Conference 04 - 2009 Case: 2 20090930

Signalment:

6-year-old, male Siberian husky (Canis familiaris).This dog was presented to the veterinary teaching hospital initially with hind limb paraparesis. Mild atrophy of hind limb muscles was also observed. Abdominal radiographs revealed severe calcification in the abdominal aorta. Despite treatment with levothyroxine, the rear legs became paralyzed. Gangrene of the extremities appeared and worsened. The dog was euthanized due to poor prognosis and necropsied. This animal had not been given a high-cholesterol diet.

Gross Description:

1. Systemic arteriosclerosis showing marked calcification in the arterial wall and luminal narrowing.
2. Thrombosis of the internal iliac, femoral, popliteal, and right superficial branchial arteries.
3. Atrophy of the pituitary and thyroid glands.
4. Dry gangrene in the tail, bilateral hind limbs and right forelimb.

Histopathologic Description:

Grossly, epicardial coronary arteries were prominently thickened, firm, yellow-white, and appeared as cord-like structures. Multiple whitish foci were recognized within the ventricular walls by incisions after formalin fixation. Histologically, massive deposition of cholesterol clefts and calcification with infiltration of foamy macrophages was noted in the thickened wall of epicardial arteries. Staining for elastin demonstrated the structural disorganization, such as the destruction of internal and external elastic membranes, intimal thickening, and the disappearance of the medial smooth muscle layer. Small foci of granulation tissue were scattered in the ventricular wall. Atherosclerotic lesions were also found in many organs, including aorta, spleen, kidney, lung, prostate, and brain. Both elastic arteries and large to middle-sized muscular arteries were involved.

Morphologic Diagnosis:

Heart (left ventricle): Coronary atherosclerosis, with small multifocal myocardial infarcts, Siberian husky, canine.

Lab Results:

Serum biochemical profile before starting levothyroxine treatment revealed elevated cholesterol, triglyceride, alkaline phosphatase and creatine kinase (total cholesterol, 1560 mg/dL; triglyceride, 596 m/dL; ALKP, 8434 U/L; CK, 1178 U/L) and subnormal levels of thyroid hormones (T3, 0.3 ng/mL; T4, 0.2 ng/mL; free T4, 0.3 ng/mL).

Condition:

Atherosclerosis (hypothyroidism)

Contributor Comment:

Atherosclerosis occurs only infrequently in animals and rarely leads to clinical diseases, such as infarction of heart or brain.(6) Naturally occurring atherosclerosis has been reported in aged pigs and birds, and in dogs with hypothyroidism that develop an accompanying hypercholesterolemia.(6) Hypothyroidism in most dogs results from progressive loss of functional thyroid tissues due to primary dysfunction of the gland.(2) Histological changes in the thyroid glands of this dog were replacement of parenchyma by adipose tissue with the absence of inflammatory cell infiltrates. Acute degeneration and necrosis of secretory cells, including TSH immunoreactive cells, were observed in the adenohypophysis; however, the cause and relationship of this lesion with the thyroid atrophy were unclear.

JPC Diagnosis:

Heart: Coronary arterial atherosclerosis, transmural and circumferential, diffuse, marked, with mineralization and multifocal chronic myocardial infarcts.

Conference Comment:

Conference participants engaged in a lively discussion regarding the areas of myocardial infarction in the submitted sections. Specifically, opinions on the age of the lesions varied widely, with participants who felt the lesions consisted of immature granulation tissue favoring a subacute process, while those who felt there was increased collagen deposition favored a chronic process. We consulted with the AFIP Department of Cardiovascular Pathology and estimate the infarcts to be over one month old. The evolution of the histomorphologic changes in myocardial infarction in humans is well-characterized, and is summarized below:(5)

Time	Light Microscope Findings
0 to 0.5 hr	None
0.5 to 4 hrs	None, or myofiber waviness at the border of the lesion
4 to 12 hrs	Early coagulation necrosis with hemorrhage and edema
12 to 24 hrs	Coagulation necrosis; myocyte hypereosinophilia and pyknosis, contraction band necrosis; early neutrophilic infiltrate
1 to 3 days	Coagulation necrosis; loss of cross striations and loss of nuclei; increased neutrophilic infiltrate
3 to 7 days	Early myofibers disintrigration; necrosis of neutrophils; macrophages at the border of the lesion
7 to 10 days	Increased macrophage infiltrate with phagocytosis of necrotic cells; early granulation tissue at infarct margins
10 to 14 days	Well-developed granulation tissue
2 to 8 weeks	Increased collagen deposition; decreased cellularity; regression of granulation tissue capillaries
>2 months	Dense collagenous scar

In addition to hypothyroidism-induced hypercholesterolemia, diabetes mellitus is often associated with atherosclerosis in dogs. In one study, dogs with atherosclerosis were over 53 times more likely than dogs without atherosclerosis to have diabetes mellitus, and over 51 times more likely to have hypothyroidism than dogs without atherosclerosis, but were not more likely to have hyperadrenocorticism than dogs without athoersclerosis.(1) Dogs are otherwise considered relatively atheroresistant, as are cats, cattle, goats, and rats. While this condition is only rarely clinically significant in domestic animals, nonhuman primates and pigs are the most popular animal models of human disease. As atherosclerosis is a significant cause of human mortality, it merits considerable research interest. Pigs, rabbits, and chickens are atherosensitive, and develop the disease in response to high dietary cholesterol intake, particularly when the proportion of very low density lipoproteins (VLDL) is increased.(3)

