Cyberfriends: The help you're looking for is probably here.

Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.

DoctorGeorge.com is a larger, full-time service. There is also a fee site at www.afraidtoask.com.

If you have a Second Life account, please visit my teammates and me at the Medical Examiner's office.

With one of four large boxes of "Pathguy" replies.

I'm still doing my best to answer everybody. Sometimes I get backlogged, sometimes my E-mail crashes, and sometimes my literature search software crashes. If you've not heard from me in a week, post me again. I send my most challenging questions to the medical student pathology interest group, minus the name, but with your E-mail where you can receive a reply.

Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource. Someday you may be able to access these pictures directly from this page.

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Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles that you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Clinical Queries -- PubMed from the National Institutes of Health. Take your questions here first.
HealthWorld
Yahoo! Medline lists other sites that may work well for you

Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review linked below. If you are interested in complementary medicine, then I would urge you to visit my new Alternative Medicine page. If you are looking for something on complementary medicine, please go first to the American Association of Naturopathic Physicians. And for your enjoyment... here are some of my old pathology exams for medical school undergraduates.

I cannot examine every claim that my correspondents share with me. Sometimes the independent thinkers prove to be correct, and paradigms shift as a result. You also know that extraordinary claims require extraordinary evidence. When a discovery proves to square with the observable world, scientists make reputations by confirming it, and corporations are soon making profits from it. When a decades-old claim by a "persecuted genius" finds no acceptance from mainstream science, it probably failed some basic experimental tests designed to eliminate self-deception. If you ask me about something like this, I will simply invite you to do some tests yourself, perhaps as a high-school science project. Who knows? Perhaps it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship by suspending their own reasoning and simply accepting a single authority that seems wise and good. I've learned that they leave the movements when, and only when, they discover they have been maliciously deceived. In the meantime, nothing that I can say or do will convince such people that I am a decent human being. I no longer answer my crank mail.

This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.

This page was last updated February 9, 2008.

During the thirteen years my site has been online, it's proved to be one of the most popular of all internet sites for undergraduate physician and allied-health education. It is so well-known that I'm not worried about borrowers. I never refuse requests from colleagues for permission to adapt or duplicate it for their own courses... and many do. So, fellow-teachers, help yourselves. Don't sell it for a profit, don't use it for a bad purpose, and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about your successes. And special thanks to everyone who's helped and encouraged me, and especially the people at KCUMB for making it possible, and my teaching assistants over the years.

Whatever you're looking for on the web, I hope you find it, here or elsewhere. Health and friendship!

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Search ANY word  Search ALL words  Search EXACT phrase    Help

Chest wall problems

structural... THE CHEST DEFORMITIES

neuromuscular...THE PARALYSIS & WEAKNESS SYNDROMES

Obstructed upper airway

structural... QUINSY ("PERITONSILLAR ABSCESS"); CROUP ("LTB"")

functional...THE SLEEP APNEAS

Obstructed large bronchi

all, subtotal... CHRONIC BRONCHITIS

one, total... OBSTRUCTIVE ATELECTASIS; ENDOGENOUS LIPID PNEUMONIA

Constricted small bronchi

mast-cell / inflammation mediated... THE ASTHMAS

platelet-mediated... PULMONARY EMBOLUS

apudoma products... CARCINOID SYNDROME

dense collagen... SOME CHRONIC BRONCHITIS VARIANTS

Fibrotic respiratory bronchioles... SILICOSIS

Collapsed respiratory bronchioles... EMPHYSEMA/"CHRONIC BRONCHITIS"

Fluid-filled alveolar spaces

transudate... ALVEOLAR PULMONARY EDEMA

exudate & pus... THE PNEUMONIAS

exudate, fibrin, debris... THE RESPIRATORY DISTRESS SYNDROMES

surfactant... ALVEOLAR LIPOPROTEINOSIS; ENDOGENOUS LIPID PNEUMONIAS

other lipid... EXOGENOUS LIPID PNEUMONIAS

blood... GOODPASTURE'S DISEASE; ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY DISEASES, ACUTE MOUNTAIN SICKNESS, OTHER PULMONARY BLEED SYNDROMES

