Membranous nephropathy associated with primary biliary cirrhosis

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He was antimitochondrial antibody positive, and renal and liver biopsy findings revealed membranous nephropathy. (MN) and primary biliary cirrhosis (PBC), ...
Membranous nephropathy associated with primary biliary cirrhosis and acute meningitis Shuzo Sato, Rie Saito, Haruyo Iwadate, Tomoyuki Asano, Kazumichi Abe, Atsushi Takahashi, Hiroko Kobayashi, Hiroshi Watanabe, et al. Clinical Journal of Gastroenterology ISSN 1865-7257 Clin J Gastroenterol DOI 10.1007/s12328-012-0321-6

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Author's personal copy Clin J Gastroenterol DOI 10.1007/s12328-012-0321-6

CASE REPORT

Membranous nephropathy associated with primary biliary cirrhosis and acute meningitis Shuzo Sato • Rie Saito • Haruyo Iwadate • Tomoyuki Asano Kazumichi Abe • Atsushi Takahashi • Hiroko Kobayashi • Hiroshi Watanabe • Hiromasa Ohira



Received: 13 March 2012 / Accepted: 3 July 2012 Ó Springer 2012

Abstract A 40-year-old man with acute meningitis, nephrotic syndrome, elevated antinuclear antibody (25609), and liver dysfunction was referred to our hospital. He was antimitochondrial antibody positive, and renal and liver biopsy findings revealed membranous nephropathy (MN) and primary biliary cirrhosis (PBC), respectively. This extremely rare MN accompanied by PBC was detected while the patient was undergoing treatment for acute meningitis. Keywords Membranous nephropathy  Primary biliary cirrhosis  Meningitis

Introduction Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease that is thought to have an autoimmune pathogenesis. The disease can progress to liver fibrosis and eventually to liver failure [1]. PBC is often complicated with other autoimmune diseases such as chronic thyroiditis, rheumatoid arthritis, and Sjo¨gren’s syndrome, but complication with membranous nephropathy (MN) is rare. So far, only 13 cases have been described in literature [2–13]. Here, we describe extremely rare MN accompanied by PBC that was identified in a patient who was undergoing treatment for acute meningitis.

S. Sato (&)  R. Saito  H. Iwadate  T. Asano  K. Abe  A. Takahashi  H. Kobayashi  H. Watanabe  H. Ohira Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Fukushima 960-1295, Japan e-mail: [email protected]

Case report A 40-year-old Japanese man with acute meningitis, nephrotic syndrome, an elevated anti-nuclear antibody (ANA) titer (25609), and liver dysfunction was referred to our hospital. A traffic accident at 17 years of age had caused a cerebral contusion, and he had undergone an appendectomy at the age of 30 years. He had also been hospitalized for bacterial pneumonia at the age of 36 years. A routine health check in 1997 (23 years old) detected proteinuria, but he did not consult a general physician. Liver dysfunction was not detected at that time. Thirteen years later, high fever, knee joint pain and severe headache developed. He was admitted to the same hospital as before with suspected acute meningitis. Laboratory data revealed severe inflammation, high hepato-biliary enzyme levels, a high ANA titer (25609, centromere positive; normal range, below 809), and low albumin levels. He was diagnosed with acute meningitis based on the headache and fever although he did not undergo a lumbar puncture at that time. The symptoms continued under administration of the antibiotic ceftriaxone (CTRX) and he was transferred to our hospital for further investigation of the elevated ANA titer and inflammation. He was 162 cm tall and weighed 58.5 kg upon admission. He had a temperature of 37.1 °C, blood pressure of 154/114 mmHg indicating hypertension and a heart rate of 84 beats per minute with no arrhythmia. On physical examination, he had no thyroid swelling. His liver and spleen were not palpable. No joint swelling or pretibial edema was evident. On neurological examination, no symptoms were evident except for slight neck stiffness. Tables 1 and 2 show the laboratory data upon admission. Elevated total cholesterol (TC), decreased total protein (TP) and albumin (Alb), together with positive urinary protein (?4) indicated nephrotic syndrome. Serum free

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Author's personal copy Clin J Gastroenterol Table 1 Laboratory data upon admission (1) Hematology WBC

Blood chemistry 6200 l/L 4

TP

5.8 g/dL ;

CK

76 IU/L

RBC

425 9 10 l/L

Alb

1.9 g/dL ;

BS

95 mg/dL

Hb

12.9 g/dL ;

TB

0.4 mg/dL

BUN

7 mg/dL

Ht

37.9 % ;

DB

0.1 mg/dL

Cre

0.65 mg/dL

PLT

46.2 9 104 l/L :

AST

83 IU/L :

UA

4.0 mg/dL

ALT

85 IU/L :

Na

140 mEq/L

Coagulation PT

85.5 %

LDH

434 IU/L :

K

4.3 mEq/L

APTT

35 s

ALP

928 IU/L :

Cl

103 mEq/L

Fibrinogen

466 mg/dL :

cGTP

284 IU/L :

TC

237 mg/dL :

