Note that ferrous iron in heme groups (hemoglobin, myoglobin, cytochromes) does not stain. Neither does the ferric iron stored as ferritin, since the apoferritin protein shields the iron atoms.

Normally there is some stainable hemosiderin in marrow, spleen, liver.

Lack of stainable iron of course indicates systemic iron deficiency.

Localized accumulations of iron ("local hemosiderosis") reflect longstanding congestion (lungs, leg veins), repeated minor injury (shrapnel fragments, sports, etc.).

Too much iron in the whole body ("generalized hemosiderosis") has several causes that are worth learning now:

• many red cell transfusions without blood loss

• (i.e., diseases that ruin red cell precursors)

• too much iron being absorbed by the gut

• longstanding hemolysis

• heavy drinking (any kind of booze; this is very minor compared with the others)

• hemochromatosis gene (chromosome 6, common)

• no transferrin in serum (liver becomes loaded, marrow empty: NEJM 326: 1705, 1992)

• problems using the iron

• ineffective erythropoiesis (thalassemia, others)

• "sideroblastic anemia" (inability to put iron into the heme units, stranding it in mitochondria)

• interleukin 1 effect (blocks uptake of iron by normoblasts, "anemia of chronic disease")

• gross excess of ferrous iron in the diet

• "iron supplements"

• vitamin C abuse (extreme)

• certain foreign wines (iron is added -- wine-making is a racket in many countries)

• Bantu beer (brewed in old steel oil drums, infamous; genetics and environment collaborate to cause a serious public health problem: NEJM 326: 95, 1992)

Excess hemosiderin eventually causes organ injury by generating free oxygen radicals. This leads to organ failure, called "hemochromatosis". ("Hemochromatosis is generalized hemosiderosis that has made you sick.") This is a major, under-diagnosed, treatable disease in the U.S.

In a few cases, the disease has been detected by sufferers' tripping airport metal detectors.

* The oral iron chelators (alpha-ketohydroxypyridines, L1, etc.) were orphan drugs introduced in the early 1990's that have helped people with transfusional hemosiderosis. You'll learn about them soon.

{34364} hemosiderin at site of hemorrhage in a malignant brain tumor
{37592} hemosiderin, Prussian blue stain; there is also black carbon
{38491} hemosiderin-laden macrophages in the lung ("heart failure cells")

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

Hemochromatosis Liver, H&E stain KU Collection

Hemochromatosis, liver Photo and mini-review Brown U.

Pulmonary macrophages Mixed pigment -- iron, carbon, tobacco Dave Barber MD, KCUMB

A special case of iron deposition is the ferruginous body of asbestosis -- iron-calcium salts encrusted on an asbestos fiber in the lungs.

{36189} ferruginous body in asbestosis

Copper pigment

Copper penny and blue copper-salt colors. Deposited in the liver and/or basal ganglia in Wilson's disease, an important diagnosis not to miss.

* Minocycline, an antibiotic, is acted upon by the peroxidases in the thyroid and turns the gland black. For keeps.

Homogentisic acid polymer ("alkapton"):

Patients with the hereditary arthritis syndrome "alkaptonuria" accumulate this substance, which breaks down into black pigment, in their cartilages (nose, ears), joints, sweat. The accumulation itself is called "ochronosis". Histopathology: Am. J. Clin. Path. 90: 95, 1988. Genetics: Nat. Gen. 14: 19, 1996.

{18252} ochronosis (black cartilage in the ear)

Hemozoin: This is a ferric iron pigment that looks like hemosiderin when unstained, but that does not exhibit the Prussian Blue reaction because the iron is sequestered by protein.

It consists of polymerized heme with each iron atom joined to a carboxyl group on the next porphyrin unit (Proc. Nat. Acad. Sci. 88(2): 325, 1991).

It is seen in RE cells in malaria; the plasmodia protect themselves from free iron-heme complex by converting it into this substance. Once it's been deposited, it apparently autocatalyzes its own production (Nature 374: 269, 1995). Some of the antimalarials work by preventing the bugs from producing this stuff.