organisms alone... PNEUMOCYSTOSIS, CRYPTOCOCCOSIS

Fluid-filled alveolar septa

transudate... INTERSTITIAL PULMONARY EDEMA

exudate...THE PNEUMONITIS FAMILY; VIRUSES; MYCOPLASMA

Fibrosis around ulcerated bronchi...BRONCHIECTASIS

Fibrosis of alveolar septa

slow... THE INTERSTITIAL RESTRICTIVE LUNG DISEASES; (Hamman-Rich, rheumatoid lung, sarcoid, asbestosis, many others)

fast... THE RESPIRATORY DISTRESS SYNDROMES

Collapsed alveoli

extrapulmonary disease... COMPRESSIVE ATELECTASIS

large-airway disease... OBSTRUCTIVE ATELECTASIS

alveolar disease... THE RESPIRATORY DISTRESS SYNDROMES

ischemia... PULMONARY EMBOLUS, SEVERE SHOCK

Necrotic lung ("cavities", etc.)

infarction... PULMONARY EMBOLUS (COMPLICATED)

suppurative... NECROTIZING PNEUMONIAS; LUNG ABSCESS

caseous... TUBERCULOSIS, HISTOPLASMOSIS, BLASTOMYCOSIS, COCCIDIOIDOMYCOSIS

weird immune... WEGENER'S GRANULOMATOSIS

malignant... LUNG CANCER

Pulmonary Hypertension

secondary to low alveolar oxygen... see above; also MOUNTAIN DWELLERS

secondary to alveolar fibrosis... see above

Left-to-right shunts / Eisenmenger's

primary... PULMONARY EMBOLUS; VASCULITIS; IDIOPATHIC

High P_aCO₂... all whole-lung ventilation problems

Low PO₂...

all whole-lung ventilation problems

perfusing non-ventilated lung

fluid/fibrosis in alveolar septa

MOUNTAIN DWELLERS

STUDY OBJECTIVES

Describe the essential gross and microscopic anatomy of the airways, from trachea to alveolar sacs. Distinguish the two principal types of pneumocytes (I and II). Describe the anatomic and functional barrier to gas exchange at the alveolar-capillary level.

Describe the factors that influence P_aCO₂ and P_aO₂. Describe how P_aO₂ correlates with the actual oxygen content of the blood. Give the conditions when cyanosis will appear.

List the principal causes of edema in the lung, and compare these to things that cause edema anywhere else in the body. Distinguish interstitial and alveolar edema. Explain why edema of the lung is bad for one's health.

Describe pulmonary congestion, and mention its pathologic sequelae.

Review the pathology and pathophysiology of pulmonary thromboemboli. Describe their frequency and clinical correlations.

List the common causes of increased resistance in the pulmonary arteries (the usual cause of "pulmonary hypertension"), and other causes of pulmonary hypertension. Explain why these things are so harmful. Explain hypoxic pulmonary vasoconstriction, why it is useful in health, and why it is such a problem in disease.

Define acute / adult respiratory distress syndrome and list a few of the many synonyms. Tell about the etiologies, gross and microscopic pathology, the pathophysiology, and the common clinical picture.

Explain the pathophysiology and clinical correlations of neonatal respiratory distress syndrome.

Define atelectasis. Tell how lung collapses due to obstruction, compression, and lack of surfactant, and give clinical examples of each situation.

Define "sudden infant death syndrome". Briefly describe what we think causes genuine "SIDS", and give a "differential diagnosis".

* Review how to order "arterial blood gases", what you get, and what they tell you. (Be able to do this at 3 AM as the only doctor on the ward.) This might be a good time to look at the Blood Gases" handout.

Describe the abnormal anatomy and functional problems that every cigaret smoker should expect.

Explain the importance of elastic recoil in keeping respiratory bronchioles patent during exhalation. Explain how this relates to the classic definition of emphysema as "an abnormal, permanent dilatation of part of all of the acinus, with destruction of alveolar walls."

Distinguish the two "classic" types of emphysema, and mention their alleged causes. Tell what we think causes emphysema in cigaret smokers and alpha-1 antitrypsin deficient patients. Tell what a "pink puffer" looks like clinically, and how emphysematous lungs look at autopsy. Describe the complication of "bullous emphysema".

Define "chronic bronchitis" and mention its common causes. Describe the gross and microscopic pathology and the pathophysiology. Be able to define the "Reid Index". Tell what a "blue bloater" looks like clinically, and mention the common organisms that superinfect these patients' lungs.

