What is the pathophysiology of liver transplantation-related osteoporosis?

Updated: Jul 02, 2020
  • Author: Carmel M Fratianni, MD, FACE; Chief Editor: George T Griffing, MD  more...
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A minority of patients awaiting liver transplantation have normal bone density. In a large series of 243 consecutive patients undergoing evaluation for liver transplantation, only 15% had normal bone density. [22] Moreover, vertebral fractures were present in 35% of patients prior to transplantation in this same population. [23]

End-stage liver disease (ESLD) itself is associated with osteoporosis. Vitamin D deficiency is extremely common among patients with cirrhosis who are awaiting transplant. Cirrhosis is associated with significantly depressed levels of 25-hydroxyvitamin D-3, 1,25-dihydroxyvitamin D, osteocalcin, and PTH. [24] Cirrhosis is also associated with low osteocalcin levels and with histomorphometric evidence of decreased bone formation.

In chronic liver disease, low vitamin D levels predict bone loss. [25] In one study of 27 patients awaiting orthotopic liver transplantation, 74% had subnormal 25-hydroxyvitamin D levels at baseline. Vitamin D levels were inversely associated with more advanced Child-Pugh classification, and more advanced Child-Pugh class is associated with increased bone loss at the LS spine. [26]

Chronic obstructive liver disease may interfere with the enterohepatic circulation of vitamin D metabolites. The cholestasis observed in persons with primary biliary cirrhosis (PBC) may inhibit normal osteoblast function by an uncertain mechanism, resulting in a low bone turnover osteoporosis. Although the specific pathophysiological mechanisms in PBC have not been defined, histomorphometry findings reveal depressed bone formation and inactive remodeling. [27, 28]

Polymorphism in the gene encoding collagen type I alpha1 (COLA1) Sp1 is a recently recognized genetic predictor of peak bone mass. Not surprisingly, COLA1 has been found to be a marker of bone mass in patients with PBC, although the degree of cholestasis remains the more important risk factor for osteoporosis. [29]

Along the same line, allelic polymorphism of the vitamin D receptor is also thought to be predictive of BMD in healthy patients and in patients with primary osteoporosis. The vitamin D receptor genotype influences bone loss after liver transplantation and also predicts lower BMD in patients with PBC. Specifically, the bb genotype is partially protective against posttransplant bone loss. [30, 31]

In general, more severe liver disease and more severe cholestasis are associated with more severe bone loss. [32] In fact, bone loss was predicted by the degree of hyperbilirubinemia in a Swedish study. [26] Cholestasis-related osteopenia appears to be more severe than osteopenia associated with viral liver disease. In one cross-sectional study, BMD z scores were more than twice as depressed in cholestatic patients than in patients with viral liver disease, although viral liver disease is itself associated with significant osteopenia. [33]

In a study of 32 consecutive viral cirrhotic patients in whom alcoholism had been excluded, Gallego-Rojo et al found reduced BMD at all sites measured, and established osteoporosis in 53% of patients. Serum immunoglobulin F-1 levels were lower in viral cirrhotic subjects than in control subjects, and levels differed significantly between cirrhotic patients with and without osteoporosis. Therefore, low immunoglobulin F-1 levels may play a role in osteopenia associated with viral cirrhosis. [33, 34]

Alcohol abuse is a well-known cause of cirrhosis; it is also a well-known risk factor for osteoporosis, which is likely multifactorial in origin. Malnutrition and chronic pancreatitis are common in persons with alcoholism and are frequently associated with concomitant vitamin D and magnesium depletion. [35, 36] In humans, magnesium deficiency is known to result in hypocalcemia, impaired PTH secretion, and low serum concentrations of 1,25-dihydroxyvitamin D. [37] Ultimately, alcohol itself may directly suppress bone formation, as evidenced by a direct correlation between bone GLA protein levels and days of abstinence from alcohol. [38]

Hypogonadism is a known risk factor for osteopenia and occurs frequently in persons with alcoholism and ESLD. Both low testosterone and high sex hormone–binding globulin levels correlate with worsening Child-Pugh classification.

Monegal et al have documented osteoporosis in 43% of cirrhotic patients at the time of referral for liver transplantation. In the first year post transplantation, bone mass declined further, with LS spine BMD falling 3.5-24%. [24, 39] By 3 years after liver transplantation, a third of the patients developed fractures. In this cohort, age and low bone mass were identified as pretransplant risk factors for fracture.

As with cardiac transplantation, the highest fracture incidence rate occurs in the first year following liver transplantation. Estimates range from 24-65%, with the highest rate being reported in women with PBC. In a study of women with PBC by Eastell et al, BMD at the LS spine was inversely related to the severity of liver disease. The overall rate of bone loss in half the patients with PBC was twice that of healthy controls. Following liver transplantation, BMD in the LS spine fell at 3 months and was associated with atraumatic fractures in 13 of 20 women. [32]

Histomorphometric analysis of transiliac bone biopsy specimens prior to and 3 months after liver transplantation in 21 patients with chronic liver disease demonstrated a highly significant and quantitatively large increase in bone turnover within the first 3 months after liver transplantation. The bone turnover rate was low preoperatively, with thinner walls and erosion depth. The bone formation rate increased after transplantation. A small increase in osteoid seam width was noted postoperatively, with a decrease in the mineralization lag time. [40]

A high incidence of vertebral fracture in the first 3 months after liver transplantation is well recognized. As in other cohorts, prevalent vertebral fracture pretransplant is an important risk factor for the subsequent development of fracture in the liver transplant population. [23]

Significant recovery of BMD following transplantation was noted in this population. By 12 months, the median BMD at the LS spine was similar to the pretransplantation BMD; by 24 months, BMD was actually 5% higher than the pretransplant baseline. Bone mass may return to normal within 2-3 years following liver transplant. [32]

Several other studies have reported some long-term recovery of BMD in the liver transplant population. In a Dutch cohort treated with a prednisolone- and azathioprine-based immunosuppressant regimen and with follow-up care extending to 5-15 years, improvement in BMD was mainly observed in the second postoperative year, with stabilization thereafter. [41] Despite this interval improvement, approximately one third of patients were left with a BMD below the fracture threshold. In general, the outcome was less favorable in men than in women and in patients who received transplants for cholestatic liver disease, who may initially have had more severe bone disease. [41]

Not all series have demonstrated recovery and stabilization of BMD following liver transplantation, and some show continued decline. [33]

The most common sites to fracture in the liver transplant recipient are the vertebrae and ribs. In a prospective study by Ninkovic et al in 37 patients with ESLD, vertebral fractures were evident in 35% of patients before transplantation, and new fractures developed by 3 months after transplantation in 27%. [23] Although osteoporosis (defined as a t score < -2.5) was found in 39% of patients prior to transplantation, BMD did not reliably predict fracture risk. However, subsequent vertebral fractures were significantly more common in those with a prevalent vertebral fracture.

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