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(LUP)
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Lupus (2015) 0,
1–4
http://lup.sagepub.com
CASE REPORT
SLE presenting as multiple hemorrhagic complications MC Abdulla1, J Alungal1, S Hashim1, MM Ali1 and M Musambil2 1
Department of Internal Medicine, M.E.S. Medical College, Perinthalmanna, India; and 2Medical biotechnology Central Research Laboratory, M.E.S. Medical College, Perinthalmanna, India
A 24 year old female with hereditary spastic paraplegia presented with intermittent headache for one year. She also had lower abdominal pain and vomiting for two months. She was pale, had icterus and mild splenomegaly. On diagnostic evaluation she was found to have hemolytic anemia, thrombocytopenia and bilateral adrenal, subdural, soft tissue (scalp and orbit) hemorrhages due to systemic lupus erythematosus (SLE). However, antiphospholipid syndrome (APS) antibodies were negative. Bilateral adrenal hemorrhage without associated APS is a rare phenomenon in SLE. We describe a case of SLE presenting with sequence of rare hemorrhagic complications in concert. Lupus (2015) 0, 1–4. Key words: Systemic lupus erythematosus; neuropsychiatric lupus; bilateral adrenal hemorrhage; subdural hemorrhage; hematologic changes; antiphospholipid syndrome
Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organ systems with protean manifestations. Bilateral adrenal, subdural, soft tissue (scalp and orbit) hemorrhages are uncommon manifestations in patients with SLE. The mechanisms underlying hemorrhagic manifestations in SLE have not been elucidated amply. A female with bilateral adrenal, subdural, soft tissue (scalp and orbit) hemorrhages as the initial manifestations of SLE is described. Bilateral adrenal hemorrhage in SLE forces one to look for coexisting antiphospholipid syndrome (APS). Our patient had bilateral adrenal hemorrhage without APS and presented with a sequence of rare hemorrhagic complications.
Case report 24 year old female known to have hereditary spastic paraplegia presented with intermittent headache for one year, and a two month history of lower abdominal pain and vomiting. Born out of a non-consanguineous union, four of her siblings had heriditary Correspondence to: Mansoor C. Abdulla, Department of Internal Medicine, M.E.S. Medical College, Perinthalmanna, Kerala, India. E-mail: [email protected] Received 4 September 2014; accepted 28 January 2015
spastic paraplegia. She was found to be severely pale, icteric, all peripheral pulsations were palpable equally and blood pressure was 90/60 mm of Hg. Systemic examination showed mild splenomegaly and spastic paraplegia. Hemoglobin was 3.1 g/dl, total leucocyte count 4200/ml, platelet count 0.76 109/L, ESR 105 mm in1h and CRP was normal. The hematocrit-corrected ESR level was 21 mm/hr. In the peripheral smear RBCs were microcytic, hypochromic with polychromasia, dacryocytes and nucleated red blood corpuscles (RBCs), white blood corpuscles (WBCs) were normal and platelet count was reduced mildly. The corrected reticulocyte count was 3%, direct and indirect Coombs tests were negative. Urinalysis showed trace albumin with 2–4 leucocytes/high power fields. Biochemical parameters showed random blood sugar (RBS) 121 mg%, urea13 mg/dl, creatinine 0.6 mg/dl, sodium 134 mmol/l, potassium 3.6 mmol/l, aspartate transaminase (AST) 39 IU/l, alanine transaminase (ALT) 31 IU/l, alkaline phosphatase 76 IU/l, total bilirubin 3.1 mg/dl, direct bilirubin 0.1 mg/dl, total protein 6.1 g/dl, albumin 3.1 g/dl,globulin 3.0 g/dl. Chest X-ray and electrocardiogram were normal. Prothrombin time and partial thromboplastin times were normal. Serum LDH was 2549 IU/L. HIV, hepatitis B and hepatitis C serologies were negative. Ultrasonography of abdomen showed minimal left perinephric collection, a right renal calculus, mild splenomegaly and bilateral polycystic ovaries. CT scan of abdomen showed diffusely enlarged bilateral adrenal glands suggestive of
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(LUP)
[1–4] [PREPRINTER stage]
SLE presenting as multiple hemorrhagic complications MC Abdulla et al.