Define bronchial asthma. Describe its important causes, and distinguish "allergic" and "idiosyncratic" kinds. Describe the common pathophysiology. Tell what you will see at the autopsy of an asthmatic. Mention other causes of wheezing.

Define bronchiectasis. Describe the important causes, the abnormal anatomy, and the typical clinical picture.

Describe the various breathing problems that occur during sleep. Recognize sleep apnea as a common cause of several illnesses.

Describe the normal flora of the lungs in non-smokers and smokers, and recognize the range of micro-organisms that have caused lung infections. Recognize the tremendous clinical importance of lung infections.

Distinguish bronchopneumonia, lobar pneumonia, and pneumonitis. Describe the typical histopathology of lung infections caused by various agents.

List the etiologic agents of lobar pneumonia, the classic stages in its progression, the major complications, and those at risk for each form.

Describe the causes, underlying problems, pathophysiology, and morbid anatomy of bronchopneumonia, aspiration pneumonia, legionellosis, pneumocystosis, lung abscess, and viral and mycoplasmal pneumonias. Describe the distinctive features of hantavirus infection and SARS (the 2003 epidemic).

Describe the anatomic pathology, pathophysiology, and clinical picture of the "idiopathic pulmonary fibrosis" family of diseases. Identify "Hamman-Rich" syndrome, and mention its likely cause.

Define sarcoidosis, and describe a typical sarcoidosis patient. Explain the usual effects of sarcoidosis on the lungs, skin, and eyes. Mention the serious consequences of untreated sarcoidosis. Describe the histology, and give a differential diagnosis for a granuloma found on biopsy. Explain how sarcoidosis causes abnormalities of calcium metabolism. Recognize the Kveim test as of limited usefulness. Tell how to make the diagnosis of sarcoidosis, and how to treat sarcoid patients.

Explain the essential lesion of Goodpasture's disease involving the lung, and mention the clinical picture and diagnostic lab test, and essential treatment. Mention some "related" (?) causes of bleeding from the pulmonary alveoli.

Briefly describe the eosinophilic pneumonias, and the various lipid pneumonias and lipoproteinosis, focusing on their histopathology.

Give the numbers of new cases of lung cancer in U.S. men and women expected this year. Explain how rates are changing, and why. Describe the risk factors for lung cancer, mentioning the importance of cigaret smoking, industrial exposure, radon in the home, and indoor air pollution.

Explain how and why pathologists subclassify lung cancers. Recognize each of the nine members of the WHO-1999 classification:

• squamous cell carcinoma


• adenocarcinoma


• bronchioloalveolar carcinoma


• large-cell undifferentiated carcinoma


• small-cell ("oat cell") carcinoma


• carcinoid


• atypical carcinoid


• intermediate ("large cell") neuroendocrine carcinoma


• malignant lymphoma

Describe the important distinctions among the various types. Identify the common lung cancers under the microscope. Explain how pathologists use each of these to distinguish primary lung tumors:

• electron microscopy for neurosecretory granules (small-cell, carcinoids, atypical carcinoids, and intermediate neuroectodermal tumors positive)
• mucicarmine (many adenocarcinomas and bronchioloalveolars positive, others negative)
• immunoperoxidase for common leukocyte antigen (lymphomas positive, all others negative)
• immunoperoxidase for epithelial membrane antigen (lymphomas negative, all carcinomas positive)
• immunoperoxidase for chromogranin (typical carcinoid and atypical carcinoid positive, most large-cell neuroendocrines and oat-cells positive )
• immunoperoxidase for erbB product (adenocarcinomas, large-cell, squamous-cell positive; oat cell negative)
• immunoperoxidase for neuron-specific enolase (oat-cell, typical and atypical carcinoids, neuroendocrine CA positive)

Tell how bronchogenic carcinomas present. Describe the various paraneoplastic syndromes seen with lung cancer, especially the hypercalcemia syndromes and the small cell undifferentiated carcinoma syndromes.

Identify bronchial carcinoid, tell how it looks grossly and microscopically, how to recognize it, and describe its origin and its variants.

List the common problems that affect the larynx or trachea. List the different kinds of pleural effusions, and tell the significance of each. Describe the various kinds of pneumothorax and why they are important. Tell how pleural plaques look and what causes them.

