LETTERS
Letters that report new clinical or laboratory observations, cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; no more than five references and one figure or table can be used. See "Information for Authors" on page 1-6 for form of references. Manuscripts should include an abstract of length not exceeding 100 words. Letters will be reviewed by consultants when, in the opinion of the editors, such review is needed. The Editor reserves the right to shorten letters and to make changes that accord with our style. Association of Partial Lipodystrophy and Sjogren's Syndrome WHILE SERVING as a manuscript consultant for this journal, one of us (D.A.S.) became aware of the acceptance for publication of "Sicca Syndrome and Total Lipodystrophy. A Case in a Fifteen-Year-Old Female Patient'' by M. M. Ipp, N. J. Howard, R. C. Tervo, and E. W. Gelfand. With the permission of the Editor, we submitted this brief report of two cases having related interest. Our two adult patients had partial, rather than total, lipodystrophy concurrent with Sjogren's syndrome. The three patients suggest a causal relation between the lipodystrophies and Sjogren's syndrome. Patient 1 was a 67-year-old woman who developed arthritis and severe progressive dyspnea 6 months before consultation. She had had typical keratoconjunctivitis sicca for 15 years and severe xerostomia for 6 years. Onset of xerostomia coincided with weight loss, muscle weakness, skin hyperpigmentation, and loss of subcutaneous fat of the face and buttocks. At that time, she had a diabetic glucose tolerance test, and shortly thereafter she began having hypoglycemia. She had difficulty walking due to aseptic necrosis of the left femoral head. Because of subcutaneous atrophy, the skin hugged the zygomas, the nose, and the muscles of the face and made a trough over the eyes. There was severe keratoconjunctivitis sicca and xerostomia, and the left parotid gland was enlarged. The subcutaneous fat on both shoulders and both buttocks was atrophic, and, in the latter, hard nodules, apparently due to previous intramuscular injections, could be seen (Figure 1). Synovitis was found in the hands and wrists. Abnormal laboratory findings included an elevated erythrocyte sedimentation rate (ESR); a polyclonal hypergammaglobulinemia of 3.28 g/dl, with IgG of 2520 mg/dl, IgA of 246 mg/dl, and IgM of 83 mg/dl; and 8% cryoglobulins. There was a 1:40 positive rheumatoid factor and low titer antibodies to denatured DNA and thyroglobulin. The C3 level was 60 mg/dl (normal, 80 to 120). Roentgenogram of the chest showed interstitial fibrosis. Pulmonary function tests showed a pure restrictive pattern that did not change with bronchodilators. Scintiscan of both salivary glands was characteristic of Sjogren's syndrome. Failure to improve on salicylate therapy prompted the use of chlorambucil, with improvement of both the arthralgias and the dyspnea. After 4 months, recurrence of dyspnea required the use of prednisone (30 mg/day). She improved again, and fat began to reappear on her face, particularly on the left side. Facial fat increased until she showed mild features of Cushing's 474
Downloaded from https://annals.org by Karolinska Institute user on 01/12/2019
syndrome, although asymmetrical because of some persistent lipodystrophy on the left side. After 7 months on small doses of prednisone, she suddenly developed an extensive pneumonitis and died in respiratory failure. Patient 2 was a 41-year-old woman who began having typical Raynaud's phenomenon at age 31. Five years before consultation she began having dry cough, dyspnea, severe xerostomia, and recurrent left parotid swelling. Four months before consultation she noticed diminution of the subcutaneous fat of the cheeks. She had left parotid enlargement, superficial ulceration of the soft palate, and mild inflammation of the vocal chords. Schirmer's and rose bengal tests were strongly positive. Lipodystrophy was limited to the face. Abnormal laboratory findings included an elevated ESR and IgM (308 mg/dl), a high titer (1:5120) rheumatoid factor, a false-positive VDRL, and antinuclear antibodies at a titer of 1:256 with homogeneous and speckled patterns. The C3, C4, and total hemolytic complement levels were initially normal, but C3 level later fell to 39 mg/dl while C4 level increased to 51 mg/dl (normal, 15 to 30). Scintillation scan of the salivary glands was also characteristic of Sjogren's syndrome. She subsequently developed keratoconjunctivitis sicca. The sicca symptoms became so severe that she was placed on 15 mg of prednisone daily. The symptoms improved little, but the lipodystrophy disappeared. A short trial of azathioprine re-