2
Figure 1
CT Abdomen showing diffusely enlarged bilateral adrenal glands suggestive of bilateral adrenal hemorrhage.
bilateral adrenal hemorrhage and mild splenomegaly (Figure 1). Morning serum cortisol was 1.8 mg/dL. CT scan of brain revealed sub-acute to chronic subtle subdural hemorrhage on left side, nonspecific soft tissue thickening over scalp possibly hemorrhage/ edema and preseptal soft tissue thickening seen in both orbits (Figure 2). Bone marrow was hypercellular with marked erythroid hyperplasia and increased normoblasts, normal myeloid series and megakaryocytes were increased in number with normal maturation. ANA was positive and anti double stranded DNA was strongly positive. C3 and C4 levels were low (50 mg/dl and 11 mg/dl, respectively). IgG, IgM aPL, IgG and IgM beta2 glycoprotein and lupus anticoagulant tests were negative. This 24 year old female who presented with bilateral adrenal, subdural, soft tissue (scalp and orbit) hemorrhages had SLE with negative APS. She was started on high dose steroids; she became well and was sent home on oral steroids. When she returned for review after one month, blood counts were normal, antiphospholipid antibodies were still negative and she was symptom free.
Discussion Bilateral adrenal, subdural, soft tissue (scalp and orbit) hemorrhages are unusual in SLE. In SLE bilateral adrenal hemorrhage makes can suggest
coexisting APS. Bilateral adrenal hemorrhage may be associated with primary or secondary APS.1 All APS antibodies were negative in our patient. We were unable to find cases of bilateral adrenal hemorrhage in SLE without coexisting APS during a literature review. There is an extremely rare possibility of seronegative APS in this case. Patients with clinical manifestations highly suggestive of APS but persistently negative for conventional APS are classified as having sero-negative APS.2 SLE may be associated with pulmonary and nervous system hemorrhage.3,4 Current knowledge holds ischaemia to be the main cause of CNS manifestations in SLE. Rarely are CNS syndromes due to intracranial and intra-spinal hemorrhage but the factors that lead to the rupture of vessel walls have not yet been analyzed sufficiently. Findings in case series, reports of single cases and post-mortem investigations support an increased incidence of various types of intracranial and intraspinal hemorrhage, including intracerebral, subarachnoid, subdural5,6 and epidural hemorrhage in SLE. The mechanisms underlying hemorrhage have not been elucidated sufficiently but have been surmised to be related to several causes: hypertension, hypercholesterolaemia, prolonged corticosteroid medication and changes induced by SLE.7 Thrombocytopenia may also play a role.5 In a study of 234 patients with systemic lupus erythematosus, Kitagawa et al. noted cerebral infarction in eight, cerebral
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(LUP)
[1–4] [PREPRINTER stage]
SLE presenting as multiple hemorrhagic complications MC Abdulla et al.
3
Figure 2 CT Brain showing subtle subdural hemorrhage on left side, nonspecific soft tissue thickening over scalp and preseptal soft tissue thickening in both orbits (a) and (b) which resolved completely after treatment (c) and (d).