Identify the cell of origin, risk factor, gross and microscopic appearance, and prognosis for malignant mesothelioma.

Mention the basic biology of ciliary dyskinesia syndromes, tell when you would suspect one, and how you would verify it.

As usual, given a gross lung or larynx, or a biopsy of any level of the respiratory tract, recognize any of the lesions exhibited in this section with at least 70% accuracy.

Healthy lungs Freshly-opened at autopsy WebPath

Healthy lung Formalin-inflated WebPath

Pulmonary surface lymphatics A bit accentuated due to pulmonary edema WebPath

Healthy lung Photomicrograph WebPath

Life is not measured by the number of breaths you take, but by the number of moments that take your breath away.

-- Attributed to George Carlin

* Click here for Dr. Karius's scheme for normal respiration. You must know this perfectly if you are going to be able to make sense out of lung pathology. Thanks Diane!

All about the uvula. A human's is much bigger than any other mammal's, and the uvula's job is probably to keep us from getting hoarse while talking (amazing, Yearbook of Path 1994, p. 97 describes its anatomy).

Review the gross anatomy of the respiratory system, and the general histology of a bronchus.

Bronchi are usually defined to be the airways with cartilage and/or complex glands (precise usage varies). The orders of bronchi end in membranous bronchioles.

* Future pathologists: Histopathology of the bronchioles. Am. J. Clin. Path. 101: 109, 1998.

The bronchioles divide further, leading to the terminal bronchioles, the last division with a continuous non-simple-squamous epithelium (which by this time is probably more likely to be made out of simple-columnar, Clara-cell rich epithelium).

Remember the importance of the mucociliary elevator provided by this epithelium. The cilia are supposed to be extremely easy to damage and hard to recover, but they almost always are present in my autopsies, even on people who have been very sick for a very long time.

The portion of lung parenchyma supplied by one terminal bronchiole is called an acinus ("respiratory unit", diameter about 7 mm).

From the terminal bronchiole arise several orders of respiratory bronchioles, which have part of their walls alveolated and part with pseudostratified respiratory epithelium. These in turn give rise to alveolar ducts and then atria. The alveoli themselves are wide-mouthed sacs that open into all three of these divisions.

Remember that the elastic recoil of the surrounding lung tissue is what keeps the respiratory bronchioles from collapsing when a person starts to exhale.

Schematic diagram of the alveolar wall:



* Look closely. Did you know that the "thin" side has fused basement membranes, the "thick" side with more collagen has them separate?

type I pneumocytes: simple squamous, stretchy, permeable to O₂ and CO₂, easily injured, do not divide

type II pneumocytes: reserve cells; cuboidal, granular cytoplasm, produce and process surfactant ("lamellar bodies" in the cytoplasm), divide and flatten to become new type I pneumocytes.

* In health, look for them at the corners of alveoli (hence "corner cells").

The interstitium contains a few fibroblasts, smooth muscle cells, collagen, elastin.

There are probably no lymphatics in the respiratory membranes themselves, but there are many lymphatics in the fibrous septa between groups of alveoli.

Contrast the alveolar epithelium with that of the bronchi and bronchioles, which includes ciliated, goblet, reserve (basal), Kulchitsky ("K-"), Clara , and other types of cells.

* Future pathologists: Clara cells have a typical sort of dense granule on electron microscopy. Type II pneumocytes contain lamellar spirals that represent surfactant. Kulchitsky cells have neuronal-type granules.

Macrophages in the alveoli spaces ("alveolar macrophages") and in the septa ("interstitial macrophages") eat surfactant and most anything else that comes along, in addition to modulating the immune response locally.

Traditionally we've taught that these cells are monocyte-derived, but they undergo mitosis in various sorts of lung injury.

Remember that the lung receives a dual blood supply, from the pulmonary and bronchial arteries. The bronchial arterial supply is one of the first to stop in low-output states (left heart failure, shock; why?)

Bronchial lymphoid tissue (BALT) shouldn't be present until a baby is a few months old. Lymphocyte clusters in a newborn's large airways means infection. Smokers have much more "BALT" than do non-smokers.

Remember blood P_aCO₂ is almost entirely a function of overall alveolar ventilation.

Remember blood P_aO₂ is a function of the quality of ventilation-perfusion matching, alveolar septal thickening (if excessive), and overall ventilation. And remember that lung structures are generally much less permeable to O₂ than to CO₂ (a fact that becomes important only in disease.)