Figure 1. Lipodystrophy at the buttocks in Patient 1 . Nodules are apparently due to previous intramuscular injections. Annals of Internal Medicine 85:474-481, 1976
suited in marked improvement of the sicca symptoms. In both patients the distribution of the lipodystrophy was typical of the partial form that affects primarily the face and, less frequently, the shoulder and pelvic girdles ( 1 ) . Both patients have had symptomatic Sjogren's syndrome with systemic manifestations, but a distinct connective tissue disease could not be diagnosed in either of them. Previous observations suggest that the association of Sjogren's syndrome and lipodystrophy may be more than coincidental. An early recorded patient with total lipodystrophy had enlarged parotid glands with extensive lymphocytic infiltration, acinar atrophy, and duct proliferation (2). Diseases commonly associated with immunologic abnormalities, such as glomerulonephritis (1) and lupus erythematosus ( 3 ) , may coexist with partial lipodystrophy. Low C 3 levels such as those found in both our patients are common in partial lipodystrophy, but, as it occurred in our second patient, they apparently result from activation of the alternate rather than the classic pathway ( 4 ) . Reappearance of facial fat in both of our patients after prednisone treatment is of interest, particularly since the bodily distribution of partial lipodystrophy resembles that of the increased fat deposition in Cushing's syndrome. Indeed, the various endocrine disturbances that occur in the lipodystrophies have been thought to reflect a hypothalamic disturbance ( 5 ) . Reappearance of fat at corticosteroid treatment in our patients may give some insight as to this question. DONATO ALARCON-SEGOVIA, M.D., F.A.C.P. FRANCISCO RAMOS-NIEMBRO, M.D.
Department of Immunology and Rheumatology Instituto Nacional de la Nutrition Mexico 22, D.F., Mexico Received 19 April 1976. REFERENCES
1. SENIOR B, GELLIS SS: The syndrome of total lipodystrophy and of partial lipodystrophy. Pediatrics 33:593-612, 1964 2. LAWRENCE RD: Lipodystrophy and hepatomegaly with diabetes, lipaemia, and other metabolic disturbances. A case throwing new light on the action of insulin. Lancet 1:724-731, 1946 3. MANSOUR A, WORDSALL PA, ROY LP: Complement studies in
partial lipodystrophy (abstract). Florence, Proceedings of the Sixth International Congress of Nephrology, Abstract 435, 8-12 June 1975 4. SISSONS JGP, WEST RJ, FALLOWS J, et al: The complement ab-
normalities in lipodystrophy. N Engl J Med 294:461-465, 1976 5. MABRY CC, HOLLINGSWORTH DR, UPTON GV, et al: Pituitary-
hypothalamic dysfunction in generalized lipodystrophy. J Pediatr 82:625-633, 1973
Dilantin® Toxicity: Miliary Pulmonary Infiltrates and Hypoxemia A NUMBER of serious adverse effects have been reported in association with diphenylhydantoin (Dilantin®) therapy (1), including hepatitis, pancytopenia, and purpura fulminans. Although morbidity from these reactions can be significant, Dilantin toxicities are usually not life-threatening. We recently saw a patient who developed miliary chest infiltrates and severe hypoxemia with Dilantin treatment. In addition, extensive dermatitis and hepatitis were observed. Since serious pulmonary reactions to Dilantin have been infrequently cited, we report this unusual case. A 47-year-old man was admitted to Harbor General Hospital on 18 September 1975 with sudden onset of headache and
