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Microscopic polyangiitis presenting with liver dysfunction preceding rapidly progressive necrotizing glomerulonephritis.

Abstract: The authors describe a 52-year-old woman diagnosed with microscopic polyangiitis. She presented with abnormal liver function tests accompanied by fever, headache, and fatigue. Two months later, rapidly progressive necrotizing glomerulonephritis developed together with seropositivity for perinuclear antineutrophil cytoplasmic antibody. Although liver dysfunction from microscopic polyangiitis is very rare, especially at presentation, this diagnostic possibility should be kept in mind to permit prompt consideration of steroid therapy.

Key Words: liver dysfunction, microscopic polyangiitis, perinuclear antineutrophil cytoplasmic antibody

**********

Microscopic polyangiitis (MPA) is a systemic vasculitis that involves small vessels, as is the case with Wegener granulomatosis and Churg-Strauss syndrome. (1,2) MPA is distinct from classic polyarteritis nodosa, which does not involve small vessels. (2) Unlike patients with polyarteritis nodosa, those with MPA often have demonstrable perinuclear antineutrophil cytoplasm antibodies (p-ANCA) (2-5) in the serum.

Apart from such nonspecific symptoms as generalized fatigue and fever, (1,6) one of the most frequently observed clinical findings in MPA is rapidly progressive necrotizing glomerulonephritis (RPGN) with histologically evident crescent formation. Alveolar hemorrhage or interstitial pneumonitis also may occur. (7-9) Liver dysfunction is rare in MPA, especially as an initial symptom. We describe a 52-year-old woman presenting with liver dysfunction before onset of RPGN, who was diagnosed with MPA.

Case Report

A 52-year-old woman was in good health until early in July 2002, when she developed intermittent headaches, generalized fatigue, and recurring fever up to 39[degrees]C. The C-reactive protein (CRP) concentration was elevated (18.5 mg/dL), and there was evidence of moderate liver dysfunction. The patient had no previous history of liver dysfunction and drank alcoholic beverages only on social occasions. Viral markers for hepatitis types A, B, and C were negative. No renal dysfunction was detected. Treatment with antibiotics (imipenem/cilastatin) for possible infection was initiated, but symptoms and laboratory data showed no evidence of remission. The administration of antibiotics was discontinued. As the headache and fever worsened, the patient was referred to our hospital on August 23, 2002.

On clinical examination, several small palpable purpuric lesions (about 1 X 1 cm) were evident over the upper and lower extremities. There was no evidence of lymphadenopathy, peripheral neuropathy, or arthropathy. The results of hematologic and blood chemistry tests are summarized in Table 1. Blood and urine cultures were negative; magnetic resonance imaging of the brain, cerebrospinal fluid examination, abdominal computed tomography, and ultrasonography were all normal. On September 10, renal dysfunction became evident for the first time (serum creatinine and blood urea nitrogen, 2.3 mg/dL and 37 mg/dL, respectively). Urinalysis showed mild proteinuria and marked hematuria. Antineutrophil cytoplasmic antibodies with a perinuclear staining pattern (p-ANCA) were detected; ANCA with a cytoplasmic staining pattern (c-ANCA) were not evident. An enzyme-linked immunosorbent assay indicated a high concentration of antibody to myeloperoxidase (MPO-ANCA). The results of these immunologic tests are displayed in Table 2.

Considering these findings, the patient was diagnosed with RPGN associated with MPA. Pulse steroid therapy (1.0 g/d of methylprednisolone by intravenous infusion for 3 days) was followed by oral steroid therapy (prednisolone 60 mg/d). One day after initiation of pulse steroid therapy, symptoms began to resolve. The white blood cell count and serum CRP concentration gradually decreased, and the liver function values greatly improved.

Because renal dysfunction had not fully improved, a renal biopsy was performed. Histologic findings (Fig. 1, A-C) were consistent with crescentic glomerulonephritis caused by MPA. With ongoing oral steroid therapy, renal function gradually improved, and the dose of prednisolone was reduced gradually. Her clinical course is shown in Figure 2.

Discussion

In the case here presented, antibiotic-induced liver dysfunction should be considered, although it is not likely because liver dysfunction persisted after the antibiotic therapy had been discontinued for more than 1 month.

