NDT Advance Access originally published online on December 2, 2005
Nephrology Dialysis Transplantation 2006 21(3):792-795; doi:10.1093/ndt/gfi299
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Systemic lupus erythematosus, eosinophilic vasculitis and acalculous cholecystitis
1 Department of Renal Medicine, and 2 Department of Immunology, Hope Hospital, Salford, 3 Department of Renal Medicine, St James University Teaching Hospital, Leeds, 4 Rheumatism Research Centre, Central Manchester and Manchester Children's University Hospitals Trust, Manchester, UK
Correspondence and offprint requests to: Janet Hegarty, Department of Renal Medicine, Hope Hospital, Salford, UK. Email: janet.hegarty{at}srht.nhs.uk
Keywords: acalculous cholecystitis; eosinophilic vasculitis; renal failure; systemic lupus erythematosus
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Introduction |
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Patients with atypical features of a common disease often pose diagnostic challenges, as they may have two distinct disease entities, a rare manifestation of the common illness, or even a new syndrome. We describe a case of a 30-year-old woman with what we feel was a rare acute presentation of systemic lupus erythematosus (SLE), with hypereosinophilia, acalculous cholecystitis and biopsy proven eosinophilic vasculitis affecting the kidney, responding successfully to immunomodulatory therapy to date.
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Case |
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A 30-year-old woman presented with a 5 day history of fever, diarrhoea and vomiting. Closer questioning revealed a 6 week history of fatigue and flitting polyarthralgia involving wrists, hands and feet. There was no past medical history of note, in particular no respiratory tract illnesses and no history of allergy. She took no prescribed or over the counter medications. On examination she was unwell, pyrexial (39.9°C) and markedly intravascularly deplete, although her limbs were oedematous. There were no cutaneous, nail-fold or joint abnormalities present. A sinus tachycardia of 126 bpm was present, blood pressure was 122/55 mmHg and heart sounds were normal. Oxygen saturation was normal on air, and examination of the respiratory system was unremarkable. There was local tenderness in the right upper quadrant but the abdomen was soft.
Initial investigations showed acute renal failure, mild hepatic dysfunction in an obstructive pattern, a low albumin, and deranged clotting with low platelets [Na 130 mmol/l, K 3.7 mmol/l, Ur 18.9 mmol/l, Cr 323 µmol/l, bilirubin 62 µmol/l (<20), Aspartate amino transferase (AST) 40 U/l (<40), Alkaline phosphatase (ALP) 213 U/l (30–135), albumin 33 g/l (36–42), Prothrombin time (PT) 18.6 s (12.5–15.5), Activated Partial Thromboplastin Time (APTT) 46.9s (25.0–37.0), platelets 51 x 109/l]. The blood count was normal but the differential white cell count showed a relative (19.7%) and absolute eosinophilia (1.9 x 109/l). Arterial blood gases showed adequate oxygenation on air with no evidence of acidosis (pH 7.45, pO2 16.4 kPa, pCO2 3.3 kPa, standard bicarbonate 22 mmol/l, base excess –4 mmol/l). Urinalysis revealed moderate amounts of blood and bilirubin, and a trace of protein. Bloods taken 4 h after admission showed a further derangement of clotting factors, a drop in platelet count to 9 x 109/l, a drop in haemoglobin (13.1 g/dl to 9.2 g/dl) and raised d-dimers >2 mg/l (<0.5 g/l). She was resuscitated with fluids, fresh frozen plasma, platelets and high-dose broad spectrum antibiotics, but despite this, she rapidly deteriorated and required intensive care for 12 h after admission, with full ventilatory, inotropic, nutritional and renal support. Ultrasound examination of the abdomen showed a 13 mm thick-walled oedematous gall bladder with no dilatation of the common bile duct or intrahepatic ducts. The liver, spleen, pancreas and renal tract had normal appearances. She was judged unfit for theatre and so percutaneous drainage of the gall bladder was performed under ultrasound guidance 3 days later when her consumptive coagulopathy had stabilized. This revealed clear yellow fluid which proved sterile on culture. Tests for hepatitis A, B and C, HIV1 and 2, leptospirosis, legionnaires disease and tuberculosis were negative. Repeated examination for bacterial infection (blood, urine, sputum, stool, pleural aspirate, ascitic tap and cervical swab) and parastic infection were all negative. Serology, however, revealed a polyclonally raised serum ImmunoglobulinG, positive anti-nuclear antibody at 1 : 200 titre, positive double-stranded DNA (dsDNA) antibodies (Farr assay) at 28 iu/ml and low C3 and C4 levels. Antibodies to neutrophil cytoplasmic antigens, myeloperoxidase (MPO) and proteinase 3 (PR3), and glomerular basement membrane were negative. The eosinophilia persisted with levels as high as 10.5 x 109/l (48.1% of total white blood cell).