seizures. Except for pulmonary tuberculosis in 1965, cured with isoniazid and para-aminosalicylic acid therapy, there were no significant prior illnesses. At physical examination his temperature was 37 °C; blood pressure, 140/60 mm Hg; pulse, 68/min; and respirations, 32/ min'. Bilateral papilledema and nuchal rigidity were noted. Chest and cardiac examinations were normal. Detailed neurologic evaluation, aside from lethargy, was negative. The remainder of the physical examination was unremarkable. At admission, laboratory values included a hematocrit of 42% and a leukocyte count of 14 000/mm3 with 85% neutrophils, 12% lymphocytes, and 3% eosinophils. Serum electrolytes, urea nitrogen, creatinine, liver function tests, and urinalysis were normal. Arterial blood gas values on room air were Po2, 124 mm Hg; Pco2, 13 mm Hg; and pH, 7.52. Chest X ray findings were normal. Lumbar puncture showed elevated pressure (340 mm H 2 0) and xanthochromia. Gram's stain smear, as well as all cultures of the cerebrospinal fluid (CSF), were negative. Skin testing with purified protein derivative was positive, while coccidioidin and mumps skin tests were negative. Cerebral angiography showed a cerebellar artery aneurysm. Therapy was begun with dexamethasone, 4 mg orally every 6 h; diphenylhydantoin, 100 mg orally every 6 h; phenobarbitol, 60 mg every 6 h; and epsilon-aminocaprioic acid, 2 g every 2h. By the 19th hospital day, all neurologic signs and CSF abnormalities were resolving, and dexamethosone therapy was discontinued. On the 24th hospital day, shaking chills, cough, dyspnea, and rash developed. Pertinent physical findings were a temperature of 38.2 °C, respiratory rate of 26/min, bilateral lower lobe rales, and a macular morbilliform eruption over the trunk and extremities. Leukocyte count was 9400/mm3 with 65% neutrophils, 20% bands, 5% lymphocytes, and 10% eosinophils (Table 1). Chest X ray now showed diffuse reticulonodular infiltrates in all lung fields. Arterial blood gas values on room air were Po2, 59 mm Hg; Pco2, 31 mm Hg; and pH, 7.47. Serum liver function test findings included a bilirubin value of 0.5 mg/dl; glutamic oxalacetic transaminase, 172 IU/dl (normal, 10 to 30); glutamic pyruvic transaminase, 200 IU/dl (normal, 10 to 30); lactic acid dehydrogenase, 248 IU/dl (normal, 109 to 193); and alkaline phosphatase, 254 IU/dl (normal, 36 to 92). Cultures of blood, urine, sputum, and CSF were negative for bacterial, fungal, viral, and mycobacterial pathogens. Serum hemolytic complement (CH50) level was depressed to 10 U/ml (normal, 25 to 85). Absolute eosinophil count was elevated to 1232/mm3 (normal, 50 to 350). Serum antinuclear antibody and hepatitis B surface antigen were not detected. Serum creatinine level and urinalysis findings were normal. Percutaneous liver biopsy showed noncaseating granulomatous hepatitis and dense periportal infiltration with eosinophils. All cultures of this tissue were negative. The diphenylhydantoin was withdrawn, and during the next 10 days fever, rash, cough, and dyspnea disappeared. Chest X ray findings markedly improved, and the arterial blood gas values normalized. By the 50th hospital day, the chest X ray was clear, and arterial blood gases, serum liver function tests, serum complement, leukocyte count, and differential were normal. Serious pulmonary toxicities related to Dilantin use have been rarely described. This agent has been associated with the drug-induced systemic lupus erythematosus syndrome in which pleural effusions are seen and with the pseudolymphoma syndrome in which hilar or mediastinal adenopathy, or both, have been commonly noted ( 2 ) . Moore (3) described 31 patients on a long-term Dilantin treatment (2 to 12 years) of whom 87% had abnormalities of the pulmonary parenchyma on chest radiography, usually consisting of increased bronchovascular markings and occasionally resembling diffuse interstitial fibrosis. However, other workers studying patients on long-term Dilantin Letters
Downloaded from https://annals.org by Karolinska Institute user on 01/12/2019
475
Table 1 . Laboratory Values During Hospitalization*
Test
Normal
Hematocrit, % Leukocytes, no./mm3 Percent eosinophils SGOT, W/dl SGPT, W/dl LDH, W/dl Alkaline phosphatase, W/dl Bilirubin, mg/dl Arterial blood gases Vo2,mmHg PCO2, mmHg pH
37-42 4000-8000 0-3 10-30 10-30 109-193 39-92
