Risk factors associated with hepatic osteopathy in HBV related cirrhosis measured by liver stiffness: An Observational study.

To investigate the differences in bone mineral density between patients with liver cirrhosis and healthy control, and to analyze the risk factors of hepatic osteoporosis in patients with HBV related liver cirrhosis.A total of 189 patients with liver cirrhosis and 207 health controls were enrolled. The bone mineral density of lumbar spine and femoral neck was examined by dual energy X-ray absorptiometry. -2.0 <T value <-1.0 defined as osteopenia, T value ≤-2.0 defined as osteoporosis.Bone mineral density in the cirrhotic group was significantly lower than that in the control group (lumbar: 1.02 ± 0.16 vs 1.08 ± 0.13, P < .001; femoral neck: 0.86 ± 0.14 vs 0.91 ± 0.14, P < .001). Both 2 groups showed a tendency that decrease bone density correlated with age and decrease body mass index (BMI). Multivariate correlation analysis showed that women (OR = 6.931, P = .002), age (OR = 1.096, P < .001), low BMI (OR = 0.874, P = .037), and high liver stiffness value (OR = 1.125, P = .046) were independent risk factors for osteopenia and low body weight (OR = 0.934, P = .006) and high liver stiffness value (OR = 1.246, P = .034) were independent risk factors for osteoporosis.Our study shows that bone mineral density in patients with liver cirrhosis decreased significantly, especially in the elderly and low BMI patient. For HBV-related cirrhosis with risk factors, a regular bone density screening should be given, and timely intervention should be taken into consideration.

Introduction

It is estimated that 240 million people are chronically infected with hepatitis B virus (HBV) worldwide.[ In Asia-Pacific region, such as China, Japan and South Korea accounts for nearly 50% of chronic hepatitis B (CHB) patients worldwide.[ Patients with chronic HBV infection have an increased risk of many diseases, including cirrhosis, liver failure, and hepatocellular carcinoma.[ Hepatic related osteopathy is one of the complications of chronic infection with HBV. Hepatic osteopathy including hepatic osteopenia and hepatic osteoporosis. Hepatic osteoporosis can lead to a decrease in Bone mineral density, which increases the risk of fracture. Hepatic osteoporosis and its related fractures reduce the quality of life and prognosis of patients with CHB related cirrhosis.

Although study reported before found that chronic liver disease is closely related to hepatic related osteopathy. The pathophysiological mechanism and risk factors are still not fully recognized.[ Since the best strategy for hepatic related osteopathy is early diagnosis and intervention. A comprehensive and systematic analysis of the risk factors for hepatic osteopathy in patients with CHB related cirrhosis is needed to effectively screen high-risk patients for early treatment to prevent fractures, thereby improving the quality of life and prognosis of patients.[

In our study, a retrospective cohort was conducted and used to analyze the bone mineral density (BMD) of patients with CHB related cirrhosis and healthy controls. We also analyzed the risk factors associated with hepatic osteopathy, thereby to provide evidences of prevention and management of hepatic related osteopathy.

Subjects and methods

Subjects

All patients were enrolled at the Shandong Provincial Qianfoshan Hospital between August 2015 and September 2017. A total of 396 patients were enrolled. Among them, there are 189 patients diagnosed with CHB related cirrhosis (Cirrhosis group) and 207 as health control (Controls group). The criteria for enrollment in the cirrhosis group were as follows:

The diagnostic criteria for CHB was that HBsAg persisted positive for more than 6 months [;

Patients diagnosed as CHB-associated cirrhosis with Child-Pugh Stage A.[

Patients were excluded if:

Patient with HCV/HIV infection, or other chronic liver disease, such as hepatolenticular degeneration, alcoholic liver disease, cholestatic liver disease;

Patients with long-term use of glucocorticoids;

Patients are receiving anti-osteoporosis drugs.

Bone mineral density assessment

The BMD of the lumbar spine and hip was measured using a Discovery A dual-energy X-ray absorptiometry (Hologic, US). The testing process is carried out by a professional physician. All subjects were examined for BMD using a uniform position to minimize the interference of individual position. According to the WHO diagnostic criteria, −2.0 < T value < −1.0 is defined as osteopenia, and T value ≤ −2.0 is defined as osteoporosis. Hepatic related osteopathy is defined as the presence of cirrhosis-related osteopenia or osteoporosis.

Liver stiffness measurement

All patients enrolled in our study were HBV related cirrhosis diagnosed by liver stiffness >12 Kpa.[ The value of liver stiffness was measured by Fibroscan (Echosens Corp., Paris, France). A total of 10 measurements were carried out, and the liver stiffness value was record only if the interquartile range did not exceed 40% in any of the measurements. The results were expressed in kilopascals. The median value was taken as representative.