* Malaria kills as many or more people as AIDS. Almost every one of the deaths could be prevented fairly easily. The ongoing stupidity is a prime example of Virchow's dictum that its overriding public health problem is its politicians. See Br. Med. J. 328: 1033 & 1086 & 1378, 2004; Lancet 363: 237, 2004; lots more.

* Hematin, sometimes deposited in RE cells in other cases of heavy hemolysis, is ferriprotoporphyrin IX hydroxide.

Bilirubin

{12220} jaundice

Jaundice WebPath Photo	Jaundice WebPath Photo
Bile plugs Cholestasis WebPath Photo	Kidney, conjugated jaundice Urbana Atlas of Pathology

This is the non-iron-containing, yellow-orange pigment that results from breakdown of porphyrin rings (mostly hemoglobin).

Bilirubin by itself is insoluble in water and is carried on albumin to the liver, where hepatocytes conjugate it with glucuronic acid and pour it into the bile.

Elevated levels of bilirubin in the blood mean jaundice. Mechanisms:

• Too many red cells being broken down:

• all the hemolytic processes (from jogging to sickle cell disease to the intramedullary lysis of normoblasts in thalassemia minor and pernicious anemia; pathologists look for bilirubin gallstones and elevated urinary urobilinogen, why?)

• Liver cells can't conjugate bilirubin fast enough:

• most diseases of liver cells

• just being a newborn ("physiologic jaundice of the newborn")

• hereditary defects. Most common is Gilbert's non-disease (francophiles say zheeel-BAYRRRR's), a must-know for today's clinicians. Nasty alleles are Crigler-Najjar.

• Something is blocking bile output:

• something is blocking the common bile duct (gallstone, pancreatic cancer)

• patient is taking drugs, typically anabolic steroids (i.e., body-builders)

You may see bile plugs (bile in distended canaliculi; big ones that ruptured are "bile lakes") or intracellular bilirubin in the liver in obstructive jaundice or primary cancer of hepatocytes.

{24559} liver that is green from biliary obstruction
{39787} bile plug

Of course, if you find a cancer cell is making bile, you know the cancer arose from a hepatocyte.



* Trivia: Two proteins, ligandin and protein Z, process bilirubin in the hepatocyte. Phenobarbital increases ligandin and speeds processing of bilirubin. Once it was fashionable to treat everyone with Gilbert's "disease" with phenobarbital, thereby turning healthy adults with a slightly abnormal lab value into chronically and iatrogenically sick adults with a normal lab value.

CALCIFICATION: A subject of interest to most physicians, not just radiologists.

Calcium salts (hydroxides, phosphate-hydroxides) are deposited. Regardless of cause, calcium salts stain dark blue on H&E. (* If there is any doubt, special stains like the Von Kossa of Alizarin red demonstrate it is calcium.)

Dystrophic calcification

This is calcification that takes place locally, in the presence of normal overall calcium-phosphorus metabolism.

The calcifications may be of any size.

"Dystrophic" means "seeking out the bad". While a necrotic cell whose mitochondria calcified may provide a nidus for stone-building, some texts suggest that only dead things calcify. This is simply not true.

* In extracellular calcification, calcium salt is complexed to coagulation factors II, VII, IX, and X, the ones that contain gamma-carboxy glutamic acid (and therefore require vitamin K, etc.)

In intracellular calcification, the first organelle to calcify is usually the mitochondrion. Of course, that's the end of the cell....

Several normal structures tend to calcify during adult life.

This includes the pineal gland, the cartilages in the airways, the media of large arteries ("Monckeberg's") and the mitral valve annulus. These are probably harmless.

Around 1% of adults develop calcifications in their otherwise-normal sinuses of Valsalva, causing deadly aortic valve stenosis.

