Calcif Tissue Int (2014) 95:218–221 DOI 10.1007/s00223-014-9884-1
ORIGINAL RESEARCH
Areal Bone Mineral Density in Pediatric Patients with Chronic Hepatitis B or Chronic Hepatitis C Stefano Mora • Vania Giacomet • Alessandra Vigano` Katia Maruca • Silvia Capelli • Pilar Nannini • Gian Vincenzo Zuccotti
•
Received: 17 March 2014 / Accepted: 2 June 2014 / Published online: 24 June 2014 Ó Springer Science+Business Media New York 2014
Abstract Decreased bone mineral density (BMD) is a known complication of chronic liver disease in adults. Data on bone mass, an important factor for the development of osteoporosis in adult life, in young patients with chronic hepatitis B (HBV) and C virus (HCV) infections are scarce. We measured BMD at the lumbar spine and whole skeleton by dual-energy X-ray absorptiometry in 11 HBV- and 21 HCV-vertically infected untreated youths (3.9–21.1 years). BMD measurements were compared to those of 202 healthy subjects (3.0–21.9 years). The median BMD Z-score of the lumbar spine of HBV-infected patients was -0.3, ranging from -1.6 to 0.6, while the median whole skeleton BMD Z-score was 0.1 (-0.8 to 0.6). HBV-infected patients showed a median Z-score of the lumbar spine of 0.6 (-1.6 to 1.9), and a median whole skeleton BMD Z-score of 0.6, ranging from -1.5 to 1.4. Multivariate analyses have been performed to correct for differences in sex, age, and anthropometric measurements. Lumbar spine BMD values of HBV and HCV-infected patients were not significantly different from those of controls. Similarly, no differences were found between groups in total body BMD measurements. Our data suggest that, unlikely adult patients, untreated young patients with chronic HBV and HCV infection may not have impaired bone mass measurements.
S. Mora, V. Giacomet, A. Vigano`, K. Maruca, S. Capelli, P. Nannini and G.V. Zuccotti declare that they have no conflict of interest. S. Mora (&) K. Maruca S. Capelli Laboratory of Pediatric Endocrinology, BoNetwork, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, MI, Italy e-mail: [email protected] V. Giacomet A. Vigano` P. Nannini G. V. Zuccotti Department of Pediatrics, L. Sacco Hospital, University of Milan, Milan, Italy
123
Keywords Bone mass Bone mineral density Chronic hepatitis B Chronic hepatitis C
Introduction Hepatitis B and hepatitis C infections are chronic viral diseases representing a major worldwide health problem, which may lead to acute liver failure, acute hepatitis, chronic hepatitis, liver cirrhosis, and hepatocarcinoma. Chronic liver disease has been associated to extrahepatic complications, reduced bone mineral density (BMD), and osteoporosis in adult patients [1]. Chronic hepatitis B (HBV) and hepatitis C (HCV) infections are also associated with a number of extrahepatic manifestations [2, 3]. However, controversy exists about skeletal involvement in adult patients with HBV and HCV infection [4–9]. While some studies reported reduced BMD measurements [4, 6–8], others found normal BMD values [5, 9]. Currently, no studies are available for young patients with chronic HBV and HCV infections. BMD changes occur during growth, and the attainment of an optimal peak bone mass is an important determinant for the prevention of osteoporosis in adult life [10]. We hypothesized that young patients with chronic liver infection due to HBV or HCV may have reduced bone mass measurements. We, thus, measured BMD in young patients with chronic HBV and HCV infection, and we compared the measurements with those obtained in a large group of healthy subjects.