ChE

249 IU/L

TG

209 mg/dL :

CRP

0.54 mg/dL :

LDL

151 mg/dL :

ESR

52 mm/h :

HDL

40 mg/dL ;

Ferritin

796 ng/dL :

FT4

1.01 ng/mL

TSH

2.13 lIU/L

Italicized values indicate abnormal values. Arrows indicate higher (:) or lower (;) levels compared with normal range FT4 free thyroxine, TSH thyroid stimulating hormone Table 2 Laboratory data upon admission (2) Viruses

Immunology

HBs-Ag

-

IgG

1012 mg/dL

HBc-IgM

-

IgA

268 mg/dL

HCV antibody

-

IgM

199 mg/dL

Coxsackie B

-

ANA

25609, CE :

EBV (VCA)-IgM

-

Double-strand anti-DNA Antibody

0.5 IU/mL

EA-IgG

-

Anti-mitochondrial antibody

409 :

HSV-PCR

-

Anti-mitochondrial M2 antibody

94 index :

MPO-ANCA

\10 EU

pH

6.5

PR3-ANCA

\10 EU

U-Glucose

-

Anti-SS-A antibody

-

Anti-SS-B antibody

-

Urinalysis

U-Protein

4? :

U-Blood

1? :

Cerebrospinal fluid

Urine specific gravity

1.025

Glucose

41 mg/dL :

RBC

1–4/HPF

Protein

59 mg/dL :

WBC Hyaline casts

1–4/HPF 0–1/1/HPF :

Cl Cells

125 mEq/L 68/lL :

Fat cell casts

0–1/1/HPF :

Monocytes

96.6 % :

Granular casts

0–1/1/HPF :

Polymorphonuclear leukocytes

3.4 %

Italicized values indicate abnormal values. Arrows indicate higher (:) or lower (;) levels compared with normal range ANA anti-nuclear antibody, CE centromere, EA early antigen, EBV (VCA)-IgM Epstein–Barr virus (VCA: viral capsid antigen)-IgM, HBc-IgM hepatitis B core IgM, HBs-Ag hepatitis B surface antigen, HCV hepatitis C virus, HSV-PCR herpes simplex virus-PCR

thyroxine and thyroid-stimulating hormone showed within normal limits. Serum HBs-antigen and HBc-antibody were negative. Other viral infections including hepatitis C virus (HCV), coxsackie B virus, Epstein–Barr virus (EBV), and herpes simplex virus (HSV) were negative. He received lumbar puncture by a neurologist. The cerebrospinal fluid

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(CSF) examination showed a slightly increased cell count (mononuclear cell dominant), elevated protein, and decreased glucose. Head MRI was not performed. These findings indicated partially treated bacterial meningitis or aseptic meningitis. We suspected asymptomatic PBC based on the elevated hepato-biliary enzymes and positive

Author's personal copy Clin J Gastroenterol

findings for ANA (centromere), antimitochondrial (AMA) or antimitochondrial M2 antibodies (M2-Ab). A liver biopsy specimen revealed lymphocyte infiltration of the portal area and portal bile ducts with granuloma formation around the periportal area, indicating stage I PBC (Fig. 1a, b). A renal biopsy specimen stained with periodic acidmethenamine-silver revealed a diffuse, irregular wall thickness and punched-out lesions of the glomerular basement membrane (GBM) (Fig. 2). Electron microscopy revealed an irregularly thickened GBM with resorption of electron dense deposits. Stage 4 MN was diagnosed based on these findings. The patient was administered with antibiotics (CTRX) and acyclovir to treat the acute meningitis, followed by ursodeoxycholic acid (UDCA) and angiotensin receptor-blocker for the MN associated with PBC. Laboratory data and symptoms gradually improved thereafter (Fig. 3).

Discussion

Fig. 1 Findings of liver biopsy specimen. a Lymphocyte infiltration of portal area with granuloma formation is compatible with primary biliary cirrhosis (PBC; H&E stain, 9100). b Some lymphocytes have infiltrated the intrahepatic bile ducts (9400)

Fig. 2 Findings of renal biopsy specimen. Periodic acid-methenamine-silver stain shows irregular wall thickness and punched-out lesion of glomerular basement membrane (GBM) indicating stage 4 MN. (9400)