Autoimmune hepatitis type 1 and primary biliary cirrhosis are other possible causes of liver dysfunction, but serum antinuclear antibody and antimitochondrial antibody were not detected. Primary sclerosing cholangitis is also unlikely because of the clinical picture and the favorable response to steroid therapy. Moreover, although p-ANCA often is detected in autoimmune hepatitis type 1 or primary sclerosing cholangitis, they are atypical ANCA (a-ANCA) (10-13) rather than the MPO-ANCA shown in our case. The patient did not drink alcohol in significant quantity, and viral markers for hepatitis were not present. Abdominal ultrasonography and computed tomography did not detect any abnormalities. After considering all possibilities, we believe that the liver dysfunction was caused by MPA.

[FIGURE 1 OMITTED]

We know of only two similar reported cases. (14,15) Both presented with liver dysfunction and nonspecific symptoms, such as fever of unknown origin and fatigue. Only several weeks later did renal dysfunction develop. As for the pattern of liver dysfunction, elevations of alkaline phosphatase (ALP) and [gamma]-glutamyl transpeptidase ([gamma]-GTP) were more pronounced than those of transaminases such as aspartate aminotransferase or alanine aminotransferase. The pattern was similar in our patient.

[FIGURE 2 OMITTED]

Regrettably, we could not perform a liver biopsy. In the most similar case, Goritsas et al (14) reported that the liver biopsy specimen findings were compatible with vasculitis. We believe that, as they suggested, liver dysfunction in MPA, characterized by relatively selective elevation of ALP and [gamma]-GTP, reflects vasculitis involving small intrahepatic vessels that causes ischemic cholangitis. Although the other reported case (15) was similar to ours, a high titer of serum antinuclear antibody was present. The coexistence of autoimmune hepatitis type 1 therefore cannot be excluded.

We believe that a subtype of MPA with these atypical features exists, although it is very rare. Because early diagnosis of MPA and prompt initiation of steroid therapy might limit the severity of renal impairment, MPA with an atypical clinical course is an important diagnostic consideration in hepatic dysfunction.

Conclusion

We encountered a patient who developed liver dysfunction from MPA before any evidence of renal impairment. Early diagnosis depends on maintaining suspicion for this rare form of MPA.
Human history becomes more and more a race between education and
catastrophe.
--H. G. Wells

Table 1. Results of hematologic and biochemical examinations

Hematologic Biochemistry

WBC 15400/[micro]L TP 7.3 g/dL
 Poly 83% AST 38 U/L
 Lympho 8.0% ALT 105 U/L
 Mono 8.0% ALP 1159 U/L
 Eosino 1.0% LDH 265 U/L
RBC 339 X [10.sup.4]/[micro]L [gamma]-GTP 315 U/L
Hb 9.7 g/dL T-Bil 0.72 mg/dL
Ht 30.1% BUN 18 mg/dL
Plt 51.3 X [10.sup.4]/[micro]L
 Cr 0.7 mg/dL
 Na 142 mEq/L
 K 4.2 mEq/L
Urinalysis
Hematuria (-) IgM-HA-Ab Syphilis
 (-)
Proteinuria
 (-) HbsAg (-) RPR (-)
Glucose (-) HbcAb (-) TPHA (-)
 HCV-Ab (-)

Hematologic Biochemistry

WBC Cl 96 mEq/L
 Poly Ca 4.8 mg/dL
 Lympho UA 7.5 mg/dL
 Mono CPK 11 U/L
 Eosino CRP 23.5 mg/dL
RBC ESR 117 mm/h
Hb
Ht Tumor markers
Plt
 AFP <10
 CEA 1.0
 CA-19-9 11.1

Urinalysis
Hematuria (-) IgG 2350 mg/dL
Proteinuria
 (-) IgA 375 mg/dL
Glucose (-) IgM 105 mg/dL

Table 2. The result of immunologic tests (a)

 Normal values

Antinuclear antibody Negative (<40)
Antimitochondrial antibody Negative (<10/mL)
Rheumatoid factor Negative (<40)
MPO-ANCA 394 (<9.91 EU)
PR3-ANCA Negative (<9.91 EU)
Anti-GBM antibody Negative (Negative)
C3 194 (65-135 mg/dL)
C4 28 (13-35 mg/dL)
CH50 42.1 (29.0-48.0 U/mL)

(a) MPO-ANCA, antineutrophil cytoplasmic antibody against
myeloperoxidase; PR3-ANCA, antineutrophil cytoplasmic antibody against
proteinase 3; GBM, glomerular membrane; C3, serum complement 3; C4,
serum complement 4.