Subjects and Methods Eligibility for this cross-sectional observational study was all patients with an established infection with either HBV or
S. Mora et al.: Areal Bone Mineral Density in Pediatric Patients
HCV, attending the Pediatric Infectious Disease Unit at L. Sacco Hospital. Excluded were all patients with HIV coinfection, and those with concomitant skeletal, endocrine or renal chronic diseases, and patients taking medications known to affect bone metabolism. Recruitment started in May 2010, and ended in April 2012. We enrolled 11 HBVinfected and 21 HCV-infected patients (aged 3.9–21.1 years). All patients were vertically infected. As a control group, we studied 202 healthy children and adolescents (92 girls and 110 boys) of comparable age (3.0–21.9 years). None had a history of endocrine, nutritional, growth, or renal problems. Informed consent was obtained from each patient’s and healthy control’s legal guardian and from the patients when appropriate, before enrollment. The study was approved by the ethical committee of the L. Sacco Hospital. All subjects underwent physical examination to obtain anthropometric measures. Body weight was measured to the nearest 0.1 kg on a balance beam scale (Seca, Hamburg, Germany), and height was measured to the nearest millimeter using a wall-mounted stadiometer (Holtain Ltd., Crosswell, U.K.). BMI was then calculated as weight on height2 (kg/m2). Standard deviation scores (SDS) of anthropometric measurements for study subjects younger than 20 years were calculated using specific Italian standards [11]. The hepatic function of all patients was monitored by blood measurements of platelet, total and indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatinine, total protein, albumin, prothrombin time (international normalized ratio, INR), and partial thromboplastin time (PTT). Bone mineral measurements were performed at the L2–L4 vertebrae level and in the whole skeleton on a dualenergy X-ray absorptiometer (Lunar Prodigy Advance, GELunar Radiation Corp., Madison, WI, software version 13.60). The instrument was calibrated on a daily basis according to the manufacturer’s instructions. Reproducibility of our instrument is 1.4 % for the lumbar spine and 1.5 % for the whole skeleton. Data are presented as BMD in g/cm2 and as BMD Z-scores by using the database provided by the manufacturer. Body composition analysis (lean and fat masses) has been performed on total body scans according to manufacturer’s recommendations. All study subjects were scanned with the same instrument and using the same scanning protocol. All variables were not normally distributed, and were log-transformed before analysis when parametric tests were performed. Data are presented as median (range). Statistical analyses were performed at an alpha level of 5 %, and were two-tailed. The JMPÒ software version 7.0 (SAS Institute, Inc., Cary, NC) was used for analyses. Comparisons between HBV- and HCV-infected youths and control subjects were performed by multivariate
219 Table 1 Age, sex distribution, hepatic function, and bone mineral measurements of the 32 young patients with HBV or HCV infection HBV-infected
HCV-infected
Subjects (n)
11
21
Sex (n)
7 girls
15 girls
4 boys
6 boys
Age (year)
9.3 (4.1–14.7)
12.5 (3.9–21.1)
Weight (kg)
29.8 (15–44)
35 (16–64)
-0.74 (-1.87 to 0.77)
-0.38 (-1.76 to 2.62)
137 (100–160)
148 (104–173.5)
-0.09 (-1.82 to 1.08)
-0.11 (-1.93 to 1.46)
15.6 (14.9–22.1)
17.9 (6.2–24.4)
-0.97 (-1.91 to 1.30) 269,500 (181,000–438,000)
-0.07 (-0.99 to 2.26) 279,000 (189,000–363,000)
Total bilirubin (mg/dL)
0.48 (0.20–0.94)
0.39 (0.21–1.53)
Indirect bilirubin (mg/dL) AST (U/L)
0.28 (0.10–0.56)
0.25 (0.11–1.05)
55.5 (33–140)
34.5 (19–80)
ALT (U/L)
72.5 (21–152)
43.5 (15–117)
ALP (U/L)
257.5 (167–384)
145 (20–254)
Creatinine (mg/dL)
0.425 (0.350–0.710)
0.525 (0.390–0.680)
Total protein (g/L)
71.5 (64–78)
71 (64–80)
Albumin (%)
58.2 (54.4–61.6)
58.5 (53.7–62.7)
INR
1.01 (0.96–1.06)
0.985 (0.91–1.16)
PTT/time
31.3 (26.5–37.3)
31.4 (28.1–39.3)
PTT/ratio
1.115 (0.95–1.33)
1.10 (1.01–1.40)
FBN
277 (220–416)
252 (171–373)
HBV DNA (IU/mL)
31,582,433 (10–980,582,996)
Z-score Height (cm) Z-score BMI (kg/m2) Z-score Platelet (n/mm3)
HCV RNA (IU/mL)
70,537 (10–7,268,646)
Lumbar spine BMD (g/cm2)
0.718 (0.530–1.107)
0.924 (0.552–1.498)
Total body BMD (g/cm2) Total body BMC (g)
0.867 (0.718–1.077)
0.972 (0.747–1.349)
1,117 (502–1876)
1,752 (556–3286)
Total body BMD less head (g)
822 (283–1540)
1,369 (305–2731)
Data are expressed as median (range)
analyses to correct for the effect of confounding variables. The backwards procedure was used to build the best model for each variable.
