Primary biliary cirrhosis (PBC) is a liver-specific autoimmune disease that primarily affects women (female-to-male ratio, 10:1) between 40 and 60 years of age. Metabolic bone disease is a common complication of PBC, affecting 14% to 52% of patients, depending on the duration and severity of liver disease. The osteoporosis seen in PBC seems mainly due to low bone formation, although increased bone resorption may contribute. Treatment of osteoporosis consists primarily of antiresorptive agents. Additional large prospective, long-term studies in patients with PBC are needed to determine efficacy in improving bone density as well as reducing fracture risk.
Key points
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Primary biliary cirrhosis (PBC) is a liver-specific autoimmune disease that primarily affects women (female-to-male ratio, 10:1) between 40 and 60 years of age.
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Metabolic bone disease is a common complication of PBC, affecting 20% to 52% of patients, depending on the duration and severity of liver disease.
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The osteoporosis seen in PBC seems mainly due to low bone formation, although increased bone resorption may contribute.
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Treatment of osteoporosis consists primarily of the antiresorptive agents that are typically used to treat postmenopausal patients with osteoporosis without liver disease. Bisphosphonates appear to be the most promising given their efficacy, as well as the lack of potential adverse side effects that are associated with other agents such as HRT.
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Additional large prospective, long-term studies in patients with PBC are needed in order to determine efficacy in improving bone density as well as reducing fracture risk.
Overview of primary biliary cirrhosis
PBC is a liver-specific autoimmune disease that primarily affects women between the ages of 40 and 60 years, although there are rare patients diagnosed in their teens or even into their 90s. Although some epidemiologic studies have reported a rising incidence over the past 2 decades, others report stable numbers. A systematic review of data from Europe, North America, and Australia reports an incidence of 0.9 to 5.8 per 100,000 people. Disease prevalence varies from 1.9 to 40.2 per 100,000 people, depending on geographic location, with increased rates of disease in North America and Northern Europe, likely due to earlier recognition of the disease.
The exact pathophysiology of PBC is unknown, but, as with other autoimmune diseases, both genetic and environmental factors are involved. The prevalence of PBC in first-degree relatives is more than 10 times higher than in the general population. Genetic studies have shown an association between the HLA alleles DRB1*08, DR3, and DPB1*0301 and increased risk of disease, whereas DRB1*11 and DRB1*13 confer protection from PBC. The advent of genome-wide association studies have uncovered many potential pathways affected in PBC, including B-cell function, antigen presentation, and T-cell differentiation. Several potential environmental exposures include various bacteria (in particular, Escherichia coli and Mycobacterium gordonae ), viruses, and toxic compounds, but none is definitive. PBC is characterized by T-cell–mediated inflammation of the intralobular bile duct epithelium, which leads to their damage and subsequent loss. The resultant cholestasis leads to retention of toxic bile acids and eventual cirrhosis.
Approximately 90% to 95% of patients with PBC are women. As with most other autoimmune diseases, the etiology of such female predominance in PBC is unclear; however, based on more recent genetic research, pathogenesis may include a combination of sex hormone abnormalities and X chromosome instabilities and defects. The X chromosome contains genes that control sex hormone levels and that are critical in maintaining immune tolerance. Furthermore, preliminary data have shown there is an increased frequency of X monosomy in the circulating leukocytes of women with PBC compared with controls and that this frequency increases with patient age. Although the relationship between these associations and disease pathogenesis remains to be fully understood, the findings are intriguing.
Patients can present with fatigue and pruritus or they are diagnosed on further investigation of an elevated alkaline phosphatase found on routine liver chemistries. The serologic hallmark of the disease is an elevated antimitochondrial antibody (AMA), which is present in 95% of PBC cases and in less than 1% of the normal population. Liver biopsy is not always required to make the diagnosis if both alkaline phosphatase and AMA levels are elevated, but it would confirm the diagnosis if laboratory tests are inconclusive as well as stage the extent of liver disease.
The only approved treatment of PBC in the United States is ursodeoxycholic acid (UDCA). Treatment response is associated with increased survival and decreased liver transplantation, especially in long-term follow-up of patients with early-stage disease. Proposed beneficial effects of UDCA include its ability to stimulate ductular secretions and to protect against injury from toxic bile acids as well as to down-regulate B cells and AMA production. Response to treatment is measured by improvement in alkaline phosphatase and bilirubin. Normalization of liver tests is seen in just over half of patients at 5 years.
Overview of primary biliary cirrhosis
PBC is a liver-specific autoimmune disease that primarily affects women between the ages of 40 and 60 years, although there are rare patients diagnosed in their teens or even into their 90s. Although some epidemiologic studies have reported a rising incidence over the past 2 decades, others report stable numbers. A systematic review of data from Europe, North America, and Australia reports an incidence of 0.9 to 5.8 per 100,000 people. Disease prevalence varies from 1.9 to 40.2 per 100,000 people, depending on geographic location, with increased rates of disease in North America and Northern Europe, likely due to earlier recognition of the disease.
