DiCORATO AND SCHNED
191
Lymphoepithelial Cyst of the Pancreas Truong LD, Rangdaeng S, Jordan P. Lymphoepithelial cyst of the pancreas. Am J Surg Pathol 1987; 11:899-903. Weidner N, Geisinger K, Sterling R, et al. Benign lymphoepithelial cysts of the parotid gland. Am J Clin Pathol 1986:85:395-401. Doll DC, List AF, Yarbro JW. Evans' syndrome associated with microcystic adenoma of the pancreas. Cancer 1987; 59:1366-1368. Compagno J, Oertel JE. Mucinous cystic neoplasms of the pancreas with overt and latent malignancy (cystadenocarcinoma and cystadenoma). Am J Clin Pathol 1978;69:573-580.
2. Howard JM. Cystic neoplasms and true cysts of the pancreas. Surg Clin North Am 1989;69:651-666. 3. Assawamatiyanont J, King A. Dermoid cysts of the pancreas. Am Surg 1977;43:503-504. 4. Luchtrath H, Schriefers K. Pankreaszyste unter dem bild einer sogenannten branchiogenen zyste. Der Pathologe 1985;6:217-219. 5. Mockli GC, Stein RM. Cystic lymphoepithelial lesion of the pancreas. Arch Pathol Lab Med 1990; 114:885-887.
The Heart in Tangier Disease Severe Coronary Atherosclerosis with Near Absence of High-Density Lipoprotein Cholesterol
Cardiac necropsy findings are described in a 72-year-old man with Tangier disease whose plasma total cholesterol levels averaged 70 mg/dL, low-density lipoprotein cholesterol level was 45 mg/dL, and high-density lipoprotein cholesterol level was 1.4 mg/dL, and who had coronary artery bypass grafting for severe atherosclerotic coronary artery disease. At necropsy, 24 of the 72 (33%) 5-mm segments of the 4 major (right, left main, left anterior descending, and left circumflex) native coronary arteries and 4 of the 27 (15%) 5-mm segments of the saphenous vein aortocoronary bypass conduits were narrowed by more than 75% in cross-sectional area by atherosclerotic plaques. The plaques
were composed primarily (91% to 97%) of fibrous tissue. Oil red O staining, polarized light microscopy, and electron microscopy revealed cholesterol deposits in the plaques and in the walls of coronary arteries, saphenous vein grafts, and aorta. Such deposits also were found in foam cells of histiocytic origin, fibroblasts in all four cardiac valves, and in Schwann cells of cardiac nerves. (Key words: Tangier disease; Atherosclerosis; High-density lipoprotein; Low-density lipoprotein; Coronary artery disease; Coronary artery bypass surgery) Am J Clin Pathol 1992; 98: 191-198
Tangier disease, a rare disorder of lipoprotein metabolism, is characterized by extremely low plasma levels of highdensity lipoprotein (HDL) cholesterol and low levels of total and low-density lipoprotein cholesterol. The low levels of HDL are due to rapid catabolism of HDL rather than to defective biosynthesis of HDL.' Patients with Tangier disease have accumulation of cholesteryl esters in various tissues, including tonsils, lymph nodes, thymus, bone marrow, intestinal mucosa, liver, spleen, skin, and
cornea. The disease is manifested by enlarged orange-yellow tonsils, splenomegaly, and peripheral neuropathy and is transmitted in an autosomal co-dominant mode. Little information is available on clinical and morphologic aspects of coronary artery disease in patients with genetic syndromes characterized by HDL deficiency, and no reports are available describing cardiovascular findings at necropsy in patients with Tangier disease. Such is the purpose of this report. REPORT OF A PATIENT
From the Pathology and Molecular Disease Branches, National Heart, Lung, and Blood Institute, National Institutes of Health. Bethesda. A 72-year-old white man, who had been an oil-refinery Maryland. Received August 28, 1991; received revised manuscript and accepted for publication February 28, 1992. Address reprint requests to Dr. Mautner: Pathology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 2N-258, Bethesda, Maryland 20892.
worker, had a tonsillectomy at age 14 years because of markedly enlarged tonsils. He remained well until age 42 years, when he noted excessive fatigue. At age 43 years (in 1962), he was found to have malabsorption, thrombocytopenia, and splenomegaly that resulted in splenec-
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SUSANNE L. MAUTNER, M.D., JULIAN A. SANCHEZ, M.D., DANIEL J. RADER, M.D. GISELA C. MAUTNER, M.D., VICTOR J. FERRANS, M.D., PH.D., DONALD S. FREDRICKSON, M.D., H. BRYAN BREWER, JR., M.D., AND WILLIAM C. ROBERTS, M.D.
192
ANATOMIC PATHOLOGY Single Case Report 1963) until age 72 years (in 1990): the systolic pressures averaged 120 mmHg and the diastolic averaged 77 mmHg. In May 1979 (at age 60 years), the patient underwent coronary artery bypass grafting with insertion of saphenous venous grafts from the aorta to the left anterior descending, first diagonal, and right coronary arteries. Repeated angiography in 1986 and 1989 revealed narrowing of the grafts and total occlusion of the right coronary artery, 75% diameter narrowing of the left main and left anterior descending coronary arteries, and total occlusion of the saphenous vein graft to the right coronary artery. At age 64 years, dementia was first observed and it progressed thereafter. A progressive wasting illness developed, the origin of which was never determined, and he died of bronchopneumonia at age 72 years. During a 17-year period (1973 to 1990), multiple determinations of plasma lipoproteins were made: total cholesterol ranged from 43 to 101 mg/dL (mean, 70 mg/dL); HDL cholesterol ranged from 0 to 7 mg/dL (mean, 1.4 mg/dL); low-density lipoprotein cholesterol ranged from 26 to 65 mg/dL (mean, 45 mg/dL); and triglyceride levels ranged from 113 to 396 mg/dL (mean, 203 mg/dL) (Table 1).