Results The characteristics of the HBV- and HCV-infected patients are shown in Table 1. Five patients with HBV infection
123
220
presented a mild liver steatosis and one had a mild increased stiffness at fibroscan. Patients with HCV infection did not have signs of advanced diseases. Therefore, none of the patients was receiving treatment for the disease. Abnormal values of AST were defined as [55 U/L for children aged 1–9, and[45 U/L for children and young adults aged 10–19. Abnormal values of ALT were defined as [45 U/L for all ages. AST values were abnormal in four, whereas ALT values were abnormal in 8 out of 11 HBV infected-patients. AST values were abnormal in seven, whereas ALT values were abnormal in 10 out of 21 HCV-infected patients. Viral load was compatible with persistent viral replication, since patients were not treated with antiviral drugs. Bone mineral measurements of the two groups of patients and healthy control subjects are shown in Table 1. The median BMD Z-score of the lumbar spine of HBVinfected patients was -0.3, ranging from -1.6 to 0.6, while the median whole skeleton BMD Z-score was 0.1 (-0.8 to 0.6). HBV-infected patients showed a median Z-score of the lumbar spine of 0.6 (-1.6 to 1.9), and a median whole skeleton BMD Z-score of 0.6, ranging from -1.5 to 1.4. Due to the differences in age, sex distribution, and anthropometric measurements, we performed multivariate analyses to compare patients and healthy control subjects. The model for lumbar spine included sex, height, and bone area as confounding variables (R2 = 0.83), and showed that the differences observed between groups were not statistically significant (P = 0.24). The multivariate model for the whole body BMD included sex, height, and bone area as confounding variables (R2 = 0.87). The differences observed between groups were not statistically significant (P = 0.23). Young patients with HBV infection had a median total body lean mass of 20.9 kg (ranging from 11.7 to 37.0 kg). The median fat mass was 4.2 (1.5–14.3) kg, and the percentage on total mass was 13.8 (6.8–40.6). Total body lean mass of patients with HCV infection was 30.1 (13.8–58.4) kg, and total fat mass was 10.1 (2.2–25.5) kg. The percentage of fat mass on total mass was 23.6 (7.8–43.6). Multivariate analyses, correcting for sex, age, and weight differences, showed that the two groups differed significantly for total fat mass (R2 = 0.56; P = 0.024), and percent fat/total mass (R2 = 0.42; P = 0.03), indicating that patients with HBV infection had lower fat mass.
