{08111} amyloid, heart
{24519} amyloid heart, gross (looks and feels like candle wax)
{10685} congo red stain (my case)
{10688} congo red, polarized (my case again)

Amyloidosis Heart WebPath photo

Chronic rejection Amyloidosis Heart -- apple green

The vessel walls everywhere are often heavily involved, though infarcts are unusual. Both amyloid AA and amyloid AL involve vessels heavily (Mod. Path. 3: 4, 1990); particularly, the coronary arteries are likely to be narrowed (Am. J. Med. 118: 1287, 2005).

{03386} amyloid, coronary artery (left: Sirius stain; right: crystal violet)

Amyloid-laden vessels are brittle. This produces problems ranging from trivial "post-proctoscopy palpebral purpura" to dread intracranial hemorrhage (fortunately rare in the common systemic amyloidosis syndromes).

GI TRACT (Dig. Dis. Sci. 15: 155, 1997)

Stiff tongue is a well-known problem in both systemic (AL) and localized (organ-specific) amyloidosis.

Amyloid deposits around the blood vessels of the gut result in malabsorption.

Amyloid in the ganglia and wall of the gut makes normal peristalsis impossible.

{24551} amyloid in small bowel (vessels and outer layer of muscularis propria)
{10370} amyloid in gut wall (Congo red and unstained slices)

LIVER

Amyloid is deposited first in the perisinusoidal spaces, and this appears to crunch the hepatocytes after a while.

However, because the sinusoids remain open and unscrambled, the liver seldom fails, and pressure in the portal vein usually remains normal.

Although it has long been taught that liver biopsy is very dangerous if amyloidosis is suspected (i.e., the amyloid holds the sinusoids wide-open, inviting massive hemorrhage), Mayo's recently found the danger isn't real. Series Medicine 82: 291, 2003; also confirms the poor prognosis.

{39805} amyloid in the liver

ADRENAL GLAND

Amyloidosis can and does present as adrenal cortical insufficiency ("Addisonism").

{24607} amyloid, adrenal (looks and feels like candle wax)

BLEEDING TENDENCY

First problem: amyloid deposited around small blood vessels renders them more fragile.

Thus, problems similar to those seen in scurvy result. Look for little hemorrhages in the tissues around the eyeballs.

* Second problem: amyloid AL can soak up coagulation factor X, requiring plasma exchange (Am. J. Haem. 54: 68, 1997).

SPLEEN

Amyloid deposition in the spleen is usual in systemic amyloidosis.

Most patients get increased circulating platelets, but the relative loss of splenic function is among the least of these peoples' problems.

There are two classic, unappetizing descriptions of amyloid-loaded spleens seen at autopsy.

A "sago spleen" has its amyloid in the white pulp. (Sago is tapioca.) A "lardaceous spleen" has its amyloid in the red pulp (* and usually indicates amyloid AL -- see Mod. Path. 3: 419, 1990). It looks like lard. The distinction is of no practical importance, but every physician seems to remember it!)

SKIN

The skin may be involved trivially in generalized disease.

{12215} amyloid, eyelids

* Several minor skin diseases feature local accumulations of an amyloid derived from a keratin ("amyloid D").

NERVES

Some weakness and loss of sensation is common in amyloidosis, with or without unpleasant sensations. (* This is especially common in hereditary amyloidosis syndromes. It also occurs early in amyloidosis AL -- be suspicious.) Morphology Arch. Path. Lab. Med. 124: 114, 2000.

WRIST

Carpal tunnel syndrome (too-tight flexor retinaculum) developing in an older person makes the astute clinician suspect amyloidosis. (* Check Tinel's sign.)

LUNGS

At least three patterns occur: nodules (usually asymptomatic), diffuse interstitial infiltration (dyspnea), and tracheobronchial amyloidosis (obstructing the larger airways; Medicine 79: 69, 2000; treatment with the new external-beam machine Mayo Clin. Proc. 76: 853, 2001).

MAKING THE DIAGNOSIS

To diagnose amyloidosis, you must send the lab some solid tissue and the pathologist must find amyloid in it.

* (Don't try the old intravenous Congo Red test on your patients. Allergic responses are common.)

If the amyloid is discovered on biopsy of kidney, liver, or other organ, you have the diagnosis. (This is often a big surprise.)

Your pathologist can distinguish the common amyloids histochemically. Pitfall: Especially on kidney biopsy, immunostatining is often unreliable and a pathologist should stain both for immunoglobulin and serum amyloid A (Arch. Path. Lab. Med. 131: 917, 2007).

Be suspicious that your older patients have amyloidosis. ("Amyloidosis is in the differential diagnosis of just about every symptom".)

