174
Alerts, Notices, and Case Reports Superior Mesenteric Artery Thrombosis Associated With Antiphospholipid Syndrome MAURICE E. HAMILTON, MD Sacramento, California
THE ASSOCIATION of antiphospholipid antibodies (anticardiolipin antibodies, the lupus anticoagulant, and reagin) with thrombosis, recurrent fetal loss, and thrombocytopenia has recently been classified as the antiphospholipid syndrome. 1-8 Thrombotic events associated with this syndrome most often involve the venous system, especially the deep veins of the leg, but also the renal vein, hepatic vein, portal vein, pulmonary vein, and inferior vena cava.2 4 7 8 Arterial thrombosis may also occur, affecting the cerebral, coronary, renal, and retinal arteries.3 47' 8 Only rarely has mesenteric artery thrombosis been noted.9'10 This report describes thrombosis of the superior mesenteric artery leading to small bowel infarction in a woman with the antiphospholipid syndrome. Report of a Case
The patient, a 29-year-old woman, was admitted to the hospital because of nausea with progressively worsening epigastric and lower abdominal pain of four days' duration. An upper gastrointestinal series done the day before admission was normal. Nausea and abdominal pain first developed four months earlier, at which time gastroduodenoscopy revealed gastritis, duodenitis, and a duodenal ulcer. These symptoms resolved during therapy with cimetidine. The patient had a history of migraine headaches. Proteinuria (2 +) was noted on routine urinalysis two years before admission; urinary protein excretion was 5.4 grams per 24 hours the month before admission. A biologically falsepositive serologic test for syphilis was detected ten years previously. The patient was married without children. She had had five spontaneous abortions, always occurring during the first trimester, most recently four months before admission. She was placed on a regimen of an oral contraceptive norgestrel and ethinyl estradiol-after the last abortion. She smoked a pack per day of cigarettes. On admission her temperature was 37.60 C. The abdomen was diffusely tender without organomegaly or abnormal masses. Erythematous macules and subsequently livedo reticularis were noted on the palms. The physical examination revealed no other abnormalities. Laboratory test results included a leukocyte count of 11.6 x 109 per liter (11,600 per pl) with normal differential count, hematocrit 0.34 (34%), platelet count 170 x 109 per liter (170,000 per /tl), sedimentation rate 58 mm per hour, serum albumin 33 grams per liter (3.3 grams per dl), and serum creatinine 70 /tmol per liter (0.8 mg per dl). A urinalysis showed 4 + protein with many
granular and hyaline casts. A plain x-ray film and computed tomographic scan of the abdomen were normal. Endoscopy showed mild gastritis; the duodenal mucosa was friable with a mottled, granular appearance. A superficial ulceration was present in the third portion of the duodenum; a biopsy of the duodenum revealed no definite abnormalities. Barium enema was normal. On the seventh hospital day the patient had severe abdominal pain associated with a rigid abdomen and a temperature of 39.9° C. An exploratory laparotomy revealed infarction of most of the jejunum and ileum; the superior mesenteric artery was hard with no pulse. About 200 cm of jejunum and ileum was resected, leaving the proximal 68 cm of jejunum and the terminal 3 cm of ileum. An activated partial thromboplastin time was prolonged (patient, 42.9 seconds; control, 26 seconds) and failed to correct following the addition of an equal amount of normal plasma; the prothrombin time was normal. The platelet count decreased to 38 x 109 per liter. High-dose corticosteroid therapy was administered. The patient was anticoagulated with heparin for presumed antiphospholipid syndrome. Total parenteral nutrition was instituted. During a second laparotomy the next day, an additional 8 cm of distal jejunum appeared nonviable and was resected; the gross appearance of the remaining bowel had improved. Histologic examination of the specimen of bowel showed areas of mucosal necrosis but no evidence of vasculitis (Figure 1). Over the next several days, the thrombocytopenia resolved and the palmar rash faded. No further bowel resection was required. Because of increasing proteinuria (13.8 grams per 24 hours), a renal biopsy was taken on the 18th hospital day. This showed mild to moderate focal mesangial cell hyperplasia with focal segmental glomerular staining for immunoglobulin (Ig) M, C3, Clq, properdin, and fibrin(ogen), characteristic of focal segmental glomerulosclerosis (Figure 2). No electron-dense deposits were detected. Serologic studies done before corticosteroid therapy was initiated revealed a high level of IgG anticardiolipin antibody (16 standard deviations above normal) without IgM or IgA anticardiolipin antibody. A C4 level was mildly decreased0.11 grams per liter (11 mg per dl; normal >0.15 grams per liter)-but total hemolytic complement (CHso) determina-
_ 'T;E,~~S'.,'','"'.'"''-
D
'A.~~~~~~7
IA 0
(Hamilton ME: Superior mesenteric artery thrombosis associated with antiphospholipid syndrome. West J Med 1991 Aug; 155:174-176) From the Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, Medical Center, Sacramento. Reprint requests to Maurice E. Hamilton, MD, 534 East Pine St, Suite B, Stockton, CA 95204.
