Lymphangiomatosis, Compression
of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)
|
A new way of classifying types of PH was proposed at the World Health
Organization's World Symposium on PPH in Evian, France, in the fall
of 1998 (the classification included in the Second Edition of the
Survival Guide). These categories were further refined at the WHO
World Symposium on PAH in Venice, Italy, in 2003. It's a pain learning
new terms every couple of years. But each time, the categories make
more sense, and make it possible to speak more clearly about the
disease. Because of the "final common pathway" that the disease
often takes, many treatments for PH work for all groups in a category.
By generalizing therapies, larger pools of patients are available
for drug trials, which can speed the search for a cure. The chart
… contains the official, jargon-laden categories. Explanations in
plain English … follow….
Category Pulmonary Arterial Hypertension
(PAH)
This means high blood pressure occurs in the arteries of the lungs,
that it is not the result of pulmonary venous hypertension, hypoxemia,
or thromboembolic disease. It is also called "pre-capillary PH,"
because it is the disease of the pulmonary arteries themselves
that causes the problem, and it is not related to anything going
on downstream from the arteries (i.e., the lung air sacs, the
pulmonary veins, etc.).
1.1 Idiopathic (IPAH)
Idiopathic means unexplained, or, as some jokers put it, that
"doctors are idiots" because they don't know what causes a disease.
This is the most baffling form of PH, but the category shrinks
year by year as more causes are found. As explained earlier, it
used to be included in the category called primary pulmonary hypertension
(PPH), and some articles still use the old term. Much of the research
on "PPH" actually included patients who had FPAH, or PH triggered
by the HIV virus, anorectic diet pills, etc. IPAH looks just the
same under the microscope as FPAH (see below), and patients have
the same symptoms, the same gender ratio, and mortality rates.
Even some of the same genetic mutations appear to be involved
in both.
A small percentage of IPAH is thought to be due to DNA errors
that were not inherited, but acquired some time after birth. The
rest are called sporadic IPAH. This is the most poorly understood
type of PH. Sporadic means that the disease just popped up out
of the blue in somebody with no family history of the disease.
About 10 to 20 percent of what appears to be sporadic IPAH is
really FPAH. Because so many people who carry the FPAH gene never
develop PH, it's easy to overlook the presence of the gene in
a family. …
1.2 Familial (FPAH)
If more than one person in your family has PAH, you are said to
have "familial" FPAH. PAH is inherited in at least 6 to 10 percent
of cases. More accurately, the predisposition to PAH is inherited;
only about 20 percent of persons who inherit the genetic predisposition
actually develop the disease….
It is believed that a single gene out of the toughly 30,000 on
the human genome is responsible for most cases of inherited FPAH.
The FPAH gene was discovered in July 2000 by two independent research
teams. One team was based in Columbia University (New York, NY),
The other group included PH researchers from both the U.S. (Vanderbilt
University) and Europe; the International PPH Consortium.
The FPAH gene is on chromosome 2. It codes for a protein called
"bone morphogenetic protein receptor 2" (BMPR2). It is part of
the transforming growth factor beta (TSF-beta) family. Don't let
the name fool you: these "bone morphogenetic" proteins were first
identified as helping to regulate the growth, differentiation,
and destruction of other types of cells. BMPR2 affects the growth
and differentiation of cells that line the blood vessel of the
lungs. It does not appear to control vasodilatation or vasoconstriction.
The Columbia researchers found at least five different mutations
on the gene that may make it more likely someone will get FPAH….
1.3 PAH Associated with Other Diseases or
Things (APAH)
PAH (including IPAH and FPAH) is strongly associated with various
autoimmune diseases. An autoimmune disease happens when something
causes your immune system to make antibodies that attack your
body's own normal tissues. …
1.3.1 Connective Tissue Disease (a.k.a.
Collagen Vascular Disease)
Collagen is the strong fibrous stuff found in connective tissue.
Connective tissue, as its name implies, connects and supports
parts of the body. It is usually dense with blood vessels. This
group of immunologic, rheumatic diseases includes scleroderma,
CREST syndrome, rheymatoid arthritis, systemic lupus erythematous
(SLE), vasculitis, and mixed connective-tissue disease. …
1.3.2 Congenital Heart & Lung Disease
"Congenital" means something you're born with. Doctors think faulty
genes interacting with things in the womb environment might cause
congenital defects. The environmental factor often can't be identified.