Statistical analysis

In this study, the continuous variables are expressed as the mean ± standard deviation (SD), and the categorical variables are expressed as a percentage. The χ2 test and the t test were used to detect whether the 2 sets of data were statistically different. One-way ANOVA was used to detect whether there was a statistical difference in clinical characteristics between the 3 groups of patients with cirrhosis. Univariate and multivariate analysis were used to explore the risk factors associated with the hepatic osteopathy. The data analysis and quality control were assessed by SPSS for windows, version 13.0.

Results

Demographic data

A total of 396 patients were included, including 189 in the cirrhosis group. The average age is 56.89 ± 10.26 years old. The control group consisted of 207 people with an average age of 56.67 ± 9.45 years. The range of liver stiffness among all the patients were 4.92 to 24.59 Kpa. There was no significant difference in sex and age between the 2 groups. There was no statistical difference in age, height, weight, and body mass index (BMI) between the 2 groups. The BMD of patients with cirrhosis was significantly lower than that of the control group (spine: 1.02 ± 0.16 vs 1.08 ± 0.13, P < .001; hip: 0.86 ± 0.14 vs 0.91 ± 0.14, P < .001). As shown in Table 1.

Table 1

Characteristics of cirrhosis group and health control group.

Sub-population analysis of BMD among CHB patients with cirrhosis

The sub-population analysis of BMD is shown in Figure 1.

Figure 1

Sub-analysis of BMD among CHB patients with cirrhosis and controls. Spine (A): 1.05 ± 0.16 in cirrhosis group vs 1.07 ± 0.12 in controls (Male, P < .001); 0.92 ± 0.13 in cirrhosis group vs 1.02 ± 0.13 in controls (Female, P < .001); 1.09 ± 0.19 in cirrhosis group vs 1.12 ± 0.10 in controls (Age <40 years, P < .001); 1.04 ± 0.16 in cirrhosis group vs 1.06 ± 0.11 in controls (40 < Age < 60 years, P < .001); 0.99 ± 0.16 in cirrhosis group vs 1.04 ± 0.13 in controls (Age >60 years, P < .001); 0.89 ± 0.13 in cirrhosis group vs 1.00 ± 0.12 in controls (BMI <18, P = .001); 1.02 ± 0.16 in cirrhosis group vs 1.06 ± 0.12 in controls (18 < BMI < 24, P < .001); 1.03 ± 0.15 in cirrhosis group vs 1.07 ± 0.11 in controls (BMI >24, P < .001). Hip (B): 0.88 ± 0.15 in cirrhosis group vs 0.93 ± 0.11 in controls (Male, P < .001); 0.80 ± 0.10 in cirrhosis group vs 0.89 ± 0.11 in controls (Female, P < .001); 0.95 ± 0.10 in cirrhosis group vs 1.01 ± 0.12 in controls (Age <40 years, P < .001); 0.89 ± 0.14 in cirrhosis group vs 0.93 ± 0.12 in controls (40 < Age < 60 years, P < .001); 0.81 ± 0.14 in cirrhosis group vs 0.90 ± 0.09 in controls (Age >60 years, P < .001); 0.78 ± 0.13 in cirrhosis group vs 0.91 ± 0.14 in controls (BMI <18, P = .001); 0.85 ± 0.14 in cirrhosis group vs 0.92 ± 0.09 in controls (18 < BMI < 24, P < .001); 0.89 ± 0.14 in cirrhosis group vs 0.93 ± 0.11 in controls (BMI >24, P < .001). BMI, body mass index; BMD, bone mineral density.

Sex: the bone density of male patients is higher than that of female patients regardless patients were in the cirrhosis group or in the control group. When we compared the BMD of the cirrhosis group with control group, we observed that the BMD of the control group was higher than that of the cirrhosis group except for the lumbar spine BMD of the male patient.

Age: Both the cirrhosis group and control group showed a trend of decreasing BMD with age. However, when the cirrhosis group was compared with the control group, there was no statistical difference in BMD between the 2 groups when the patient was <40 years old. However, when the patient was >60 years old, the bone density of the cirrhosis group was significantly lower than that of the control group.

BMI: Both the cirrhosis group and the control group showed an increase in BMD with an increase in BMI. The comparison between the cirrhosis group and the control group indicated that when BMI <18, the BMD of patients with cirrhosis was significantly lower than that of the control group. However, when BMI >24, no statistical difference was found in BMD between the 2 groups.

Differences in CHB related cirrhosis patients with or without osteopathy

The clinical features of hepatic related osteopathy in patients with CHB related cirrhosis are shown in Table 2. Among them, 62 people were diagnosed with normal BMD, 95 were osteopenia, and 32 were osteoporosis. There were statistical differences in gender distribution, age, height, weight, and BMI between the 3 groups. The proportion of women in osteoporosis group was higher (P < .001), the mean age was longer (P < .001), and the BMI was lower (P = .037).

Table 2

Demographic data in CHB related cirrhosis with hepatic osteopathy.