Figure 1.-The intestinal artery appears normal, without evidence of vasculitis (original magnification x 200, hematoxylin and eosin stain) (prepared by David Jensen, MD).
THE WESTERN JOURNAL OF MEDICINE
*AUGUST 1991
_ 155
*
ABBREVIATIONS USED IN TEXT Ig = immunoglobulin SLE = systemic lupus erythematosus
tion was normal. Circulating anti-DNA antibody was present in low quantity (260 IU per ml; normal < 160 IU per ml). A rapid plasma reagin test was positive, and microhemagglutination assay for Treponema pallidum antibodies was negative. The following tests were normal or negative: antinuclear antibody, rheumatoid factor, cryoglobulins, C lq binding assay, Coombs' test, antithrombin III, protein C, protein S, factor VIII, and factor IX. Subsequent C4 and antiDNA determinations were normal. No IgG anticardiolipin antibody was detected a month after initiating methylprednisolone sodium succinate therapy, but IgM anticardiolipin antibody was noted at that time. The IgG anticardiolipin antibody reappeared as the corticosteroid dosage was tapered and discontinued. We have now had the opportunity to observe the patient for four years following the bowel infarction. Her IgG anticardiolipin antibody has returned to a high level, and she remains anticoagulated with warfarin sodium therapy. She has had no evidence of recurrent thrombosis, and her renal status is stable. She receives 1,700 calories of parenteral nutrition on alternate days to supplement her oral caloric intake. Comments Mesenteric artery thrombosis as a manifestation of the antiphospholipid syndrome has been documented rarely. This article appears to be the first report of superior mesenteric artery thrombosis associated with bowel infarction in a patient with the antiphospholipid syndrome. Thrombosis of the inferior mesenteric artery and splenic artery necessitating colectomy and splenectomy has been reported in a 44year-old woman with systemic lupus erythematosus (SLE) and antiphospholipid antibodies.9 In addition, the case of a 53-year-old man with antiphospholipid antibodies and occlusion of several abdominal arteries, including the mesenteric arteries, has been described.'0
Figure 2.-A glomerulus stained for fibrinogen shows prominent staining of peripheral segmental areas, characteristic of focal segmental glomerulosclerosis (original magnification x 285, fluorescein isothiocyanate-conjugated antifibrin[ogen] stain) (prepared by Charles N. Gamble, MD).
2
175
The patient in this report also showed other features ofthe antiphospholipid syndrome. Her proteinuria was caused by focal segmental glomerulosclerosis, a lesion associated with glomerular thrombosis in SLE patients with the lupus anticoagulant. " Spontaneous abortions, noted five times in this patient, have been linked to the presence of antiphospholipid antibodies, which may predispose to placental thrombosis and infarction.21-14 Thrombocytopenia, livedo reticularis, and migraine headaches are additional manifestations of this syndrome noted in our patient."I-'7 Anticardiolipin antibody, lupus anticoagulant, and reagin, representing related but nonidentical antiphospholipid antibodies, were all detected in this patient. Several investigators have reported a correlation between the presence of IgG anticardiolipin antibody and antiphospholipid syndrome, although IgM and IgA anticardiolipin antibodies have also been associated with this syndrome."' When initially tested, our patient showed only IgG anticardiolipin antibody. After the administration of high-dose corticosteroid therapy, only IgM anticardiolipin antibody was detected; after the discontinuation of corticosteroids, a high level of IgG anticardiolipin antibody reappeared. Whether corticosteroid therapy resulted in the differential expression of these isotypes is speculative. Antiphospholipid antibodies have been described most often in patients with systemic lupus erythematosus, with recent studies reporting these antibodies in 30% to 40% of SLE patients.78,"9 Patients with the antiphospholipid syndrome often display features of lupus but lack circulating antinuclear antibody. "8 Our patient was typical of this group: she fulfilled 3 ofthe 11 criteria for the classification of SLEproteinuria, thrombocytopenia, and immunologic disorder (a biologically false-positive test for syphilis)-but had negative antinuclear antibody determinations.20 Indeed, some data suggest that patients with the most serious manifestations of antiphospholipid syndrome are within this antinuclear antibody-negative group.'8 Antiphospholipid antibodies may also develop following the ingestion of drugs such as chlorpromazine and in association with malignant neoplasms and infections, including the acquired immunodeficiency syndrome.4'2' The mechanism predisposing to thrombosis in the