Don't forget either that blood with P_aO₂ of 65 torr is carrying almost as much oxygen as blood with P_aO₂ of 100 torr or higher, because most oxygen is bound to hemoglobin (recall the hemoglobin-oxygen dissociation curve....) It's when P_aO₂ drops to around 60 that you start getting into trouble, because the hemoglobin stops binding oxygen as well as it should.

Cyanosis appears when the arterial blood contains 5 gm % or more of unoxygenated hemoglobin.

All of the first group of diseases on the handout (except pulmonary thromboemboli) are patterns of lung injury, each of which has many different causes.

PULMONARY CONGESTION AND EDEMA

{37956} pulmonary edema gestalt

Pulmonary edema classically results from the same factors that cause edema in the rest of the body. These are:

1. Increased venous hydrostatic pressure (left-sided heart failure)

2. Fluid overload (renal failure, iatrogenic, etc.)

3. Decreased albumin in the blood (liver disease, nephrotic syndrome, poor nutrition, etc.)

4. Lymphatic obstruction (cancer, etc.)

5. Endothelial damage (i.e., the pneumonias; most striking is the hantavirus that first struck in the US southwest; also remember poisons, especially phosgene)

6. Getting strangled / physically asphyxiated (negative pressure)

You have to learn these causes of pulmonary edema for which the mechanisms are not well understood:

7. Acute CNS injury

8. Opiate overdose

9. Exposure to high altitudes (unacclimatized people) The fluid is an exudate with some red cells. The conventional wisdom is that the veins as well as the arteries participate in the hypoxic pulmonary vasoconstriction response, and that the much-increased blood pressure in the lung capillaries forces fluid out of them and causes some of them to burst. This is consistent with the results of lavage studies (JAMA 287: 2228, 2002). However, this can't be the full story, because of the pharmacology (Br. Med. J. 321: 267, 2000). Dexamethasone (the familiar glucocorticoid) apparently prevents acute hypoxia from making endothelial cells more permeable, while how acetazolamide (a carbonic anhydrase inhibitor) works is anybody's guess. The finding that a beta-agonist helps is attributed to increased active transport of sodium from the alveolar fluid into the bloodstream (NEJM 346: 1631, 2002).

* The roles of various mediators are being worked out (endothelin 1: Circulation 99: 2665, 1999), and the whole business remains rather puzzling (see for example Lancet 357: 1342, 2001.)

* Populations that inhabit high mountains seem to survive only by making huge amounts of nitric oxide, which you can measure on their breath. See Nature 414: 411, 2001. Natural selection or physiologic adaptation? We don't yet know. It's finally documented that mountain dwellers have greatly expanded chest cavities: Resp. Phys. Neuro. 132: 223, 2002.

In each case, when the capacity of the lymphatics to drain the interstitial fluid is exceeded, interstitial edema develops, with loss of lung compliance and a barrier to oxygen exchange (alveolar-capillary block.)

As the interstitial pressure rises still further, the tight junctions between the alveolar epithelial cells open and fluid pours into the alveolar spaces, causing alveolar edema and stopping ventilation.

Alveolar edema fluid is a good culture medium for bacteria. Secondary pneumonia is common.

When you hear crackles (rales) through your stethoscope, you're hearing the little air bubbles in the alveoli. Your patient has alveolar pulmonary edema, and you must figure out why.

{10145} pulmonary edema (just enough protein content to stain...)
{11666} pulmonary edema

Pulmonary Edema Text and photomicrographs. Nice. Human Pathology Digital Image Gallery

Pulmonary edema Some stainable protein, hence an exudate WebPath

Pulmonary congestion of course results from increased pulmonary venous hydrostatic pressure, typically from left-sided heart failure especially mitral valve disease.

If marked or longstanding, microhemorrhages, fibrosis, and iron pigmentation ("brown induration") occur in the lungs. (Hemosiderin-laden macrophages are called "heart-failure cells.")

Heart Failure Cells Slide from Andrea McCollum MD Cuyahoga County Coroner's Office

Heart Failure Cells Hemosiderin-laden macrophages in the lung KU Collection

PULMONARY EMBOLIZATION ("embolism") AND INFARCTION (NEJM 358: 1209, 2008; Lancet 363: 1295, 2004)

Pulmonary thromboemboli are very common (and still under-diagnosed -- see Arch. Int. Med. 148: 1345, 1988, also still good). Thrombi in unoperated pulmonary arteries are almost always emboli.