The pathogenesis of atherosclerosis in humans is well-studied, and the currently-accepted model, the response-to-injury hypothesis, characterizes atherosclerosis as a chronic response of the arterial wall to endothelial injury. An exhaustive review of the pathogenesis is beyond the scope of this report. Briefly, hypothyroidism or diabetes mellitus results in dyslipoproteinemia (i.e. increased low density lipoprotein (LDL) cholesterol, decreased high density lipoprotein (HDL) cholesterol, and/or increased levels of abnormal lipoprotein (a)). This causes endothelial damage by a variety of mechanisms, including oxygen free radical production that speeds the decay of nitric oxide and decreases its vasodilator activity. The damaged endothelium allows lipoproteins to accumulate in the intima, where they are oxidized by free radicals generated by macrophages and endothelial cells. Oxidized LDLs, which are directly toxic to endothelium and smooth muscle cells, are ingested by macrophages and smooth muscle cells, which become characteristic so-called foam cells. Damaged endothelium also allows the adhesion of platelets and expresses vascular cell adhesion molecule 1 (VCAM-1), which binds monocytes and T lymphocytes. Platelets and migrating leukocytes elaborate platelet-derived growth factor, interleukin-1, and interferon-gamma, which promote smooth muscle proliferation and extracellular matrix synthesis.(4) The resulting characteristic histologic lesion is the deposition of lipid in the vessel wall (i.e. atheroma), which is overlain by fibrosis and mineralization. The lesion in dogs differs from that of humans with respect to the location of lipid, which is primarily within the tunica media and adventitia in dogs, but primarily within the tunica intima in humans. With chronicity, atheromas may cause luminal narrowing and/or ulceration, leading to thrombosis, hemorrhage, or aneurysm.(3)

Most affected are the aorta, iliac, carotid, coronary, and femoral arteries. Grossly, affected vessels are enlarged and firm, with prominent yellow-brown nodules that project into the lumen. Other degenerative arterial diseases in domestic species include arteriosclerosis, and medial calcification, summarized in the table below.(6)

Name	Clinical and Gross Findings	Histomorphology
Atherosclerosis	Pigs, rabbits, chickens are atherosensitive; dogs, cats, cattle, goats, and rats are atheroresistant; affects large elastic and large and medium muscular arteries; seen most commonly in dogs with hypothyroidism or diabetes mellitus; gross = vessel wall thickened and firm with yellow-brown nodules projecting into the lumen	Fibrofatty plaque or atheroma in the vessel wall (tunica intima and media) and lipid-laden macrophages and/or smooth muscle cells (i.e. "foam cells") in the media and intima
Arteriosclerosis	Occurs in many species but rarely clinically significant; age-related, degenerative change; means "arterial hardening"; results in loss of elasticity; abdominal aorta most frequently affected; also occurs at arterial branching sites (turbulent blood flow); gross = raised, firm, white plaques	Intimal thickening by mucopolysaccharides (early) or medial thickening by proliferating smooth muscle cells and fibrosis that infiltrates into the intima (later); splitting of the internal elastic lamina
Arterial medial calcification	Common; affects elastic and muscular arteries; caused by certain plant toxins (e.g. Cestrum diurnum, Solanum malacoxylon, Trisetum flavescens), vitamin D toxicosis, renal disease (aged guinea pigs and rats), and paratuberculosis; spontaneous in rabbits; gross = solid, pipe-like vessels with white, solid, raised intimal plaques	Prominent, granular, basophilic material on medial elastic fibers; form a circumferential ring of mineralization in muscular arteries

In horses, intimal bodies in small arteries and arterioles, and siderocalcinosis of cerebral vessels are usually incidental findings of no clinical significance.(3,6)

References:

1. Hess RS, Kass PH, Van Winkle TJ: Association between diabetes mellitus, hypothyroidism or hyperadrenocorticism, and atherosclerosis in dogs. J Vet Intern Med 17:489-94, 2003
2. Kemppainen RJ, Clark TP: Etiopathogenesis of canine hypothyroidism. Vet Clin North Am Small Anim Pract 24:467-476, 1994
3. Maxie MG, Robinson WF: Cardiovascular system. In: Jubb, Kennedy, and Palmers Pathology of Domestic Animals, ed. Maxie MG, 5th ed., vol. 2, pp. 56-62. Elsevier Saunders, Philadelphia, PA, 2007
4. Mitchell RN, Schoen FJ: Blood vessels. In: Robbins and Cotran Pathologic Basis of Disease, eds. Kumar V, Abbas AK, Fausto N, Aster JC, 8th ed., pp. 496-504. Saunders Elsevier, Philadelphia, PA, 2010
5. Schoen FJ, Mitchell RN: The heart. In: Robbins and Cotran Pathologic Basis of Disease, eds. Kumar V, Abbas AK, Fausto N, Aster JC, 8th ed., pp. 547-559. Saunders Elsevier, Philadelphia, PA, 2010
6. Van Vleet JF, Ferrans VJ: Cardiovascular system. In: Pathologic Basis of Veterinary Disease, eds. McGavin MD, Zachary JF, 4th ed., pp. 599-602. Mosby Elsevier, St. Louis, MO, 2007