antiphospholipid syndrome is unknown. Antiphospholipid antibodies may directly activate platelets by binding to membrane phospholipids, leading to platelet aggregation and thrombosis." Alternatively, antiphospholipid antibodies may bind to phospholipids in the membrane of endothelial cells, causing decreased production of prostacyclin (increasing platelet aggregation) or decreased release of plasminogen activator (decreasing fibrinolysis).2223 Moreover, plasma from patients with the lupus anticoagulant has been reported to inhibit prekallikrein activity, suggesting another possible cause of decreased fibrinolysis leading to thrombosis.24 The differential diagnosis of hypercoagulable states includes abnormalities of coagulation proteins, such as deficiency of protein C, protein S, or antithrombin III; levels of these proteins were normal in this patient. The nephrotic syndrome may predispose to thrombosis due to urinary loss of antithrombin III or to hypoalbuminemia, which may lead to increased platelet aggregation.25'26 As the antithrombin III level in our patient was normal and the degree of hypoalbuminemia initially noted was mild, it seems unlikely that nephrotic syndrome contributed significantly to her throm-
ALERTS, NOTICES, AND CASE
176
bosis. It is noteworthy that our patient started using an oral contraceptive only months before the diagnosis of mesenteric artery thrombosis. Asherson and colleagues recently reported that ten patients with antiphospholipid antibodies had thrombosis or other complications develop while they were taking oral contraceptives." Whether smoking contributed to the thrombosis described in this patient is uncertain. The treatment of thrombosis from antiphospholipid syndrome is anticoagulation. The importance of continuing anticoagulant therapy in patients with thrombosis and persistently high anticardiolipin antibody levels has been emphasized.28 The role of corticosteroid therapy appears to be limited, but it has been used in patients with recurrent thrombotic events despite anticoagulation and in extremely ill patients.4 29 Plasmapheresis combined with the use of cyclophosphamide has been proposed as adjunctive therapy for patients with devastating vasculopathy.29 In summary, a young woman with several manifestations of the antiphospholipid syndrome presented with jejunal and ileal infarction requiring resection of most of the small intestine. After four years' follow-up, the patient remains anticoagulated without evidence of recurrent thrombosis but with a high level of IgG anticardiolipin antibody. Measurement of antiphospholipid antibodies is indicated in the evaluation of clinical manifestations consistent with antiphospholipid syndrome, including thrombosis, recurrent fetal loss, and thrombocytopenia.
REPORTS
consecutive patients by activated partial thromboplastin time, Russell viper venom time, and anticardiolipin antibody level. Ann Intern Med 1987; 106:524-531 20. Tan EM, Cohen AS, Fries JF, et al: The 1982 revised criteria for the classifica-
tion of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271-1277 21. Cohen AJ, Philips TM, Kessler CM: Circulating coagulation inhibitors in the acquired immunodeficiency syndrome. Ann Intern Med 1986; 104:175-180 22. Carreras LO, Defreyn G, Machin SJ, et al: Arterial thrombosis, intrauterine death, and 'lupus' anticoagulant: Detection of immunoglobulin interfering with prostacyclin formation. Lancet 1981; 1:244-246 23. Angeles-Cano E, Sultan Y, Clauvel JP: Predisposing factors to thrombosis in systemic lupus erythematosus: Possible relation to endothelial cell damage. J Lab Clin Med 1979; 94:313-323 24. SanFelippo MJ, Drayna CJ: Prekallikrein inhibition associated with the lupus anticoagulant: A mechanism of thrombosis. Am J Clin Pathol 1982; 77:275-279 25. Kauffmann RH, Veltkamp JJ, Van Tilburg NH, Van Es LA: Acquired antithrombin Ill deficiency and thrombosis in the nephrotic syndrome. Am J Med 1978; 65:607-613 26. Jackson CA, Greaves M, Patterson AD, Brown CB, Preston FE: Relationship between platelet aggregation, thromboxane synthesis and albumin concentration in nephrotic syndrome. Br J Haematol 1982; 52:69-77 27. Asherson RA, Harris EN, Hughes GRV: Complications of oral contraceptives and antiphospholipid antibodies (Letter). Arthritis Rheum 1988; 31:575-576 28. Asherson RA, Chan JK, Harris EN, Gharavi AE, Hughes GRV: Anticardiolipin antibody, recurrent thrombosis, and warfarin withdrawal. Ann Rheum Dis 1985; 44:823-825 29. Ingram SB, Goodnight SH, Bennett RM: An unusual syndrome of a devastating noninflammatory vasculopathy associated with anticardiolipin antibodies: Report of two cases. Arthritis Rheum 1987; 30:1167-1172
Metastasis-induced Acute Pancreatitis SHAUN S. J. HUNG, MD BACH ARDALAN, MD
Miami, Florida