Most originate in the deep veins of the legs; they may also come from the pelvic veins, rarely elsewhere.

Thrombosis in a leg vein can be uncomfortable ("thrombophlebitis"), but is most often asymptomatic. As a junior clerk, you will compare calf circumferences, check Homan's sign (be careful you don't break the thrombus off), etc.

The majority of pulmonary thromboemboli do no harm and eventually organize or lyse; many are fatal.

Pathologists report pulmonary emboli in 8-25% of autopsies on hospital patients. But in 3-5% of autopsies (figures vary), the embolus is the fatal event, and estimates of the number of U.S. deaths from pulmonary emboli are in the 50,000-150,000 range. (Without an autopsy, the clinicians will often tell the family, "heart attack".)

* Future pathologists: In animal models, thromboemboli often rapidly shrink and fragment after reaching the lungs, even after death. Big news when I was in training (Circulation 48: 179, 1973); to this day, whether a fatal pulmonary thromboembolus can "just disappear" remains unknown.

Virchow's triad. Typical settings for deep vein thrombosis and pulmonary thromboemboli include:

1. stasis
• immobilization of an extremity (bed rest, long plane flights -- see Lancet 2: 497, 1988; I first mentioned long plane flights years before Dan Quayle did, and now the New Zealand study has made it is clear that this is a major risk, about 1%: Lancet 362: 2039, 2003)


• right-sided congestive heart failure


• sickle cell anemia


• morbid obesity (Virchows Archiv 434: 529, 1999)

2. hypercoagulable states

• cancer (especially cancer of the pancreas)


• following burns, surgery, severe trauma


• pregnancy


• women on the old-fashioned high-estrogen oral contraceptive pill (suppressed antithrombin III levels)


• lupus anticoagulant, hereditary anti-coagulant deficiencies (protein S, protein C, antithrombin III, V-leiden, homocystine)


• smokers (not really super-strong relationship, but real)


• and don't forget the nephrotic syndrome, in which you lose proteins S and C (Am. J. Clin. Path. 101: 230, 1994)

3. damaged endothelium

• the one to remember is intravenous lines; CVP catheters occasionally serve as a nidus for a thrombus that embolizes.

For some reason, babies very seldom get or die of pulmonary thromboemboli: Arch. Path. Lab. Med. 114: 142, 1990.

Pulmonary thromboemboli cause several types of problems.

• Instant death ("saddle embolus" occluding the pulmonary trunk and/or both main pulmonary arteries)
• Acute "cor pulmonale" (maybe; this usually requires occlusion of 50% or more of the pulmonary arterial tree)
• Increase in non-perfused pulmonary "dead space" (of course); when enough of the lung becomes dead space and the remainder is receiving the entire right cardiac output, there won't be enough oxygen here and hypoxemia will result
• Ischemia with loss of surfactant and alveolar collapse (atelectasis; sometimes)
• Actual infarction of lung substance due to a pulmonary embolus may occur if the bronchial circulation is inadequate due to left-sided heart failure, shock, etc.

  Pulmonary infarcts are peripheral and hemorrhagic (and can even cause hemolytic jaundice if the patient survives. Rising bilirubin and rising LDH-3 -- think of a pulmonary infarct.) Listen for a friction rub; look for fibrin on the pleural surface at autopsy (why?). They can be distinguished best from regular intrapulmonary hemorrhages by the necrosis. Most will have the classic "wedge" shape.

  Infected thromboemboli can cause "septic infarcts". These may become lung abscesses.

• Bronchoconstriction and wheezing (sometimes, perhaps due to release of serotonin from platelets.)
• Chronic embolization leads to increased pulmonary vascular resistance ("pulmonary hypertension") and eventually cor pulmonale (* once considered rare, we now know this is fairly common, especially when the emboli turn into rather large scars: NEJM 350: 2257, 2004)

Any patient with sudden anxiety, chest pain, dyspnea, cough, hemoptysis or sudden death should make you think of pulmonary emboli. You'll learn how to make the diagnosis while on rotations -- but don't get over-confident; pulmonary embolization is the most-often-missed diagnosis in the hospital (Arch. Path. Lab. Med. 129: 201, 2005).