Letters that report new clinical or laboratory observations, cases of unusual importance, and new developments in medical care will be considered for publication in this section. Manuscripts must be typed double-spaced. Text length must not exceed 750 words; no more than five references and one figure or table can be used. See "Information for Authors" on page 1-6 for form of references. Manuscripts should include an abstract of length not exceeding 100 words. Letters will be reviewed by consultants when, in the opinion of the editors, such review is needed. The Editor reserves the right to shorten letters and to make changes that accord with our style. Association of Partial Lipodystrophy and Sjogren's Syndrome WHILE SERVING as a manuscript consultant for this journal, one of us (D.A.S.) became aware of the acceptance for publication of "Sicca Syndrome and Total Lipodystrophy. A Case in a Fifteen-Year-Old Female Patient'' by M. M. Ipp, N. J. Howard, R. C. Tervo, and E. W. Gelfand. With the permission of the Editor, we submitted this brief report of two cases having related interest. Our two adult patients had partial, rather than total, lipodystrophy concurrent with Sjogren's syndrome. The three patients suggest a causal relation between the lipodystrophies and Sjogren's syndrome. Patient 1 was a 67-year-old woman who developed arthritis and severe progressive dyspnea 6 months before consultation. She had had typical keratoconjunctivitis sicca for 15 years and severe xerostomia for 6 years. Onset of xerostomia coincided with weight loss, muscle weakness, skin hyperpigmentation, and loss of subcutaneous fat of the face and buttocks. At that time, she had a diabetic glucose tolerance test, and shortly thereafter she began having hypoglycemia. She had difficulty walking due to aseptic necrosis of the left femoral head. Because of subcutaneous atrophy, the skin hugged the zygomas, the nose, and the muscles of the face and made a trough over the eyes. There was severe keratoconjunctivitis sicca and xerostomia, and the left parotid gland was enlarged. The subcutaneous fat on both shoulders and both buttocks was atrophic, and, in the latter, hard nodules, apparently due to previous intramuscular injections, could be seen (Figure 1). Synovitis was found in the hands and wrists. Abnormal laboratory findings included an elevated erythrocyte sedimentation rate (ESR); a polyclonal hypergammaglobulinemia of 3.28 g/dl, with IgG of 2520 mg/dl, IgA of 246 mg/dl, and IgM of 83 mg/dl; and 8% cryoglobulins. There was a 1:40 positive rheumatoid factor and low titer antibodies to denatured DNA and thyroglobulin. The C3 level was 60 mg/dl (normal, 80 to 120). Roentgenogram of the chest showed interstitial fibrosis. Pulmonary function tests showed a pure restrictive pattern that did not change with bronchodilators. Scintiscan of both salivary glands was characteristic of Sjogren's syndrome. Failure to improve on salicylate therapy prompted the use of chlorambucil, with improvement of both the arthralgias and the dyspnea. After 4 months, recurrence of dyspnea required the use of prednisone (30 mg/day). She improved again, and fat began to reappear on her face, particularly on the left side. Facial fat increased until she showed mild features of Cushing's 474
Downloaded from https://annals.org by Karolinska Institute user on 01/12/2019
syndrome, although asymmetrical because of some persistent lipodystrophy on the left side. After 7 months on small doses of prednisone, she suddenly developed an extensive pneumonitis and died in respiratory failure. Patient 2 was a 41-year-old woman who began having typical Raynaud's phenomenon at age 31. Five years before consultation she began having dry cough, dyspnea, severe xerostomia, and recurrent left parotid swelling. Four months before consultation she noticed diminution of the subcutaneous fat of the cheeks. She had left parotid enlargement, superficial ulceration of the soft palate, and mild inflammation of the vocal chords. Schirmer's and rose bengal tests were strongly positive. Lipodystrophy was limited to the face. Abnormal laboratory findings included an elevated ESR and IgM (308 mg/dl), a high titer (1:5120) rheumatoid factor, a false-positive VDRL, and antinuclear antibodies at a titer of 1:256 with homogeneous and speckled patterns. The C3, C4, and total hemolytic complement levels were initially normal, but C3 level later fell to 39 mg/dl while C4 level increased to 51 mg/dl (normal, 15 to 30). Scintillation scan of the salivary glands was also characteristic of Sjogren's syndrome. She subsequently developed keratoconjunctivitis sicca. The sicca symptoms became so severe that she was placed on 15 mg of prednisone daily. The symptoms improved little, but the lipodystrophy disappeared. A short trial of azathioprine re-