Discussion Decreased bone density and osteoporosis are known complications of chronic liver disease [1], with an incidence of 40 % in patients with end-stage liver disease [12]. Few data are available on BMD measurements in early stages of
123
S. Mora et al.: Areal Bone Mineral Density in Pediatric Patients
chronic hepatitis. Some studies suggest that reduced measurements are already present in noncirrhotic patients with viral hepatitis, but controversies are still present [4, 5, 7–9]. The available studies have been conducted on adult patients, leaving the early stages of life largely uncovered. We, thus, focused our attention to the BMD measurement in children and adolescents with chronic hepatitis due to HBV and HCV infection, and we hypothesized the presence of a reduced areal BMD in these patients. BMD changes remarkably during growth, and changes are not only a function of age, but they occur at different times in girls and boys [10]. For this reason, we examined a large sample of healthy children and adolescents, and we compared their measurements to those of patients with viral hepatitis, correcting for the effects of confounding variables. Our study showed that young patients with chronic HBV infection have BMD measurements not significantly different from those of healthy controls at both skeletal sites. Similarly, patients with HCV infection had BMD measurements comparable with those of healthy subjects. This finding could be due to the general good health of our patients, despite the high median viral replication and altered AST and ALT values found: in fact all patients did not receive antiviral treatment at the time of the study. Treatment options of pediatric patients are limited and restricted to patients with advanced disease. Currently, only combination treatment with pegylated interferon (PEG-IFN) and ribavirin can be used to treat HCV in children. However, PEG-IFN has adverse effect on growth in children, and should be avoided during growth spurts. New direct-acting antiviral agents against HCV have been approved for treatment of liver disease in adults, and phase I and II trials of many other new compounds are underway. For HBV infection, there is no established benefit of treatment of children and there is a very high risk of development of drug resistance. Interferon is the agent of choice, while nucleoside and nucleotide analogs (lamivudine, tenofovir) are secondary therapies, and children who receive these agents require monitoring for development of resistance. The current study has several limitations. The results may be taken as preliminary evidence, due the small number of patients in each group. The wide age range may be also a problem in the interpretation of the results. To address this problem, we studied a large group of healthy subjects covering the age range of the patient with viral hepatitis. Finally, the cross-sectional design of the study does not allow any inference on the evolution of the BMD measurements in HBV- and HCVinfected youths. Longitudinal surveys may help to address this issue. Nevertheless, this is the first study describing the bone mass in young patients with viral hepatitis.
S. Mora et al.: Areal Bone Mineral Density in Pediatric Patients
In conclusion, our data suggest that bone mineral measurements of children and adolescents with chronic HBV and HCV may not be different to those of healthy subjects. However, due to the small number of subjects, further studies are needed to confirm our results, and to elucidate the evolution of bone mass during growth in these patients. Human and Animal Rights and Informed Consent statements All procedures followed were in accordance with the ethical standards of the responsible institutional committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all parents and legal guardians of the patients for being included in the study.
221
5.
6.
7.
8.
9.
References 1. Rouillard S, Lane NE (2001) Hepatic osteodystrophy. Hepatology 33:301–307 2. Global surveillance and control of hepatitis C (1999). Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat 6: 35–47 3. Han S-HB (2004) Extrahepatic manifestations of chronic hepatitis B. Clin Liver Dis 8:403–418 4. Schiefke I, Fach A, Wiedmann M et al (2005) Reduced bone mineral density and altered bone turnover markers in patients
10. 11.
12.