Angiography's the gold standard while the patient is alive.

Fibrin D-dimer is sensitive, but not specific: Arch. Path. Lab. Med. 123: 235, 1999. Some folks consider this the best screening test: Lancet 363: 1295, 2004.

As we have already mentioned, pulmonary emboli organize into fibrous bands that remain in the lung for the rest of the person's life (Arch. Path. Lab. Med. 123: 170, 1999).

{29052} pulmonary embolus, ancient, organized and turned into fibrous bands

Pulmonary Embolus Photo and mini-review Brown U.

Pulmonary Thromboembolus Australian Pathology Museum High-tech gross photos

Pulmonary thromboembolus Autopsy photo KU Collection

Pulmonary thromboembolus WebPath

Saddle embolus WebPath

Lung infarct WebPath

Lung infarct WebPath

Pulmonary embolus Actually, ALL antemortem thrombi are layered WebPath

Pulmonary embolus WebPath

Pulmonary embolus WebPath

Pulmonary embolus WebPath

Old pulmonary embolus Organized WebPath

Pulmonary infarct Urbana Pathology

Pulmonary embolus Animation Thanks, Webpath

Other causes of lung infarction (immune or infection vasculitis, other things embolizing) are rare but not unheard-of (Chest 127: 1178, 2005).

Fat embolization remains mysterious. You're familiar with this dread complication of a bony fracture. Today's pathologists make the diagnosis during life by finding fat in the cells obtained by pulmonary lavage.

The deadly chest syndrome in sickle cell anemia may also result (at least sometimes) from fat embolization after a bony infarct (NEJM 342: 1904, 2000). The same picture can appear in sicklers with bacterial or viral infection or thromboembolization; often no cause is found. I suspect that cells sickling in the presence of reduced oxygen tension is part of the cause.

PULMONARY HYPERTENSION

Reviews JAMA 284: 3160, 2000; Am. Fam. Phys. 63: 1789, 2001 (by my fraternity brother Trent Nauser MD)

Pulmonary Arterial Sclerosis From Chile In Spanish

Vascular Lung Disease Text and links to photos Case Western Reserve

A good working definition is pulmonary systolic pressure >25 mmHg (rest) and/or >30 mmHg (exercise), with wedge <15 mmHg.

Generally analogous to systemic arterial hypertension, pulmonary hypertension also results from a variety of causes.

1. Left-sided heart failure (especially mitral stenosis)

2. Increased blood flow into the pulmonary arteries (i.e., congenital cardiac malformations with left-to-right shunts, or after resection of a lung)

3. Increased pulmonary vascular resistance from any cause.

• Alveolar hypo-oxygenation from any cause (high altitude, ARDS, emphysema, sleep apnea, etc. etc.)

NOTE: This is important. The normal response to hypoxia in the alveoli ("hypoxic pulmonary vasoconstriction"; formerly the "hypoxic vascular response") causes constriction of arterioles supplying underoxygenated alveoli. If all the alveoli are underoxygenated, all the arterioles constrict, and the pulmonary arterial blood pressure has to rise. To this day, nobody knows which mediator produces the response. Update Ann. Thor. Surg. 78: 360, 2004.

• Fibrosing disease of the alveolar walls -- collagen around the vessels chokes them off
• Pulmonary emboli
• * Jamaican bush-tea drinking (getting high off the herb crotalaria specifically damages the pulmonary vessels)
• Immune disease with particular involvement of the pulmonary vessels, especially CREST syndrome, scleroderma, Wegener's

Persistent pulmonary hypertension of the newborn results from hyperplasia of the smooth muscle in the arteries, present at birth (usually term). It is likely to prevent closure of the foramen ovale and/or ductus, and produce a cyanotic baby. It is quite common, often causes serious brain damage, and has been overlooked for too long. One cause seems to be SSRI antidepressants taken late in pregnancy (NEJM 354: 579, 2006).

• "Idiopathic" ("Primary pulmonary vascular sclerosis / primary pulmonary hypertension"" -- an uncommon, deadly illness typically seen in young women -- probably caused by longstanding endothelin-mediated pulmonary vasoconstriction / hypertension that eventually damages the vessels irreversibly.)
Histopathology: Am. J. Path. 146: 389, 1995.