REFERENCES 1. Harris EN, Gharavi AE, Boey ML, et al: Anticardiolipin antibodies: by radioimmunoassay and association with thrombosis in systemic lupus sus. Lancet 1983; 2:1211-1214 2. Elias M, Eldor A: Thromboembolism in patients with the 'lupus' type ing anticoagulant. Arch Intern Med 1984; 144:510-515 3. Harris EN, Gharavi AE, Asherson RA, Boey ML, Hughes GRV: Cerebral infarction in systemic lupus erythematosus: Association with anticardiolipin ies. Clin Exp Rheumatol 1984; 2:47-51 4. Harris EN, Gharavi AE, Hughes GRV: Anti-phospholipid antibodies. Rheum Dis 1985; 11:591-609 5. Harris EN, Chan JKH, Asherson RA, Aber VR, Gharavi AE, Hughes GRV: Thrombosis, recurrent fetal loss, and thrombocytopenia: Predictive value of the cardiolipin antibody test. Arch Intern Med 1986; 146:2153-2156 6. Hughes GRV, Harris EN, Gharavi AE: The anticardiolipin syndrome. Rheumatol 1986; 13:486-489 7. Kalunian KC, PeterJB, Middlekauff HR, et al: Clinical significance of test for anticardiolipin antibodies in patients with systemic lupus erythematosus. Med 1988; 85:602-608 8. Asherson RA, Khamashta MA; Ordi-RosJ, et al: The 'primary' antiphospholipid syndrome: Major clinical and serological features. Medicine 1989; 9. Asherson RA, Morgan SH, Harris EN, Gharavi AE, Krausz T, Hughes Arterial occlusion causing large bowel infarction-A reflection of clotting diathesis SLE. Clin Rheumatol 1986; 5:102-106 10. Asherson RA, Mackworth-Young CG, Harris EN, Gharavi AE, Hughes GRV: Multiple venous and arterial thromboses associated with the lupus anticoagulant antibodies to cardiolipin in the absence of SLE. RheumatolInt 1985; Detection
erythemato-
circulat-
antibod-
Clin
anti-
J
a
single
J
Am
68:366-374
GRV:
in
and
5:91-93
11. Kant KS, PollakVE,Weiss MA, Glueck HI,
Miller MA,
Hess EV:
Glomerular
thrombosis in systemic lupus erythematosus: Prevalence and significance. (Baltimore) 1981; 60:71-86 12. Branch DW, Scott JR, Kochenour NK, Hershgold E: Obstetric associated with the lupus anticoagulant. N Engl J Med 1985; 13. Feinstein DI: Lupus anticoagulant, thrombosis, and fetal loss. N Engl 1985; 313:1348-1350 14. Lockshin MD, Druzin ML, GoeiS, et al: Antibody to cardiolipin as of fetal distress or death in pregnant patients with systemic lupus erythematosus. EngI J Med 1985; 313:152-156 15. Khamashta MA, Harris EN,Gharavi AE, et al: Immune mediated for thrombosis: Antiphospholipid antibody binding to platelet membranes. Dis 1988; 47:849-854 16. Asherson RA, Mayou SC, Merry P, Black MM, Hughes GRV: The
Medicine
complications
THE COMMON CAUSES of acute pancreatitis include alcoholism, biliary tract disease, trauma, surgical therapy, hyperlipidemia, hypercalcemia, and infections. In addition, acute pancreatitis can be induced by chemotherapy,12 tumor lysis,3 or tumor itself in patients with malignancy. The association of pancreatitis and pancreatic carcinoma is well recognized.
Of 255 consecutive patients with pancreatic or ampullary carcinoma, significant pancreatitis by histologic criteria was present in 26.4 Metastatic lesions of the pancreas have been reported from a wide variety of primary tumors5; those associated with clinical pancreatitis are rare, however. Chowhan and Madajewicz documented a 3.3% incidence,6 and Yeung and colleagues reported a 7.5% incidence of metastasisinduced acute pancreatitis in patients with small-cell lung cancer.7 Similarly, McLatchie and Imrie reported only 7 cases due to metastasis among 360 patients with acute pancreatitis seen during a six-year period.8 The objectives of this study are to report this incidence in a county hospital and to review the literature on this disorder. Patients and Methods
313:1322-1326
J
Med
predictor
mechanism
Ann
The medical records of all patients
discharged from JackMemorial Hospital, Miami, Florida, between January 1980 and December 1987 with a diagnosis of primary nonpancreatic malignancy and acute pancreatitis were reviewed retrospectively. A histology-proven malignant disorder was son
spectrum
livedo reticularis and anticardiolipin
antibodies. Br
J Dermatol
17. Levine SR,Welch KMA: The spectrum of neurologic antiphospholipid antibodies. Arch Neurol 1987; 44:876-883 18.
Colaco CB, Elkon KB: The
lupus anticoagulant:
nuclear antibody negative lupus that is
1989;
120:215-221
disease associated
with
A disease marker in anti-
cross-reactive with
antibodies
to
double-
stranded DNA. Arthritis Rheum 1985; 28:67-74 19. Petri M, Rheinschmidt M,Whiting-O'Keefe Q, Hellmann D, Corash L: frequency of lupus anticoagulant in systemic lupus erythematosus: A study of
The
sixty
(Hung SSJ, Ardalan B: Metastasis-induced 1991 Aug; 155:176-178)
acute pancreatitis. West J Med
of Miami School of Medicine, Medicine, Kaiser Permanente Medi-
From the Department of Oncology, University Florida. Dr Hung is now with the Department of cal Center, Santa Clara, California.