Figure 1. Lipodystrophy at the buttocks in Patient 1 . Nodules are apparently due to previous intramuscular injections. Annals of Internal Medicine 85:474-481, 1976
suited in marked improvement of the sicca symptoms. In both patients the distribution of the lipodystrophy was typical of the partial form that affects primarily the face and, less frequently, the shoulder and pelvic girdles ( 1 ) . Both patients have had symptomatic Sjogren's syndrome with systemic manifestations, but a distinct connective tissue disease could not be diagnosed in either of them. Previous observations suggest that the association of Sjogren's syndrome and lipodystrophy may be more than coincidental. An early recorded patient with total lipodystrophy had enlarged parotid glands with extensive lymphocytic infiltration, acinar atrophy, and duct proliferation (2). Diseases commonly associated with immunologic abnormalities, such as glomerulonephritis (1) and lupus erythematosus ( 3 ) , may coexist with partial lipodystrophy. Low C 3 levels such as those found in both our patients are common in partial lipodystrophy, but, as it occurred in our second patient, they apparently result from activation of the alternate rather than the classic pathway ( 4 ) . Reappearance of facial fat in both of our patients after prednisone treatment is of interest, particularly since the bodily distribution of partial lipodystrophy resembles that of the increased fat deposition in Cushing's syndrome. Indeed, the various endocrine disturbances that occur in the lipodystrophies have been thought to reflect a hypothalamic disturbance ( 5 ) . Reappearance of fat at corticosteroid treatment in our patients may give some insight as to this question. DONATO ALARCON-SEGOVIA, M.D., F.A.C.P. FRANCISCO RAMOS-NIEMBRO, M.D.
Department of Immunology and Rheumatology Instituto Nacional de la Nutrition Mexico 22, D.F., Mexico Received 19 April 1976. REFERENCES
1. SENIOR B, GELLIS SS: The syndrome of total lipodystrophy and of partial lipodystrophy. Pediatrics 33:593-612, 1964 2. LAWRENCE RD: Lipodystrophy and hepatomegaly with diabetes, lipaemia, and other metabolic disturbances. A case throwing new light on the action of insulin. Lancet 1:724-731, 1946 3. MANSOUR A, WORDSALL PA, ROY LP: Complement studies in
partial lipodystrophy (abstract). Florence, Proceedings of the Sixth International Congress of Nephrology, Abstract 435, 8-12 June 1975 4. SISSONS JGP, WEST RJ, FALLOWS J, et al: The complement ab-
normalities in lipodystrophy. N Engl J Med 294:461-465, 1976 5. MABRY CC, HOLLINGSWORTH DR, UPTON GV, et al: Pituitary-
hypothalamic dysfunction in generalized lipodystrophy. J Pediatr 82:625-633, 1973
Dilantin® Toxicity: Miliary Pulmonary Infiltrates and Hypoxemia A NUMBER of serious adverse effects have been reported in association with diphenylhydantoin (Dilantin®) therapy (1), including hepatitis, pancytopenia, and purpura fulminans. Although morbidity from these reactions can be significant, Dilantin toxicities are usually not life-threatening. We recently saw a patient who developed miliary chest infiltrates and severe hypoxemia with Dilantin treatment. In addition, extensive dermatitis and hepatitis were observed. Since serious pulmonary reactions to Dilantin have been infrequently cited, we report this unusual case. A 47-year-old man was admitted to Harbor General Hospital on 18 September 1975 with sudden onset of headache and