hemorrhage in two and subarachnoid hemorrhage in three.8 Alveolar hemorrhage in SLE, characterized by bland alveolar wall changes, is pathogenetically similar to the lupus microangiopathy of the kidney. In both lung and kidney, the pathogenesis of the microvascular injury appears to be related to immune complex deposition and the induction of apoptosis. Since SLE patients are prone to developing hemorrhagic complications, the adrenal and soft tissue hemorrhage in this case may be due to similar mechanisms compounded by thrombocytopenia. Our patient had Coombs negative hemolytic anemia without evidence of microangiopathic hemolysis. Patients with SLE and hemolytic anemia have an acquired deficiency of either CD55 or CD59 erythrocytic expression, or both. CD55 and CD59 are glycosylphosphatidylinositol-anchored type I cell surface proteins which inhibit formation of the C3 convertases and prevent the terminal polymerization of the membrane attack complex. These surface-bound complement regulatory proteins protect cells from uncontrolled complementmediated lysis. The deficiency of these glycoprotein I anchored proteins may contribute to the
hemolytic process by increasing the susceptibility to complement mediated lysis. Complement receptor 1 (CR1) is a single pass trans-membrane glycoprotein that, through its ability to bind key components of the complement cascade, can inhibit both the classical and alternative pathways. Activation of complement cascade via the antibody-mediated classical pathway can initiate red blood cell destruction. A functional defect in CR1 or loss of CR1 on erythrocytes in SLE patients has also been proposed as a cause for hemolysis9. Deficiency of these proteins, may contribute to the hemolytic process by increasing the susceptibility to complement mediated lysis and might be responsible for Coombs’ negative hemolytic anemia in SLE.9,10 Evans syndrome (ES) is defined as autoimmune destruction of at least two peripheral blood cell types. ES is a diagnosis of exclusion, and other confounding disorders must be ruled out before establishing the diagnosis. Since ANA and Anti double stranded DNA were strongly positive in our case a possibility of ES was less likely. We describe a patient with sequence of rare hemorrhagic complications in SLE at different sites in concert, which, to our knowledge, is the first such report. Bilateral adrenal hemorrhage in SLE Lupus
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(LUP)
[1–4] [PREPRINTER stage]
SLE presenting as multiple hemorrhagic complications MC Abdulla et al.
4
without coexisting APS adds to the complexity of this case and we hope this case may help the readers to be aware of such rare presentations.
Conflict of Interest Statement The authors have no conflicts of interest to declare.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
References 1 Espinosa G, Santos E, Cervera R, et al. Adrenal involvement in the antiphospholipid syndrome: clinical and immunologic characteristics of 86 patients. Medicine 2003; 82: 106–118.
2 Nayfe R, Uthman I, Aoun J, Saad Aldin E, Merashli M, Khamashta MA. Seronegative antiphospholipid syndrome. Rheumatol 2013; 52: 1358–1367. 3 Jennekens FGI, Kater L. The central nervous system in systemic lupus erythematosus. Part 2. Clinical syndromes: a literature investigation. Rheumatol 2002; 41: 605–618. 4 Hughson MD, He Z J, Henegar J, McMurray R. Alveolar hemorrhage and renal microangiopathy in systemic lupus erythematosus: immune complex small vascular injury with apoptosis. Archiv Pathol Lab Med 2001; 125: 475–483. 5 Bovim G, Størker J, Schrader H. Subdural hematoma presenting as headache in systemic lupus erythematosus. Cephalalgia 1990; 10: 25–29. 6 Futran J, Shore A, Urowitz MB, Grossman H. Subdural hematoma in systemic lupus erythematosus: report and review of the literature. J Rheumatol 1987; 14: 378–381. 7 Rahman P, Aguero S, Gladman DD, Hallett D, Urowitz MB. Vascular events in hypertensive patients with systemic lupus erythematosus. Lupus 2000; 9: 672–675. 8 Kitagawa Y, Gotoh F, Koto A, Okayasu H. Stroke in systemic lupus erythematosus. Stroke 1990; 21: 1533–1539. 9 Giannouli S, Voulgarelis M, Ziakas PD, Tzioufas AG. Anaemia in systemic lupus erythematosus: from pathophysiology to clinical assessment. Ann Rheum Dis 2006; 65: 144–148. 10 Ruiz-Argu¨elles A, Llorente L. The role of complement regulatory proteins (CD55 and CD59) in the pathogenesis of autoimmune hemocytopenias. Autoimmun Revs 2007; 6: 155–161.