Accepted June 26, 2003.

References

1. Davson J, Ball J, Platt R. The kidney in periarteritis nodosa. Q J Med 1948;17:175.

2. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: Proposal of an international consensus conference. Arthritis Rheum 1994;37:187-192.

3. Hauschild S, Schmitt WH, Csernok E, et al. ANCA in systemic vasculitides, collagen vascular diseases, rheumatic disorders and inflammatory bowel diseases. Adv Exp Med Biol 1993;336:245-251.

4. Davenport A, Lock RJ, Wallington TB, et al. Clinical significance of anti-neutrophil cytoplasm antibodies detected by a standardized indirect immunofluorescence assay. Q J Med 1994;87:291-299.

5. Adu D, Pall A, Luqmani RA, et al. Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis. Q J Med 1997;90:401-409.

6. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: Clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999;42:421-430.

7. D'Agati V, Chander P, Nash M, et al. Idiopathic microscopic polyarteritis nodosa: Ultrastructural observations on the renal vascular and glomerular lesions. Am J Kidney Dis 1986;7:95-110.

8. Savage CO, Winearls CG, Evans DJ, et al. Microscopic polyarteritis: Presentation, pathology and prognosis. Q J Med 1985;56:467-483.

9. Adu D, Howie AJ, Scott DG, et al. Polyarteritis and the kidney. Q J Med 1987;62:221-237.

10. Targan SR, Landers C, Vidrich A, et al. High-titer antineutrophil cytoplasmic antibodies in type-1 autoimmune hepatitis. Gastroenterology 1995;108:1159-1166.

11. Duerr RH, Targan SR, Landers CJ, et al. Neutrophil cytoplasmic antibodies: A link between primary sclerosing cholangitis and ulcerative colitis. Gastroenterology 1991;100:1385-1391.

12. Mulder AH, Horst G, Haagsma EB, et al. Prevalence and characterization of neutrophil cytoplasmic antibodies in autoimmune liver diseases. Hepatology 1993;17:411-417.

13. Lesavre P, Noel LH, Gayno S, et al. Atypical autoantigen targets of perinuclear antineutrophil cytoplasm antibodies (P-ANCA): Specificity and clinical associations. J Autoimmun 1993;6:185-195.

14. Goritsas CP, Repanti M, Papadaki E, et al. Intrahepatic bile duct injury and nodular regenerative hyperplasia of the liver in a patient with polyarteritis nodosa. J Hepatol 1997;26:727-730.

15. Nakamoto T, Yoshikawa M, Nakatani T, et al. Microscopic polyangiitis that presented liver dysfunction prior to noted renal manifestations. Intern Med 2000;39:517-521.

RELATED ARTICLE: Key Points

* Although microscopic polyangiitis is frequently complicated with rapidly progressive necrotizing glomerulonephritis, coexistence with liver dysfunction is very rare, especially as an initial symptom.

* We encountered a patient with microscopic polyangiitis who developed liver dysfunction before renal impairment.

Kohzo Takebayashi, MD, Yoshimasa Aso, MD, Hiroshi Kitamura, MD, Yusei Sakurai, MD, Sadao Wakabayashi, MD, and Toshihiko Inukai, MD

From the Department of Medicine, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya; the Department of Pathology, Nippon Medical School, Tokyo; and the Department of Medicine, Kasukabe Syuwa Hospital, Kasukabe, Japan.

Reprint requests to Kohzo Takebayashi, MD, Department of Medicine, Koshigaya Hospital, Dokkyo University School of Medicine, 2-1-50, MinamiKoshigaya, Koshigaya 343-8555, Japan. Email: takeb@gmail.plala.or.jp
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Title Annotation:Case Report
Author:Inukai, Toshihiko
Publication:Southern Medical Journal
Date:Sep 1, 2004
Words:1748
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