TABLE 1. LIPID CUMULATIVE FLOW SHEET (MG/DL)
Date 10/01/73 10/03/73 10/05/73 10/07/73 10/09/73 06/17/74 06/19/74 11/07/75 06/21/78 09/30/78 04/23/79 05/21/79 06/17/79 06/20/79 06/25/79 07/02/79 07/09/79 • 12/03/79 12/07/79 09/08/80 01/23/81 01/30/81 07/06/82 07/13/82 09/21/82 04/14/83 03/05/84 06/25/84 10/10/84 02/20/90 Average
Total Cholesterol
Triglycerides
HDL Cholesterol
LDL Cholesterol
101 71 78 81 66 91 76 75 74 85 77 75 83 78 66 43 53 61 74 72 60 58 69 62 65 79 64 61 59 52
362 396 212 263 238 172 175 137 207 251 214 245 256 251 183 160 153 164 174 185 188 139 216 219 227 213 113 116 143 113
0 0 0 0 0 0 0 2 2 6 0 0 0 0 0 0 0 0 2 7 5 4 1 1 0 1 1 1 4 4
65 48 46 42 32 56 55 59 47 43 55 40 52 48 46 26 41 44 51 39 32 38 46 39 47 57 39 45 39 36
70
203
1.4
45
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tomy. At age 44 years, he was referred to the National Institutes of Health, where the diagnosis of Tangier disease was made on the basis of clinical and biochemical studies. Some of these studies have been subjects of previous publications.2"4 Morphologic examination of various tissues from this patient constituted part of the original description of the pathologic features of Tangier disease (including the presence of lipid deposits in lymph nodes, spleen, bone marrow, liver, rectal mucosa, skin, and small nerves). At age 45 years, gynecomastia and an omental mass developed. At age 48 years, peripheral neuropathy was evident. At age 50 years, bilateral neural hearing loss developed and 4 years later glucose intolerance and corneal opacities were discovered. Angina pectoris developed at age 59 years. Angiography at that time disclosed severe coronary arterial narrowing with total occlusion of the left circumflex and 75% and 50% diameter narrowing of the left anterior descending and right coronary arteries, respectively. He smoked fewer than 10 cigarettes a month, was slightly overweight (weight, 88 kg; height, 179 cm), and had no history of systemic hypertension. Eighteen indirect systemic arterial pressure measurements were recorded from age 44 (in
MAUTNER ET AL. The Heart in Tangier Disease His father had hearing loss and died at age 75 years of an acute myocardial infarct; his mother died at age 84 years of natural causes. One sister had systemic hypertension and died of an acute myocardial infarct, as did the patient's brother, who was homozygous for Tangier disease and who developed angina at age 42 years. He died suddenly at age 48 years and autopsy was not performed. Two younger siblings died in infancy of "diphtheria." The son of the patient, who is obligate heterozygous for Tangier disease, had a tonsillectomy at age 7 years but is otherwise asymptomatic. The father and mother were distant cousins with no known relationship to the Chesapeake Bay Tangier kindred (Fig. 1 ).4 Gross Findings
cific deposits. No sections of skeletal muscle were available for examination. The heart weighed 310 g. There were no gross foci offibrosisor necrosis in the left ventricular myocardium. Calcific deposits were present in the mitral anulus (2+/4+) and in the bases of the aortic valve cusps (1+/4+). Atherosclerotic plaques were present in the descending thoracic and abdominal aorta. Microscopic Findings Tissue samples from left ventricular myocardium, ventricular septum, all 4 cardiac valves, coronary arteries, saphenous venous grafts, coronary sinus, and thoracic aorta were fixed in buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Frozen sections of formalin-fixed tissues from these sites were stained with oil red O. Unstained and oil red Ostained sections from these blocks were examined by polarized light microscopy to detect birefringent materials. These sections also were examined using Nomarski differential interference contrast microscopy to obtain further details of tissue morphology. The Schultz reaction,5 specific for cholesterol, was performed in sections of aortic valve leaflet, aorta, coronary arteries, and saphenous vein grafts. Additional pieces of tissue that had been fixed in
a
75 AMI
ja "diphtheria"
84
0
= Gender unknown
0-
deceased with age of death
6-i-D
"diphtheria"
= homozygous = heterozygous for Tangier disease
63 AMI
rW, stillborn
FIG. 1. Genealogical tree of affected family. It represents an update of the pedigree illustrated in 1965 by Hoffman and Fredrickson.4 The propositus (arrow) was homozygous for Tangier disease, had coronary bypass surgery at age 60 years, and died of pneumonia at age 72 years. His brother, who also was homozygous for Tangier disease, died at age 48 years of an acute myocardial infarct, as did one heterozygous sister. Two siblings died at age 2 years of presumed "diphtheria." The obligate heterozygous children of the brother and the son of the propositus are in good health. The latter had tonsillectomy at age 7 years. The parents of the propositus were both heterozygotes; the father had hearing loss and died of a myocardial infarct at age 75 years, and the mother died of natural causes at an advanced age.
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Autopsy was performed at the Chief Medical Examiner's Office in Louisville, Kentucky. The heart and other tissues were submitted to the National Institutes of Health for examination. Necropsy confirmed the presence of extensive acute bronchopneumonia. Foamy macrophages were found in lymph nodes. The liver weighed 1,200 g; most portal areas were fibrotic and foamy macrophages were located in the periportal and pericentral vein areas. In the omentum, a firm, yellow mass was present and consisted of densefibrosiswith cholesterol clefts and cal-
193
194
ANATOMIC PATHOLOGY Case Report
HEART, ANTERIOR VIEW
=80-100% narrowed
FlG. 2. Diagram of the heart showing distribution and extent of areas of severe narrowing of the coronary arteries and saphenous venous bypass grafts (SVG). PT = Pulmonary trunk.
FiGS. 3A and B. Histologic section of a saphenous vein graft to the right mainly of fibrous tissue (Movat stains; A, X27; B, X39).
The myocardium revealed normal myocytes but the amount of interstitial myocardial fibrous tissue was increased. The location of the stenoses in the coronary arteries and histologic examples are shown in Figures 2 and 3. Thirty-three percent of the 72 5-mm segments of the
(A) and of a left circumflex coronary artery (B). The plaques consist
A.J.C.P. • August 1992
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0
formalin were refixed in glutaraldehyde and prepared for electron microscopic examination. For quantitative assessment of the degree of narrowing and evaluation of plaque composition in the coronary arteries and in saphenous venous grafts, the vessels were dissected from the heart, decalcified, and sectioned transversely at 5-mm intervals. They were dehydrated, cleared, embedded in paraffin, cut, and stained by the Movat method. Seventy-two segments of the major epicardial coronary arteries and 27 segments of the saphenous venous grafts were taken. Evaluation was done by planimetry,6 outlining the internal elastic membrane, residual lumen, and components of the plaque, such as fibrous tissue, calcified tissue, pultaceous debris, and foam cells. The area of each component of plaque was then converted to a percentage of the total plaque area. The degree of cross-sectional luminal narrowing was categorized into 5 groups: 0 to 25%, 26% to 50%, 51% to 75%, 76% to 95%, and 96% to 100%.
195
MAUTNER ET AL. The Heart in Tangier Disease CROSS-SECTIONAL AREA NARROWING of 5-mm Segments of the Major Epicardial Coronary Arteries (n=72) and Saphenous Vein Grafts (n=27)
# &P
J&i*
Percent of 5-mm Coronary Segments 70 Aorto-coronary Saphenous Vein Grafts
51-75%
76-95%
96-100%
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26-50%
0-25%
Cross-Sectional Area Narrowing
FIG. 4. Histogram demonstrating the percentage of cross-sectional area narrowing of 5-mm segments of the four major epicardial coronary arteries (n = 72) and saphenous vein grafts (n = 27). In the native coronary arteries, 57% of all segments were narrowed less than 25% and 33% had plaques with narrowing of the lumen of more than 75% in cross-sectional area. The saphenous vein grafts showed a more homogeneous distribution of atherosclerotic plaques with less segments in the first category but also less in the category of narrowing more than 75% in cross-sectional area.
