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Hypophosphatemic osteomalacia and renal Fanconi syndrome induced by low-dose adefovir dipivoxil: a case report and literature review suggesting ethnic predisposition

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  • Case Report

    Hypophosphatemic osteomalacia and renal Fanconi syndrome induced by low-dose adefovir dipivoxil: a case report and literature review suggesting ethnicpredisposition

    C. Wu* MSc, H. Zhang MD, Y. Qian* MSc, L. Wang* MSc, X. Gu MD and Z. Dai* MSc*Department of Endocrinology, The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, Department of Endocrinology, Key Laboratory ofEndocrinology, Ministy of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, andDepartment of Endocrine and Metabolic Diseases, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China

    Received 3 August 2012, Accepted 28 January 2013

    Keywords: adefovir dipivoxil, hypophosphatemic osteomalacia, renal Fanconi syndrome, review

    SUMMARY

    What is known and Objective: Adefovir dipivoxil (ADV) is oneof the commonly used antiviral agents in the treatment ofchronic hepatitis B (CHB) infection. Safety of a daily dose of 10mg ADV is advocated by the registration trials. We report a caseof severe hypophosphatemic osteomalacia and renal Fanconisyndrome induced by low-dose ADV in a CHB-related cirrhosispatient, and discuss the case through a thorough review of othercases reported in the literature.Case summary: A 48-yr-old Chinese man with CHB-relatedcirrhosis developed severe progressive generalized bone painand muscle weakness after receiving ADV 10 mg daily for 54months. The laboratory results showed severe hypophosphate-mia and features of proximal renal tubule dysfunction. Imagingstudies were consistent with osteomalacia. After discontinuationof ADV, his symptoms resolved, laboratory abnormalitiesnormalized and imaging studies showed improvement. Inaddition to our case, 12 other patients have been reported tohave developed hypophosphatemic osteomalacia induced bylow-dose ADV. Most of the reported cases were of subjects ofEast-Asian ethnicity. After discontinuation or reduction of ADV,serum phosphate level increased and clinical symptoms sig-nificantly improved in all cases.What is new and Conclusion: Hypophosphatemic osteomalaciaand renal Fanconi syndrome can be associated with low-doseADV. Clinicians treating CHB patients with ADV 10 mg dailyover long periods of time should be aware of this infrequent butserious complication

    WHAT IS KNOWN AND OBJECTIVES

    Adefovir dipivoxil (ADV) is a nucleotide analogue of adenosinemonophosphate that is effective in viral suppression.1 ADV wasinitially assessed at higher doses for the treatment of humanimmunodeficiency virus (HIV) infection,2 but a daily dose of 60

    120 mg ADV was associated with significant rates of renaldysfunction 35 and ADV is no longer used for this indication. Adaily dose of 10 mg to treat patients infected with the hepatitis Bvirus (HBV) has been found to be safe.6, 7 Currently, its major roleis in the treatment of drug-nave or lamivudine-resistant HBVinfection.811 Adefovir has an elimination half-life of 75 h, whichis prolonged in renal impairment.12 Excretion of adefovir is mainlythrough urine (45% as active metabolite within 24 h).12

    Here, we report a case of severe hypophosphatemia osteoma-lacia and renal Fanconi syndrome induced by low-dose ADV in apatient with CHB-related cirrhosis. All cases previously reportedin the literature are also reviewed.

    DETAILS OF THE CASE

    We report a case of a 48-year-old male with CHB-related cirrhosiswho developed severe hypophosphatemia osteomalacia and renalFanconi syndrome after the introduction of low-dose ADV. Then,we searched PubMed database for articles describing low-doseADV induced hypophosphatemia osteomalacia. We retrospec-tively review the published reports of 12 patients other than ourown.

    A 48-year-old Chinese man was admitted to our hospital inDecember 2010. We obtained written informed consent from thepatient. He had a 14-month history of severe progressive general-ized bone pain involving the low back, sacrum, rib cage, bilateralhips and knees in the absence of antecedent trauma. The pain wasdull and persistent, and was accompanied by limitation of activityof both lumbar spine and hips. He began to experience weakness inhis leg muscles, with difficulty in walking and climbing stairs sinceJuly 2010, and could only ambulate with the assistance of a cane.Since September 2010 he had difficulty turning in bed and had beenbed-bound for most of the time. He had a history of CHB-relatedcirrhosis of Child-Pugh class A and had been on ADV (Hepsera)10 mg daily since April 2005. He underwent splenectomy forsplenomegaly complicated by hypersplenism in March 2010. Hewas not on any medication or herbal remedy known to affectskeletal health or associated with nephrotoxicity. On admission, hewas 165 cm in height, 50 kg inweight and had a bodymass index of183 kg/m2. He presented with a waddling gait. Clinical examina-tion disclosed generalized bony tenderness, especially in the lumbarspine, sacrum, thoracic wall and bilateral hips. Laboratory profiling