{03560} calcified aortic valve, x-ray
{06461} calcified aortic valve, gross
{45702} calcified carotid artery (the proximal portion of the common carotid, and the proximal portions of both internal and external carotid arteries are visible; look carefully!)
{15856} dystrophic calcification in heart muscle (myocarditis patient)

Calcification From Chile In Spanish

Calciphylaxis Wash. U., St. Louis Illustrated notes

Dystrophic calcification WebPath Photo

Little bits of calcium help mammographers recognize breast cancer.

Breast cancer with microcalcification
WebPath Photo


Advanced atherosclerotic plaques undergo calcification, but this is not the principal problem in atherosclerosis.

Severe atherosclerosis with calcium
WebPath photo


* Nobody knows why most dystrophic calcifications happen. One suspect is certain nanobacteria that thrive on the hydroxyapatite surfaces that they build. Tetracycline-sensitive -- let's wait and see. PNAS 95: 7896 & 8274, 1998.

* "Chelation therapy" (infusions of EDTA) is a perennial health fraud that claims to "cure atherosclerosis by removing calcium from the walls of vessels". Patients feel their fingers tingle during the infusion, and they are told that this is "proof that the circulation was being restored." Explain.

Dystrophic calcification is characteristic of other diseases as well. The reasons are generally obscure.

Malformed or damaged cardiac valves tend to calcify, especially congenitally bicuspid aortic valves (another common cause of aortic valve stenosis).

Caseous granulomas (tuberculosis, histoplasmosis, others) often calcify.

Scars (surgical, myocardial) often calcify.

The fingertip pulp calcifies in scleroderma and CREST syndrome.

Certain tumors contain "psammoma bodies", little spherules of basement membrane that calcify. (Think of thyroid cancer, ovarian cancer, meningioma, somatostatinoma). Little spherical calcifications inside giant cells in granulomas are called "Schaumann bodies" or "conchoid bodies". More about these things later.

{35552} Schaumann bodies in giant cells of granulomas (berylliosis case)

* Uterine fibroids (smooth muscle tumors) often calcify. (This is an ancient finding: Arch. Path. 107: 91, 1983.)

* Calcification of the pinna of the ear occurs for some reason in some cases of longstanding adrenocortical insufficiency (Addison's disease; there are other causes too).

If a fetus dies and calcifies, it may be retained for years as a "lithopedion" ("stone child" -- * read Michael Bishop's famous non-supernatural horror story, "Within the Walls of Tyre").

A special case of dystrophic calcification is precipitation of calcium stearate in pancreatitis-associated fat necrosis. If the celiac plexus is involved, this produces one of medicine's most intractable pain syndromes.

Metastatic calcification:

"Metastatic" means "another place". Here the serum calcium and/or phosphate ion concentration is already elevated for some reason. Healthy tissues calcify.

* High blood calcium is usually due to cancer destroying bone, high hPTH levels (parathyroid adenomas and hyperplasias, squamous cell carcinoma of the lung, rarely others), sarcoid, vitamin D abuse, milk and antacid abuse.

High blood phosphate is almost always due to kidney failure or massive tumor lysis.

* Virchow first explained the mechanism, relating metastatic calcification of lung and stomach to demineralization of the bones and kidney failure.

* The most grisly example of metastatic calcification is the severe autosomal recessive disease familial tumoral calcinosis. Gene GALNT3: Nat. Genet. 36: 579, 2004.

Metastatic calcification occurs predictably in the alveolar walls, the gastric fundic epithelium (near parietal cells), the basement membranes of certain renal tubules, and the walls of small blood vessels.

Note that all but the last are sites of pH gradients. The calcium precipitates first where there is excess hydroxyl ions.

In very severe lung or kidney involvement, respiratory insufficiency (* "pumice lung") or renal tubular failure can occur. But usually metastatic calcification is harmless evidence of serious disease elsewhere.

* Future pathologists: A few calcifications around the thin limb of Henle's loop is "normal" and does not imply a calcium problem.

