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

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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

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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: [e-mail]