These problems can be complex, and it is important to get an exact
diagnosis. The good news is that, along with standard PH treatment
medicines, there are often surgical treatment options not available
to other PH patients. Some congenital problems can now be corrected
in infancy or even while the fetus is still in the uterus, which
greatly reduces the chances of getting PH. ..
1.3.3 Portopulmonary Hypertension
The liver is a wonderful machine - part sewage treatment plant,
part factory - and it's practically maintenance free. Blood flows
through the big portal vein that goes from your intestines to
your liver. Inside the liver, poisons, other waste materials,
and some drugs are removed, and yummy proteins are manufactured.
But if liver disease causes obstructions in the liver, then the
blood pressure in the portal vein rises. When this high pressure
is found in association with PH, the syndrome is called portopulmonary
hypertension (we'll call it "portoPH").
The lungs are downstream from the liver. In portoPH, blood that
normally goes through the liver before going to the lungs ends
up going directly to the lungs, injuring the pulmonary arteries.
Even the experts are still baffled by exactly how liver disease,
portal hypertension, and the pulmonary circulation relate to one
another…
1.3.4 HIV Infection
If you are infected with the human immunodeficiency virus (HIV),
you have an increased risk of developing PAH, even if you haven't
developed AIDS. (In Paris, nearly a third of the HIV/PAH patients
don't have symptoms of AIDS.) Still, only a very few people with
an HIV infection ever develop PH; a genetic trait might influence
which persons do.
By the year 2000, over 131 persons infected with HIV had been
found who also had PH. Now that people with HIV are living longer,
more are developing PH. The time between diagnosis of HIV infection
and the diagnosis of PPH ranges from 0 to 9 years; a survey in
2000 found the mean interval to be 33 months. The median time
from diagnosis to death was six months. Most deaths of HIV / PH
patients are due to the PH. A look at the genes fo 19 patients
with HIV/PH found no germ cell mutations of the "PH gene" that
might have made them vulnerable to the disease.
Scientists aren't sure why HIV infection triggers PH. Perhaps
it does so indirectly, through recurrent respiratory disease.
)This is an argument for the aggressive treatment of such opportunistic
infections.) Or the HIV virus might cause higher levels of platelet-derived
growth factor (a substance that can cause smooth muscle cells
and fibroblasts to grow and migrate) or some other growth factor.
It is also conceivable that the HIV virus itself acts directly
on pulmonary endothelial or smooth muscle cells. (If this is so,
might not other viruses trigger PH in some persons?) Or, because
fo weakened immune systems, HIV patients might be more likely
to catch another virus (such as a herpesvirus or cytomegalovirus)
that, in turn, injures the vessels and causes PH.
1.3.5 Drugs & Toxins
At the 1998 WHO Evian World Symposium on PPH a consensus, of sorts,
was reached on which drugs and toxins might be linked to the onset
of PAH. Not all doctors and researchers agree on all of these.
One noted researcher, for example, suspects a link between oral
contraceptives and estrogen replacement therapy that she would
like to see investigated more thoroughly. Here is a summary of
the consensus:
Definitive link to PAH: aminorex (European diet
pills), fenfluramine, dexfenfluramine, toxic rapeseed oil. (Basic
at least one major controlled study or epidemic.)
Very likely link: amphetamines, a contamination of some
L-tryptophan. (Basis: several large case series and studies not
attributable to considered biases, or a general consensus among
experts.) [A "case series" or "case control study" is a paper
that describes several patients rather than just one, and that
compares the PH patients to healthy controls who are otherwise
similar to them.]
Possible link: methamphetamines, cocaine, and chemotherapeutic
agents. (mitomycin-C, carmustine, etoposide, and cyclophosphamide).
(Basis: an association based on case control studies, registries,
or expert opinions.)
Unlikely to be linked: anti-depressants, birth control
pills, estrogen therapy, cigarette smoking. (Basis: risk factors
that have been proposed byt not yet found to have any association
from controlled studies.) [While cigarette smoking is not directly
linked to PH, it is indirectly linked because it causes emphysema
and bronchitis that can, in turn, trigger PH.]…
1.3.6 Other (Thyroid Disorders, Glycogen
Storage Disease, Gaucher's Disease, Hemorrhagic Telangiecctasia,
Hemoglobinopathies, Myeloproliferative Disorders, Splenectomy)
The author regrets the doctors' failure to invite her to the 2003
WHO symposium. She has always wanted to ride in a gondola. Because
of the tardy dissemination of the new classifications, she was
unable to thoroughly research the link between Gaucher's Disease,
Glycogen Storage Disease, and the Hemoglobinopathies (other than
sickle cell) and PH.