{39670}calcification, metastatic, in the lung;
{08099} calcification, metastatic, in the lung

Metastatic calcification Lung WebPath Photo

* Modern-era pathologists: calcification of collagen is diagnostic of sustained electrical injury (happens at the cathode during electrical torture; J. Clin. Path. 53: 569, 2000; Nature 301: 75, 1983).

Any kind of calcification can ossify, i.e., produce bone and even bone marrow. (It's commonplace to see bone, with active marrow, in airway sections of elderly patients, in calcified atherosclerotic plaques, and so forth.)

HYALINE: Any substance (intracellular or extracellular) that stains a homogeneous (say "homo-JEAN-yuss") pink on routine H&E stains.

{17485} treatise on hyaline

When patient are losing lots of protein trough their glomeruli, it's common to see eosinophilic droplets in the proximal tubular epithelial cells. This is a good autopsy marker, especially if the patient was not well worked-up during life.

{46308} hyaline droplets in proximal tubules
{17440} hyaline droplets in proximal tubules

Russell bodies are round accumulations of monoclonal immunoglobulin that are (or used to be) inside constipated plasma cells. Nobody knows how or why they form.

Russell Body UHS Case Photo by Ed

Russell Bodies Four in one cell Photo by Ed

Viral inclusions are crystalloids of virus components within infected cells. The most famous are herpes inclusions -- look in the cell nucleus, since they will give you the diagnosis.

Mallory's alcoholic hyaline is scrambled prekeratin intermediate filaments plus ubiquitin, typically in liver cells. This usually reflects weeks of heavy drinking ("alcoholic hepatitis" -- * there are other rare causes). The stuff is eosinophilic and flocculent (i.e., it looks like pink cottage cheese).

Dideoxyinosine therapy for HIV is another cause of Mallory bodies. Am. J. Clin. Path. 108: 280, 1997.

Mallory's hyaline

WebPath Photo

{09103} Mallory's alcoholic hyaline, electron micrograph (upper right)
{17418} Mallory's alcoholic hyaline, H&E and electron micrograph

Alpha-1 protease inhibitor ("antitrypsin") globules look like multi-sized cherries within hepatocytes that are unable to secrete this product (inborn error, regenerating cells).

* Certain alleles of alpha1-antitrypsin produce globbies in end-stage livers regardless of cause: Am. J. Clin. Path. 107: 692, 1997.

Alpha-1 antitrypsin globules

WebPath Photo

* Biotin causes eosinophilic inclusions and optically-clear nuclei in the endometrial glands in pregnancy: Lancet 364: 532, 2004.

* Giant mitochondria, a feature of alcoholic liver disease. If you can spot these, you have exceeded undergraduate pathology expectations. These are called "Yokoo bodies", having been discovered by one of my teachers.

Collagen can hyalinize, especially in keloids / hypertrophic scars and other abnormal fibrous proliferations.

{17646} keloid, gross
{17647} keloid, histology
{17648} keloid, histology
{46351} keloid, histology

Keloids (hypertrophic scars?)
Actor Benjamin Bratt
UCSF Skin-In-Cinema

Keloid Glassy fibers KU Collection

Excess basement membrane and other proteins "hyalinizes" the body's small arteries in high blood pressure and diabetes.

Of course this narrows the lumens. * Complement components also bind to the structural components of the vessel, etc., etc.

Thickening and excesses of basement membrane are a major theme in renal glomerular disease, and in diabetes mellitus. Much more about this later.

{17472} hyaline arteriolar sclerosis (right, one on left is normal)

Amyloid, mentioned above, is another extracellular accumulation that always has a hyaline appearance.

{13613} amyloid, H&E

Amyloid From Chile In Spanish

Amyloid
Congo red
WebPath Photo

Fibrin, when the meshwork is crunched down, can be intensely eosinophilic and appear "hyaline".