Reprint manente
requests to
Shaun S.J. Hung, MD, Department of Medicine, Kaiser PerKiely Blvd, Santa Clara, CA 95051.
Medical Center, 900
Alerts, Notices, and Case Reports Superior Mesenteric Artery Thrombosis Associated With Antiphospholipid Syndrome MAURICE E. HAMILTON, MD Sacramento, California
THE ASSOCIATION of antiphospholipid antibodies (anticardiolipin antibodies, the lupus anticoagulant, and reagin) with thrombosis, recurrent fetal loss, and thrombocytopenia has recently been classified as the antiphospholipid syndrome. 1-8 Thrombotic events associated with this syndrome most often involve the venous system, especially the deep veins of the leg, but also the renal vein, hepatic vein, portal vein, pulmonary vein, and inferior vena cava.2 4 7 8 Arterial thrombosis may also occur, affecting the cerebral, coronary, renal, and retinal arteries.3 47' 8 Only rarely has mesenteric artery thrombosis been noted.9'10 This report describes thrombosis of the superior mesenteric artery leading to small bowel infarction in a woman with the antiphospholipid syndrome. Report of a Case
The patient, a 29-year-old woman, was admitted to the hospital because of nausea with progressively worsening epigastric and lower abdominal pain of four days' duration. An upper gastrointestinal series done the day before admission was normal. Nausea and abdominal pain first developed four months earlier, at which time gastroduodenoscopy revealed gastritis, duodenitis, and a duodenal ulcer. These symptoms resolved during therapy with cimetidine. The patient had a history of migraine headaches. Proteinuria (2 +) was noted on routine urinalysis two years before admission; urinary protein excretion was 5.4 grams per 24 hours the month before admission. A biologically falsepositive serologic test for syphilis was detected ten years previously. The patient was married without children. She had had five spontaneous abortions, always occurring during the first trimester, most recently four months before admission. She was placed on a regimen of an oral contraceptive norgestrel and ethinyl estradiol-after the last abortion. She smoked a pack per day of cigarettes. On admission her temperature was 37.60 C. The abdomen was diffusely tender without organomegaly or abnormal masses. Erythematous macules and subsequently livedo reticularis were noted on the palms. The physical examination revealed no other abnormalities. Laboratory test results included a leukocyte count of 11.6 x 109 per liter (11,600 per pl) with normal differential count, hematocrit 0.34 (34%), platelet count 170 x 109 per liter (170,000 per /tl), sedimentation rate 58 mm per hour, serum albumin 33 grams per liter (3.3 grams per dl), and serum creatinine 70 /tmol per liter (0.8 mg per dl). A urinalysis showed 4 + protein with many
granular and hyaline casts. A plain x-ray film and computed tomographic scan of the abdomen were normal. Endoscopy showed mild gastritis; the duodenal mucosa was friable with a mottled, granular appearance. A superficial ulceration was present in the third portion of the duodenum; a biopsy of the duodenum revealed no definite abnormalities. Barium enema was normal. On the seventh hospital day the patient had severe abdominal pain associated with a rigid abdomen and a temperature of 39.9° C. An exploratory laparotomy revealed infarction of most of the jejunum and ileum; the superior mesenteric artery was hard with no pulse. About 200 cm of jejunum and ileum was resected, leaving the proximal 68 cm of jejunum and the terminal 3 cm of ileum. An activated partial thromboplastin time was prolonged (patient, 42.9 seconds; control, 26 seconds) and failed to correct following the addition of an equal amount of normal plasma; the prothrombin time was normal. The platelet count decreased to 38 x 109 per liter. High-dose corticosteroid therapy was administered. The patient was anticoagulated with heparin for presumed antiphospholipid syndrome. Total parenteral nutrition was instituted. During a second laparotomy the next day, an additional 8 cm of distal jejunum appeared nonviable and was resected; the gross appearance of the remaining bowel had improved. Histologic examination of the specimen of bowel showed areas of mucosal necrosis but no evidence of vasculitis (Figure 1). Over the next several days, the thrombocytopenia resolved and the palmar rash faded. No further bowel resection was required. Because of increasing proteinuria (13.8 grams per 24 hours), a renal biopsy was taken on the 18th hospital day. This showed mild to moderate focal mesangial cell hyperplasia with focal segmental glomerular staining for immunoglobulin (Ig) M, C3, Clq, properdin, and fibrin(ogen), characteristic of focal segmental glomerulosclerosis (Figure 2). No electron-dense deposits were detected. Serologic studies done before corticosteroid therapy was initiated revealed a high level of IgG anticardiolipin antibody (16 standard deviations above normal) without IgM or IgA anticardiolipin antibody. A C4 level was mildly decreased0.11 grams per liter (11 mg per dl; normal >0.15 grams per liter)-but total hemolytic complement (CHso) determina-
_ 'T;E,~~S'.,'','"'.'"''-
D
'A.~~~~~~7
IA 0
(Hamilton ME: Superior mesenteric artery thrombosis associated with antiphospholipid syndrome. West J Med 1991 Aug; 155:174-176) From the Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, Medical Center, Sacramento. Reprint requests to Maurice E. Hamilton, MD, 534 East Pine St, Suite B, Stockton, CA 95204.