Current practice is to cut off a piece of gingival or rectal tissue and send it to the pathologist. It is polite and helpful to mention you are looking for amyloid.

Such a biopsy will demonstrate amyloid ("the biopsy is positive") in majority of advanced cases. Negative biopsy does NOT exclude systemic amyloidosis!

Aspiration of subcutaneous fat is an okay way to start looking for amyloid (Am. J. Med. 82: 412, 1987 -- detects the common amyloids but not amyloid H). It's now mainstream, with a claimed sensitivity of up to 90% (Arth. Rheum. 54: 2015, 2006. Gastric biopsy has been promoted as high-yield (Hum. Path. 16: 1206, 1986), and more recently the value of the lip ("minor salivary gland") biopsy has been reaffirmed (you'll pick up Sjogren's in the process: Arth. Rheum. 59: 714, 2008).

If you find amyloidosis, you may want to check the patient over for some underlying disorder (i.e., B-cell neoplasm, chronic infection). If you find something treatable, you can slow down, but probably not reverse, the amyloid deposition.

TREATMENT AND PROGONSIS

We wish we had more to offer people with systemic amyloidosis.

Untreated patients with amyloidosis AL usually die around one year after diagnosis from heart problems, but about 5% make it to ten years with today's chemotherapy (Blood 93: 1062, 1999).

Patients with amyloidosis AA usually die around ten years after diagnosis from kidney failure.

Some specific ways of helping do exist.

Eprodisate is one of a new class of medications that interferes with the polymerization of amyloid fibrils and their deposition. So far, it's been shown to slow renal disease in amyloidosis A (NEJM 356: 2349, 2007).

Aggressive treatment of amyloidosis AL (Hosp. Pract. 31(8): 67, Aug 15, 1996) is becoming popular. Options include bone marrow transplantation (Br. J. Haem. 100: 229, 1998 & 101: 766, 1998), super-intense melphalan plus stem cell support (Blood 91: 3662, 1998; Am. J. Med. 113: 549, 2002; "not clearly better than melphalan plus dexamethasone" NEJM 357: 1083, 2007; "lots of apparent cures" Blood 110: 3561, 2007), lenaldinomide (as for plasma cell myeloma Blood 109: 465, 2007; Blood 109: 492, 2007), and alfa-interferon.

The treatment of amyloidosis AA is that of the underlying disease. Sometimes amyloid regresses when the underlying disease is cured. But don't count on it. The amount of SSA in the blood, and whether the kidneys have been damaged, determine the outcome (NEJM 356: 2361, 2007).

Cardiac amyloidosis causing heart block can be treated by inserting an electrical pacemaker to keep the ventricles beating properly.

Most hereditary amyloidosis syndromes require genetic counselling.

Congophilic angiopathy will result in intracranial bleeding regardless of any treatment.

* Watch for undiscovered, relative non-toxic anthracyclines that will bind to the beta-pleated sheets, render them more soluble and prevent additional amyloid from being laid down on them. Such anthracyclines are available now, but unfortunately they're deadly poison.

INTRODUCTION TO IMMUNODEFICIENCY

Immunodeficiency I From Chile In Spanish

Immunodeficiency II From Chile In Spanish

The immunodeficiency states are hereditary, infectious, and iatrogenic disorders. Patients have extra trouble fighting infections.

Systemic diseases that result in immunodeficiency include alcoholism, diabetes, nephrotic syndrome, uremia, and Cushing's syndrome. Cancer is associated by immune suppression by a variety of mechanisms. Malnutrition is another important cause of immunodeficiency. Immunosuppressive drugs are often given to treat autoimmune disease or cancer, or to halt transplant rejection. More about all this later.

In immunodeficiency states that might be due to some mysterious T-cell defect (including all the mysterious B-cell defects), patients generally have a high chance of developing "autoimmune diseases" of various sorts.

Patients with primary deficits in CELL-MEDIATED IMMUNITY almost all have oral candidiasis (thrush, yeast infection), and go on to have problems with intracellular parasites like CMV and pneumocystis. Bacterial infections are likely to be sepsis rather than localized. If severe, these will show up soon after birth.

Patients with primary deficits in HUMORAL IMMUNITY have most problems with pyogenic bacteria (staph, pneumococcus, H. 'flu, etc.) These won't show for the first few months of life because of Mom's antibodies.

NEUTROPHIL PROBLEMS include such illnesses as chronic granulomatous disease, Chediak-Higashi disease, adhesion molecule problems, etc., etc. that are not part of today's unit. Expect problems especially with staph, pseudomonas, candida, nocardia, and aspergillus.

