114 SICCA-LIKE SYNDROME IN TYPE V HYPERLIPOPROTEINEMIA JAMES L. REINERTSEN, ERNST J. SCHAEFER, H. BRYAN BREWER, and HARALAMPOS M. MOUTSOPOULOS Patients with type-I1 and type-IV hyperlipoproteinemia may also have four rheumatic problems. First, younger patients with type-I1 disease develop migratory polyarthralgias that resemble rheumatic fever (1). Second, a variety of miscellaneous musculoskeletal complaints occur in patients with typeI1 and type-IV hyperlipoproteinemia; such symptoms include arthralgias with morning gel phenomenon, “palindromic rheumatism,” and tenosynovitis (24). Third, hyperuricemia and gout often are associated with hypertriglyceridemia (type-IV) (5). Finally, Goldman and Julian (6) and Kaltreider and Tala1 (7) have described parotid enlargement similar to that of Sjogren’s syndrome in 13 patients, 12 whom had type-I1 or type-IV hyperlipoproteinemia. The remaining patient had typeV hyperlipoproteinemia. The Sjogren-like syndrome of these hyperlipoproteinemias is characterized primarily by parotid enlargement, without prominent ocular or oral sicca symptoms, and has been attributed to fatty infiltration of the parotids (6,7). The incidence of such parotid enlargement and the frequency of associated sicca symptoms in the hyperlipoproteinemias is not known. Furthermore, non-parotid rheumatic symptoms have not been described in type-V hyperlipoproteinemia. Ac- James L. Reinertsen, MD: Arthritis and Rheumatism Branch, National Institute of Arthritis, Metabolism and Digestive Diseases; Ernst J. Schaefer, MD: Molecular Disease Branch, National Heart, Lung, and Blood Institute; H. Bryan Brewer, MD: Molecular Disease Branch, National Heart, Lung, and Blood Institute; Haralampos M. Moutsopoulos, MD: Clinical Immunology Section, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20205. Address reprint requests to Dr. James L. Reinertsen, St. Louis Park Medical Center, 5000 West 39th Street, Minneapolis, Minnesota 55416. Submitted May 7, 1979; accepted in revised form August 29, 1979. Arthritis and Rheumatism, Vol. 23, No. 1 (January 1980) cordingly, we have surveyed 25 patients with type-V hyperlipoproteinemia who were examined at the National Institutes of Health (NIH) for a history of arthritis or sicca symptoms or both. Four of the 25 patients had significant sicca symptoms and were studied further. Findings in these patients form the basis of this report. Patients and methods. The diagnosis of type-V hyperlipoproteinemia was confirmed in all patients by the following methods. Blood was obtained in 0.1% EDTA after an overnight fast (12-14 hours), and the plasma was separated at 4°C in a refrigerated centrifuge. All subjects were sampled while on an ad libitum diet and were not receiving medication known to affect plasma lipoproteins. Plasma cholesterol and triglyceride levels were measured with an Auto Analyzer I1 (8). High-density lipoprotein (HDL) cholesterol was measured after heparin-manganese precipitation of plasma or the 1.006 gm/ml infranate (9). Plasma was ultracentrifuged at its own density (1.006 gm/ml) for 18 hours at 39,000 rpm (4°C) in a Beckman 40.3 rotor (Beckman Instruments, Fullerton, California), and the very low-density lipoproteins (VLDL) were separated from the other plasma lipoproteins by tube slicing (10). The cholesterol content in the 1.006 gm/ml infranatant fraction was determined by these methods, and VLDL and low-density lipoprotein (LDL) were calculated (9). Plasma and the 1.006 gm/ml supernate and infranate also were subjected to paper electrophoresis for lipoprotein phenotyping (9). Results of these studies are shown in Table 1. ’ The four sicca patients also underwent other laboratory studies, including complete blood count, erythrocyte sedimentation rate, urinalysis, and measurements of uric acid, blood urea nitrogen, triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), calcium, phosphorus, rheumatoid factor, and antinuclear antibody. BRIEF REPORTS 115 Table 1. Plasma lipid, lipoprotein, and cholesterol levels in 4 patients with type-V hyperlipoproteinemia Cholesterol levels+ Cholesterol Triglyceride VLDL LDL HDL 564* 636 804 265 2529 3339 3885 1872 477 557 74 1 180 67 66 53 71 20 13 10 14 87 + 43 16+ 11 123 + 35 50 & 14 Case 1 Case 2 Case 3 Case 4 Normalt (N = 1088) Cholesterol* 189 f 40 * For each case these values represent the mean of 3 determinations. t + 1 standard deviation. * mg %. All 25 type-V patients were questioned for ocular and oral features of sicca (Sjogren’s) syndrome. Special studies were done only in those with sicca symptoms. The ophthalmologic assessment included Schirmer’s test (1 1) and slit-lamp examination after rose bengal staining (12). Parotid gland function was evaluated by salivary flow rate and salivary gland scintigraphy (13). Labial biopsy was performed as previously described (14). The outcomes in the four patients are shown in Table 2. Case report. A 5 1-year-old white woman was noted to have marked hypertriglyceridemia and hypercholesterolemia in the course of evaluation for abdominal pain. Type-V hyperlipoproteinemia and chronic pancreatitis with pseudocyst were found. She had prominent symptoms of morning stiffness in the small joints of her hands (including distal interphalangeal joints), shoulders, and feet. Moreover, she complained of burning, gritty eyes and a constantly dry mouth, which required her to keep a glass of water nearby at all times. ’ Examination revealed mild symmetrical parotid enlargement. The distal interphalangeal (DIP) and proximal interphalangeal (PIP) joints had typical Heberden’s and Bouchard’s nodes. Tender, nodular thickening of both palmar and plantar fasciae was present. The remainder of the musculoskeletal examination was normal. Hand x-rays showed osteoarthritic changes of DIP and PIP joints. Biopsy of a tender plantar nodule revealed fibrous thickening of the plantar aponeurosis. Results of rheumatologic and sicca studies are shown in Table 2. Pertinent findings include an elevated ESR, abnormal Schirmer’s test, punctate corneal erosions, class 111 salivary scintiscan, and normal salivary flow rate, and labial salivary gland biopsy (Figure 1). A summary of the clinical and laboratory features of cases 1-4 are presented in Table 2. Discussion. We surveyed 25 patients with type-V hyperlipoproteinemia for symptoms of sicca syndrome and identified 4 women with prominent ocular or oral sicca symptoms. Although this sort of survey cannot de- Table 2. Features of rheumatic and sicca syndrome in 4 patients with type-V hyperlipoproteinemia Age at Case Diagnosis Onset of symptoms Musculoskeletal syndrome* Salivary flow 99Tc salivary scan Labial salivary biopsy Sed rate RF uric ANA Acid I 51 51 OA Oral, ocular 4mm Normal Abnormal class 111 Normal 54 Neg Neg 4.0 1 mm Punctate erosions of cornea Normal 2 45 47 Gout 3 43 45 OA Oral, ocular Ocular Normal Normal 61 Neg Neg 8.6 5.5 mm Normal Decreased Normal 87 Neg Neg 10.3 1Omm Normal Decreased Abnormal, class 111 Abnormal, class 111 Abnormal, class 111 4 50 48 RA Oral Normal 91 Pos Neg 6.4 Sicca Schirmer’s Slit symptoms test lamp *OA = inflammatory osteoarthritis; RA = rheumatoid arthritis. BRIEF REPORTS 116 -~~- ~~ ~~~~ Figure 1. Lip biopsy from patient with type-V lipoproteinemia.The minor salivary gland is normal (X 130). Figure 2. Lip biopsy from a patient with Sjogren’ssyndrome. Focal lymphocytic infiltrate of the minor salivary gland is evident, with acinar destruction (X 80). BRIEF REPORTS fine a true incidence, it does suggest that xerostomia and xerophthalmia are not rare in this lipid disorder. Ocular and oral dryness can result from a number of different pathologic processes (15). One such cause, primary Sjogren’s syndrome, is characterized by lacrimal and salivary gland infiltration by lymphocytes and plasma cells, as well as a wide array of clinical and serologic autoimmune phenomena (16). It is important to distinguish true Sjogren’s syndrome (Figure 2) from other causes of decreased exocrine secretion, especially in patients with associated musculoskeletal symptoms. While superficially similar to true Sjogren’s syndrome, the sicca-like syndrome in the 4 type-V lipoproteinemia patients described here is clearly quite different. Although the presence of an elevated sedimentation rate, arthritis, sicca symptoms, and low salivary flow would make the diagnosis of sicca syndrome quite possible in these patients, the finding of normal salivary gland biopsies makes the