Figure 1.-The intestinal artery appears normal, without evidence of vasculitis (original magnification x 200, hematoxylin and eosin stain) (prepared by David Jensen, MD).
THE WESTERN JOURNAL OF MEDICINE
*AUGUST 1991
_ 155
*
ABBREVIATIONS USED IN TEXT Ig = immunoglobulin SLE = systemic lupus erythematosus
tion was normal. Circulating anti-DNA antibody was present in low quantity (260 IU per ml; normal < 160 IU per ml). A rapid plasma reagin test was positive, and microhemagglutination assay for Treponema pallidum antibodies was negative. The following tests were normal or negative: antinuclear antibody, rheumatoid factor, cryoglobulins, C lq binding assay, Coombs' test, antithrombin III, protein C, protein S, factor VIII, and factor IX. Subsequent C4 and antiDNA determinations were normal. No IgG anticardiolipin antibody was detected a month after initiating methylprednisolone sodium succinate therapy, but IgM anticardiolipin antibody was noted at that time. The IgG anticardiolipin antibody reappeared as the corticosteroid dosage was tapered and discontinued. We have now had the opportunity to observe the patient for four years following the bowel infarction. Her IgG anticardiolipin antibody has returned to a high level, and she remains anticoagulated with warfarin sodium therapy. She has had no evidence of recurrent thrombosis, and her renal status is stable. She receives 1,700 calories of parenteral nutrition on alternate days to supplement her oral caloric intake. Comments Mesenteric artery thrombosis as a manifestation of the antiphospholipid syndrome has been documented rarely. This article appears to be the first report of superior mesenteric artery thrombosis associated with bowel infarction in a patient with the antiphospholipid syndrome. Thrombosis of the inferior mesenteric artery and splenic artery necessitating colectomy and splenectomy has been reported in a 44year-old woman with systemic lupus erythematosus (SLE) and antiphospholipid antibodies.9 In addition, the case of a 53-year-old man with antiphospholipid antibodies and occlusion of several abdominal arteries, including the mesenteric arteries, has been described.'0
Figure 2.-A glomerulus stained for fibrinogen shows prominent staining of peripheral segmental areas, characteristic of focal segmental glomerulosclerosis (original magnification x 285, fluorescein isothiocyanate-conjugated antifibrin[ogen] stain) (prepared by Charles N. Gamble, MD).
2
175
The patient in this report also showed other features ofthe antiphospholipid syndrome. Her proteinuria was caused by focal segmental glomerulosclerosis, a lesion associated with glomerular thrombosis in SLE patients with the lupus anticoagulant. " Spontaneous abortions, noted five times in this patient, have been linked to the presence of antiphospholipid antibodies, which may predispose to placental thrombosis and infarction.21-14 Thrombocytopenia, livedo reticularis, and migraine headaches are additional manifestations of this syndrome noted in our patient."I-'7 Anticardiolipin antibody, lupus anticoagulant, and reagin, representing related but nonidentical antiphospholipid antibodies, were all detected in this patient. Several investigators have reported a correlation between the presence of IgG anticardiolipin antibody and antiphospholipid syndrome, although IgM and IgA anticardiolipin antibodies have also been associated with this syndrome."' When initially tested, our patient showed only IgG anticardiolipin antibody. After the administration of high-dose corticosteroid therapy, only IgM anticardiolipin antibody was detected; after the discontinuation of corticosteroids, a high level of IgG anticardiolipin antibody reappeared. Whether corticosteroid therapy resulted in the differential expression of these isotypes is speculative. Antiphospholipid antibodies have been described most often in patients with systemic lupus erythematosus, with recent studies reporting these antibodies in 30% to 40% of SLE patients.78,"9 Patients with the antiphospholipid syndrome often display features of lupus but lack circulating antinuclear antibody. "8 Our patient was typical of this group: she fulfilled 3 ofthe 11 criteria for the classification of SLEproteinuria, thrombocytopenia, and immunologic disorder (a biologically false-positive test for syphilis)-but had negative antinuclear antibody determinations.20 Indeed, some data suggest that patients with the most serious manifestations of antiphospholipid syndrome are within this antinuclear antibody-negative group.'8 Antiphospholipid antibodies may also develop following the ingestion of drugs such as chlorpromazine and in association with malignant neoplasms and infections, including