The exact pathophysiology of PBC is unknown, but, as with other autoimmune diseases, both genetic and environmental factors are involved. The prevalence of PBC in first-degree relatives is more than 10 times higher than in the general population. Genetic studies have shown an association between the HLA alleles DRB1*08, DR3, and DPB1*0301 and increased risk of disease, whereas DRB1*11 and DRB1*13 confer protection from PBC. The advent of genome-wide association studies have uncovered many potential pathways affected in PBC, including B-cell function, antigen presentation, and T-cell differentiation. Several potential environmental exposures include various bacteria (in particular, Escherichia coli and Mycobacterium gordonae ), viruses, and toxic compounds, but none is definitive. PBC is characterized by T-cell–mediated inflammation of the intralobular bile duct epithelium, which leads to their damage and subsequent loss. The resultant cholestasis leads to retention of toxic bile acids and eventual cirrhosis.
Approximately 90% to 95% of patients with PBC are women. As with most other autoimmune diseases, the etiology of such female predominance in PBC is unclear; however, based on more recent genetic research, pathogenesis may include a combination of sex hormone abnormalities and X chromosome instabilities and defects. The X chromosome contains genes that control sex hormone levels and that are critical in maintaining immune tolerance. Furthermore, preliminary data have shown there is an increased frequency of X monosomy in the circulating leukocytes of women with PBC compared with controls and that this frequency increases with patient age. Although the relationship between these associations and disease pathogenesis remains to be fully understood, the findings are intriguing.
Patients can present with fatigue and pruritus or they are diagnosed on further investigation of an elevated alkaline phosphatase found on routine liver chemistries. The serologic hallmark of the disease is an elevated antimitochondrial antibody (AMA), which is present in 95% of PBC cases and in less than 1% of the normal population. Liver biopsy is not always required to make the diagnosis if both alkaline phosphatase and AMA levels are elevated, but it would confirm the diagnosis if laboratory tests are inconclusive as well as stage the extent of liver disease.
The only approved treatment of PBC in the United States is ursodeoxycholic acid (UDCA). Treatment response is associated with increased survival and decreased liver transplantation, especially in long-term follow-up of patients with early-stage disease. Proposed beneficial effects of UDCA include its ability to stimulate ductular secretions and to protect against injury from toxic bile acids as well as to down-regulate B cells and AMA production. Response to treatment is measured by improvement in alkaline phosphatase and bilirubin. Normalization of liver tests is seen in just over half of patients at 5 years.
Bone disease in primary biliary cirrhosis
Hepatic Osteodystrophy
The term, hepatic osteodystrophy , refers to metabolic bone disease that can accompany advanced liver disease, in particular cholestatic liver diseases, such as PBC and primary sclerosing cholangitis, and includes both osteomalacia and osteoporosis ( Table 1 ). Both disorders weaken bones and increase the risk of low-trauma fractures, particularly of the vertebrae, proximal femur, and distal forearms. Osteoporosis is a skeletal bone disorder of decreased bone mass with a normal ratio of mineral and osteoid matrix, whereas osteomalacia causes softening of the bone because of defective mineralization of newly formed osteoid, which results in a decreased ratio of mineral to osteoid matrix.
| Definition | Pathogenesis/Diagnosis | Treatment | |
|---|---|---|---|
| Hepatic osteodystrophy |
| — | — |
| Osteomalacia |
|
| High-dose vitamin D and calcium supplementation |
| Osteoporosis |
|
| See Table 2 |
Osteomalacia
Osteomalacia, or decreased bone mineralization, is not as common as osteoporosis in patients with PBC and is usually associated with vitamin D deficiency, which can arise in the setting of cholestasis and fat malabsorption. Other laboratory findings include low or low-normal calcium and phosphate and high parathyroid hormone (PTH) levels. As with those with osteoporosis, patients can present with pain, fragility fractures, and similar abnormal imaging characteristics. Patients with osteomalacia also can have muscle wasting, weakness, and pain with movement. High PTH with low levels of phosphate and vitamin D are thought to contribute to the myopathy. Definitive diagnosis is made by bone biopsy, but clinical diagnosis is often used when blood work reveals low 25-hydroxyvitamin levels (<20 ng/mL) and high PTH levels. Treatment consists of repletion of 25-hydroxyvitamin D with calcium and high doses of vitamin D 2 or vitamin D 3 at 50,000 IU once to twice per week for 6 to 8 weeks. Ongoing daily supplementation at lower doses should be continued indefinitely because patients with PBC and cholestasis continue to be at risk for recurrent deficiency.