Watch for more immune problems as the bioengineered "biological response modifiers*  gain popularity. The TNF-binders infliximab and etanercept, while obviously powerful and useful, have caused opportunistic infections, especially by mycobacteria (NEJM 345: 1098, 2001) and fungi.

Patients with defects in some of the COMPLEMENT components involved in membrane attack (C5, C6, C7, C8, also properdin; C9 is asymptomatic) are especially troubled with neisseria. Patients with defects in C2 are at some risk for increased infections, even if heterozygous (J. Clin. Imm. 23: 297, 2003); homozygotes lacking C2 or C4 are likely to have a lupus-like syndrome (butterfly rash, arthritis, nephritis) . The reason why remains mysterious, and the disease is often very severe (Arch. Derm. 136: 1508, 2000).

Patients with SPLEEN LOSS (sicklers, post-surgery) have particular problems with salmonella, pneumococci, *  listeria, and *  DF2 dogbite bacterium.

HEREDITARY IMMUNODEFICIENCIES ("primary immunodeficiencies"; reviews Ped. Clin. N.A. 47(6): Dec. 2000, whole issue; Mayo Clin. Proc. 73: 865, 1998; J. Allerg. Clin. Imm. 111(2S): S-571, 2003. molecular diagnosis of 75 of the ~100 known syndromes is now available, review Lancet 357: 1863, 2001; Nat. Imm. 5: 23, 2004; the Budapest Classification of 2005: J. Allerg. Clin. Imm. 117: 883, 2006.)

X-LINKED AGAMMAGLOBULINEMIA (Bruton's disease, etc.)

The B-cells are absent, fail to mature, or at least fail to respond to infection. The lymph nodes are tiny, without germinal centers. Molecular biology: Science 261: 355 & 358, 1993; J. Imm. 161: 3925, 1998. The deficiency is in Bruton's B-cell progenitor tyrosine kinase (btk, Cell 72: 279, 1993), which is a gene that tells B-cells to multiply when they are stimulated. More on the gene: Nature 361: 226, 1993; alleles Pediatrics 101: 276, 1998.

Less often, the mutation is on the mu heavy chain gene (NEJM 335: 1486, 1996).

All classes of immunoglobulins are absent or nearly absent. When mother's immunoglobulins are gone (six months after birth), severe pyogenic bacterial infections begin.

The disease is controlled with injections of gamma globulin. Usually they do quite well.

* Survivors have high prevalence of lupus, polymyositis-dermatomyositis, polyarteritis, rheumatoid arthritis, etc.

* Don't give these kids live polio vaccine.

Primary care physicians: These patients present with early and intractable otitis media. You'll be criticized very harshly if you miss Bruton's (J. Ped. 41: 566, 2002).

ISOLATED IgA DEFICIENCY ("selective IgA deficiency")

"The commonest immunodeficiency syndrome", affecting around one in maybe 300 people (* estimates vary.) No one understands the cause; there's a familial tendency but no obvious pattern of inheritance (update J. Immuno. 169: 4637, 2002).

Serum and secretory IgA are very low or absent. *  There is disagreement about whether these patients have "more colds" and "more GI infections", or "have worse allergies", or "are more likely to get collagen-vascular disease", etc., etc.

The most serious hazard is iatrogenic anaphylaxis from the second administration of blood plasma.

* Isolated IgM deficiency also occurs but is much less common than isolated IgA deficiency. Yet other people lack certain subclasses of IgG.

*  "Transient hypogammaglobulinemia of infancy" features some extra infections, with a delay in producing some antibody subclass (usually IgG₂). These children do produce antibodies in response to challenge immunization, and usually no treatment is required.

DIGEORGE SYNDROME ("thymic dysembryogenesis")

The third and fourth branchial pouches fail to form properly. While the patient is being treated for tetany and cardiac malformations just after birth, the lack of T-cells becomes evident as a fungal, viral, or other infection.

*  It is not familial. Most of these kids have monosomy 22q11 (Am. J. Hum. Genet. 51: 964, 1992).

A graft of fetal thymus can be very helpful to some of these patients -- even restorative (NEJM 341: 1227, 1999). But the best seems to be a HLA-matched thymus transplant (Blood 102: 1121, 2003). Update Blood 104: 2574, 2004.

* "Nezelof's syndrome" is a possibly related syndrome; these patients have very little thymic tissue but normal parathyroid hormone levels; some of these patients lack purine nucleoside phosphorylase.

DiGeorge syndrome
Pittsburgh Pathology Cases


SEVERE COMBINED IMMUNODEFICIENCY (SCID) SYNDROMES

A variety of profound deficiencies of both T-cell and B-cell function. Genetics update J. Clin. Inv. 114: 1409, 2004.