Sickle Cell Disease. (This condition might also be put
under category 4.3, below - there really isn't a consensus yet.)
Millions of people around the world, primarily those with roots
in Africa, the Mediterranean, or India, suffer from this inherited
disease. It is through to affect 80,000 or so people in the U.S.
…
Sickle cell patients with PH are in real trouble: less than two
years after being diagnosed with PH, up to 40 percent have died.
PH/sickle cell patients might have mean PAPs that suggest only
mild PH and still be in danger….
Thyroid disorders. A retrospective record review of 41
"PPH" patients done by the Cleveland Clinic Foundation, Ohio,
and published in 1999, found a much higher rate (22.5 percent)
of hypothyroidism (when the thyroid gland produces too little
hormone) than is found in the general population….
Myelofibrosis. It is not known what causes this disease,
in which blood cells in the bone marrow are replaced with fibrous
tissue. Oddly shaped red blood cells, anemia, and enlarged spleens
result. …
Gaucher's Disease. People with this disease have difficulties
metabolizing fat, and products of fat metabolism called glucoverebrosides
accumulate in tissues. It's most common in eastern European Jews,
and leads to an enlarged liver and spleen and bone abnormalities.
Hereditary Hemorrhagive Telangiectasia. Also called Rendu-Osler-Weber
disease, malformed blood vessels are really fragile and prone
to leaking. When vessels under the skin on the face break, bruise-like
discolorations occur. It might be that the structure of the air
saves if affected, causing some interstitial lung disease (if
this proves to be the case, this condition really belongs in category
3, below, which covers PH triggered by hypoxemia).
Splenectomy. A German study found that persons who had
had their spleens removed were more likely than others to develop
IPAH. Some speculate that this might be due to the loss of the
spleen's role in filtering out old platelets; patients with very
high platelet counts have an increased risk of PH.
1.4 Associated with Significant Venous or
Capillary Involvement
1.4.1 Pulmonary veno-Occlusive Disease (Clogging
of Pulmonary Veins)
Sometimes the pulmonary veins get clogged from the inside by fibrous
material. This is called veno-occlusive disease (PVOD). The cause
is unknown. PVOD is about 10 times less frequent than IPAH/FPAH,
which makes it a really rare disease. A lung biopsy is the best
way to find out if you have it, but suck biopsies are dangerous
for PH patients and may delay the only presently known remedy,
lung transplantation. A biopsy might possibly be necessary to
distinguish PVOD from interstitial lung disease, for which there
are treatments other than transplant. Clubbing of fingers might
be present in PVOD.
Although tumors usually create problems be pressing on pulmonary
veins, sometimes they invade the veins as well (lung cancer is
usually involved). And this can lead to PH.
1.4.2 Pulmonary Capillary Hemangiomatosis
Many benign vascular tumors can form on pulmonary capillaries,
blocking the blood flow and causing pressures to rise in pulmonary
arteries. This type of PH is rare. Researchers in Barcelona, Spain,
scanned the literature and identified 35 cases. Chest x-rays and
CAT scans will usually show signs of these blockages, but they
look a lot like veno-occlusive disease/PH. This si one of those
rare situations where a pulmonary biopsy might be needed to find
out what's really going on, but such biopsies are dangerous for
PH patients, and might unnecessarily delay lung transplantation.
There is not yet an accepted drug treatment for this type of PH
(prostanoids are not helpful; interferon has been tried, but still
lacks a promising track record).
1.5 Persistent Pulmonary Hypertension of
the Newborn (PPHN)
See Chapter 8, Children and PH.
Category 2: Pulmonary Venous Hypertension
Hypertension in the veins of the lungs - after the blood has passed
by the air sacs.
2.1 Left-Sided Atrial or Ventricular heart
Disease
Various left-heart problems that develop after birth can dam up
blood flow and cause back pressure in the lungs, triggering mild
increase in the thickness fo pulmonary veins (although the veins
themselves are passive in this process), This is the sequence
fo events: left ventricular diastolic pressure (and/or left atrial
pressure increases, which leads to an increase in pulmonary vein
pressure, which leads to an increase in pulmonary artery pressure.