4 major (right, left main, left anterior descending, and left circumflex) coronary arteries were narrowed more than 75% in cross-sectional area by plaque and 15% of the 27 5-mm segments of the saphenous vein grafts were COMPOSITION OF ATHEROSCLEROTIC PLAQUES in 5-mm Segments of the Major Epicardial Coronary Arteries (n=72) and Saphenous Vein Grafts (n=27) Puttaceous Debris 0.5% v
\
„
Roam Cells
05%
Fibrous Tissue
91% Native Coronary Arteries
Pultacaous Debris
Fibrous Tissue
97% Aorto-Coronary Saphenous Vein Grafts
FIG. 5. Composition of atherosclerotic plaques in all 5-mm segments of the four major epicardial coronary arteries (n = 72) and saphenous vein grafts (n = 27). The plaques of the saphenous veins grafts consisted to a higher percentage offibroustissue (97%) compared to native coronary arteries (91%). The latter contained more calcific deposits (8% versus 2%) and foam cells.
FIGS. 6A-C. Photomicrographs of lipid deposits in frozen sections of the mitral valve, using different techniques (A) showing positive oil red 0 staining; (B) same area examined with polarized light microscope and (Q using Nomarski interference contrast optics to demonstrate details of tissue morphology in an area surrounding lipid-containing fibroblasts (X400, A, B, Q.
narrowed more than 75% in cross-sectional area by plaques (Fig. 4). The plaques in both native coronary arteries and in the saphenous vein grafts consisted almost entirely of fibrous tissue (91% and 97%, respectively); the native coronary
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FIGS. 7A-D. Ultrastructure of four different types of lipid-containing cells. A. Smooth muscle cell in the left anterior descending coronary artery. The cell has basement membrane, many actin-type filaments, and peripherally located myofilament insertion sites. It contains prominent lipid deposits, which correspond to those shown in other smooth muscle cells by polarized light microscopy (X4.000). B. Foam cells, probably of histiocytic origin, located in the adventitia of a coronary artery. It lacks a basement membrane and it contains many lipid droplets (X4,000). C. Smooth muscle cell in a saphenous venous bypass graft demonstrates ultrastructural characteristics similar to those of the smooth muscle cell in the coronary artery shown in (A). The lipid deposits in these cells tend to be more extensive and confluent (X6,000). D. Cell containing large amounts of endoplasmic reticulum and abundant lipid droplets was present in connective tissue of the mitral valve and was considered to represent a valvular fibroblast (X5.000).
MAUTNER ET AL.
197
The Heart in 1^angier Disease artery plaques had a higher content of calcium (8% versus 2%), and intra- and extracellular lipid deposits were minimal (Fig. 5). Oil Red O stain, Polarized Light Microscopy and Schultz Reaction
DISCUSSION
Electron Microscopy
The only previously reported information on cardiovascular morphologic findings in Tangier disease was the description of coronary intimal thickening and the presence of patchy lipid deposits in the mitral and tricuspid valves in a 5-year-old boy7 and the presence of focal lipid deposits in the wall of the pulmonary artery in a 10-yearold girl.2 The present study documents the occurrence of severe atherosclerosis in a patient with Tangier disease. Quantitative analysis revealed narrowing of more than 75% in cross-sectional area in 33% and 15% of all 5-mm segments of the native coronary arteries and saphenous vein grafts, respectively. Analysis of the plaque composition revealed that fibrous tissue was the major component, a finding similar to those reported in patients without Tangier disease having fatal atherosclerotic coronary artery disease. 68 "" This is especially interesting in light of the fact that Tangier disease results in the abnormal accumulation of cholesteryl ester in the histiocytes of many organs, and therefore may have been expected to result in an abnormal form of atherosclerosis as well.2
The endothelial cells of the coronary arteries and capillaries were free of lipid deposits. The oil red O-positive lipid deposits observed by light microscopy in the coronary arteries were located in both smooth muscle cells and in foam cells. The number of lipid droplets in the smooth muscle cells varied considerably. These droplets were electronlucent and were not limited by membranes (Fig. 1A). The foam cells were oval or round in shape. They were usually larger in size than the smooth muscle cells (Fig. IB). They did not have basement membranes, and their cytoplasm was completely filled by small lipid droplets, which at times tended to become confluent. In the saphenous vein grafts, no foam cells were observed and lipid deposits were present only in smooth muscle cells (Fig. 1C). On the basis of electron microscopic observations, it was not possible to distinguish extracellular lipid deposits in the atherosclerotic plaques specifically related to Tangier disease, that is, those containing masses of cholesterol, from those occurring as nonspecific components of ordinary atherosclerotic plaques. In cardiac valves, lipid deposits were found in both foam cells and in fibroblasts. The latter cells were identified by their content of cisterns of rough-surfaced endoplasmic reticulum, elongated shape, and lack of basement mem-
In both plaques and in the walls of the vessels, cholesterol was present in smooth muscle cells. Accumulation of cholesterol often was not suspected in preparations stained with hematoxylin and eosin and was recognized only by the positive reaction with oil red O stain, birefringence in polarized light microscopy, Schultz reaction, and by the ultrastructural appearance. Cholesterol deposits also were present in cardiac valves and cardiac nerves, resembling those described in several patients with Tangier disease. 2,7 ' 2 It was demonstrated in previous studies that the lipid deposits in various organs of patients affected with Tangier disease were histochemically similar. They were birefringent, stainable by lipid-soluable dyes, such as oil red O, and by the Schultz reaction for cholesterol. These results are concordant with the extensive chemical data showing that an increased content of cholesteryl esters in those lipid droplets was the consistent abnormality. 1 ' 213 -' 6 Epidemiologically, plasma concentrations of HDL cholesterol are inversely associated with risk of premature atherosclerotic cardiovascular disease.'7 Apolipoprotein (apo) A-I is the primary protein in HDL and serves a variety of structural and functional roles in HDL metabolism.18 Genetic defects that result in the inability to syn-
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Cardiac myocytes did not contain birefringent lipids. The four cardiac valves showed diffuse oil red O-positive reaction (Fig. 6A), which corresponded to areas of birefringence suggesting cholesterol deposits (Fig. 6B). Examination with Nomarski optics showed that the lipid deposits were intracellular (Fig. 6C). The distribution of oil red O-positive material in the coronary arteries and saphenous venous grafts was inhomogeneous and variable in location and amount, with this material present in media, adventitia, and plaque. Sections of left main and left anterior descending coronary arteries showed birefringence only in some atherosclerotic plaques. The left circumflex coronary artery revealed extensive birefringence in adventitia and in atherosclerotic plaques (corresponding to oil red O-positive areas). The saphenous vein grafts showed extensive birefringence in adventitia, media, and in plaques. In the sections examined with the Schultz reaction, the areas of birefringence partially corresponded to areas stained positive for cholesterol.
branes. Foam cells were larger in size and resembled those in coronary arteries (Fig. ID). The changes in the thoracic aorta were similar to those in the coronary arteries and saphenous vein grafts. Lipid deposits also were present in epicardial nerves and consisted of small droplets in the cytoplasm of Schwann cells enveloping unmyelinated axons, and within the axons.