There are several autosomal SCID syndromes.

Perhaps half of autosomal-recessive SCID are due to adenosine deaminase deficiency or another (J. Ped. 128: 373, 1996) defect in purine salvage. The problem is that too much adenosine builds up, and gets turned into dATP, which is very poisonous for all lymphocytes. Or maybe the problem is that adenosine deaminase, which normally binds to CD26, the T-cell activation receptor, makes it work; Science 261: 466, 1993, adult alleles Blood 89: 2849, 1997. HLA-matched bone marrow transplant is curative or....

ADA deficiency was the first disease to be cured by introduction of the normal gene into cells. Beginnings: MWN 9/22/86, p. 42; outcome Br. Med. J. 304: 1202, 1992; Science 258: 744, 1992 (both girls are now healthy and in public schools).

*  CD45 deficiency: Nat. Med. 6: 343, 2000.

* Deficiencies of the RAG-1 or RAG-2 genes ("recombination activating") that produce lymphocyte diversity cause a severe combined immunodeficiency; there is a forme fruste (Blood 06: 2099, 2005) called Omenn's syndrome (lymphedema, rash -- still a severe disease), and an even milder version with exuberant granulomatous response to Epstein-Barr and some other problems (NEJM 358: 2030, 2008.)

At least three X-linked combined immunodeficiency are known.

In one form of X-linked SCID (* SCIDX1 -- the most common single SCID variant), the interleukin 2 receptor (* gamma chain, IL2RG, which it shares with the interleukin 4 and 7 receptors) is defective (Blood 83: 626, 1994; Science 263: 1453, 1994; Science 262: 1887 & 1880, 1993; Blood 88: 1708, 1996, J. Clin. Invest. 99: 160, 1997).

As a result, there are no T-cell and no NK-cells.

This affected David Vetter "the bubble boy". See JAMA 251: 1929 and 1935, 1984; JAMA 253: 74 & 78, 1985 for this fiasco.

In one series, all 12 SCID children whose biochemistry remained obscure were boys, telling me that the major autosomal SCID loci had already been found: J. Ped. 130: 378, 1997.

Gene therapy succeeds for SCID: Science 288: 669, 2000; NEJM 346: 1185, 2002. Gene therapy continues to succeed for SCID by providing a good IL2RG (Blood 110: 67, 2007). Sadly, at least three of these people have gotten leukemia, apparently from the bioengineered cells (J. Allerg. Clin. Imm. 117: 865, 2006).

In 2002, one boy in France developed leukemia with the retroviral vector found to be inserted next to an oncogene. The FDA banned the technique even though it was an obvious life-saver for other kids, while the British talked (more sensibly, I think) about benefits vs. risks (Nature 419: 545, 2002; Br. Med. J. 325: 791, 2002).

* Another autosomal recessive form has been found to result from deficient Jak3 protein kinase, which binds to the IL2-R gamma chain cited above (Nature 37: 65, 1995; Science 270: 797, 1995; Blood 90: 3996, 1997; Blood 91: 949, 1998).

Yet another is the human equivalent of the nude mouse (Blood 97: 800, 2001).

And there are at least two interferon receptor deficiencies now known (Nat. Genet. 33: 388, 2003).

* The white cells in a single blood transfusion will give SCID patients graft-versus-host disease, and this can even happen from the maternal lymphocytes that enter the child's bloodstream during childbirth.

ATAXIA-TELANGIECTASIA (* "Louis-Bar syndrome", NEJM 325: 1831, 1991; Medicine 70: 99, 1991; QJM 82(299): 197, 1992)

A poorly-understood, autosomal-recessive (* probably several alleles on chromosome 11) systemic problem involving brain (* lack of Purkinje cells), vessels, and the immune system. Something is wrong with gene expression and tissue differentiation. The disease is inherited as an autosomal recessive * on 11q22-23 -- gene cloned Science 268: 1749, 1995; NEJM 333: 777, 1995), and patients have fragile chromosomes, with notable break points at sites involved in T-cell receptors and immunoglobulins.

* Interestingly, most of the recombination events take place within, rather than between, individual chromosomes (Science 260: 1327, 1993.)

AT heterozygotes (around 0.5% of humankind) have poor tolerance for radiation therapy; they may need to be distinguished from other patients in designing protocols, establishing doses, etc. They also have a clear increase (3.5 x others) in cancer risk. Stay tuned for improved identification of these unfortunates.

Cellular immunity against viruses is poor, and many of these patients cannot make IgA or IgE. Patients eventually die from lung infections or cancer.