Severe vitamin D deficiency in a patient treated for hepatitis B with tenofovir

INTRODUCTION

Tenofovir disoproxil has been used extensively and safely in the treatment of HIV-infected patients ¹ and is now recommended by National Institute for Health and Clinical Excellence in the management of chronic hepatitis B infection. Close monitoring for adverse effects is advisable, following evidence that tenofovir may precipitate Fanconi's syndrome and renal failure, particularly in those co-infected with hepatitis B. ^2–7 Hypophosphataemia is often a heralding biochemical marker for Fanconi's syndrome. However, this case emphasizes the importance of considering alternative diagnoses resulting in hypophosphataemia, such as vitamin D deficiency, before discontinuing therapy with tenofovir and delaying appropriate management.

CASE REPORT

An asymptomatic 55-year-old white British man was diagnosed with ‘e’ antigen-positive chronic hepatitis B infection. Imaging and biochemical investigations demonstrated normal liver synthetic function and renal function. He was commenced on tenofovir monotherapy, with subsequent successful suppression of hepatitis B DNA replication.

A year following the initiation of tenofovir, he presented with lethargy, myalgia and lower-back pain. His weight remained unchanged and physical examination did not reveal an obvious cause. Serum biochemistry demonstrated low phosphate levels of 0.31 mmol/L (normal range 0.80–1.40 mmol/L). This remained low on repetition at 0.42 mmol/L, with a raised alkaline phosphatase of 151 U/L and normal serum corrected calcium of 2.23 mmol/L. Renal function remained normal with a creatinine of 80 µmol/L (normal range 60–125 µmol/L) and a calculated glomerular filtration rate of 93 mL/minute.

Urine dipstick assessment to investigate for Fanconi's syndrome failed to reveal proteinuria or glycosuria. Laboratory urine analysis also did not demonstrate significant proteinuria, with a urinary protein to creatinine ratio of <10 mg/mmol, and normal urinary amino acid excretion. Thus, the presumed diagnosis of Fanconi's syndrome was negated as an explanation for the hypophosphataemia.

Further investigations revealed a mildly elevated serum parathyroid hormone level of 7.4 pmol/L (normal range 1.1–6.8 pmol/L), and vitamin D deficiency measuring only 21 nmol/L (normal range 70–150 nmol/L).

He was commenced on vitamin D replacement therapy, with successful resolution of his symptoms and normalization of his serum biochemistry within four weeks.

DISCUSSION

With the increasing use of tenofovir therapy in HIV and hepatitis B infection, recognized complications such as Fanconi's syndrome are likely to increase in frequency. ^3–7 Biochemical features diagnosing Fanconi's syndrome include hypophosphataemia, excess urinary phosphate loss, proteinuria with hyperaminoaciduria and glycosuria despite a normal serum glucose level. ⁸ Monitoring serum phosphate levels and urine analysis for protein and glucose is recommended in patients receiving tenofovir. Hypophosphataemia often prompts investigation for Fanconi's syndrome. But what alternative diagnoses result in hypophosphataemia?

Common mechanisms resulting in chronic hypophosphataemia include excess urinary loss of phosphate, reduced gastrointestinal absorption and hyperparathyroidism. Excess urinary losses may be secondary to renal tubular dysfunction and Fanconi's syndrome. ⁹ Reduced gastrointestinal absorption is commonly due to vitamin D deficiency, but may result from malnutrition or malabsorption states.

Vitamin D deficiency has a high prevalence worldwide. ¹⁰ Mostly patients remain asymptomatic. Severe deficiency may present with non-specific constitutional symptoms including pain in weight-bearing joints or areas, myalgia and proximal muscle weakness. Untreated, this may progress to osteomalacia with bone fragility and pathological fractures. ¹⁰

Vitamin D is obtained from the diet and sun exposure, and metabolized at the liver and kidneys. It increases phosphate and calcium absorption from the gut. Significant vitamin D deficiency results in elevation of parathyroid hormone to maintain normal serum calcium levels. Parathyroid hormone increases calcium absorption from bone but also increases renal losses of phosphate. ¹⁰ This explains our patient's biochemical picture, with normal calcium levels maintained by elevated parathyroid hormone levels, resulting in hypophosphataemia and increased bone turnover signified by raised alkaline phosphatase levels. However, a recent study has also shown an association of tenofovir with a rise in alkaline phosphatase independent of renal disease, suggesting a possible link of this drug with the future development of osteomalacia. ¹¹

Risk factors for vitamin D deficiency include poor sun exposure, skin pigmentation, renal failure, malabsorption and malnutrition. There is some evidence that significant synthetic dysfunction of the liver may result in vitamin D deficiency. ^10,12 Despite chronic hepatitis B infection, our patient's liver synthetic function was normal based on normal serum albumin levels and prothrombin time. Furthermore, our patient followed a typical ‘western’ diet with average sun exposure and normal renal function. Thus, without an obvious risk factor, his underlying cause for severe vitamin D deficiency remains undetermined. Tenofovir has not been directly associated with vitamin D deficiency and it is unlikely that the short course of tenofovir that this patient received contributed to the low levels observed although further studies are needed. ¹³

It is likely that tenofovir, either as monotherapy or as part of combination therapy, will be increasingly used in the treatment of hepatitis B. While it is important to monitor for adverse effects, this case reminds physicians to consider all differential diagnoses resulting in hypophosphataemia to prevent erroneous cessation of tenofovir.