ANATOMIC
198
PATHOLOGY
Single Case Report
In summary, we describe in this report the first cardiac necropsy findings in an adult patient with Tangier disease. This patient had clinical symptoms of coronary artery disease by age 59 years and was found at necropsy to have severe atherosclerotic disease that did not differ histologically from atherosclerosis occurring in patients without Tangier disease. However, cholesterol deposits in cardiac valves and cardiac nerves found in our patient were considered to be more specific features of Tangier disease. REFERENCES 1. Assmann G. Schmitz G, Brewer HB Jr. Familial high density lipoprotein deficiency: Tangier disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Stanbury JB, Wyngaarden JB, Fredrickson DS, consulting eds. The Metabolic Basis of Inherited Disease. I. Sixth Edition. New York: McGraw-Hill, 1989, pp 1267-1282. 2. Ferrans VJ, Fredrickson DS. The pathology of Tangier disease. A light and electron microscopic study. Am J Pathol 1975:78:101158. 3. Schaefer EJ, Zech LA, Schwartz DE, Brewer HB Jr. Coronary heart disease prevalence and other clinical features in familial highdensity lipoprotein deficiency (Tangier disease). Ann Intern Med 1980;93:261-266.
4. Hoffman HN II, Fredrickson DS. Tangier disease (familial high density lipoprotein deficiency). Clinical and genetic features in two adults. Am J Med 1965;39:582-593. 5. Luna LG. Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology, Third Edition. New York: McGrawHill, 1968, p 140. 6. Kragel AH, Shanthasundari GR, Wittes JT, Roberts WC. Morphometric analysis of the composition of atherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarction and in sudden coronary death. Circulation 1989; 80: 1747-1756. 7. Bale PM, Clifton-Bligh P, Benjamin BN, Whyte HM. Pathology of Tangier disease. J Clin Pathol 1971;24:609-616. 8. Kragel AH, Reddy SG, Wittes JT, Roberts WC. Morphometry analysis of the composition of coronary arterial plaques in isolated unstable angina pectoris with pain at rest. Am J Cardiol 1990; 66: 562-567. 9. Kragel AH, Roberts WC. Composition of atherosclerotic plaques in the coronary arteries in homozygous familial hypercholesterolemia. Am Heart J 1991;121:210-211. 10. Dollar AL, Kragel AH, Fernicola DJ, et al. Composition of atherosclerotic plaques in coronary arteries in women < 40 years of age with fatal coronary artery disease and implications for plaque reversibility. Am J Cardiol 1991;67:1223-1227. 11. Gertz SD, Malekzadeh S, Dollar AL, et al. Composition of atherosclerotic plaques in the four major epicardial coronary arteries in patients & 90 years of age. Am J Cardiol 1991;67:1228-1233. 12. Schmalbruch H, Stender S, Boysen G. Abnormalities in spinal neurons and dorsal root ganglion cells in Tangier disease presenting with a syringomyelia-like syndrome. J Neuropathol Exp Neurol 1987;46(5):533-543. 13. Herbert PN, Forte T, Heinen RJ, Fredrickson DS. Tangier disease. One explanation of lipid storage. N Engl J Med I978;299(10): 519-521. 14. Schmitz G, Bruening T, Williamson E, Nowicka G. The role of HDL in reverse cholesterol transport and its disturbances in Tangier disease and HDL deficiency with xanthomas. Eur Heart J 1990; ll(SupplE): 197-211. 15. Katz SS, Small DM, Brook JG, Lees RS. The storage lipids in Tangier disease. A physical chemical study. J Clin Invest 1977;59:10451054. 16. Assmann G, Schaefer HE. High density lipoprotein deficiency and lipid deposition in Tangier disease. In: Carlson LA, Paoletti R, Sirtori CR, Weber G, eds. International Conference on Atherosclerosis. New York: Raven Press, 1978, pp 97-101. 17. Gordon DJ, Rifkind BM. High-density lipoprotein-the clinical implications of recent studies. N Engl J Med 1989:321:1311-1316. 18. Brewer HB Jr, Gregg RE, Hoeg JM, Fojo SS. Apolipoproteins and lipoproteins in human plasma: An overview. Clin Chem 1988:34: 4-8. 19. Norum RA, Lakier JB, Goldstein S, et al. Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease. N Engl J Med 1982;306:1513-1519. 20. Schaefer EJ, Ordovas JM, Law SW, et al. Familial apolipoprotein A-I and C-III deficiency, variant II. J Lipid Res 1985;26:10891101. 21. Matsunaga T, Hiasa Y, Yanagi H, et al. Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene. Proc Natl Acad Sci USA 1991;88:2793-2797. 22. Schaefer EJ, Blum CB, Levy RI, et al. Metabolism of high-density lipoprotein apolipoproteins in Tangier disease. N Engl J Med 1978;299:905-910. 23. Schaefer EJ, Anderson DW, Zech LA, et al. Metabolism of high density lipoprotein subfractions and constituents in Tangier disease following the infusion of high density lipoproteins. J Lipid Res 1981;22:217-228. 24. Bojanovski D, Gregg RE, Zech LA, et al. In vivo metabolism of proapolipoprotein A-I in Tangier disease. J Clin Invest 1987:80: 1742-1747. 25. Schaefer EJ. Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. Arteriosclerosis 1984;4:303-322.
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thesize apoA-I result in very low plasma concentrations of HDL cholesterol and premature coronary artery disease.18"21 Conversely, in Tangier disease, plasma levels of HDL cholesterol and apoA-I are very low as a result of exceptionally rapid catabolism.22"24 Are the very low HDL cholesterol and apoA-I concentrations in Tangier disease a risk factor for premature atherosclerotic cardiovascular disease? In a review of the clinical features of Tangier disease,3'25 five of eight homozygous patients older than 40 years had definite clinical evidence of atherosclerotic cardiovascular disease, with four having onset of symptoms before age 60 years. Obligate heterozygotes for Tangier disease have HDL cholesterol levels approximately one half of normal.3,25 Of 14 heterozygous patients older than 40 years, 7 had clinical evidence of atherosclerotic cardiovascular disease, with 5 having onset of symptoms before age 60 years. However, no homozygous or heterozygous patient developed symptoms of atherosclerotic cardiovascular disease before the age of 40 years. The conclusion is that patients with Tangier disease are at some increased risk for premature vascular disease, but not to the degree expected from the extremely low plasma HDL cholesterol levels. Two factors may potentially offset this enhanced risk. First, Tangier disease patients almost always have significantly lower plasma low-density lipoprotein cholesterol levels than the normal population,3,25 and thus may be partially protected from the usual atherogenic process. Second, the mechanism of the low HDL cholesterol, specifically normal synthesis with markedly accelerated catabolism of HDL, allows a high "flux" of HDL and may permit some HDL-mediated removal of excess cholesterol from tissues (reverse cholesterol transport), despite the very low steady-state plasma levels of HDL.