with non-cirrhotic chronic hepatitis B or C infection. World J Gastroenterol 11:1843–1847 Yenice N, Gu¨mrah M, Mehtap O, Kozan A, Tu¨rkmen S (2006) Assessment of bone metabolism and mineral density in chronic viral hepatitis. Turk J Gastroenterol 17:260–266 George J, Ganesh HK, Acharya S et al (2009) Bone mineral density and disorders of mineral metabolism in chronic liver disease. World J Gastroenterol 15:3516–3522 Lin J-C, Hsieh T-Y, Wu C-C et al (2012) Association between chronic hepatitis C virus infection and bone mineral density. Calcif Tissue Int 91:423–429 Gaudio A, Pennisi P, Muratore F et al (2012) Reduction of volumetric bone mineral density in postmenopausal women with hepatitis C virus-correlated chronic liver disease: a peripheral quantitative computed tomography (pQCT) study. Eur J Intern Med 23:656–660 Pelazas-Gonza´lez R, Gonza´lez-Reimers E, Alema´n-Valls MR et al (2013) Bone alterations in hepatitis C virus infected patients. Eur J Intern Med 24:92–96 Mora S, Gilsanz V (2003) Establishment of peak bone mass. Endocrinol Metab Clin N Am 32:39–63 Cacciari E, Milani S, Balsamo A et al (2006) Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest 29:581–593 Guichelaar MMJ, Kendall R, Malinchoc M, Hay JE (2006) Bone mineral density before and after OLT: long-term follow-up and predictive factors. Liver Transpl 12:1390–1402
123
ORIGINAL RESEARCH
Areal Bone Mineral Density in Pediatric Patients with Chronic Hepatitis B or Chronic Hepatitis C Stefano Mora • Vania Giacomet • Alessandra Vigano` Katia Maruca • Silvia Capelli • Pilar Nannini • Gian Vincenzo Zuccotti
•
Received: 17 March 2014 / Accepted: 2 June 2014 / Published online: 24 June 2014 Ó Springer Science+Business Media New York 2014
Abstract Decreased bone mineral density (BMD) is a known complication of chronic liver disease in adults. Data on bone mass, an important factor for the development of osteoporosis in adult life, in young patients with chronic hepatitis B (HBV) and C virus (HCV) infections are scarce. We measured BMD at the lumbar spine and whole skeleton by dual-energy X-ray absorptiometry in 11 HBV- and 21 HCV-vertically infected untreated youths (3.9–21.1 years). BMD measurements were compared to those of 202 healthy subjects (3.0–21.9 years). The median BMD Z-score of the lumbar spine of HBV-infected patients was -0.3, ranging from -1.6 to 0.6, while the median whole skeleton BMD Z-score was 0.1 (-0.8 to 0.6). HBV-infected patients showed a median Z-score of the lumbar spine of 0.6 (-1.6 to 1.9), and a median whole skeleton BMD Z-score of 0.6, ranging from -1.5 to 1.4. Multivariate analyses have been performed to correct for differences in sex, age, and anthropometric measurements. Lumbar spine BMD values of HBV and HCV-infected patients were not significantly different from those of controls. Similarly, no differences were found between groups in total body BMD measurements. Our data suggest that, unlikely adult patients, untreated young patients with chronic HBV and HCV infection may not have impaired bone mass measurements.
S. Mora, V. Giacomet, A. Vigano`, K. Maruca, S. Capelli, P. Nannini and G.V. Zuccotti declare that they have no conflict of interest. S. Mora (&) K. Maruca S. Capelli Laboratory of Pediatric Endocrinology, BoNetwork, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, MI, Italy e-mail: [email protected] V. Giacomet A. Vigano` P. Nannini G. V. Zuccotti Department of Pediatrics, L. Sacco Hospital, University of Milan, Milan, Italy
123
Keywords Bone mass Bone mineral density Chronic hepatitis B Chronic hepatitis C
Introduction Hepatitis B and hepatitis C infections are chronic viral diseases representing a major worldwide health problem, which may lead to acute liver failure, acute hepatitis, chronic hepatitis, liver cirrhosis, and hepatocarcinoma. Chronic liver disease has been associated to extrahepatic complications, reduced bone mineral density (BMD), and osteoporosis in adult patients [1]. Chronic hepatitis B (HBV) and hepatitis C (HCV) infections are also associated with a number of extrahepatic manifestations [2, 3]. However, controversy exists about skeletal involvement in adult patients with HBV and HCV infection [4–9]. While some studies reported reduced BMD measurements [4, 6–8], others found normal BMD values [5, 9]. Currently, no studies are available for young patients with chronic HBV and HCV infections. BMD changes occur during growth, and the attainment of an optimal peak bone mass is an important determinant for the prevention of osteoporosis in adult life [10]. We hypothesized that young patients with chronic liver infection due to HBV or HCV may have reduced bone mass measurements. We, thus, measured BMD in young patients with chronic HBV and HCV infection, and we compared the measurements with those obtained in a large group of healthy subjects.