Lupus Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on February 26, 2015
(LUP)
[1–4] [PREPRINTER stage]
Lupus (2015) 0,
1–4
http://lup.sagepub.com
CASE REPORT
SLE presenting as multiple hemorrhagic complications MC Abdulla1, J Alungal1, S Hashim1, MM Ali1 and M Musambil2 1
Department of Internal Medicine, M.E.S. Medical College, Perinthalmanna, India; and 2Medical biotechnology Central Research Laboratory, M.E.S. Medical College, Perinthalmanna, India
A 24 year old female with hereditary spastic paraplegia presented with intermittent headache for one year. She also had lower abdominal pain and vomiting for two months. She was pale, had icterus and mild splenomegaly. On diagnostic evaluation she was found to have hemolytic anemia, thrombocytopenia and bilateral adrenal, subdural, soft tissue (scalp and orbit) hemorrhages due to systemic lupus erythematosus (SLE). However, antiphospholipid syndrome (APS) antibodies were negative. Bilateral adrenal hemorrhage without associated APS is a rare phenomenon in SLE. We describe a case of SLE presenting with sequence of rare hemorrhagic complications in concert. Lupus (2015) 0, 1–4. Key words: Systemic lupus erythematosus; neuropsychiatric lupus; bilateral adrenal hemorrhage; subdural hemorrhage; hematologic changes; antiphospholipid syndrome
Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organ systems with protean manifestations. Bilateral adrenal, subdural, soft tissue (scalp and orbit) hemorrhages are uncommon manifestations in patients with SLE. The mechanisms underlying hemorrhagic manifestations in SLE have not been elucidated amply. A female with bilateral adrenal, subdural, soft tissue (scalp and orbit) hemorrhages as the initial manifestations of SLE is described. Bilateral adrenal hemorrhage in SLE forces one to look for coexisting antiphospholipid syndrome (APS). Our patient had bilateral adrenal hemorrhage without APS and presented with a sequence of rare hemorrhagic complications.
Case report 24 year old female known to have hereditary spastic paraplegia presented with intermittent headache for one year, and a two month history of lower abdominal pain and vomiting. Born out of a non-consanguineous union, four of her siblings had heriditary Correspondence to: Mansoor C. Abdulla, Department of Internal Medicine, M.E.S. Medical College, Perinthalmanna, Kerala, India. E-mail: [email protected] Received 4 September 2014; accepted 28 January 2015
spastic paraplegia. She was found to be severely pale, icteric, all peripheral pulsations were palpable equally and blood pressure was 90/60 mm of Hg. Systemic examination showed mild splenomegaly and spastic paraplegia. Hemoglobin was 3.1 g/dl, total leucocyte count 4200/ml, platelet count 0.76 109/L, ESR 105 mm in1h and CRP was normal. The hematocrit-corrected ESR level was 21 mm/hr. In the peripheral smear RBCs were microcytic, hypochromic with polychromasia, dacryocytes and nucleated red blood corpuscles (RBCs), white blood corpuscles (WBCs) were normal and platelet count was reduced mildly. The corrected reticulocyte count was 3%, direct and indirect Coombs tests were negative. Urinalysis showed trace albumin with 2–4 leucocytes/high power fields. Biochemical parameters showed random blood sugar (RBS) 121 mg%, urea13 mg/dl, creatinine 0.6 mg/dl, sodium 134 mmol/l, potassium 3.6 mmol/l, aspartate transaminase (AST) 39 IU/l, alanine transaminase (ALT) 31 IU/l, alkaline phosphatase 76 IU/l, total bilirubin 3.1 mg/dl, direct bilirubin 0.1 mg/dl, total protein 6.1 g/dl, albumin 3.1 g/dl,globulin 3.0 g/dl. Chest X-ray and electrocardiogram were normal. Prothrombin time and partial thromboplastin times were normal. Serum LDH was 2549 IU/L. HIV, hepatitis B and hepatitis C serologies were negative. Ultrasonography of abdomen showed minimal left perinephric collection, a right renal calculus, mild splenomegaly and bilateral polycystic ovaries. CT scan of abdomen showed diffusely enlarged bilateral adrenal glands suggestive of
! The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
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10.1177/0961203315573853
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(LUP)
[1–4] [PREPRINTER stage]
SLE presenting as multiple hemorrhagic complications MC Abdulla et al.