191
Lymphoepithelial Cyst of the Pancreas Truong LD, Rangdaeng S, Jordan P. Lymphoepithelial cyst of the pancreas. Am J Surg Pathol 1987; 11:899-903. Weidner N, Geisinger K, Sterling R, et al. Benign lymphoepithelial cysts of the parotid gland. Am J Clin Pathol 1986:85:395-401. Doll DC, List AF, Yarbro JW. Evans' syndrome associated with microcystic adenoma of the pancreas. Cancer 1987; 59:1366-1368. Compagno J, Oertel JE. Mucinous cystic neoplasms of the pancreas with overt and latent malignancy (cystadenocarcinoma and cystadenoma). Am J Clin Pathol 1978;69:573-580.
2. Howard JM. Cystic neoplasms and true cysts of the pancreas. Surg Clin North Am 1989;69:651-666. 3. Assawamatiyanont J, King A. Dermoid cysts of the pancreas. Am Surg 1977;43:503-504. 4. Luchtrath H, Schriefers K. Pankreaszyste unter dem bild einer sogenannten branchiogenen zyste. Der Pathologe 1985;6:217-219. 5. Mockli GC, Stein RM. Cystic lymphoepithelial lesion of the pancreas. Arch Pathol Lab Med 1990; 114:885-887.
The Heart in Tangier Disease Severe Coronary Atherosclerosis with Near Absence of High-Density Lipoprotein Cholesterol
Cardiac necropsy findings are described in a 72-year-old man with Tangier disease whose plasma total cholesterol levels averaged 70 mg/dL, low-density lipoprotein cholesterol level was 45 mg/dL, and high-density lipoprotein cholesterol level was 1.4 mg/dL, and who had coronary artery bypass grafting for severe atherosclerotic coronary artery disease. At necropsy, 24 of the 72 (33%) 5-mm segments of the 4 major (right, left main, left anterior descending, and left circumflex) native coronary arteries and 4 of the 27 (15%) 5-mm segments of the saphenous vein aortocoronary bypass conduits were narrowed by more than 75% in cross-sectional area by atherosclerotic plaques. The plaques
were composed primarily (91% to 97%) of fibrous tissue. Oil red O staining, polarized light microscopy, and electron microscopy revealed cholesterol deposits in the plaques and in the walls of coronary arteries, saphenous vein grafts, and aorta. Such deposits also were found in foam cells of histiocytic origin, fibroblasts in all four cardiac valves, and in Schwann cells of cardiac nerves. (Key words: Tangier disease; Atherosclerosis; High-density lipoprotein; Low-density lipoprotein; Coronary artery disease; Coronary artery bypass surgery) Am J Clin Pathol 1992; 98: 191-198
Tangier disease, a rare disorder of lipoprotein metabolism, is characterized by extremely low plasma levels of highdensity lipoprotein (HDL) cholesterol and low levels of total and low-density lipoprotein cholesterol. The low levels of HDL are due to rapid catabolism of HDL rather than to defective biosynthesis of HDL.' Patients with Tangier disease have accumulation of cholesteryl esters in various tissues, including tonsils, lymph nodes, thymus, bone marrow, intestinal mucosa, liver, spleen, skin, and
cornea. The disease is manifested by enlarged orange-yellow tonsils, splenomegaly, and peripheral neuropathy and is transmitted in an autosomal co-dominant mode. Little information is available on clinical and morphologic aspects of coronary artery disease in patients with genetic syndromes characterized by HDL deficiency, and no reports are available describing cardiovascular findings at necropsy in patients with Tangier disease. Such is the purpose of this report. REPORT OF A PATIENT
From the Pathology and Molecular Disease Branches, National Heart, Lung, and Blood Institute, National Institutes of Health. Bethesda. A 72-year-old white man, who had been an oil-refinery Maryland. Received August 28, 1991; received revised manuscript and accepted for publication February 28, 1992. Address reprint requests to Dr. Mautner: Pathology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 2N-258, Bethesda, Maryland 20892.
worker, had a tonsillectomy at age 14 years because of markedly enlarged tonsils. He remained well until age 42 years, when he noted excessive fatigue. At age 43 years (in 1962), he was found to have malabsorption, thrombocytopenia, and splenomegaly that resulted in splenec-
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SUSANNE L. MAUTNER, M.D., JULIAN A. SANCHEZ, M.D., DANIEL J. RADER, M.D. GISELA C. MAUTNER, M.D., VICTOR J. FERRANS, M.D., PH.D., DONALD S. FREDRICKSON, M.D., H. BRYAN BREWER, JR., M.D., AND WILLIAM C. ROBERTS, M.D.
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ANATOMIC PATHOLOGY Single Case Report 1963) until age 72 years (in 1990): the systolic pressures averaged 120 mmHg and the diastolic averaged 77 mmHg. In May 1979 (at age 60 years), the patient underwent coronary artery bypass grafting with insertion of saphenous venous grafts from the aorta to the left anterior descending, first diagonal, and right coronary arteries. Repeated angiography in 1986 and 1989 revealed narrowing of the grafts and total occlusion of the right coronary artery, 75% diameter narrowing of the left main and left anterior descending coronary arteries, and total occlusion of the saphenous vein graft to the right coronary artery. At age 64 years, dementia was first observed and it progressed thereafter. A progressive wasting illness developed, the origin of which was never determined, and he died of bronchopneumonia at age 72 years. During a 17-year period (1973 to 1990), multiple determinations of plasma lipoproteins were made: total cholesterol ranged from 43 to 101 mg/dL (mean, 70 mg/dL); HDL cholesterol ranged from 0 to 7 mg/dL (mean, 1.4 mg/dL); low-density lipoprotein cholesterol ranged from 26 to 65 mg/dL (mean, 45 mg/dL); and triglyceride levels ranged from 113 to 396 mg/dL (mean, 203 mg/dL) (Table 1).