Osteoporosis
Background
Osteoporosis is the most common bone disease and currently affects more than 10 million people in the United States. It is characterized by decreased cortical bone mass as well as deterioration of the trabecular bone architecture, both of which reduce bone strength and increases risk of fracture. Low-trauma or fragility fractures are responsible for more than 400,000 hospitalizations and approximately 200,000 nursing home admissions annually in the United States. Hip fractures, in particular, account for 14% of all fractures and 72% of the fracture costs. They increase 1-year mortality by 10% to 20%; 20% of patients require long-term nursing home care and only 40% regain independence after a hip fracture. Bone densitometry measures bone mass, which is the best predictor of bone strength. The gold standard of bone mineral density (BMD) measurement technology is dual-energy x-ray absorptiometry (DXA). Because bone density in the general population follows a bell-shaped curve, DXA results are reported as a z score, which is the number of SDs either above or below that of age-matched controls, and the T-score is the number of SDs above or below the mean of a young adult population. The World Health Organization defines osteoporosis in postmenopausal women and men above age 50 years as BMD at the proximal femur or spine that is greater than or equal to 2.5 SDs below the mean normal young adult reference population (T score <−2.5). Osteopenia is defined as a T score between −1 SD and −2.5 SDs. For premenopausal patients and men below the age of 50 years, osteoporosis is defined as a z score of greater than or equal to −2.0 SDs below the mean of an age-matched population.
Osteoporosis is a common complication of PBC that affects between 20% and 52% of patients, depending on the characteristics of the study population (gender, age, and PBC stage) as well as the diagnostic criteria for osteoporosis (based on z score or T score). The incidence of osteoporosis increases as the liver disease progresses; only approximately 20% of patients with advanced PBC have normal BMD. The prevalence of osteoporosis in patients with PBC increases with female gender, age, postmenopausal state, body mass index less than 19 kg/m 2 , increased severity of liver disease, and advanced fibrosis on liver biopsy. Overall, 7% to 14% of patients with PBC sustain fractures and this risk rises to 20% in patients with end-stage PBC. Because the estrogen deficiency in menopause is a well-known risk factor of osteoporosis and PBC is primarily a disease of postmenopausal women, there has been some speculation about whether PBC specifically increases the risk of osteoporosis. Patients with PBC are 4 times more likely to have osteoporosis and are twice as likely to sustain a fracture compared with age-matched controls, confirming the association between liver disease and osteoporosis. More recent data suggest that the overall prevalence decreased from 57% to 26% in PBC patients awaiting transplant from 1985 to 1989 versus 1996 to 2000, respectively, likely related to improved nutrition as well as earlier recognition and treatment of PBC.
Pathogenesis in Primary biliary cirrhosis
Normal bone metabolism consists of continuous remodeling that requires a fine balance between osteosynthesis carried out by osteoblasts and osteoclast-driven bone resorption. This remodeling is largely controlled by a trimolecular complex comprised of osteoprotegerin (OPG), the receptor activator of nuclear factor κB ligand (RANKL), and RANK. RANKL is located on osteoblast membranes and its binding with RANK strongly activates osteoclast activity and therefore bone resorption. OPG, produced by the liver, can bind to RANKL to inhibit the binding of RANK and prevent osteoclast maturation and activation. Bone metabolism changes significantly in women in the perimenopausal period when estrogen levels decline significantly; specifically, estradiol levels fall by 85% to 90%, causing accelerated bone loss of up to 30% in the 6-year to 10-year menopausal transition. Estrogen is known to greatly influence bone metabolism by inhibiting osteoclast activity by increasing the expression of OPG and inducing osteoclast apoptosis.
The exact mechanism of osteoporosis in PBC is not completely understood, but there is evidence that hormone balance, genetics, and cholestasis may contribute. There has been conflicting evidence as to whether PBC-related osteoporosis results from diminished bone formation, which is a low-turnover state, or from increased bone resorption, which is a high-turnover state. The mechanism may differ as the liver disease progresses and there may be gender-related differences in bone metabolism in PBC, making it difficult to clearly define the pathogenesis. For example, bone biopsies in patients with advanced cholestatic liver disease had evidence of decreased bone formation ; however, 1 study showed that only the women were more likely to also have markers of increased bone resorption, including increased osteoclast numbers and eroded bone surfaces whereas the men did not. This difference cannot necessarily be explained by estrogen effects, because premenopausal women had similarly severe abnormalities as postmenopausal women. Additionally, levels of the liver-derived protein OPG can decrease as liver dysfunction worsens, which can then prevent the inhibition of osteoclast activity and, therefore, increase bone resorption. In theory, calcium or vitamin D deficiencies could develop in the setting of decreased bile salt flow in advanced cholestasis, leading to secondary hyperparathyroidism and, finally, increased osteoclast bone resorption. There are no definitive data, however, to support this given that patients with PBC osteoporosis often have normal levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D ; additionally, complete vitamin D repletion did not have a significant impact on BMD in PBC patients with osteoporosis.
Alternatively, there is more evidence that bone formation can be diminished, leading to low-turnover osteoporosis. Cirrhosis is associated with the reduction of specific growth factors, such as insulinlike growth factor 1, which impairs osteoblast function and bone formation. Severe cholestasis can allow build-up of lithocholic acid, which inhibits osteoblast activity and can interfere with genetic regulation of bone formation. It can also lead to vitamin K deficiency, which has been shown to impair osteoblast formation and facilitate osteoclast activity in vitro. There is some evidence to suggest that vitamin K repletion can improve BMD, but this study was performed in patients without liver disease.
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