Background

Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by non-suppurative destruction of interlobular bile ducts [1, 2]. Serologically, PBC is accompanied by increased concentrations of serum immunoglobulin M (IgM) and the presence of circulating anti-mitochondrial antibodies [1]. Although bone diseases such as osteoporosis or osteodystrophy, are commonly associated with PBC, osteomalacia, which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency, has not been frequently complicated with PBC [3, 4]. In renal complication of PBC, distal renal tubular acidosis (RTA) has been reported with the prevalence rates of 30 to 60 % generally in asymptomatic or latent condition [5, 6]. Tubulointerstitial nephritis (TIN) and subsequent Fanconi syndrome, a type of proximal tubular defects, have been more rarely reported in patients with PBC [7–9].

We report herein a rare case of hypophosphatemic osteomalacia caused by TIN with Fanconi syndrome in asymptomatic PBC. Multiple fractures due to hypophosphatemic osteomalacia were almost ameliorated after the administration of 1,25 dihydroxyvitamin D3, neutral potassium phosphate, and sodium bicarbonate. The renal function also remained stable after subsequent administration of middle-dose corticosteroids.

Case presentation

In November 2007, a 49-year-old Japanese woman was referred to our hospital from an orthopaedist complaining of a one year history of sustained difficulty walking and severe bilateral hip pain. Her height was 155.5 cm and body weight was 61.0 kg. Laboratory data showed a creatinine of 1.4 mg/dl, potassium 2.8 mmol/l, calcium 9.5 mg/dl, phosphorus 2.5 mg/dl, uric acid 1.5 mg/dl, normoglycaemic glycosuria and metabolic acidemia (pH 7.30, HCO3− 17.4 mmol/l) (Table 1). Bilateral transcervical fractures were confirmed by MRI (Fig. 1a) and bone scintigraphy showed multiple hot spots in her joints and ribs, compatible with osteomalacia (Fig. 2). Hypophosphatemic osteomalacia was diagnosed clinically from a low serum level of phosphorus, 1,25-dihydroxyvitamin D3 (11.0 pg/dl), high levels of bone specific alkaline phosphatase (67.5 IU/l), and the findings of bone scintigram, although a bone biopsy was not performed. Tumor-induced osteomalacia (TIO) was ruled out by total body survey with whole body computed tomography or endoscopic surveillances and a normal blood FGF23 (22.1 pg/ml, 10–50 pg/ml) level.

Table 1 Baseline data of the patient on admission in November 2007
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Fig. 1
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MRI findings of incomplete bilateral transcervical fractures (Arrows) before (a) and after (b) the treatment

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Fig. 2
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Bone scintigram showing multiple hot spots especially over multiple joints and ribs

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Urinalysis showed pH 6.0 and twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate (Tmp/GFR 0.91), increased fractional excretion of uric acid (FEUA 43.9 %) and generalized aminoaciduria.

The calculated anion gap was 12.4 meq/l, with an inappropriately alkaline urine (pH 6.0), suggestive of distal type of renal tubular acidosis (RTA). An intravenous bicarbonate loading test to assess the tubular dysfunction demonstrated that the increased fractional excretion of bicarbonate (FEHCO3− 13.25 %) and urine-blood (UB) Pco2 gradient (U-Bpco2 50.1 mmHg), suggesting the presence of proximal type of RTA. NH4Cl loading test was not performed because of the presence of apparent metabolic acidemia. These biochemical data of blood and urine indicated Fanconi syndrome with proximal type of RTA. Tests for anti-SSA and anti-SSB were negative and serum angiotensin converting enzyme levels were normal. Furthermore, serum and urine immunoelectrophoresis revealed no monoclonal component. Any of the patient’s medication did not seem to be related to Fanconi syndrome. Light microscopic examination of a kidney biopsy demonstrated cellular infiltration of interstitium and proximal tubular epithelium composed mainly of CD3+ lymphocytes without glomerular involvement, consistent with features of TIN (Fig. 3a ,b).