If this causes the tiny arteries to constrict, pulmonary artery
pressure goes way up (as does right ventricular pressure, which
reflects the PAP).
When a left-heart problem can be corrected, it usually resolves
the PH….
2.2 Left-Sided Valvular Heart Disease
Heart valves, particularly the mitral valve, may not work well.
For examples, mitral stenosis, a narrowing of the mitral valve,
is common in patients who had rheumatic fever….
Category 3: PH Associated with Hypoxemia
3.1 Chronic Obstructive Pulmonary Disease
(COPD)
Diseases that block the airways of the lungs include chronic bronchitis,
emphysema, and asthma. You can have more than one of these diseases
at the same time. Ay people have one or more of these diseases
are said to have COPD. Over 16 million people in the U.S. have
COPD, and in some of them it will lead to hypoxemia …and to PH.
Long-term cigarette smoking (and age) account for 85 percent of
the risk of getting COPD…
Cystic fibrosis is an inherited disease that occurs most
often (but not exclusively) in white people. It affects several
body systems and can manifest itself as COPD, bronchiectasis…,
bronchitis, respiratory failure, etc. PH develops in a significant
portion of cystic fibrosis patients who have too little oxygen
in their blood, but it is usually mild.
3.2 Interstitial Lung Disease
"Interstitial" refers to the spaces between the individual air
sacs (alveoli) in the lungs. This is a sprawling family of roughly
180 types of disease caused by breathing in various substances.
They all involve an inflammation of the walls of the lower respiratory
tract and problems with the walls of the air spaces in the lungs.
(Sometimes these diseases are lumped in with COPD.) Interstitial
lung diseases are chronic, noninfectious, and nonmalignant. Patients
with these diseases are short of breath and might sometimes develop
PH. Sometimes the cause of the interstitial lung disease isn't
known, so it's called idiopathic pulmonary fibrosis….
3.3 Sleep Disordered Breathing
About 12 million Americans have sleep apnea: they stop breathing
several or many times an hour while they sleep. This disease wasn't
well known until recently, and most people who have it are unaware
that they do. There is much more to be learned about sleep apnea.
…
To be classified as having sleep apnea you generally have to
stop breathing for at least 10 seconds at least 30 times in a
70-hour period (and often over 100 times in an hour!). The condition
is found most frequently in very heavy middle-aged men who snore,
but it is certainly not limited to them….
If you don't breathe often enough, you don't maintain enough
oxygen in your blood (the saturation falls below 90 percent for
a significant time). This lack of oxygen can cause pulmonary vasoconstriction
…and a resulting rise in PAPs.
Those who have the most common kind of sleep apnea, obstructive
sleep apnea, keep trying to breathe but can't pull in enough air
because of a blockage in the upper airway….
3.4 Alveolar Hypoventialtion Disorders &
Hyposemia
Alveiolar hypovenitation happens when there is not enough air
exchange in the small lung sacs. This is usually due to mechanical
or neurological problems involving muscles, nerces, ro the brain….
When there is not enough fresh air in the lungs, too little oxygen
is available to be taken into the blood, and hypoxemia results.
Sensing this lack of oxygen, the pulmonary arteries tighten up
in their effort to direct blood to other places, where there might
be more oxygen. Hypoxemia is a potent vasoconstrictor; vasoconstriction
might eventually lead to PH….
3.5 Living Too High: Altitude & PH
A lack of oxygen in the air you are breathing (hypoxia) can also
cause hypoxemia. As is the case with alveolar hypotension, your
pulmonary arteries tighten up in their effort to direct blood
to places where there might be oxygen. Living at a high altitude
is one reason for hypoxia.
Three highs that can make you low: elevation, temperature, and
humidity. As you climb above sea level, the air pressure drops
as the air thins, resulting in less available oxygen for your
lungs to absorb. The higher the elevation, the more likely you
are to get hypoxic vasoconstriction….
High temperatures and high humidity also thin out the air….Of
the three (altitude, temperature, and humidity), humidity is the
least important to us. Really dry air can also be hard on lungs.
Symptoms of hypoxia include impairment of vision, euphoria, lightheadedness,
breathlessness, hot and cold flashes, reasoning difficulties (like
repetitive thought patterns), headache, slowed motor responses,
tingling fingers and toes, increased perspiration, nausea, vomiting,
and finally unconsciousness.