the acquired immunodeficiency syndrome.4'2' The mechanism predisposing to thrombosis in the antiphospholipid syndrome is unknown. Antiphospholipid antibodies may directly activate platelets by binding to membrane phospholipids, leading to platelet aggregation and thrombosis." Alternatively, antiphospholipid antibodies may bind to phospholipids in the membrane of endothelial cells, causing decreased production of prostacyclin (increasing platelet aggregation) or decreased release of plasminogen activator (decreasing fibrinolysis).2223 Moreover, plasma from patients with the lupus anticoagulant has been reported to inhibit prekallikrein activity, suggesting another possible cause of decreased fibrinolysis leading to thrombosis.24 The differential diagnosis of hypercoagulable states includes abnormalities of coagulation proteins, such as deficiency of protein C, protein S, or antithrombin III; levels of these proteins were normal in this patient. The nephrotic syndrome may predispose to thrombosis due to urinary loss of antithrombin III or to hypoalbuminemia, which may lead to increased platelet aggregation.25'26 As the antithrombin III level in our patient was normal and the degree of hypoalbuminemia initially noted was mild, it seems unlikely that nephrotic syndrome contributed significantly to her throm-
ALERTS, NOTICES, AND CASE
176
bosis. It is noteworthy that our patient started using an oral contraceptive only months before the diagnosis of mesenteric artery thrombosis. Asherson and colleagues recently reported that ten patients with antiphospholipid antibodies had thrombosis or other complications develop while they were taking oral contraceptives." Whether smoking contributed to the thrombosis described in this patient is uncertain. The treatment of thrombosis from antiphospholipid syndrome is anticoagulation. The importance of continuing anticoagulant therapy in patients with thrombosis and persistently high anticardiolipin antibody levels has been emphasized.28 The role of corticosteroid therapy appears to be limited, but it has been used in patients with recurrent thrombotic events despite anticoagulation and in extremely ill patients.4 29 Plasmapheresis combined with the use of cyclophosphamide has been proposed as adjunctive therapy for patients with devastating vasculopathy.29 In summary, a young woman with several manifestations of the antiphospholipid syndrome presented with jejunal and ileal infarction requiring resection of most of the small intestine. After four years' follow-up, the patient remains anticoagulated without evidence of recurrent thrombosis but with a high level of IgG anticardiolipin antibody. Measurement of antiphospholipid antibodies is indicated in the evaluation of clinical manifestations consistent with antiphospholipid syndrome, including thrombosis, recurrent fetal loss, and thrombocytopenia.
REPORTS
consecutive patients by activated partial thromboplastin time, Russell viper venom time, and anticardiolipin antibody level. Ann Intern Med 1987; 106:524-531 20. Tan EM, Cohen AS, Fries JF, et al: The 1982 revised criteria for the classifica-
tion of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271-1277 21. Cohen AJ, Philips TM, Kessler CM: Circulating coagulation inhibitors in the acquired immunodeficiency syndrome. Ann Intern Med 1986; 104:175-180 22. Carreras LO, Defreyn G, Machin SJ, et al: Arterial thrombosis, intrauterine death, and 'lupus' anticoagulant: Detection of immunoglobulin interfering with prostacyclin formation. Lancet 1981; 1:244-246 23. Angeles-Cano E, Sultan Y, Clauvel JP: Predisposing factors to thrombosis in systemic lupus erythematosus: Possible relation to endothelial cell damage. J Lab Clin Med 1979; 94:313-323 24. SanFelippo MJ, Drayna CJ: Prekallikrein inhibition associated with the lupus anticoagulant: A mechanism of thrombosis. Am J Clin Pathol 1982; 77:275-279 25. Kauffmann RH, Veltkamp JJ, Van Tilburg NH, Van Es LA: Acquired antithrombin Ill deficiency and thrombosis in the nephrotic syndrome. Am J Med 1978; 65:607-613 26. Jackson CA, Greaves M, Patterson AD, Brown CB, Preston FE: Relationship between platelet aggregation, thromboxane synthesis and albumin concentration in nephrotic syndrome. Br J Haematol 1982; 52:69-77 27. Asherson RA, Harris EN, Hughes GRV: Complications of oral contraceptives and antiphospholipid antibodies (Letter). Arthritis Rheum 1988; 31:575-576 28. Asherson RA, Chan JK, Harris EN, Gharavi AE, Hughes GRV: Anticardiolipin antibody, recurrent thrombosis, and warfarin withdrawal. Ann Rheum Dis 1985; 44:823-825 29. Ingram SB, Goodnight SH, Bennett RM: An unusual syndrome of a devastating noninflammatory vasculopathy associated with anticardiolipin antibodies: Report of two cases. Arthritis Rheum 1987; 30:1167-1172
