Pathology Iii: Multisystem Lab

Front 1

Case History:
A 62-year-old year old man presented with orthopnea and nocturia which was gradually worsening over the past 6 months.
Additionally, the patient complained of passing frequent, bulky, greasy stools.
Physical examination demonstrated features consistent with pulmonary edema.
What is rouleaux formation? What causes it?

Back 1

RBC’s arranged like a coin stack. Caused by elevated plasma
fibrinogen or globulins.

Front 2

What is the patient’s most likely diagnosis?

Back 2

Primary amyloidosis, AL fibril protein, likely due to immunocyte dyscrasia (Waldenström’s macroglobulinemia in this case)

Front 3

What is Waldenström’s macroglobulinemia?

Back 3

Waldenström’s macroglobulinemia is a
lymphoplasmacytoid cell malignancy of
unknown cause that presents with adenopathy,
hepatosplenomegaly, neurologic symptoms
(peripheral neuropathy) and hyperviscosity

Front 4

What features on this patient’s rectal biopsy were likely “diagnostic”?

Back 4

Finding amorphous, extracellular, eosinophilic material deposited in the mucosa that, when stained with Congo red, demonstrated apple green birefringence

Rectal involvement, present in 80% of patients

Front 5

What is the most common cause of death in
primary amyloidosis?

Back 5

Cardiac involvement with arrhythmias and/or
restrictive cardiomyopathy.

Front 6

Amyloidosis: heart

Back 6

The normal red-brown myocardium has been converted to a dull, "waxy" grayish-brown. Such deposits can cause arrhythmia or restrictive physiology. Also noted is left ventricular hypertrophy.

Front 7

What two types of amyloid are most frequently associated with
cardiac involvement? Any practical reason to tell them apart?

Back 7

Transthyretin-derived (senile, AS) amyloid and immunocyte
derived (AL) amyloid. AL amyloidosis may be treated with
alkylating agents.

Front 8

What are the generalized forms of amyloidosis

Back 8

Primary type is frequently associated with multiple myeloma or other monoclonal B-cell proliferation and often involves the heart, GI tract, peripheral nerves, kidney, and tongue (AL fibril protein)
Secondary amyloidosis (reactive systemic amyloidosis) often follows a chronic inflammatory disorder and the deposits are of the AA fibril protein
Other systemic amyloidoses include hemodialysis-related (Abeta2-microglobulin) and hereditary forms (ATTF)

Front 9

Case History:
A 54-year-old man presented with nocturia and easy bruising
It was noted that he had
golden brown colored skin
a firm liver edge, palpable 5 cm beneath the right costal margin in the midclavicular line
atrophic testes on physical examination

Why the golden brown colored skin?

Back 9

Thin epidermis, increased melanin in basal layer and dermal
iron deposition

Front 10

Possible causes for hypogonadism?

Back 10

Iron deposits impair hypothalamic-pituitary function, cirrhosis.

Front 11

Hemochromatosis

Back 11

Liver. Notice the dark brown involved areas on one side and contrast this to the reddish brown normal liver.

Pigment can be seen in hepatocytes, Kupffer cells and in bile duct epithelium. A thrombus in the portal vein also reminds us that more than one disease can affect a given organ.

The cirrhotic liver shows regenerated nodules being separated by bands of connective tissue

Front 12

What is the usual cardiovascular manifestation of
hemochromatosis?

Back 12

Congestive cardiomyopathy

Front 13

What are the general genetic characteristics of this disease?

Back 13

Primary or genetic hemochromatosis
homozygous recessive disease
hemochromatosis gene located on the short arm of chromosome 6 (HLA-H)
This gene somehow affects iron absorption

The mutated gene affects iron absorption by preventing the crypt epithelial cell to sense circulating iron levels. This leads to upregulation of proteins necessary for iron absorption by the intestine and excessive absorption of dietary iron ensues.

Front 14

What laboratory tests would be useful for screening this patient’s children?

Back 14

Serum iron and ferritin (elevated if affected) - while excluding secondary causes of iron overload
Increased transferrin saturation
HLA molecular genotyping (mutant HLA-H)
Liver biopsy
Genetic testing looking for HFE mutations ( C282Y and H63D)

Front 15

What is the pathogenesis of organ damage in this disease?

Back 15

Excessive iron is directly toxic to host tissues via generation of ROS (reduced oxygen species) via Fenton reactions:
lipid peroxidation
stimulation of collagen formation
direct interactions of iron with DNA

Front 16

What are the usual causes of death in this disease?

Back 16

Cirrhosis
Heart disease
Hepatocellular carcinoma

Front 17

Organapathy associ. w/ hemochromatosis?

Back 17

hypopituitarism, skin pigmentation, cardiac failure, hepatocellular carcinoma, cirrhosis, diabetes, arthropathy, testicular atrophy

Front 18

List secondary causes of this disease process.

Back 18

Secondary hemochromatosis (hemosiderosis) - table 16-7 page 615 Robbins Basic Pathology:
parenteral iron overload
ineffective erythropoiesis
increased oral iron intake
congenital atransferrinemia
chronic liver disease

Front 19

What is ineffective erythropoiesis?

Back 19

An anemia caused by defective heme or globin synthesis
(in contrast to anemias caused by hemolysis or blood loss).