seizures. Except for pulmonary tuberculosis in 1965, cured with isoniazid and para-aminosalicylic acid therapy, there were no significant prior illnesses. At physical examination his temperature was 37 °C; blood pressure, 140/60 mm Hg; pulse, 68/min; and respirations, 32/ min'. Bilateral papilledema and nuchal rigidity were noted. Chest and cardiac examinations were normal. Detailed neurologic evaluation, aside from lethargy, was negative. The remainder of the physical examination was unremarkable. At admission, laboratory values included a hematocrit of 42% and a leukocyte count of 14 000/mm3 with 85% neutrophils, 12% lymphocytes, and 3% eosinophils. Serum electrolytes, urea nitrogen, creatinine, liver function tests, and urinalysis were normal. Arterial blood gas values on room air were Po2, 124 mm Hg; Pco2, 13 mm Hg; and pH, 7.52. Chest X ray findings were normal. Lumbar puncture showed elevated pressure (340 mm H 2 0) and xanthochromia. Gram's stain smear, as well as all cultures of the cerebrospinal fluid (CSF), were negative. Skin testing with purified protein derivative was positive, while coccidioidin and mumps skin tests were negative. Cerebral angiography showed a cerebellar artery aneurysm. Therapy was begun with dexamethasone, 4 mg orally every 6 h; diphenylhydantoin, 100 mg orally every 6 h; phenobarbitol, 60 mg every 6 h; and epsilon-aminocaprioic acid, 2 g every 2h. By the 19th hospital day, all neurologic signs and CSF abnormalities were resolving, and dexamethosone therapy was discontinued. On the 24th hospital day, shaking chills, cough, dyspnea, and rash developed. Pertinent physical findings were a temperature of 38.2 °C, respiratory rate of 26/min, bilateral lower lobe rales, and a macular morbilliform eruption over the trunk and extremities. Leukocyte count was 9400/mm3 with 65% neutrophils, 20% bands, 5% lymphocytes, and 10% eosinophils (Table 1). Chest X ray now showed diffuse reticulonodular infiltrates in all lung fields. Arterial blood gas values on room air were Po2, 59 mm Hg; Pco2, 31 mm Hg; and pH, 7.47. Serum liver function test findings included a bilirubin value of 0.5 mg/dl; glutamic oxalacetic transaminase, 172 IU/dl (normal, 10 to 30); glutamic pyruvic transaminase, 200 IU/dl (normal, 10 to 30); lactic acid dehydrogenase, 248 IU/dl (normal, 109 to 193); and alkaline phosphatase, 254 IU/dl (normal, 36 to 92). Cultures of blood, urine, sputum, and CSF were negative for bacterial, fungal, viral, and mycobacterial pathogens. Serum hemolytic complement (CH50) level was depressed to 10 U/ml (normal, 25 to 85). Absolute eosinophil count was elevated to 1232/mm3 (normal, 50 to 350). Serum antinuclear antibody and hepatitis B surface antigen were not detected. Serum creatinine level and urinalysis findings were normal. Percutaneous liver biopsy showed noncaseating granulomatous hepatitis and dense periportal infiltration with eosinophils. All cultures of this tissue were negative. The diphenylhydantoin was withdrawn, and during the next 10 days fever, rash, cough, and dyspnea disappeared. Chest X ray findings markedly improved, and the arterial blood gas values normalized. By the 50th hospital day, the chest X ray was clear, and arterial blood gases, serum liver function tests, serum complement, leukocyte count, and differential were normal. Serious pulmonary toxicities related to Dilantin use have been rarely described. This agent has been associated with the drug-induced systemic lupus erythematosus syndrome in which pleural effusions are seen and with the pseudolymphoma syndrome in which hilar or mediastinal adenopathy, or both, have been commonly noted ( 2 ) . Moore (3) described 31 patients on a long-term Dilantin treatment (2 to 12 years) of whom 87% had abnormalities of the pulmonary parenchyma on chest radiography, usually consisting of increased bronchovascular markings and occasionally resembling diffuse interstitial fibrosis. However, other workers studying patients on long-term Dilantin Letters
Downloaded from https://annals.org by Karolinska Institute user on 01/12/2019
475
Table 1 . Laboratory Values During Hospitalization*
Test
Normal
Hematocrit, % Leukocytes, no./mm3 Percent eosinophils SGOT, W/dl SGPT, W/dl LDH, W/dl Alkaline phosphatase, W/dl Bilirubin, mg/dl Arterial blood gases Vo2,mmHg PCO2, mmHg pH
37-42 4000-8000 0-3 10-30 10-30 109-193 39-92
