Clinical Research Of Hypophosphatemia Triggered By Adefovir Dipivoxil In Treatment Of Chronic Hepatitis B

Background&Objective Adefovir dipivoxil is applied to HBV mumants of lamivudine YMDD mutation（The 204 th methionine of YMDD motif of HBVDNA polymerase reverse transcriptase Area is replaced by alanine or isoleucine）. Prior to the listing for the Tenofovir dipivoxil, because ADV have irreplaceable value than other nucleoside analogues, So it is widely used, a large number of clinical datas were accumulated. The cases reports with hypophosphatemia, hypophosphatemic osteomalacia, Fanconi syndrome have continue to emerge. Using of ADV can cause Fanconi syndrome, resulting in phosphorus reabsorption disorder, causing hypophosphatemia. Hypophosphatemia can lead to disorder of bone mineralization and cause the bone density decreased in patients. Patients may easy to cause fracture if having a minor collision or fall. Severe cases may result in deformity on long bone, chest, pelvic, and seriously affecting the quality of life and prognosis. Currently, the literature mainly reported the case reports that ADV caused Fanconi syndrome and its associated complications, and analyzed that it may be related with tubular dysfunction. However, the risk factors and clinical features of hypophosphatemia caused by adefovir lack of systematic reports. After a variety ofcomplications in patients reported, antiviral drugs were adjusted to entecavir, but entecavir may inhibit DNA polymerase in mitochondrial, resulting in oxidative phosphorylation disorders, kidney is easy involed because of metabolism active. So whether entecavir can cause hypophosphatemia worthing discussion. To raise awareness of clinicians for ADV causing hypophosphatemia and in advance make a warning for hypophosphatemia and its complications, the purpose of this study was to discuss whether enticavir can give rise to hypophosphatemia,and then summarize the clinical characteristics of hypophosphatemia triggered by adefovir, further study the pathogenesis of hypophosphatemia and possible risk factors.Methods 1. Retrospective collection of patients with chronic HBV infection in the First Affiliated Hospital of Zhengzhou University, 290 patients were enrolled in adefovir treatment group, 310 patients were choosed in treatment entecavir group in according of antiviral therapy. There was no significant difference in age、gender、body weight, duration of antiviral treatment、the constituent ratio of hepatitis B cirrhosis and complications between the 2 groups. Blood phosphorus concentration before and after treatment were clollected, hypophosphatemia was divided into 3 degrees, among which the mild, moderate, severe were 0.6 < 0.81mmol/L, 0.5 < 0.6mmol /L, < 0.5 mmol/L respectively. The changes of serum phosphorus concentration and Clinical manifestations were observed before and after treatment in two groups, t test was used to analysis the changes of serum phosphorus concentration before and after treatment, χ2 test was used to analysis the incidence rate of hypophosphatemia of the two groups. 2. The liver function, renal function, electrolytes, bone density of bone mineral density, urine routine, 24 h urinary electrolytes, 25 hydroxy vitamin D3, parathyroid hormone of the patients were examined with hypophosphatemia to diagnosis. 3. The possible risk factors of the course of antivirus, age, weight, using adefovir antivirus or not, gender, liver cirrhosis, hypertension, diabetic, hyperlipidemia werechoosed as independent variables, hypophosphatemia or not was named as dependent variable. Two logistic regression analysis was used to analyze the relationship between the risk factors and the occurrence of low phosphorus, screening out the risk factors of the occurrence of hypophosphatemia. 4. Measuring the bone mineral density in patients with hypophosphatemia, Spearman correlation analysis was used to analyze the correlation between serum phosphorus and bone mineral density. 5. According to the screening risk factors, multiple linear regression analysis was used to establish the linear regression of blood phosphorus concentration and risk factors in patients with hypophosphatemia.Results 1. The blood phosphorus were（0.873 + 0.074）mmol/L,（0.782 + 0.131）mmol/L before and after treatment in adefovir dipivoxil group,compared with before treatment, Serum phosphorus after treatment was significantly decreased（t=23.375, P < 0.05）, the difference had statistically significant; The blood phosphorus were（0.869 + 0.095）mmol/L,（0.863 + 0.125）mmol/L before and after treatment in entecavir group, there was no significant difference in serum phosphorus concentrationthe before and after treatment（t=0.536, P > 0.05）. The incidence of hypophosphatemia rate was 15.9%, 0.3%（χ2 =50.114, P < 0.05） in adefovir dipivoxil group and entecavir group respectively. Compared with entecavir group, the hypophosphatemia incidence was higher in adefovir group, the difference had statistical significance.among the 46 cases of persistent hypophosphatemia in patients in adefovir, the Serum phosphorus level of mild, moderate and severe were 78.2%,15.2% and 6.6% respectively. 2. There were four patients with bone pain, 3 cases of them were severe hypophosphatemia, the examination showed that 24 hours urine phosphorus, urinary calcium, urinary protein were rising, uric acid, alkaline phosphatase, bone density were decreasing; 2 cases of patients with renal biopsy, the result showed renal tubular injury. Combined with the history of patients taking medicine and the check data, hypophosphatemic osteomalacia was diagnosised. According to the experimentalresults, the serum phosphorus concentrations had no significant difference before and after treatment in entecavir group, antivirus was adjusted to entecavir, bone pain vanished in 3 months, serum phosphorus returned to normal in 6 months. 3. Antiviral course, advanced age, using adefovir antivirus, liver cirrhosis diabetes mellitus were the risk factors of hypophosphatemia. Antiviral course increased in 2 years, the risk of hypophosphatemia increased 3.867 times; the age increased 15 years old, hypophosphatemia risk increased 2.675 times; compared with entecavir, the risk of hypophosphatemia increased 5.236 times taking adefovir antivirus; compared with CHB, the occurrence of hypophosphatemia increased 1.372 times with liver cirrhosis; compared with patients without diabetes, the risk of hypophosphatemia increased 1.178 times in diabetes. 4. The blood phosphorus and bone mineral in patients with low phosphorus were correlated in patients with low phosphorus, the lower the level of serum phosphorus, the lower the bone density, the correlation coefficient was r=0.623, the difference was statistically significant. 5. The longer the duration of treatment, the lower the blood phosphorus, the time of drug use was negatively correlated with serum phosphorus（r2=0.204, p<0.05）;the greater the age, the lower the blood phosphorus, age and blood phosphorus was negatively correlated（r²=0.249, p<0.05）. The results showed that Y_b=0.87-0.02X_b1-0.03X_b2 in linear regression analysis with antivirus age X_b1, age X_b2and blood phosphorus concentration Y_b. Antivirus course increased 1 month, blood phosphorus decreased 0.02mmol/l, the age increased 1 years, blood phosphorus decreased 0.03mmol/l.Conclusions 1. Using adefovir antivirus can trigger hypophosphatemia, entecavir does not cause hypophosphatemia. 2. Patients with mild, moderate hypophosphatemia have no symptoms, but the bone density has been reduced, Serum phosphorus concentration is severe if patients have bone pain or other symptoms. 3. The treatment time, age, using ADV antivirus, liver cirrhosis, diabetes are the risk factors of hypophosphatemia. The longer of medication time, the older of age, the lower of blood phosphorus concentration. 4. We Should aware of transient low serum phosphorus, serum phosphorus and renal function should be periodically measured. In addition the elderly and diabetic patients should not choose adefovir dipivoxil as antiviral drugs.