By day 10, although other parameters had stabilized, her liver enzymes became increasingly deranged with an obstructive pattern, peaking at a bilirubin of 156 µmol/l, ALP 1572U/l, AST 47 U/l, and she was transferred to a tertiary liver unit for assessment. Following transfer, she was successfully weaned from ventilatory and inotropic support. She then underwent percutaneous ultrasound guided renal biopsy that revealed severe concentric vasculitis involving medium-sized vessels and also changes consistent with acute tubular necrosis. The glomeruli were normal. Thus, a diagnosis of eosinophilic systemic vasculitis was made according to biopsy results. She was promptly treated with three consecutive pulses of methylprednisolone (1 g/24 h) and after the third dose her renal function improved such that she did not require further renal replacement therapy.
She continued to make progress and was discharged after 27 days in hospital with normal renal function, a mild normocytic anaemia, a normal eosinophil count and improving liver enzymes (bilirubin 32 µmol/l, ALT 45 U/l, ALP 744 U/l), having had no further treatment for the cholecystitis other than systemic immunosuppression. Over the next 4 months she remained well clinically, and her steroid regime was slowly reduced. She did, however, continue to exhibit fluctuating derangements of liver function, now mainly a transaminasaemia (for example, bilirubin 7 µmol/l, ALP 200 U/l, ALT 100 U/l, glutamyl transpeptidase (GGT) 256 U/l) and therefore went on to liver biopsy. This showed normal architecture with no evidence of inflammation or fibrosis and no evidence of vasculitis. Shortly after this time the titre of dsDNA antibodies rose, she developed positive Ro-antibodies, and was commenced on azathioprine (see Figure 1). Over the subsequent 2 years, her condition evolved to meet the American College of Rheumatology classification criteria of SLE, with arthritis, rash, anti-cardiolipin antibodies, anti-dsDNA antibodies, and persisting renal abnormalities (protein leak averaging 1 g/24 h). Serological activity fluctuated, but she managed to be maintained on just azathioprine (150 mg) for immunosuppression. However, 5 years from presentation, she suffered a clinical relapse with nephrotic proteinuria and fluid overload. She was started on high dose steroids and diuretics. The azathioprine was stopped because of leukopenia and mycophenolate mofetil (MMF) substituted in its place, which achieved good control with no further relapse. A renal biopsy was performed which showed a diffuse lupus glomerulonephritis of predominantly mesangiocapillary pattern with active and sclerosing lesions. After 18 months of MMF, her dsDNA result was negative. Subsquently, she suffered no further relapses and was able to stop MMF, with a reducing dose of prednisolone.
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Discussion |
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This case highlights the diagnostic difficulties systemic vasculitides can pose. This patient may have had a rare manifestation of lupus (eosinophilic vasculitis with an acalculous cholecystitis), two distinct disease entities, or even a ‘new’ overlap syndrome. The lack of pre-morbid respiratory tract disease or allergy made a Churg-Strauss like syndrome unlikely. The gastrointestinal features were suggestive of a polyarteritis nodosa (PAN)-like presentation of SLE; PAN can also be associated with an eosinophilia although the peripheral count seen is not usually so high. Subsequent follow-up however, revealed manifestations more commonly seen in lupus, such as arthritis, rash, anti-cardiolipin antibodies, anti-dsDNA antibodies and persisting renal abnormalities, with few atypical features beyond the acute phase.