Risk factors associated with osteopenia among CHB related cirrhosis

Univariable and multivariable analysis were conducted and the results are shown in Table 3. Univariate analysis showed that women, older age, low height, low weight, and low BMI were factors associated with osteopenia in patients with CHB related cirrhosis. However, multivariate analysis showed that only women (OR = 6.931, P = .002), older age (OR = 1.096, P < .001), low BMI (OR = 0.874, P = .037), high liver stiffness value (OR = 1.125, P = .046) were independent risk factors of osteopenia in patients with CHB related cirrhosis.

Table 3

Factors associated osteopenia among patients with CHB related cirrhosis.

Risk factors associated with osteoporosis among CHB related cirrhosis.

We also explore the risk factors for osteoporosis. The results are shown in Table 4. Univariate analysis found that women, low height and low body weight were risk factors of osteoporosis in patients with CHB related cirrhosis. However, multivariate correlation analysis suggested that only low weight (OR = 0.934, P = .006) and high liver stiffness value (OR = 1.246, P = .034) were an independent risk factor for osteoporosis in patients with CHB related cirrhosis.

Table 4

Factors associated osteoporosis with CHB related cirrhosis.

Discussion

Patients chronically infected with HBV have an increased risk of liver fibrosis, cirrhosis and other end-stage liver disease.[ Hepatic related osteopathy is one of the serious complications of patients with CHB related cirrhosis. Rapid loss of BMD in patients with hepatic related osteopathy is the most reliable predictor of late pathological fractures.[ In patients with cirrhosis, once a pathological fracture occurs, it will bring serious adverse prognosis and a decline in quality of life. However, due to the insidious symptoms of hepatic related osteopathy, it is difficult to identify those hepatic osteopathy patients. Previous reports suggested that patients with cirrhosis have a higher prevalence of osteoporosis.[ Low BMD occurs in at least 20% of patients with chronic liver disease.[ The prevalence of osteoporosis in patients with chronic liver disease is 12%5 to 5%.[ Osteoporosis and its related fractures are still common in patients with cirrhosis than in the general population.[ In this study, we demonstrated that the lumbar spine and hip BMD were significantly lower in patients with cirrhosis than in the control population. Especially in elderly and low BMI patients. In addition, our study showed that among the cirrhosis population, women, older age, and low BMI are independent risk factors for osteopenia and low body weight is the independent risk factor for osteoporosis in patients with CHB related cirrhosis. Hence, BMD monitoring should be given timely in those high-risk population and timely intervention should be taken into consideration to reduce the risk of pathological fracture.

Previous studies have reported that age is one of the most important factors associated with bone loss,[ but how age affects bone metabolism is not entirely clear. Genetic factors may play an important role. Epidemiological surveys show that more than 10 million people in the US who are older than 50 have osteoporosis, and about 1.5 million osteoporotic pathological fractures occur each year. In addition, there are 27.6 million people with age-related osteoporosis in Europe, with more than 3.5 million fractures per year.[ The results of this study suggest that aging not only accelerates bone loss in patients with cirrhosis, but also is an independent risk factor for predicting osteopenia in patients with cirrhosis. Low BMI is another risk factor associated with bone loss.[ Weight loss is closely associated with an increased risk of fracture, and weight gain is associated with a reduced risk of hip fracture.[ Based on our findings, we found that bone loss was more severe in patients with low BMI. Low BMI was an independent risk factors for osteopenia in patients with cirrhosis. In addition, low body weight and high liver stiffness value were independent risk factors for osteoporosis in patients with cirrhosis. It suggests that CHB related cirrhosis patients with low BMI and low weight should be given sufficient attention in BMD. Our study also found that patients with higher liver stiffness values are more likely to have hepatic osteopathy. This results suggests, for patients with high liver stiffness values, attention should be paid to BMD. Moreover, our results show that maybe liver stiffness value measured by Fibroscan could be used to predicted decreased BMD among HBV related cirrhosis and be regarded as a monitoring method for bone nutrition among those population.

There are some limitations in this study. First, the sample size is relatively small, so the results may be biased. The data collected in this study came from a single center and may lead to some enrollment bias. A multicenter prospective study is needed for further validate the risk factors in screening and early diagnosis of hepatic osteopathy in CHB related cirrhosis patients.

Author contributions

Conceptualization: Shujuan Cao, Wei Zhang.

Data curation: Shujuan Cao, Wei Zhang, Zengcun Su, Xuping Zhang.

Formal analysis: Wei Zhang.

Investigation: Wei Zhang, Hui Gong, Zengcun Su.

Methodology: Wei Zhang, Hui Gong.

Project administration: Xuping Zhang.

Software: Wei Zhang, Xuping Zhang.

Supervision: Shujuan Cao, Xuping Zhang.

Validation: Shujuan Cao, Hui Gong.

Visualization: Shujuan Cao, Hui Gong, Zengcun Su.

Writing – original draft: Shujuan Cao, Wei Zhang, Zengcun Su, Xuping Zhang.

Writing – review & editing: Shujuan Cao, Zengcun Su, Xuping Zhang.