TABLE 1. LIPID CUMULATIVE FLOW SHEET (MG/DL)
Date 10/01/73 10/03/73 10/05/73 10/07/73 10/09/73 06/17/74 06/19/74 11/07/75 06/21/78 09/30/78 04/23/79 05/21/79 06/17/79 06/20/79 06/25/79 07/02/79 07/09/79 • 12/03/79 12/07/79 09/08/80 01/23/81 01/30/81 07/06/82 07/13/82 09/21/82 04/14/83 03/05/84 06/25/84 10/10/84 02/20/90 Average
Total Cholesterol
Triglycerides
HDL Cholesterol
LDL Cholesterol
101 71 78 81 66 91 76 75 74 85 77 75 83 78 66 43 53 61 74 72 60 58 69 62 65 79 64 61 59 52
362 396 212 263 238 172 175 137 207 251 214 245 256 251 183 160 153 164 174 185 188 139 216 219 227 213 113 116 143 113
0 0 0 0 0 0 0 2 2 6 0 0 0 0 0 0 0 0 2 7 5 4 1 1 0 1 1 1 4 4
65 48 46 42 32 56 55 59 47 43 55 40 52 48 46 26 41 44 51 39 32 38 46 39 47 57 39 45 39 36
70
203
1.4
45
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tomy. At age 44 years, he was referred to the National Institutes of Health, where the diagnosis of Tangier disease was made on the basis of clinical and biochemical studies. Some of these studies have been subjects of previous publications.2"4 Morphologic examination of various tissues from this patient constituted part of the original description of the pathologic features of Tangier disease (including the presence of lipid deposits in lymph nodes, spleen, bone marrow, liver, rectal mucosa, skin, and small nerves). At age 45 years, gynecomastia and an omental mass developed. At age 48 years, peripheral neuropathy was evident. At age 50 years, bilateral neural hearing loss developed and 4 years later glucose intolerance and corneal opacities were discovered. Angina pectoris developed at age 59 years. Angiography at that time disclosed severe coronary arterial narrowing with total occlusion of the left circumflex and 75% and 50% diameter narrowing of the left anterior descending and right coronary arteries, respectively. He smoked fewer than 10 cigarettes a month, was slightly overweight (weight, 88 kg; height, 179 cm), and had no history of systemic hypertension. Eighteen indirect systemic arterial pressure measurements were recorded from age 44 (in
MAUTNER ET AL. The Heart in Tangier Disease His father had hearing loss and died at age 75 years of an acute myocardial infarct; his mother died at age 84 years of natural causes. One sister had systemic hypertension and died of an acute myocardial infarct, as did the patient's brother, who was homozygous for Tangier disease and who developed angina at age 42 years. He died suddenly at age 48 years and autopsy was not performed. Two younger siblings died in infancy of "diphtheria." The son of the patient, who is obligate heterozygous for Tangier disease, had a tonsillectomy at age 7 years but is otherwise asymptomatic. The father and mother were distant cousins with no known relationship to the Chesapeake Bay Tangier kindred (Fig. 1 ).4 Gross Findings
cific deposits. No sections of skeletal muscle were available for examination. The heart weighed 310 g. There were no gross foci offibrosisor necrosis in the left ventricular myocardium. Calcific deposits were present in the mitral anulus (2+/4+) and in the bases of the aortic valve cusps (1+/4+). Atherosclerotic plaques were present in the descending thoracic and abdominal aorta. Microscopic Findings Tissue samples from left ventricular myocardium, ventricular septum, all 4 cardiac valves, coronary arteries, saphenous venous grafts, coronary sinus, and thoracic aorta were fixed in buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Frozen sections of formalin-fixed tissues from these sites were stained with oil red O. Unstained and oil red Ostained sections from these blocks were examined by polarized light microscopy to detect birefringent materials. These sections also were examined using Nomarski differential interference contrast microscopy to obtain further details of tissue morphology. The Schultz reaction,5 specific for cholesterol, was performed in sections of aortic valve leaflet, aorta, coronary arteries, and saphenous vein grafts. Additional pieces of tissue that had been fixed in
a
75 AMI
ja "diphtheria"
84
0
= Gender unknown
0-
deceased with age of death
6-i-D
"diphtheria"
= homozygous = heterozygous for Tangier disease
63 AMI
rW, stillborn
FIG. 1. Genealogical tree of affected family. It represents an update of the pedigree illustrated in 1965 by Hoffman and Fredrickson.4 The propositus (arrow) was homozygous for Tangier disease, had coronary bypass surgery at age 60 years, and died of pneumonia at age 72 years. His brother, who also was homozygous for Tangier disease, died at age 48 years of an acute myocardial infarct, as did one heterozygous sister. Two siblings died at age 2 years of presumed "diphtheria." The obligate heterozygous children of the brother and the son of the propositus are in good health. The latter had tonsillectomy at age 7 years. The parents of the propositus were both heterozygotes; the father had hearing loss and died of a myocardial infarct at age 75 years, and the mother died of natural causes at an advanced age.
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Autopsy was performed at the Chief Medical Examiner's Office in Louisville, Kentucky. The heart and other tissues were submitted to the National Institutes of Health for examination. Necropsy confirmed the presence of extensive acute bronchopneumonia. Foamy macrophages were found in lymph nodes. The liver weighed 1,200 g; most portal areas were fibrotic and foamy macrophages were located in the periportal and pericentral vein areas. In the omentum, a firm, yellow mass was present and consisted of densefibrosiswith cholesterol clefts and cal-
193
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ANATOMIC PATHOLOGY Case Report
HEART, ANTERIOR VIEW
=80-100% narrowed
FlG. 2. Diagram of the heart showing distribution and extent of areas of severe narrowing of the coronary arteries and saphenous venous bypass grafts (SVG). PT = Pulmonary trunk.
FiGS. 3A and B. Histologic section of a saphenous vein graft to the right mainly of fibrous tissue (Movat stains; A, X27; B, X39).
The myocardium revealed normal myocytes but the amount of interstitial myocardial fibrous tissue was increased. The location of the stenoses in the coronary arteries and histologic examples are shown in Figures 2 and 3. Thirty-three percent of the 72 5-mm segments of the
(A) and of a left circumflex coronary artery (B). The plaques consist
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0
formalin were refixed in glutaraldehyde and prepared for electron microscopic examination. For quantitative assessment of the degree of narrowing and evaluation of plaque composition in the coronary arteries and in saphenous venous grafts, the vessels were dissected from the heart, decalcified, and sectioned transversely at 5-mm intervals. They were dehydrated, cleared, embedded in paraffin, cut, and stained by the Movat method. Seventy-two segments of the major epicardial coronary arteries and 27 segments of the saphenous venous grafts were taken. Evaluation was done by planimetry,6 outlining the internal elastic membrane, residual lumen, and components of the plaque, such as fibrous tissue, calcified tissue, pultaceous debris, and foam cells. The area of each component of plaque was then converted to a percentage of the total plaque area. The degree of cross-sectional luminal narrowing was categorized into 5 groups: 0 to 25%, 26% to 50%, 51% to 75%, 76% to 95%, and 96% to 100%.
195
MAUTNER ET AL. The Heart in Tangier Disease CROSS-SECTIONAL AREA NARROWING of 5-mm Segments of the Major Epicardial Coronary Arteries (n=72) and Saphenous Vein Grafts (n=27)
# &P
J&i*
Percent of 5-mm Coronary Segments 70 Aorto-coronary Saphenous Vein Grafts
51-75%
76-95%
96-100%
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26-50%
0-25%
Cross-Sectional Area Narrowing
FIG. 4. Histogram demonstrating the percentage of cross-sectional area narrowing of 5-mm segments of the four major epicardial coronary arteries (n = 72) and saphenous vein grafts (n = 27). In the native coronary arteries, 57% of all segments were narrowed less than 25% and 33% had plaques with narrowing of the lumen of more than 75% in cross-sectional area. The saphenous vein grafts showed a more homogeneous distribution of atherosclerotic plaques with less segments in the first category but also less in the category of narrowing more than 75% in cross-sectional area.