2
Figure 1
CT Abdomen showing diffusely enlarged bilateral adrenal glands suggestive of bilateral adrenal hemorrhage.
bilateral adrenal hemorrhage and mild splenomegaly (Figure 1). Morning serum cortisol was 1.8 mg/dL. CT scan of brain revealed sub-acute to chronic subtle subdural hemorrhage on left side, nonspecific soft tissue thickening over scalp possibly hemorrhage/ edema and preseptal soft tissue thickening seen in both orbits (Figure 2). Bone marrow was hypercellular with marked erythroid hyperplasia and increased normoblasts, normal myeloid series and megakaryocytes were increased in number with normal maturation. ANA was positive and anti double stranded DNA was strongly positive. C3 and C4 levels were low (50 mg/dl and 11 mg/dl, respectively). IgG, IgM aPL, IgG and IgM beta2 glycoprotein and lupus anticoagulant tests were negative. This 24 year old female who presented with bilateral adrenal, subdural, soft tissue (scalp and orbit) hemorrhages had SLE with negative APS. She was started on high dose steroids; she became well and was sent home on oral steroids. When she returned for review after one month, blood counts were normal, antiphospholipid antibodies were still negative and she was symptom free.
Discussion Bilateral adrenal, subdural, soft tissue (scalp and orbit) hemorrhages are unusual in SLE. In SLE bilateral adrenal hemorrhage makes can suggest
coexisting APS. Bilateral adrenal hemorrhage may be associated with primary or secondary APS.1 All APS antibodies were negative in our patient. We were unable to find cases of bilateral adrenal hemorrhage in SLE without coexisting APS during a literature review. There is an extremely rare possibility of seronegative APS in this case. Patients with clinical manifestations highly suggestive of APS but persistently negative for conventional APS are classified as having sero-negative APS.2 SLE may be associated with pulmonary and nervous system hemorrhage.3,4 Current knowledge holds ischaemia to be the main cause of CNS manifestations in SLE. Rarely are CNS syndromes due to intracranial and intra-spinal hemorrhage but the factors that lead to the rupture of vessel walls have not yet been analyzed sufficiently. Findings in case series, reports of single cases and post-mortem investigations support an increased incidence of various types of intracranial and intraspinal hemorrhage, including intracerebral, subarachnoid, subdural5,6 and epidural hemorrhage in SLE. The mechanisms underlying hemorrhage have not been elucidated sufficiently but have been surmised to be related to several causes: hypertension, hypercholesterolaemia, prolonged corticosteroid medication and changes induced by SLE.7 Thrombocytopenia may also play a role.5 In a study of 234 patients with systemic lupus erythematosus, Kitagawa et al. noted cerebral infarction in eight, cerebral
Lupus Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on February 26, 2015
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(LUP)
[1–4] [PREPRINTER stage]
SLE presenting as multiple hemorrhagic complications MC Abdulla et al.
3
Figure 2 CT Brain showing subtle subdural hemorrhage on left side, nonspecific soft tissue thickening over scalp and preseptal soft tissue thickening in both orbits (a) and (b) which resolved completely after treatment (c) and (d).
