Fanconi’s Syndrome and Dementia in a Patient With Chronic Hepatitis B Taking Nucleoside/ Nucleotide Analogue

A 58-year-old Chinese man was referred to the Endocrine Clinic for osteomalacia in Aug 2014. He started to have generalized bone pain since Apr 2013. Bone scan in Aug 2013 showed multiple active bone lesions especially at right femur. Magnetic resonance imaging (MRI) found avascular necrosis of both femoral heads with fractured right femoral neck and he underwent screw fixation of right hip in Feb 2014. In Aug 2014, his lab were as follows: serum (S) PO4 1.35(2.5–4.49)mg/dL; ALP 270 IU/ml (40–129); S creatinine (Cr) 1.36 (0.7–1.2) mg/dL; spot urine (U) PO4 23.2mg/dL.; U Cr 44.5mg/dL; parathyroid hormone 20.7 (15.1–65.1) pg/mL; 25-hydroxyvitamin D3 16.4ng/mL; TSH 3.4 uU/mL; S urate 1.7 mg/dL (3.4–7.0) mg/dL. U amino acid was increased to 5x upper limit of normal signifying U PO4 loss. He had hepatitis B (HBV) liver cirrhosis and took lamivudine 100mg qd (LAM) since 2005. Because of LAM resistance, adefovir dipivoxil 10mg qd (ADV) was added in Jul 2007. He was diagnosed Fanconi’s syndrome and osteomalacia after taking ADV for 6 years. ADV was changed to tenofovir disoproxil fumarate 300mg qd (TDF) in Dec 2014. He was given alfacalcidol 1mcg bd and PO4 mixture 1250mg/d. His S PO4 rose to 2.82mg/dL but later dropped to 2.14mg/dL because of poor drug compliance. ALP dropped to 126IU/L. His bone pain improved and could walk with stick. TDF was then switched to tenofovir alafenamide (TAF) 25mg qd in Mar 2019. His S PO4 further normalized to 3.13mg/dL in Jul 2019. His HBV remained suppressed. Alfacalcidol and PO4 solution were stopped. The patient developed depression since Sep 2017. He had poor short term memory since 2018 and was confirmed mild cognitive impairment in Apr 2019. MRI brain in May 2019 found moderate global cerebral atrophy with bilateral parietal lobes and cerebellar predilection. His cognitive assessment further declined to < 2%ile in Jan 2020. He was admitted for recurrent fall in Sep 2020 and showed Parkinsonism feature. He was given Sinemet 25/100 and rivastigmine by neurologist with some improvement. He now walked with frame. Nucleotide and nucleoside analogues (NA) can impose long term side effect on kidney. ADV and TDF are excreted from proximal renal tubule and can accumulate in the cytoplasm causing mitochondrial dysfunction. In this patient, hypoPO4 persisted after switching from ADV to TDF. TAF did not enter proximal renal tubular cells and the plasma concentration is lower than TDF and hence less nephrotoxic. The PO4 level in this patient normalized one month after changing to TAF. Low serum phosphorus level was found to have correlation with cerebral amyloid deposition on Pittburgh compound B positron tomography in a Korean study. The chronic hypoPO4 may be a contributing factor for the development of dementia in this patient which did not show reversibility. In summary, this case illustrates the nephrotoxicity of NA and importance of multi-disciplinary care as the side effect can be multi-systemic.