4 major (right, left main, left anterior descending, and left circumflex) coronary arteries were narrowed more than 75% in cross-sectional area by plaque and 15% of the 27 5-mm segments of the saphenous vein grafts were COMPOSITION OF ATHEROSCLEROTIC PLAQUES in 5-mm Segments of the Major Epicardial Coronary Arteries (n=72) and Saphenous Vein Grafts (n=27) Puttaceous Debris 0.5% v
\
„
Roam Cells
05%
Fibrous Tissue
91% Native Coronary Arteries
Pultacaous Debris
Fibrous Tissue
97% Aorto-Coronary Saphenous Vein Grafts
FIG. 5. Composition of atherosclerotic plaques in all 5-mm segments of the four major epicardial coronary arteries (n = 72) and saphenous vein grafts (n = 27). The plaques of the saphenous veins grafts consisted to a higher percentage offibroustissue (97%) compared to native coronary arteries (91%). The latter contained more calcific deposits (8% versus 2%) and foam cells.
FIGS. 6A-C. Photomicrographs of lipid deposits in frozen sections of the mitral valve, using different techniques (A) showing positive oil red 0 staining; (B) same area examined with polarized light microscope and (Q using Nomarski interference contrast optics to demonstrate details of tissue morphology in an area surrounding lipid-containing fibroblasts (X400, A, B, Q.
narrowed more than 75% in cross-sectional area by plaques (Fig. 4). The plaques in both native coronary arteries and in the saphenous vein grafts consisted almost entirely of fibrous tissue (91% and 97%, respectively); the native coronary
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FIGS. 7A-D. Ultrastructure of four different types of lipid-containing cells. A. Smooth muscle cell in the left anterior descending coronary artery. The cell has basement membrane, many actin-type filaments, and peripherally located myofilament insertion sites. It contains prominent lipid deposits, which correspond to those shown in other smooth muscle cells by polarized light microscopy (X4.000). B. Foam cells, probably of histiocytic origin, located in the adventitia of a coronary artery. It lacks a basement membrane and it contains many lipid droplets (X4,000). C. Smooth muscle cell in a saphenous venous bypass graft demonstrates ultrastructural characteristics similar to those of the smooth muscle cell in the coronary artery shown in (A). The lipid deposits in these cells tend to be more extensive and confluent (X6,000). D. Cell containing large amounts of endoplasmic reticulum and abundant lipid droplets was present in connective tissue of the mitral valve and was considered to represent a valvular fibroblast (X5.000).
MAUTNER ET AL.
197
The Heart in 1^angier Disease artery plaques had a higher content of calcium (8% versus 2%), and intra- and extracellular lipid deposits were minimal (Fig. 5). Oil Red O stain, Polarized Light Microscopy and Schultz Reaction
DISCUSSION
Electron Microscopy
The only previously reported information on cardiovascular morphologic findings in Tangier disease was the description of coronary intimal thickening and the presence of patchy lipid deposits in the mitral and tricuspid valves in a 5-year-old boy7 and the presence of focal lipid deposits in the wall of the pulmonary artery in a 10-yearold girl.2 The present study documents the occurrence of severe atherosclerosis in a patient with Tangier disease. Quantitative analysis revealed narrowing of more than 75% in cross-sectional area in 33% and 15% of all 5-mm segments of the native coronary arteries and saphenous vein grafts, respectively. Analysis of the plaque composition revealed that fibrous tissue was the major component, a finding similar to those reported in patients without Tangier disease having fatal atherosclerotic coronary artery disease. 68 "" This is especially interesting in light of the fact that Tangier disease results in the abnormal accumulation of cholesteryl ester in the histiocytes of many organs, and therefore may have been expected to result in an abnormal form of atherosclerosis as well.2
The endothelial cells of the coronary arteries and capillaries were free of lipid deposits. The oil red O-positive lipid deposits observed by light microscopy in the coronary arteries were located in both smooth muscle cells and in foam cells. The number of lipid droplets in the smooth muscle cells varied considerably. These droplets were electronlucent and were not limited by membranes (Fig. 1A). The foam cells were oval or round in shape. They were usually larger in size than the smooth muscle cells (Fig. IB). They did not have basement membranes, and their cytoplasm was completely filled by small lipid droplets, which at times tended to become confluent. In the saphenous vein grafts, no foam cells were observed and lipid deposits were present only in smooth muscle cells (Fig. 1C). On the basis of electron microscopic observations, it was not possible to distinguish extracellular lipid deposits in the atherosclerotic plaques specifically related to Tangier disease, that is, those containing masses of cholesterol, from those occurring as nonspecific components of ordinary atherosclerotic plaques. In cardiac valves, lipid deposits were found in both foam cells and in fibroblasts. The latter cells were identified by their content of cisterns of rough-surfaced endoplasmic reticulum, elongated shape, and lack of basement mem-
In both plaques and in the walls of the vessels, cholesterol was present in smooth muscle cells. Accumulation of cholesterol often was not suspected in preparations stained with hematoxylin and eosin and was recognized only by the positive reaction with oil red O stain, birefringence in polarized light microscopy, Schultz reaction, and by the ultrastructural appearance. Cholesterol deposits also were present in cardiac valves and cardiac nerves, resembling those described in several patients with Tangier disease. 2,7 ' 2 It was demonstrated in previous studies that the lipid deposits in various organs of patients affected with Tangier disease were histochemically similar. They were birefringent, stainable by lipid-soluable dyes, such as oil red O, and by the Schultz reaction for cholesterol. These results are concordant with the extensive chemical data showing that an increased content of cholesteryl esters in those lipid droplets was the consistent abnormality. 1 ' 213 -' 6 Epidemiologically, plasma concentrations of HDL cholesterol are inversely associated with risk of premature atherosclerotic cardiovascular disease.'7 Apolipoprotein (apo) A-I is the primary protein in HDL and serves a variety of structural and functional roles in HDL metabolism.18 Genetic defects that result in the inability to syn-
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Cardiac myocytes did not contain birefringent lipids. The four cardiac valves showed diffuse oil red O-positive reaction (Fig. 6A), which corresponded to areas of birefringence suggesting cholesterol deposits (Fig. 6B). Examination with Nomarski optics showed that the lipid deposits were intracellular (Fig. 6C). The distribution of oil red O-positive material in the coronary arteries and saphenous venous grafts was inhomogeneous and variable in location and amount, with this material present in media, adventitia, and plaque. Sections of left main and left anterior descending coronary arteries showed birefringence only in some atherosclerotic plaques. The left circumflex coronary artery revealed extensive birefringence in adventitia and in atherosclerotic plaques (corresponding to oil red O-positive areas). The saphenous vein grafts showed extensive birefringence in adventitia, media, and in plaques. In the sections examined with the Schultz reaction, the areas of birefringence partially corresponded to areas stained positive for cholesterol.
branes. Foam cells were larger in size and resembled those in coronary arteries (Fig. ID). The changes in the thoracic aorta were similar to those in the coronary arteries and saphenous vein grafts. Lipid deposits also were present in epicardial nerves and consisted of small droplets in the cytoplasm of Schwann cells enveloping unmyelinated axons, and within the axons.