    Correspondence: Huabing Zhang, Department of Endocrinology,Key Laboratory of Endocrinology, Ministy of Health, PekingUnion Medical College Hospital, Peking Union Medical College,Chinese Academy of Medical Sciences, Beijing 100730, China.Tel.: +86-010-8719-7173; fax: +86-010-8719-7173; e-mail: [email protected]

    2013 John Wiley & Sons Ltd 321

    Journal of Clinical Pharmacy and Therapeutics, 2013, 38, 321326 doi: 10.1111/jcpt.12050

  • revealed severe hypophosphataemia, hypouricemia, massive nor-moglycemic glycosuria, massive aminoaciduria and proteinuria.Serum protein electrophoresis was normal. Laboratory data aresummarized in Table 1. Ultrasound of the abdomen revealed thatthe liver was cirrhotic. X-rays revealed ground-glass-like changeof the lumbar vertebrae. Awhole-body 99mTc-methylene diphosph-onate bone scintigraphy showed diffuse increased uptake inmultiple ribs, cervical spine, bilateral sacroiliac joints, left pubicramus, bilateral knees, bilateral proximal tibiae and bilateral ankles(Fig. 1a). Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DEXA) revealed severe decreases at the lumbarspine and hip (Table 2). On the basis of history and laboratoryexamination, a clinical diagnosis of ADV-induced hypophospha-temic osteomalacia due to acquired renal Fanconi syndrome wassuspected.ADVwas discontinued and entecavirwas commenced ata daily dose of 05 mg in December 2010. Three weeks after thediscontinuation of ADV, his serum phosphate level increased,glycosuria disappeared and aminoaciduria improved (Table 1).Seven weeks later, his symptoms and general status improved.This paralleled an improvement in serum phosphate and reduc-tion of proteinuria and aminoaciduria. Thirteen weeks later, hereported that bone pain and his walking ability had improvedsignificantly and no longer needed a cane for ambulation. Thelaboratory parameters further improved, including normalizationof proteinuria and aminoaciduria. DEXA showed a BMD improve-ment in the lumbar spine and hip (Table 2). Forty-eight weeksafter the discontinuation of ADV, he no longer reported bone painand was asymptomatic. DEXA showed further improvement inthe BMD at the lumbar spine and hip (Table 2). Accompanyingthese changes was a significant reduction in isotope uptake on arepeat whole-body bone scintigraphy carried out in December

    2011 (Fig. 1b). Our patient had received ADV for 54 monthsbefore the development of generalized bone pain. The dramaticclinical, laboratory and subsequent imaging improvementobserved after ADV discontinuation further supported the diag-nosis of ADV-induced renal Fanconi syndrome and hypophos-phatemic osteomalacia.

    Literature review revealed only 12 other cases of hypophospha-temic osteomalacia induced by low-dose (10 mg daily) ADV 1325

    (see Table 3). The age of these patients varied from 22 to 74 years,with a median of 516 years. Male: female ratio was 10:3. Mostcases (11/13) involved subjects of East-Asian ethnicity, includingKorean, Cambodian, Chinese and Japanese.13, 1523, 25 The othertwo cases did not specify ethnicity.14, 24 Symptoms becameclinically evident after a median 305 months (range 689 months)of ADV treatment. Major symptoms included muscle-weakness,generalized bone-pain and gait difficulties. Diagnosis of hypo-phosphatemia often takes longer (median 407 months of ADVtreatment, range 895 months). The reported serum phosphate ondiagnosis ranged from 030 to 077 mmol/L. Most of these caseshad several characteristics of renal Fanconi syndrome, includingnormoglycemic glycosuria (12/13), aminoaciduria (9/10) andproteinuria (11/12). Renal biopsy was done in three cases.Microscopical examination in one case with a history of renaltransplantation revealed acute tubular injury characterized byswelling and vacuolization of proximal tubular cells,14 the othercase revealed mild glomerular lesions but normal appearance ofrenal tubule.23 The third case revealed lesions in the proximalrenal tubule with loss of brush borders in some of the renaltubules.25 After discontinuation or reduction of ADV, serumphosphate level increased (after 48 weeks) and clinical symptomssignificantly improved (after 17 months) in all cases. This was

    Table 1. Baseline and follow-up laboratory data after discontinuation of (ADV).

    Parameters Baseline After 3 weeks After 7 weeks After 13 weeks After 48 weeks Normal range

    SerumPhosphate(mmol/L) 032 067 088 079 078 080150Calcium (mmol/L) 209 248 241 241 224 208260AKP (U/L) 297 239 278 327 324 40150Potassium (mmol/L) 350 362 397 448 423 350550Creatinine (lmol/L) 911 916 1022 964 945 50133Glucose (mmol/L) 481 537 526 503 537 390560Uric acid (lmol/L) 130 171 181 208 216 149416b2-MG (mg/L) 152 179 206 229 132 067150Bicarbonate (mmol/L) 203 225 222 216 230 220260PTH (pg/ml) 744 NA NA 419 471 1288CK (U/L) 59 45 56 62 43 38