Fig. 3
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The Findings of Kidney and Liver Biopsies. a, b Kidney biopsy specimen; light microscopy shows (a) cellular infiltration in the proximal tubules and interstitium, and the presence of atrophic tubules (Hematoxylin-eosin staining) and (b) CD3+ cells infiltration in the renal interstitium. c Liver biopsy specimen; light microscopy shows the presence of a periportal cellular infiltrate

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The patient was also suspected to be diagnosed as PBC because of high levels of alkaline phosphatase (663 IU/l), high serum IgM levels (1084 mg/dl) and the presence of anti-mitochondrial M2 antibody (1:10). Sequential liver biopsy demonstrated the presence of a periportal cellular infiltrate (Fig. 3c), compatible with PBC though biochemical liver function was normal. The combination of these findings led to the patient’s diagnosis of osteomalacia caused by TIN with Fanconi syndrome in asymptomatic PBC.

The patient was started on therapy with calcitriol (1 μg/day), neutral potassium phosphate and sodium bicarbonate (6 g/day). She was subsequently administered middle-dose corticosteroid (20 mg/day of predonisolone) and ursodeoxycholic acid (300 mg/day). One year after the treatment, the patient became asymptomatic and renal function remained stable. Furthermore, MRI showed the bilateral transcervical fractures of the femoral neck had almost fully repaired (Fig. 1b). Treatment is currently being continued in the outpatient clinic.

Discussion

We described a severe osteomalacia caused by TIN with Fanconi syndrome in asymptomatic PBC. Although osteomalcia is rarely observed in patients with PBC [4], malabsorption as a consequence of severe cholestasis and impaired ability to convert vitamin D to 25-hydroxivitamin D can cause osteomalacia in patients with advanced PBC [10, 11]. Our case was unique in that osteomalacia developed as a result of the rare renal involvement of asymptomatic PBC.

Osteomalacia is accelerated by inadequate renal phosphorus wasting and decreased uptake of active vitamin D as well as a decrease in 1α-hydroxylation of vitamin D [12, 13]. The serum concentration of 1,25 dihydroxyvitamin D3 which reflects the regulation of 1α-hydroxylation of vitamin D in the kidney is impaired in renal tubular diseases such as Fanconi syndrome [14, 15]. This patient had a low circulating level of 1,25 dihydroxyvitamin D3 which is presumed to be caused by Fanconi syndrome. Indeed, osteomalacia is a well-observed consequence of the Fanconi syndrome [16]. Fanconi syndrome also complicated with chronic hypophosphatemia and chronic acidemia, which considered to cause and aggravate osteomalacia [7, 17].

It is suggested that hepatic dysfunction is not implicated in the pathogenesis of TIN, while on the other hand, TIN in the present case may be pathogenically related to PBC [7]. First, lymphocytic infiltration is a pathological mutual feature of TIN and PBC. Autoreactive T lymphocytes of the tubular epithelium and interstitium may be driven by abnormal antigen expression such as mitochondrial antigen in hepatocytes and renal tubular cells [18]. T lymphocytes of the tubular epithelium are likely to be involved in the inhibition of proximal tubular function, leading to Fanconi syndrome. Second, Anti-M2 antibody in patients with PBC could interfere with intrarenal three mitochondrial enzymes: pyruvate dehydrogenase complex, branched-chain α-keto acid dehydrogenase complex and α-keto glutamate dehydrogenase complex [7, 9, 19]. Fanconi syndrome and TIN are typical renal features of mitochondrial cytopathies [20]. Although much remains to be elucidated about the pathogenesis of PBC and its extrahepatic complication of TIN with Fanconi syndrome, circulating anti-mitochondrial M2 antibody would induce PBC and TIN with Fanconi syndrome. Since the usual causes of Fanconi syndrome including metal intoxication were not confirmed, this patient was considered to have PBC-related TIN with Fanconi syndrome.

In summary, severe osteomalacia was considered to be caused by the rare renal involvement of asymptomatic PBC, which is TIN with Fanconi syndrome.

Conclusions

Herein, the authors present a unique case of osteomalacia developed as a result of the rare renal involvement of asymptomatic PBC. As the prevalence of osteomalacia is increasing in aged societies where homebound elderly patients suffer from nutritional insufficiency, lack of sun exposure, medical histories of gastrointestinal surgery, and the possibility of malignancy, careful inspection for the cause of multiple fractures is necessary. We suggest that PBC and its rare complication of TIN with Fanconi syndrome should be considered in adult patients with unexplained osteomalacia even in the absence of liver function tests abnormalities.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.