ANATOMIC
198
PATHOLOGY
Single Case Report
In summary, we describe in this report the first cardiac necropsy findings in an adult patient with Tangier disease. This patient had clinical symptoms of coronary artery disease by age 59 years and was found at necropsy to have severe atherosclerotic disease that did not differ histologically from atherosclerosis occurring in patients without Tangier disease. However, cholesterol deposits in cardiac valves and cardiac nerves found in our patient were considered to be more specific features of Tangier disease. REFERENCES 1. Assmann G. Schmitz G, Brewer HB Jr. Familial high density lipoprotein deficiency: Tangier disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Stanbury JB, Wyngaarden JB, Fredrickson DS, consulting eds. The Metabolic Basis of Inherited Disease. I. Sixth Edition. New York: McGraw-Hill, 1989, pp 1267-1282. 2. Ferrans VJ, Fredrickson DS. The pathology of Tangier disease. A light and electron microscopic study. Am J Pathol 1975:78:101158. 3. Schaefer EJ, Zech LA, Schwartz DE, Brewer HB Jr. Coronary heart disease prevalence and other clinical features in familial highdensity lipoprotein deficiency (Tangier disease). Ann Intern Med 1980;93:261-266.
4. Hoffman HN II, Fredrickson DS. Tangier disease (familial high density lipoprotein deficiency). Clinical and genetic features in two adults. Am J Med 1965;39:582-593. 5. Luna LG. Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology, Third Edition. New York: McGrawHill, 1968, p 140. 6. Kragel AH, Shanthasundari GR, Wittes JT, Roberts WC. Morphometric analysis of the composition of atherosclerotic plaques in the four major epicardial coronary arteries in acute myocardial infarction and in sudden coronary death. Circulation 1989; 80: 1747-1756. 7. Bale PM, Clifton-Bligh P, Benjamin BN, Whyte HM. Pathology of Tangier disease. J Clin Pathol 1971;24:609-616. 8. Kragel AH, Reddy SG, Wittes JT, Roberts WC. Morphometry analysis of the composition of coronary arterial plaques in isolated unstable angina pectoris with pain at rest. Am J Cardiol 1990; 66: 562-567. 9. Kragel AH, Roberts WC. Composition of atherosclerotic plaques in the coronary arteries in homozygous familial hypercholesterolemia. Am Heart J 1991;121:210-211. 10. Dollar AL, Kragel AH, Fernicola DJ, et al. Composition of atherosclerotic plaques in coronary arteries in women < 40 years of age with fatal coronary artery disease and implications for plaque reversibility. Am J Cardiol 1991;67:1223-1227. 11. Gertz SD, Malekzadeh S, Dollar AL, et al. Composition of atherosclerotic plaques in the four major epicardial coronary arteries in patients & 90 years of age. Am J Cardiol 1991;67:1228-1233. 12. Schmalbruch H, Stender S, Boysen G. Abnormalities in spinal neurons and dorsal root ganglion cells in Tangier disease presenting with a syringomyelia-like syndrome. J Neuropathol Exp Neurol 1987;46(5):533-543. 13. Herbert PN, Forte T, Heinen RJ, Fredrickson DS. Tangier disease. One explanation of lipid storage. N Engl J Med I978;299(10): 519-521. 14. Schmitz G, Bruening T, Williamson E, Nowicka G. The role of HDL in reverse cholesterol transport and its disturbances in Tangier disease and HDL deficiency with xanthomas. Eur Heart J 1990; ll(SupplE): 197-211. 15. Katz SS, Small DM, Brook JG, Lees RS. The storage lipids in Tangier disease. A physical chemical study. J Clin Invest 1977;59:10451054. 16. Assmann G, Schaefer HE. High density lipoprotein deficiency and lipid deposition in Tangier disease. In: Carlson LA, Paoletti R, Sirtori CR, Weber G, eds. International Conference on Atherosclerosis. New York: Raven Press, 1978, pp 97-101. 17. Gordon DJ, Rifkind BM. High-density lipoprotein-the clinical implications of recent studies. N Engl J Med 1989:321:1311-1316. 18. Brewer HB Jr, Gregg RE, Hoeg JM, Fojo SS. Apolipoproteins and lipoproteins in human plasma: An overview. Clin Chem 1988:34: 4-8. 19. Norum RA, Lakier JB, Goldstein S, et al. Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease. N Engl J Med 1982;306:1513-1519. 20. Schaefer EJ, Ordovas JM, Law SW, et al. Familial apolipoprotein A-I and C-III deficiency, variant II. J Lipid Res 1985;26:10891101. 21. Matsunaga T, Hiasa Y, Yanagi H, et al. Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene. Proc Natl Acad Sci USA 1991;88:2793-2797. 22. Schaefer EJ, Blum CB, Levy RI, et al. Metabolism of high-density lipoprotein apolipoproteins in Tangier disease. N Engl J Med 1978;299:905-910. 23. Schaefer EJ, Anderson DW, Zech LA, et al. Metabolism of high density lipoprotein subfractions and constituents in Tangier disease following the infusion of high density lipoproteins. J Lipid Res 1981;22:217-228. 24. Bojanovski D, Gregg RE, Zech LA, et al. In vivo metabolism of proapolipoprotein A-I in Tangier disease. J Clin Invest 1987:80: 1742-1747. 25. Schaefer EJ. Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency. Arteriosclerosis 1984;4:303-322.
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thesize apoA-I result in very low plasma concentrations of HDL cholesterol and premature coronary artery disease.18"21 Conversely, in Tangier disease, plasma levels of HDL cholesterol and apoA-I are very low as a result of exceptionally rapid catabolism.22"24 Are the very low HDL cholesterol and apoA-I concentrations in Tangier disease a risk factor for premature atherosclerotic cardiovascular disease? In a review of the clinical features of Tangier disease,3'25 five of eight homozygous patients older than 40 years had definite clinical evidence of atherosclerotic cardiovascular disease, with four having onset of symptoms before age 60 years. Obligate heterozygotes for Tangier disease have HDL cholesterol levels approximately one half of normal.3,25 Of 14 heterozygous patients older than 40 years, 7 had clinical evidence of atherosclerotic cardiovascular disease, with 5 having onset of symptoms before age 60 years. However, no homozygous or heterozygous patient developed symptoms of atherosclerotic cardiovascular disease before the age of 40 years. The conclusion is that patients with Tangier disease are at some increased risk for premature vascular disease, but not to the degree expected from the extremely low plasma HDL cholesterol levels. Two factors may potentially offset this enhanced risk. First, Tangier disease patients almost always have significantly lower plasma low-density lipoprotein cholesterol levels than the normal population,3,25 and thus may be partially protected from the usual atherogenic process. Second, the mechanism of the low HDL cholesterol, specifically normal synthesis with markedly accelerated catabolism of HDL, allows a high "flux" of HDL and may permit some HDL-mediated removal of excess cholesterol from tissues (reverse cholesterol transport), despite the very low steady-state plasma levels of HDL.