Metastasis-induced Acute Pancreatitis SHAUN S. J. HUNG, MD BACH ARDALAN, MD
Miami, Florida
REFERENCES 1. Harris EN, Gharavi AE, Boey ML, et al: Anticardiolipin antibodies: by radioimmunoassay and association with thrombosis in systemic lupus sus. Lancet 1983; 2:1211-1214 2. Elias M, Eldor A: Thromboembolism in patients with the 'lupus' type ing anticoagulant. Arch Intern Med 1984; 144:510-515 3. Harris EN, Gharavi AE, Asherson RA, Boey ML, Hughes GRV: Cerebral infarction in systemic lupus erythematosus: Association with anticardiolipin ies. Clin Exp Rheumatol 1984; 2:47-51 4. Harris EN, Gharavi AE, Hughes GRV: Anti-phospholipid antibodies. Rheum Dis 1985; 11:591-609 5. Harris EN, Chan JKH, Asherson RA, Aber VR, Gharavi AE, Hughes GRV: Thrombosis, recurrent fetal loss, and thrombocytopenia: Predictive value of the cardiolipin antibody test. Arch Intern Med 1986; 146:2153-2156 6. Hughes GRV, Harris EN, Gharavi AE: The anticardiolipin syndrome. Rheumatol 1986; 13:486-489 7. Kalunian KC, PeterJB, Middlekauff HR, et al: Clinical significance of test for anticardiolipin antibodies in patients with systemic lupus erythematosus. Med 1988; 85:602-608 8. Asherson RA, Khamashta MA; Ordi-RosJ, et al: The 'primary' antiphospholipid syndrome: Major clinical and serological features. Medicine 1989; 9. Asherson RA, Morgan SH, Harris EN, Gharavi AE, Krausz T, Hughes Arterial occlusion causing large bowel infarction-A reflection of clotting diathesis SLE. Clin Rheumatol 1986; 5:102-106 10. Asherson RA, Mackworth-Young CG, Harris EN, Gharavi AE, Hughes GRV: Multiple venous and arterial thromboses associated with the lupus anticoagulant antibodies to cardiolipin in the absence of SLE. RheumatolInt 1985; Detection
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thrombosis in systemic lupus erythematosus: Prevalence and significance. (Baltimore) 1981; 60:71-86 12. Branch DW, Scott JR, Kochenour NK, Hershgold E: Obstetric associated with the lupus anticoagulant. N Engl J Med 1985; 13. Feinstein DI: Lupus anticoagulant, thrombosis, and fetal loss. N Engl 1985; 313:1348-1350 14. Lockshin MD, Druzin ML, GoeiS, et al: Antibody to cardiolipin as of fetal distress or death in pregnant patients with systemic lupus erythematosus. EngI J Med 1985; 313:152-156 15. Khamashta MA, Harris EN,Gharavi AE, et al: Immune mediated for thrombosis: Antiphospholipid antibody binding to platelet membranes. Dis 1988; 47:849-854 16. Asherson RA, Mayou SC, Merry P, Black MM, Hughes GRV: The
Medicine
complications
THE COMMON CAUSES of acute pancreatitis include alcoholism, biliary tract disease, trauma, surgical therapy, hyperlipidemia, hypercalcemia, and infections. In addition, acute pancreatitis can be induced by chemotherapy,12 tumor lysis,3 or tumor itself in patients with malignancy. The association of pancreatitis and pancreatic carcinoma is well recognized.
Of 255 consecutive patients with pancreatic or ampullary carcinoma, significant pancreatitis by histologic criteria was present in 26.4 Metastatic lesions of the pancreas have been reported from a wide variety of primary tumors5; those associated with clinical pancreatitis are rare, however. Chowhan and Madajewicz documented a 3.3% incidence,6 and Yeung and colleagues reported a 7.5% incidence of metastasisinduced acute pancreatitis in patients with small-cell lung cancer.7 Similarly, McLatchie and Imrie reported only 7 cases due to metastasis among 360 patients with acute pancreatitis seen during a six-year period.8 The objectives of this study are to report this incidence in a county hospital and to review the literature on this disorder. Patients and Methods
313:1322-1326
J
Med
predictor
mechanism
Ann
The medical records of all patients
discharged from JackMemorial Hospital, Miami, Florida, between January 1980 and December 1987 with a diagnosis of primary nonpancreatic malignancy and acute pancreatitis were reviewed retrospectively. A histology-proven malignant disorder was son
spectrum
livedo reticularis and anticardiolipin
antibodies. Br
J Dermatol
17. Levine SR,Welch KMA: The spectrum of neurologic antiphospholipid antibodies. Arch Neurol 1987; 44:876-883 18.
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The
sixty
(Hung SSJ, Ardalan B: Metastasis-induced 1991 Aug; 155:176-178)
acute pancreatitis. West J Med
of Miami School of Medicine, Medicine, Kaiser Permanente Medi-
From the Department of Oncology, University Florida. Dr Hung is now with the Department of cal Center, Santa Clara, California.
Reprint manente
requests to
Shaun S.J. Hung, MD, Department of Medicine, Kaiser PerKiely Blvd, Santa Clara, CA 95051.
Medical Center, 900