Subjects and Methods Eligibility for this cross-sectional observational study was all patients with an established infection with either HBV or
S. Mora et al.: Areal Bone Mineral Density in Pediatric Patients
HCV, attending the Pediatric Infectious Disease Unit at L. Sacco Hospital. Excluded were all patients with HIV coinfection, and those with concomitant skeletal, endocrine or renal chronic diseases, and patients taking medications known to affect bone metabolism. Recruitment started in May 2010, and ended in April 2012. We enrolled 11 HBVinfected and 21 HCV-infected patients (aged 3.9–21.1 years). All patients were vertically infected. As a control group, we studied 202 healthy children and adolescents (92 girls and 110 boys) of comparable age (3.0–21.9 years). None had a history of endocrine, nutritional, growth, or renal problems. Informed consent was obtained from each patient’s and healthy control’s legal guardian and from the patients when appropriate, before enrollment. The study was approved by the ethical committee of the L. Sacco Hospital. All subjects underwent physical examination to obtain anthropometric measures. Body weight was measured to the nearest 0.1 kg on a balance beam scale (Seca, Hamburg, Germany), and height was measured to the nearest millimeter using a wall-mounted stadiometer (Holtain Ltd., Crosswell, U.K.). BMI was then calculated as weight on height2 (kg/m2). Standard deviation scores (SDS) of anthropometric measurements for study subjects younger than 20 years were calculated using specific Italian standards [11]. The hepatic function of all patients was monitored by blood measurements of platelet, total and indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatinine, total protein, albumin, prothrombin time (international normalized ratio, INR), and partial thromboplastin time (PTT). Bone mineral measurements were performed at the L2–L4 vertebrae level and in the whole skeleton on a dualenergy X-ray absorptiometer (Lunar Prodigy Advance, GELunar Radiation Corp., Madison, WI, software version 13.60). The instrument was calibrated on a daily basis according to the manufacturer’s instructions. Reproducibility of our instrument is 1.4 % for the lumbar spine and 1.5 % for the whole skeleton. Data are presented as BMD in g/cm2 and as BMD Z-scores by using the database provided by the manufacturer. Body composition analysis (lean and fat masses) has been performed on total body scans according to manufacturer’s recommendations. All study subjects were scanned with the same instrument and using the same scanning protocol. All variables were not normally distributed, and were log-transformed before analysis when parametric tests were performed. Data are presented as median (range). Statistical analyses were performed at an alpha level of 5 %, and were two-tailed. The JMPÒ software version 7.0 (SAS Institute, Inc., Cary, NC) was used for analyses. Comparisons between HBV- and HCV-infected youths and control subjects were performed by multivariate
219 Table 1 Age, sex distribution, hepatic function, and bone mineral measurements of the 32 young patients with HBV or HCV infection HBV-infected
HCV-infected
Subjects (n)
11
21
Sex (n)
7 girls
15 girls
4 boys
6 boys
Age (year)
9.3 (4.1–14.7)
12.5 (3.9–21.1)
Weight (kg)
29.8 (15–44)
35 (16–64)
-0.74 (-1.87 to 0.77)
-0.38 (-1.76 to 2.62)
137 (100–160)
148 (104–173.5)
-0.09 (-1.82 to 1.08)
-0.11 (-1.93 to 1.46)
15.6 (14.9–22.1)
17.9 (6.2–24.4)
-0.97 (-1.91 to 1.30) 269,500 (181,000–438,000)
-0.07 (-0.99 to 2.26) 279,000 (189,000–363,000)
Total bilirubin (mg/dL)
0.48 (0.20–0.94)
0.39 (0.21–1.53)
Indirect bilirubin (mg/dL) AST (U/L)
0.28 (0.10–0.56)
0.25 (0.11–1.05)
55.5 (33–140)
34.5 (19–80)
ALT (U/L)
72.5 (21–152)
43.5 (15–117)
ALP (U/L)
257.5 (167–384)
145 (20–254)
Creatinine (mg/dL)
0.425 (0.350–0.710)
0.525 (0.390–0.680)
Total protein (g/L)
71.5 (64–78)
71 (64–80)
Albumin (%)
58.2 (54.4–61.6)
58.5 (53.7–62.7)
INR
1.01 (0.96–1.06)
0.985 (0.91–1.16)
PTT/time
31.3 (26.5–37.3)
31.4 (28.1–39.3)
PTT/ratio
1.115 (0.95–1.33)
1.10 (1.01–1.40)
FBN
277 (220–416)
252 (171–373)
HBV DNA (IU/mL)
31,582,433 (10–980,582,996)
Z-score Height (cm) Z-score BMI (kg/m2) Z-score Platelet (n/mm3)
HCV RNA (IU/mL)
70,537 (10–7,268,646)
Lumbar spine BMD (g/cm2)
0.718 (0.530–1.107)
0.924 (0.552–1.498)
Total body BMD (g/cm2) Total body BMC (g)
0.867 (0.718–1.077)
0.972 (0.747–1.349)
1,117 (502–1876)
1,752 (556–3286)
Total body BMD less head (g)
822 (283–1540)
1,369 (305–2731)
Data are expressed as median (range)
analyses to correct for the effect of confounding variables. The backwards procedure was used to build the best model for each variable.