Be alert for such symptoms (okay, it's hard to be alert for unconsciousness,
but pay attention to the others) when you are flying on commercial
airliners, which are engineered to provide a cabin pressure of
at least the equivalent of 8,000 feel above sea level (in practices,
airlines usually do better than that, and pressurize to the equivalent
of 5,000 to 7,000 feet).
The low-pressure situation on airplanes is made worse by pollutants
and high levels of carbon dioxide in recirculated cabin air. Airplanes
that fly at high altitudes always carry emergency supplemental
oxygen: ask for it if you need it. (For ho to get oxygen on airplanes,
see Chapter 10.)
Category 4: PH Due to Chronic Thrombotic and/or
Embolic Disease
The PH in this category is caused by clots and other obstructions
in the lungs.
An embolus is a clump of something (even air bubbles), that has
plugged up a blood vessel. An embolism is the blockage of a vessel
by an embolus. In our case, it's usually a blood clot that has
formed somewhere else and traveled ot the lungs. A thrombus is
a fibrinous blood clot that obstructs a blood vessel. Both emboli
and thrombi can be thought of as clots. Clots probably cause around
10 percent of all cases of PH.
Nearly always, blood clots dissolve on their own, and if you
survive the original event, you need not worry about PH. If clots
do no dissolve, but persist for years and cause PH, and if they
are big enough and lodged in the larger vessels, they can often
be removed by a procedure called a pulmonary thromboendarterectomy
(see Chapter 6), so it can be good news to learn that this is
your problem.
4.1 Thromboembolic Obstruction of Proximal
Pulmonary Arteries
This category deals with clots that generally are found in medium
to small-sized arteries, but that can occur in other arteries
as well.
Clots usually form in a leg vein and travel to the lungs, where
they sometimes become wedged. Each year, about 500 to 2,500 patients
in the U.S who previously survived an acute pulmonary embolism
event, but have a volt still in their lungs, go on to develop
chronic thromboembolic PH (CTEPH). Although a big majority of
PH patients are female, slightly more men than women develop CTEPH….
Because it's possible to have a pulmonary embolism without knowing
it, or without knowing that a clot has remained, the clots often
work in secret until the PH process is well underway. After a
clot lodges in the lungs and grows into the wall of a vessel,
there may be a honeymoon period that lasts months or even decades
before PH symptoms appear and you are diagnosed….
4.2 Thromboembolic Ovstruction of Distal
Pulmonary Arteries
Sometimes very tiny clots form right in place (in situ) inside
the tiny arteries …in the lungs. This occurs in patients who already
have severe PH. Not much is known about whether tiny clots do
or do not tend to dissolve on their own. They cannot be removed
by surgery, so we take anticoagulants to prevent them from forming.
The data is still murky, but researchers believe that PH gets
worse over time even if no tiny clots are involved and that in
situ clots don't play a starring role in the progression of PH.
4.3 Non-Thrombotic Pulmonary Embolism (Tumor,
Parasites, Foreign Material)
Even small amounts of cancer can cause clots. Tumors arising from
glandular organs are particularly likely to cause clots. Small
fragments of tumors can also break off, travel,an block blood
vessels in the lungs. Or lung cancer can directly affect the small
vessels.
Schistosomiasis. Hundreds of millions of people, especially
in Asia, Africa, and South America, suffer from this parasitic
disease caused by blood flukes living in the blood vessels of
internal organs. Although this disease is seldom seen in the U.S.,
on a worldwide basis, it is one of the most common causes of PH.
It can cause PH either by causing portal hypertension (which,
in turn, leads to PH), or by fluke eggs blocking blood vessels
in the lungs and causing fibrosis.
Behcet's Disease. Behcet's disease is found mostly (but
far from exclusively) in the Turkish population. It attacks the
small vessels that provide the walls of larger vessels with blood.
Nearly every organ can be involved. In the lung vessels of these
patients, thrombotic and "inflammatory" changes lead to PH. (Symptoms
of Behcet's include recurrent canker sore-like ulcers in the mouth
and on the genitals, and eye inflammation. Behcet's can involve
any organ and can affect the central nervous system. Skin lesions,
arthritis, bowel inflammation, meningitis, and cranial nerve palsies
are other possible symptoms.)
Category 5: Miscellaneous
As in Category 4, this category involves some things that cause
PH by directly blocking the flow of blood through pulmonary vessels.
Pressures build up behind the blockage and this can lead to PH.
Schistosomiasis and sarcoidosis also involve inflammation….