Systemic lupus erythematosus is of course a disease which shows enormous heterogeneity in clinical expression. This is well illustrated by our case, with several unusual features of disease evolution. Firstly, although fatigue, arthralgia, diarrhoea and fever are common symptoms and signs in active lupus, the rapid progression to an acute fulminant illness with multi-organ failure and consumptive coagulopathy seen in this case is an unusual presentation of SLE. Secondly, although vasculitis is a common complication of SLE, it is usually a cutaneous disease manifestation in up to 18% of patients [1,2] and multi-system involvement is rare. Indeed, as outlined before, such cases have often provoked debate as to whether patients have a systemic vasculitis with a clinical pattern closely resembling SLE, two distinct disease entities, or systemic vasculitis which evolves into SLE [3]. Vasculitis has also been shown to be a comparatively rare expression of renal lupus with a reported prevalence of 0–5%. For example, in a series of 169 biopsies only four showed evidence of vasculitis, and in only one of these cases was there no associated glomerulonephritis [4]. Earlier reports suggested that patients with renal vasculitis had a more severe clinical course with rapidly progressive renal failure. Reports from the last 10–15 years have shown a more favourable outcome with a 5 year renal survival of up to 80% [5,6] – perhaps reflecting earlier diagnosis and/or more aggressive immunosuppressive therapy. Thirdly, systemic hypereosinophilic syndromes have also only rarely been described in relation to SLE. Case reports are confined to a young man with SLE and hypereosinophilia, whose Loeffler's endocarditis and acute pulmonary capillaritis was only diagnosed at post-mortem [7]; a patient with quiescent SLE, who developed hypereosinophilia with gastrointestinal involvement manifesting as diarrhoea, malabsorption and anaemia [8]; and a patient who after 26 years of SLE, developed late onset asthma and hypereosinophilia which progressed to meet the American College of Rheumatology criteria for diagnosis of Churg-Strauss syndrome [3]. In addition, vasculitis of the gall-bladder causing acute acalculous cholecystitis is an extremely rare event in SLE [9]. Acute acalculous cholecystitis unrelated to vasculitis has itself been uncommonly described, usually in relation to debilitated hospitalised patients. Its pathogenetic mechanism is unknown.
Liver disease thought to be directly related to SLE is more commonly recognized, usually manifesting as biochemical abnormalities of hepatic function in between 20–55% of patients. A more severe spectrum of disease – acute hepatitis to frank liver failure – is uncommon [10]. Finally, there were some highly unusual immunological features in this case. The patient had evidence of IgG antinuclear antibodies and double stranded DNA antibodies from disease outset, and from the time of first measurement, evidence of classical pathway complement consumption also. The dsDNA antibodies became weakly positive again in September 1998 after the acute illness, and over the subsequent 6 months the serology developed into that of classical lupus with strongly positive dsDNA antibodies, anti-Ro antibodies and very low C3 and C4 levels. At one point she also developed anti-cardiolipin antibodies (13 GPL). The striking combination of eosinophilia and raised IgE seen in the acute phase is suggestive of either an allergic response to an unknown inciting antigen, or possibly reflects disordered immune regulation. Both the eosinophilia and raised serum IgE levels responded to immunosuppression in the acute illness. IgE levels rose again in October 1998 as the dose of steroids was reduced, accompanied by other immunological change suggestive of disease activity (increase in dsDNA antibody levels, complement consumption, development of anti-Ro antibodies), as well as derangement of liver enzymes, although not at this time by an eosinophilia. Both serum IgE and IgM fell markedly to the point where they became barely detectable, presumably in response to the addition of azathioprine (see Figure 1) as no other treatment changes took place during this time, other than the addition of calcium and vitamin D3 for bone protection.
In summary, we describe a case of a 30-year-old woman with a rare acute presentation of SLE, with hypereosinophilia, acalculous cholecystitis and biopsy proven eosinophilic vasculitis affecting the kidney, responding successfully to immunomodulatory therapy to date.
Conflict of interest statement. None declared.
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References |
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- Vitali C, Bencivelli W, Isenberg DA, Smolen JS, Snaith ML, Sciuto M, Neri R, Bombardieri S and the European Consensus Study Group for disease activity in SLE. A descriptive analysis of 704 European lupus patients. Clin Exp Rheumatol 1992; 10: 527–539[Web of Science][Medline]
- D’Cruz D. Vasculitis in systemic lupus erythematosus. Lupus 1998; 74: 270–274
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- Descombes E, Droz D, Drouet l et al. Renal vascular lesions in lupus nephritis. Medicine (Baltimore) 1997; 76: 355–368[CrossRef][Medline]
- Appel GB, Pirani CL, D'Agati V. Renal vascular complications of systemic lupus erythematosus. J Am Soc Nephrol 1994; 4: 1499–1515[Web of Science][Medline]
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- Thomeer M, Moerman P, Westhovens R et al. Systemic lupus erythematosus, eosinophilia and Loeffler's endocarditis. An unusual association. Eur Resp J 1999; 13: 930–933[Abstract]
- Markusse HM, Schravenhoff R, Beerman H. Hypereosinophilic syndrome presenting with diarrhoea and anaemia in a patient with systemic lupus erythematosus. Neth J Med 1998; 52: 79–81[Web of Science][Medline]
- Swanepoel CR, Floyd A, Allison H et al. Acute acalculous cholecystitis complicating systemic lupus erythematosus: case report and review. Br Med J 1983; 286: 251–252
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Accepted in revised form: 8.11.05
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