Results The characteristics of the HBV- and HCV-infected patients are shown in Table 1. Five patients with HBV infection
123
220
presented a mild liver steatosis and one had a mild increased stiffness at fibroscan. Patients with HCV infection did not have signs of advanced diseases. Therefore, none of the patients was receiving treatment for the disease. Abnormal values of AST were defined as [55 U/L for children aged 1–9, and[45 U/L for children and young adults aged 10–19. Abnormal values of ALT were defined as [45 U/L for all ages. AST values were abnormal in four, whereas ALT values were abnormal in 8 out of 11 HBV infected-patients. AST values were abnormal in seven, whereas ALT values were abnormal in 10 out of 21 HCV-infected patients. Viral load was compatible with persistent viral replication, since patients were not treated with antiviral drugs. Bone mineral measurements of the two groups of patients and healthy control subjects are shown in Table 1. The median BMD Z-score of the lumbar spine of HBVinfected patients was -0.3, ranging from -1.6 to 0.6, while the median whole skeleton BMD Z-score was 0.1 (-0.8 to 0.6). HBV-infected patients showed a median Z-score of the lumbar spine of 0.6 (-1.6 to 1.9), and a median whole skeleton BMD Z-score of 0.6, ranging from -1.5 to 1.4. Due to the differences in age, sex distribution, and anthropometric measurements, we performed multivariate analyses to compare patients and healthy control subjects. The model for lumbar spine included sex, height, and bone area as confounding variables (R2 = 0.83), and showed that the differences observed between groups were not statistically significant (P = 0.24). The multivariate model for the whole body BMD included sex, height, and bone area as confounding variables (R2 = 0.87). The differences observed between groups were not statistically significant (P = 0.23). Young patients with HBV infection had a median total body lean mass of 20.9 kg (ranging from 11.7 to 37.0 kg). The median fat mass was 4.2 (1.5–14.3) kg, and the percentage on total mass was 13.8 (6.8–40.6). Total body lean mass of patients with HCV infection was 30.1 (13.8–58.4) kg, and total fat mass was 10.1 (2.2–25.5) kg. The percentage of fat mass on total mass was 23.6 (7.8–43.6). Multivariate analyses, correcting for sex, age, and weight differences, showed that the two groups differed significantly for total fat mass (R2 = 0.56; P = 0.024), and percent fat/total mass (R2 = 0.42; P = 0.03), indicating that patients with HBV infection had lower fat mass.