Primary biliary cirrhosis is a chronic cholestatic liver disease that is considered to have autoimmune mechanisms. The distinct pathogenesis of PBC is unclear, but multiple genetic and environmental factors are thought to be closely involved [1]. Currently, AMA or M2-Ab, which is directed against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), is thought to play an important role in the onset of PBC. In fact, over 90 % of patients with PBC have AMA. PBC is often associated with other autoimmune diseases, such as Sjo¨gren’s syndrome (31 % of patients), rheumatoid arthritis and chronic thyroiditis [14]. However, the concomitant manifestations of renal diseases are quite rare, including MN [2–13], which is the most common primary cause of adult onset nephrotic syndrome. It is characterized by GBM thickening and subepithelial immune deposits in light, immunofluorescence and electron microscopy [15]. MN is usually idiopathic, whereas secondary MN accounts for approximately 10–20 % of all adult cases. The causes of secondary MN comprise neoplastic diseases, drugs and toxins, infectious diseases such as hepatitis B, hepatitis C, and collagen-vascular diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjo¨gren’s syndrome. Although the pathogenesis of MN remains unclear, the passive trapping of circulating immune complexes in the GBM and immune complex formation in situ has been suggested [15]. Many nonrenal antigens such as hepatitis B antigen (in HBVrelated MN), double-strand DNA (in SLE), and carcinoembryonic antigen (colon cancer) have been identified in secondary MN. Furthermore, secondary MN often improves when the primary disease is successfully treated [15].

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Author's personal copy Clin J Gastroenterol Fig. 3 Clinical course. ACV acyclovir, CTRX ceftriaxone, UDCA ursodeoxycholic acid

Fig. 4 Summary of published case reports of PBC associated with MN. AMA anti-mitochondrial antibody, BM basement membrane, M2 antimitochondrial M2 antibody, MN membranous nephropathy, ND not described, PBC primary biliary cirrhosis

We considered that the patient developed secondary MN due to asymptomatic PBC, because no other suspicious causes, such as hepatitis virus infection, use of drugs, toxins, neoplastic diseases, or another autoimmune disease, were found. The occurrence of MN associated with PBC is

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rare, with only 13 patients described in the literature (Fig. 4). The mean age is 55.9 ± 11.9 (33–70) years and 78.5 % are female. All of the patients had AMA or M2-Ab. The histological stages of PBC (in four patients) were relatively early (stages 1 and 2), while their MN stage

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varied from 1 to 4. Our patient had reached the most progressive state (stage 4). Serum IgM levels were elevated to a mean of 475.3 (range 199–1086, reference range 35–220) mg/dL in 10 (90.9 %) of 11 of the described patients and 8 (57.1 %) of 14 were complicated with autoimmune diseases. These facts indicate that MN can develop during the early stage of PBC, and that various histological glomerular changes occur. Furthermore, almost all patients with PBC and MN had elevated serum IgM levels. Thus, elevated serum IgM might contribute to the development of MN during early PBC. Among the patients with elevated IgM levels, six (60 %) of ten were positive for IgM deposition in the GBM. Bindi et al. [6] reported that immunoglobulins extracted from kidney epimembranous deposits in a patient with PBC reacted to the E2 component of mitochondrial pyruvate dehydrogenase. This finding indicated that the autoimmune mechanisms between PBC and MN are similar. Therefore, we speculate that the deposition of circulating immune components including serum IgM (or M2-Ab) in the GBM during the early stage of PBC may initiate MN. It is unclear why our case did not show elevated serum IgM levels or IgM deposition in the GBM. Another mechanism might be present which drives autoimmune procedure without serum IgM elevation. Actually, Sherlock et al. [16] reported that about 30 % of PBC patents had normal serum IgM levels. Additionally, the diminished immune deposits in the GBM can be explained by the mechanism that MN stage was so advanced that almost all immune deposits including IgM subclass, was resorbed. Thus, no deposition was detected when tissue examination was performed. Normal levels of IgM in this patient may be explained by the long-standing nephrotic syndrome. Progression of stage 4 MN indicated that the patient had relatively longer disease duration (probably coexistent with asymptomatic PBC) without any treatment, which may have caused the therapy-resistant continuous high levels of urinary protein in his clinical course. In MN treatment, we usually use corticosteroids for the early stage (stage 1 and 2) of MN patients, however, steroids use to the advanced stage (3 and 4) of MN patients is thought to have less effect [15]. We only used antiangiotensin II receptor blocker for renal protection because of his advanced MN stage. Furthermore, UDCA treatment for asymptomatic PBC (primary disease) is also possibly effective for secondary MN. It is difficult to figure out whether acute meningitis is associated with PBC or not. So far, only one case of recurrent aseptic meningitis associated with PBC has been described [17]. At first, the patient had been given a diagnosis of bacterial meningitis and administered antibiotics in the previous hospital. CSF findings on admission to our hospital may have indicated aseptic meningitis, but we could not completely exclude partially treated bacterial meningitis (IgG concentration in the CSF

was not obtained). Regardless, further investigation is needed to clarify the relation between PBC and meningitis. In conclusion, various stages of MN can be present during early PBC when renal dysfunction or urinary abnormal findings are accompanied. Further investigation is required to clarify the pathogenesis of MN associated with PBC. Conflict of interest of interest

The authors declare that they have no conflict

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