The lady with a history of blood transfusion who developed palpable purpura and microhaematuria

Supported by an educational grant from Fresenius Medical Care

Thomas Höhler1, Jörj Kriegsmann2, Frank Laukhuf1, Karl-H. Meyer zum Büschenfelde1 and Eveline Wandel1

1 I. Medizinische Klinik und Poliklinik, and 2 Institut für Pathologie, Johannes Gutenberg-Universität Mainz, Germany

Correspondence and offprint requests to: Dr Eveline Wandel, I. Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1, D-55101 Mainz, Germany.

Keywords: acanthocytes; cryoglobulins; glomerolonephritis; hepatitis C virus; haematuria; interstitial vasculitis; subendothelial deposits

Case report

A 58-year-old woman was referred to the dermatology department with a vasculitic rash confined to the calfs and ankles. Over the last 6 years she had had a similar rash in the same area particularly during the winter. Because of a psychiatric illness she was on treatment with haloperidol. Seven years before admission she had had a hysterectomy; because of post-operative haemorrhage she had received several units of blood. Upon questioning she complained about occasional arthralgia in the hands and wrists. Small and confluent purpuric lesions were noted on calfs and ankles and spotty hyperpigmentation was also present. Small ulcers were seen on the lateral aspect of the ankles.

A blood count was normal apart from mild thrombocythaemia, i.e. 465/nl (normal 120–350/nl). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and bilirubin were normal. Gamma-glutamyl transferase was slightly elevated (22 U/l; normal <20 U/l). There was an elevation of the C-reactive protein (1.6 mg/dl; normal <0.5 mg/dl) and fibrinogen (666 mg/dl; normal 150–350 mg/dl). Electrolytes were normal as was the kidney function with a creatinine of 0.87 mg/dl (normal <0.9 mg/dl). The total serum protein was decreased (58.0 g/l) with normal albumin, an increased alpha-2 globulin fraction (14.2%) and markedly decreased IgA (0.57 g/l; normal 0.9–4.5 g/l) and IgG (3.9 g/l; normal 8–18 g/l). IgM was normal. Immune-electrophoresis showed a monoclonal IgM band. Rheumatoid factor was positive with 46 U/ml (normal <38 U/ml). Proteinuria was 2.6 g/24 h (mainly albumin). Microscopic urine analysis showed haematuria of glomerular origin (727 erythrocytes/ml including 8.4% acanthocytes and the typical stary sky pattern, indicating renal vasculitis (Figure 1Go).



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Fig. 1. Urine specimen taken at the time of referral to our hospital showing the typical stary sky picture of glomerular haematuria and renal vasculitis with acanthocytes (A), knizocytes (KN), kodocytes (K) and other forms of dysmorphic erythrocytes (x240 phasecontrast microscopy).

 
Further blood tests showed cryoglobulinaemia with a cryokrit of 12%. Immune-electrophoresis of the cryoglobulins revealed a mixed type II cryoglobulinaemia with polyclonal IgG and monoclonal IgG. No circulating immune complexes were detected. CH50 was decreased (8.0; normal 19.9). Complement C4 and C3 levels were normal. Screening for a panel of autoantibodies (anti-nuclear, anti-neutrophil cytoplasmic, anti-GBM) revealed no autoantibodies.

Serology was negative for hepatitis B virus and positive for hepatitis A virus (IgG). Hepatitis C virus serology was positive, active hepatitis C virus (HCV) infection was confirmed by detection of HCV-RNA using polymerase chain reaction.

A liver biopsy specimen showed chronic active hepatitis C (Figure 2Go). Kidney biopsy showed cryoglobulinaemic glomerulonephritis with mild mesangial proliferation (Figures 3 and 4GoGo). Interstitial infiltration with lymphocytes and occasional neutrophils was noted as well as modest interstitial fibrosis. Electron microscopy showed subendothelial organized glomerular deposits. The diagnosis was HCV induced type II mixed cryoglobulinaemia and cryoglubulinaemic glomerulonephritis (membranoproliferative GN).



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Fig. 2. Liver tissue with sustained architecture and slightly enlarged portal tracts. Scarce, mainly lymphocytic infiltration of the portal and periportal area. Chronic hepatitis with little inflammatory activity (x160; HE staining).

 


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Fig. 3. Kidney biopsy specimen with one glomerulum. There is slight increase in mesangial matrix and cell number within the glomerulum. Mild interstitial fibrosis and marked mixed interstitial infiltration with lymphocytes and a few neutrophils (x160; HE staining).

 


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Fig. 4. Electron microscopy of a glomerular capillary with a large subendothelial deposit with an organized structure. This picture has been reported in a large portion of patients with cryoglobulinemic glomerulonephritis (x19 000).

 
Because of psychiatric illness the patient was not treated with alpha-interferon and started on corticosteroids (1 mg/kg body weight). Under this therapy proteinuria and microhaematuria with akanthocytes disappeared almost completely (Figure 5Go). However, she developed marked depression and the steroids had to be withdrawn after 4 weeks of treatment.



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Fig. 5. Urine phase-contrast-microscopy during methylprednisone therapy demonstrating the disappearance of glomerular haematuria. No acanthocytes are visible. This finding was paralleled by a decrease in proteinuria (x240 phasecontrast microscopy).

 
Comment

In more than 50% of patients chronic hepatitis C infection is accompanied by mixed cryoglobulinaemia (MC) [1]. Membranoproliferative glomerulonephritis with subendothelial deposits (cryoglobulinaemic glomerulonephritis) develops almost exclusively in subjects with type II cryoglobulinaemia, which is characterized by polyclonal IgG and a monoclonal IgM with rheumatoid factor activity [2].

Before identification of the hepatitis C virus as principal causative agent of this disease the majority of cases were treated with corticosteroids and/or cyclophosphamide [2]. Two randomized controlled studies [3,4] have reported limited improvement of renal parameters when treating patients with HCV associated type II MC with alpha-interferon, but most patients relapsed when the treatment was stopped.

The present case illustrates the value of urinary phase-contrast microscopy to monitor the activity of glomerulonephritis lesions [5,6].

Teaching Point

Acknowledgments

The authors thank Mrs Pavisa for excellent technical assistance in performing the phase-contrast-microscopy of the urine.

References

  1. D'Amico G, Fornasieri A. Cryoglobulinemic glomerulonephritis: a membranoproliferative glomerulonephritis induced by hepatitis C virus. Am J Kidney Dis 1995; 25: 361–369[ISI][Medline]
  2. Cacoub P, Lunel Fabiani F, Musset L et al. Mixed cryoglobulinaemia and hepatitis C virus. Am J Med 1994; 96: 124–132[ISI][Medline]
  3. Johnson RJ, Gretch DR, Yamabe H et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 1993; 328: 465–470[Abstract/Free Full Text]
  4. Misiani R, Bellavita P, Fenili D et al. Interferon alfa-2a therapy in cryoglobulinaemia associated with hepatitis C virus. N Engl J Med 1994; 330: 751–756[Abstract/Free Full Text]
  5. Köhler H, Wandel E, Brunck B. Acanthocyturia: a characteristic marker for glomerular bleeding. Kidney Int 1991; 40: 115–120[ISI][Medline]
  6. Wandel E. Dysmorphic erythrocytes. Nephrol Dial Transplant 1996; 11: 1874–1875[ISI][Medline]




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