Treating it with calcium channel blockers (helps, no panacea): NEJM 327: 76, 1992; nitric oxide and continuous intravenous prostacyclin are new remedies (Chest 119: 970, 2001; Am. J. Card. 75: 51A, 1995; big review); also Lancet 352: 719, 1998; NEJM 338: 273, 1998; aerosolized iloprost (prostacyclin analogue: NEJM 342: 1866, 2000; reversal in a mouse model using a serine elastase inhibitor: Nat. Med. 6: 698, 2000.

* Bosentan, the endothelin receptor antagonist, seems to help "idiopathic" primary pulmonary hypertension: Lancet 358: 1119, 2001; NEJM 346: 896, 2002.

• Alveolar capillary dysplasia (better, "hypoplasia") is a congenital, lethal near-absence of good capillaries in the lungs. One gene has been located (Am. J. Hum. Genet. 80: 550, 2007), and there are surely more.

• Convicted: fenfluramine-family ("Pondimim", "Redux", "Fenphen", etc.) appetite suppressants, as a grisly, long-delayed after-effect. NEJM 335: 609, 1996. I predicted the fiasco two years before it happened, in these notes. Currently the explanation is that they produce a potassium channelopathy that causes excessive pulmonary vasoconstriction (Am. J. Med. Sci. 321: 292, 2001).
• * Other rare syndromes, including familial problems (one gene is bone morphogenetic protein receptor II (BMPR2): NEJM 345: 319, 2001; the finding is now robust) and Spanish toxic oil syndrome (Chest 95: 325, 1989).

The drug sildenafil, better-known as Viagra, causes the smooth muscles of the little pulmonary arteries to relax, thereby relieving pulmonary hypertension. This is already in use for idiopathic pulmonary hypertension (NEJM 353: 2148, 2005; South. Med. J. 99: 880, 2006, many others); watch it for fibrosing alveolitis (Chest 131: 897, 2007) and other lung diseases with vascular damage.

NOTE: You'll frequently hear, "This patient is disabled because of pulmonary hypertension" or "This patient has right sided heart failure due to pulmonary hypertension". Of course, the real problem is increased pulmonary vascular resistance from thickened and narrowed arterioles.

Sustained pulmonary hypertension results in changes in the anatomy of the pulmonary arteries and arterioles, some of which are irreversible.

The current, principal molecular suspect is endothelin 1, derived from damaged endothelium. It is a potent vasoconstrictor, and makes smooth muscle proliferate. See Ann. Int. Med. 114: 213, 1991; NEJM 328: 1732, 1993.

* By contrast, the ability of the lung endothelium to produce nitric oxide ("endothelium derived relaxation factor", EDRF), a potent vasodilator, is much diminished in emphysema. There's also maybe a lack of prostacyclin. Nobody really understands this.

Unlike in "benign" systemic hypertension, some of these changes clearly contribute to the ongoing process.

Lesions include:

Main arteries: atherosclerosis (never severe)

Small arteries: hyalinization ("hyaline arteriolar sclerosis"), intimal onion-skinning ("hyperplastic arteriolar sclerosis"), extra elastic, extra muscle, fibrinoid.

Arterioles: muscle appears (should be none), plexiform lesions (bad sign)

The infamous "plexiform lesions" are little networks of blood vessels that look like renal glomeruli; they probably result from helter-skelter proliferation of endothelium (Am. J. Path. 144: 275, 1994.)

* A proposed standard histologic description of the vascular lesions: J. Am. Coll. Card. 42(12 S): 25-s, 2004.

Plexiform lesions
Lung pathology series
Dr. Warnock's Collection


Pulmonary hypertension (especially, pulmonary hypertension due to increased pulmonary vascular resistance) is common and under-appreciated.

A very common mechanism of sudden death in generalized lung disease is an arrhythmia arising in the strained right ventricle.

Of course, the right ventricle undergoes hypertrophy; *  morphologists see Am. J. Card. 78: 584, 1996.

And no matter what the underlying disease, the pulmonary vascular resistance is likely to determine the patient's exercise tolerance ("quality of life"). This commonly takes precedence over the "respiratory function tests" of spirometrists (Chest 92: 387, 1987).

Using nitric oxide to control pulmonary hypertension in ARDS seems natural and physiologic: NEJM 328: 399, 1993. Update: Chest 115: 1407, 1999.