diagnosis of true Sjogren’s syndrome untenable, even in the presence of a positive rheumatoid factor as in patient 4. Several features of the sicca syndrome seen in type-V hyperlipoproteinemia are noteworthy. Parotid gland enlargement is mild or absent in 117 type-V patients, whereas it is a prominent aspect of type-IV sicca syndrome (6). Furthermore, fatty infiltration of the salivary glands, seen in type-IV patients (Figure 3), is not observed in biopsies from patients with type-V hyperlipidemia. Goldman and Julian (6) postulate that exocrine dysfunction in type-IV disease is caused by fatty infiltration of glandular tissue. We cannot extend this theory to type-V patients, since the normal biopsies of these patients do not explain the marked symptoms of xerostomia and distinctly abnormal salivary scans. Even electron microscopy of type-V patients failed to show any abnormal lipid accumulation or other abnormalities. The presence of recurrent abdominal pain in all of our patients and the firm diagnosis of chronic pancreatitis in 3 of 4 patients suggest that both pancreatic and salivary exocrine function is disturbed by similar mechanisms in type-V hyperlipoproteinemia. Biopsy of minor salivary glands sheds little light on the nature of such a process, but the prominent salivary scan abnormalities indicate that focal inflammatory, infiltrative, or obstructive lesions of the major salivary glands might be present. Parotid biopsy would perhaps shed some light Figure 3. Lip biopsy from a patient with type-IV lipoproteinemia showing intense fatty infiltration (X 130). BRIEF REPORTS 118 on this relationship, but we did not believe that the risks of this procedure were justified. In any event, the ontogenic and other similarities between the pancreas and the parotids suggest strongly that their striking coinvolvement in these patients rests on a common pathologic basis. This study demonstrates that symptoms of ocular and oral dryness are not uncommon in type-V hyperlipoproteinemia. Arthritic symptoms and elevated sedimentation rates often are present in these patients, making the distinction between true and pseudo-Sjogren’s syndrome difficult. Biopsy of minor salivary glands clearly distinguishes between these two types of sicca syndromes. Therapy with a lipid-sparing diet and eyedrops appeared to ameliorate the sicca syndrome in these patients with type-V hyperlipoproteinemia. Acknowledgment. We would like to thank Dawn M. Cardascia for her excellent secretarial assistance in the preparation of this manuscript. 5. 6. 7. 8. 9. 10. 11. 12. 13. 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J Am Med Assoc 210~2067-2070,1969 Technicon Instruments Autoanalyzer Manual, Tarrytown, New York, 1964, p 345 Lipid Research Clinics Manual, Bethesda, Maryland, National Heart, Lung and Blood Institute, DHEW (NIH) 75628, 1974, p 74 Have1 RJ, Eder HA, Bragdon JH: The distribution and chemical composition of ultracentrifugal by separated lipoproteins in human serum. J Clin Invest 34:1345, 1955 Schirmer 0: Studien zur Physiologic und Pathologie der Franenabsonberung und Tranenabtuhr. Groefe Arch Ophthal 56:197-291, 1903 Holm S: Keratoconjunctivitis sicca and sicca syndrome. Acta Ophthalmol (suppl) (Kbh) 33:l-230, 1949 Schall GL, Anderson LG, Wolf RO et al: Xerostomia in Sjogren’s syndrome. Evaluation by sequential salivary scintigraphy. JAMA 216:2109-2116, 1971 Chisholm DM, Mason DK: Labial salivary gland biopsy in Sjogren’s syndrome. J Clin Pathol 21:656-660, 1968 Talal N: Sjogren’s syndrome and connective tissue disease with other immunologic disorders, Arthritis and Allied Conditions. Eighth edition. Edited by JL Hollander, DJ McCarty. Philadelphia, Lea and Febiger, 1972 Moutsopoulos HM, Webber BL, Vlagopoulos TP, Chused TM, Decker JL: Differences in the clinical manifestations of sicca syndrome in the presence and absence of rheumatoid arthritis. Am J Med 66:733-736, 1979 Dwight J. lngle Memorial Award Perspectives in Biology and Medicine announces the Dwight J. lngle Memorial Award for authors under 35 for the best English language essay. For details contact Richard L. Landau, MD, Editor, Perspectives in Biology and Medicine, Culver 403, 1025 E. 57th Street, Chicago, Illinois 60637.