{11427} fibrin in a premature baby's lung ("hyaline membranes")

Hyaline membrane disease Fibrin membranes in lung KU Collection

Fibrin
On the epicardium
WebPath Photo

Fibrinoid is a special "material" seen in the walls of blood vessels that are dead but still contain flowing blood. A mix of plasma proteins and dead cell debris solidifies in the media and stains intensely pink.

Usually fibrinoid necrosis results from type III immune injury (immune complex precipitation and complement activation). High physical pressure ("malignant hypertension"), toxemia of pregnancy, and some infections can do the same.

Fibrinoid Damaged vessel, don't know why WebPath Photo

Fibrinoid Damaged vessel, don't know why WebPath Photo

Fibrinoid in an arterial wall Cornell

Polyarteritis Urbana Atlas of Pathology

If solid "hyaline" looks inflamed, it's usually fibrin or "fibrinoid".

* The centers of rheumatoid nodules may be filled with "fibrinoid", and it is also characteristically seen in the myocardium in rheumatic fever.

* Radiation injury to vessels appears as hyaline-fibrinoid in vessel walls. Early, there may be some inflammation and/or necrosis. Later, the vessels look more subdued, but the lumen continues to narrow throughout the patient's life-span.

{01917} radiation injury to vessels; the hyaline / fibrinoid is pink

* Future pathologists only: The Splendore-Hoeppli phenomenon of little pink-staining club-shaped things around actinomyces colonies, fungus masses, schistosome eggs, and occasionally other organic-based "foreign bodies".

* Future pathologists only: Spironolactone bodies are found in the mineralocorticoid-producing cells of the adrenal gland in people treated with this Rx. They are hyaline, laminated things, up to 15 microns, derived from S.E.R.

In kidney disease, entire glomeruli "hyalinize". Depending on the disease, these dead glomeruli are replaced by basement membrane-mesangial matrix, collagen, and/or plasma proteins.

MYXOID CHANGE

Increased ground substance.

* The comb and wattles of a rooster is the familiar example from normal comparative physiology.

There is increased ground substance throughout much of the body in hypothyroidism (myxedema).

* (Curiously) many patients with Graves' disease (which usually produces hyperthyroidism) have localized accumulation of ground substance on their shins ("pretibial myxedema"; it may be severe enough to compress the lymphatics and give superimposed elephantiasis. See Lancet 341: 403, 1993).

If there is associated damage to the connective tissue fibers, we use the term myxomatous degeneration ("myxoid degeneration").

The two real-life examples are "cystic medial necrosis" of the aorta (prelude to a lethal tearing called "aortic dissection") and Barlow's floppy mitral valve (a semi-disease that if you really search for it affects a few percent of humankind.)

* Myxoid change of the intima narrows the renal arteries in scleroderma and Balkan nephropathy, eventually causing kidney failure.

Accumulation of epithelial mucin, as large pools, may be seen in several diseases, most notably "colloid cancers". More about them later.

ABNORMAL MITOCHONDRIA

Selective damage of the mitochondria (i.e., extreme swelling seen on electron microscopy) is the essential lesion of true Reye's syndrome.

Parking-lot crystals inside mitochondria are a hallmark of the genetic diseases of mitochondria, in which a portion of their genetic code is faulty. Abnormal creatine kinase is being synthesized and accumulating.

* Most of these diseases show up primarily in muscle (why?), and the sick mitochondria accumulating around the edges of the worse-involved fibers create a "ragged red" appearance. More about this later.

Hürthle cells (oncocytes, Ashkenazy cells, oxyphil cells) have their cytoplasm so packed with mitochondria that there is little room for anything else. You already know these from parathyroid and armpit (apocrine cell) histology. We'll see them at other sites as disease markers.

Oncocytoma
Mitochondrion-rich tumor
VCU Pathology


Hürthle cell carcinoma
Thyroid
Pittsburgh Pathology Cases


We've already mentioned the giant mitochondria of the alcoholic's liver.

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