Discussion Decreased bone density and osteoporosis are known complications of chronic liver disease [1], with an incidence of 40 % in patients with end-stage liver disease [12]. Few data are available on BMD measurements in early stages of
123
S. Mora et al.: Areal Bone Mineral Density in Pediatric Patients
chronic hepatitis. Some studies suggest that reduced measurements are already present in noncirrhotic patients with viral hepatitis, but controversies are still present [4, 5, 7–9]. The available studies have been conducted on adult patients, leaving the early stages of life largely uncovered. We, thus, focused our attention to the BMD measurement in children and adolescents with chronic hepatitis due to HBV and HCV infection, and we hypothesized the presence of a reduced areal BMD in these patients. BMD changes remarkably during growth, and changes are not only a function of age, but they occur at different times in girls and boys [10]. For this reason, we examined a large sample of healthy children and adolescents, and we compared their measurements to those of patients with viral hepatitis, correcting for the effects of confounding variables. Our study showed that young patients with chronic HBV infection have BMD measurements not significantly different from those of healthy controls at both skeletal sites. Similarly, patients with HCV infection had BMD measurements comparable with those of healthy subjects. This finding could be due to the general good health of our patients, despite the high median viral replication and altered AST and ALT values found: in fact all patients did not receive antiviral treatment at the time of the study. Treatment options of pediatric patients are limited and restricted to patients with advanced disease. Currently, only combination treatment with pegylated interferon (PEG-IFN) and ribavirin can be used to treat HCV in children. However, PEG-IFN has adverse effect on growth in children, and should be avoided during growth spurts. New direct-acting antiviral agents against HCV have been approved for treatment of liver disease in adults, and phase I and II trials of many other new compounds are underway. For HBV infection, there is no established benefit of treatment of children and there is a very high risk of development of drug resistance. Interferon is the agent of choice, while nucleoside and nucleotide analogs (lamivudine, tenofovir) are secondary therapies, and children who receive these agents require monitoring for development of resistance. The current study has several limitations. The results may be taken as preliminary evidence, due the small number of patients in each group. The wide age range may be also a problem in the interpretation of the results. To address this problem, we studied a large group of healthy subjects covering the age range of the patient with viral hepatitis. Finally, the cross-sectional design of the study does not allow any inference on the evolution of the BMD measurements in HBV- and HCVinfected youths. Longitudinal surveys may help to address this issue. Nevertheless, this is the first study describing the bone mass in young patients with viral hepatitis.
S. Mora et al.: Areal Bone Mineral Density in Pediatric Patients
In conclusion, our data suggest that bone mineral measurements of children and adolescents with chronic HBV and HCV may not be different to those of healthy subjects. However, due to the small number of subjects, further studies are needed to confirm our results, and to elucidate the evolution of bone mass during growth in these patients. Human and Animal Rights and Informed Consent statements All procedures followed were in accordance with the ethical standards of the responsible institutional committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all parents and legal guardians of the patients for being included in the study.
221
5.
6.
7.
8.
9.
References 1. Rouillard S, Lane NE (2001) Hepatic osteodystrophy. Hepatology 33:301–307 2. Global surveillance and control of hepatitis C (1999). Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat 6: 35–47 3. Han S-HB (2004) Extrahepatic manifestations of chronic hepatitis B. Clin Liver Dis 8:403–418 4. Schiefke I, Fach A, Wiedmann M et al (2005) Reduced bone mineral density and altered bone turnover markers in patients
10. 11.
12.
with non-cirrhotic chronic hepatitis B or C infection. World J Gastroenterol 11:1843–1847 Yenice N, Gu¨mrah M, Mehtap O, Kozan A, Tu¨rkmen S (2006) Assessment of bone metabolism and mineral density in chronic viral hepatitis. Turk J Gastroenterol 17:260–266 George J, Ganesh HK, Acharya S et al (2009) Bone mineral density and disorders of mineral metabolism in chronic liver disease. World J Gastroenterol 15:3516–3522 Lin J-C, Hsieh T-Y, Wu C-C et al (2012) Association between chronic hepatitis C virus infection and bone mineral density. Calcif Tissue Int 91:423–429 Gaudio A, Pennisi P, Muratore F et al (2012) Reduction of volumetric bone mineral density in postmenopausal women with hepatitis C virus-correlated chronic liver disease: a peripheral quantitative computed tomography (pQCT) study. Eur J Intern Med 23:656–660 Pelazas-Gonza´lez R, Gonza´lez-Reimers E, Alema´n-Valls MR et al (2013) Bone alterations in hepatitis C virus infected patients. Eur J Intern Med 24:92–96 Mora S, Gilsanz V (2003) Establishment of peak bone mass. Endocrinol Metab Clin N Am 32:39–63 Cacciari E, Milani S, Balsamo A et al (2006) Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest 29:581–593 Guichelaar MMJ, Kendall R, Malinchoc M, Hay JE (2006) Bone mineral density before and after OLT: long-term follow-up and predictive factors. Liver Transpl 12:1390–1402
123