hemorrhage in two and subarachnoid hemorrhage in three.8 Alveolar hemorrhage in SLE, characterized by bland alveolar wall changes, is pathogenetically similar to the lupus microangiopathy of the kidney. In both lung and kidney, the pathogenesis of the microvascular injury appears to be related to immune complex deposition and the induction of apoptosis. Since SLE patients are prone to developing hemorrhagic complications, the adrenal and soft tissue hemorrhage in this case may be due to similar mechanisms compounded by thrombocytopenia. Our patient had Coombs negative hemolytic anemia without evidence of microangiopathic hemolysis. Patients with SLE and hemolytic anemia have an acquired deficiency of either CD55 or CD59 erythrocytic expression, or both. CD55 and CD59 are glycosylphosphatidylinositol-anchored type I cell surface proteins which inhibit formation of the C3 convertases and prevent the terminal polymerization of the membrane attack complex. These surface-bound complement regulatory proteins protect cells from uncontrolled complementmediated lysis. The deficiency of these glycoprotein I anchored proteins may contribute to the
hemolytic process by increasing the susceptibility to complement mediated lysis. Complement receptor 1 (CR1) is a single pass trans-membrane glycoprotein that, through its ability to bind key components of the complement cascade, can inhibit both the classical and alternative pathways. Activation of complement cascade via the antibody-mediated classical pathway can initiate red blood cell destruction. A functional defect in CR1 or loss of CR1 on erythrocytes in SLE patients has also been proposed as a cause for hemolysis9. Deficiency of these proteins, may contribute to the hemolytic process by increasing the susceptibility to complement mediated lysis and might be responsible for Coombs’ negative hemolytic anemia in SLE.9,10 Evans syndrome (ES) is defined as autoimmune destruction of at least two peripheral blood cell types. ES is a diagnosis of exclusion, and other confounding disorders must be ruled out before establishing the diagnosis. Since ANA and Anti double stranded DNA were strongly positive in our case a possibility of ES was less likely. We describe a patient with sequence of rare hemorrhagic complications in SLE at different sites in concert, which, to our knowledge, is the first such report. Bilateral adrenal hemorrhage in SLE Lupus
Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on February 26, 2015
XML Template (2015) [23.2.2015–3:52pm] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/150027/APPFile/SG-LUPJ150027.3d
(LUP)
[1–4] [PREPRINTER stage]
SLE presenting as multiple hemorrhagic complications MC Abdulla et al.
4
without coexisting APS adds to the complexity of this case and we hope this case may help the readers to be aware of such rare presentations.
Conflict of Interest Statement The authors have no conflicts of interest to declare.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
References 1 Espinosa G, Santos E, Cervera R, et al. Adrenal involvement in the antiphospholipid syndrome: clinical and immunologic characteristics of 86 patients. Medicine 2003; 82: 106–118.
2 Nayfe R, Uthman I, Aoun J, Saad Aldin E, Merashli M, Khamashta MA. Seronegative antiphospholipid syndrome. Rheumatol 2013; 52: 1358–1367. 3 Jennekens FGI, Kater L. The central nervous system in systemic lupus erythematosus. Part 2. Clinical syndromes: a literature investigation. Rheumatol 2002; 41: 605–618. 4 Hughson MD, He Z J, Henegar J, McMurray R. Alveolar hemorrhage and renal microangiopathy in systemic lupus erythematosus: immune complex small vascular injury with apoptosis. Archiv Pathol Lab Med 2001; 125: 475–483. 5 Bovim G, Størker J, Schrader H. Subdural hematoma presenting as headache in systemic lupus erythematosus. Cephalalgia 1990; 10: 25–29. 6 Futran J, Shore A, Urowitz MB, Grossman H. Subdural hematoma in systemic lupus erythematosus: report and review of the literature. J Rheumatol 1987; 14: 378–381. 7 Rahman P, Aguero S, Gladman DD, Hallett D, Urowitz MB. Vascular events in hypertensive patients with systemic lupus erythematosus. Lupus 2000; 9: 672–675. 8 Kitagawa Y, Gotoh F, Koto A, Okayasu H. Stroke in systemic lupus erythematosus. Stroke 1990; 21: 1533–1539. 9 Giannouli S, Voulgarelis M, Ziakas PD, Tzioufas AG. Anaemia in systemic lupus erythematosus: from pathophysiology to clinical assessment. Ann Rheum Dis 2006; 65: 144–148. 10 Ruiz-Argu¨elles A, Llorente L. The role of complement regulatory proteins (CD55 and CD59) in the pathogenesis of autoimmune hemocytopenias. Autoimmun Revs 2007; 6: 155–161.
Lupus Downloaded from lup.sagepub.com at UCSF LIBRARY & CKM on February 26, 2015
