1138 BONE BIOPSY AND VITAMIN D IN PRIMARY BILIARY CIRRHOSIS THAT bone and calcium metabolism may be disordered in cholestatic liver disease is well-known. Osteoporosis has been thought commoner than osteomalacia, although the two conditions often coexist. Thus Kehayglou’ reported radiological evidence of demineralisation in 10 out of 12 patients with primary biliary cirrhosis, while histological evidence of osteomalacia was present in only 1. However, Long et at2 now report a surprisingly high (75%) incidence of osteomalacia in this condition, while 50% had osteoporosis. In both these series the diagnosis was made by bone biopsy with quantititive estimation of osteoid volume. Histological assessment is essential because in most patients with metabolic bone disease osteoporosis cannot be distinguished radiologically from osteomalacia. Elaborate radiological methods such as proton absorption bone densitometry are of little help. Likewise, biochemical estimations of the serum calcium, phosphate, and alkaline phosphatase are poor discriminators.2 Histological examination should be done on non-decalcified sections, and if the patient has been given time-spaced tetracycline markers that combine with calcium and fluoresce, bone kinetics will be quantifiable from the calcification fronts in a single section.3 Histological diagnosis of osteomalacia requires demonstration of both excess osteoid and a reduction in calcification fronts, since excess osteoid alone can arise in any condition associated with increased bone turnover. With respect to osteoporosis, the histological diagnosis is difficult and unreliable because of the patchy skeletal distribution of the lesion and the very large variation in bone volume seen even in normal subjects. However, a diagnosis of osteoporosis may be presumed when radiological bone density is reduced and osteomalacia is "absent in bone sections". The aetiology of hepatic osteodystrophy (including both osteoporosis and osteomalacia) is multifactorial. Decreased bile-salt secretion into the gut lumen results in impaired absorption of fat-soluble vitamin D,4,5and hence in subnormal absorption of calcium and phosphate from the gut. Calcium absorption is further diminished by excess non-absorbed fat in the gut, which causes precipitation of insoluble calcium salts.5 Parenteral vitamin D corrects the absorptive defect for calcium in primary biliary cirrhosis, although the doses are greater than those required for correction of nutritional vitamin-D deficiency in patients with normal liver function.5 This relative resistance to parenteral vitamin D led investigators to believe that malabsorption was not the sole cause of its reduced effectiveness. One of the most interesting developments of the past decade has been the realisation that physiological functioning of vitamin D depends on hydroxylation in the liver to 25 (OH)D6 and subsequently in the kidney to 1,25 (OH)2D.7 In primary biliary cirrhosis (P.B.C.) several groups have shown that 25(OH)D levels are 1. Kehayglou, A. K., Holdsworth, C. D., Agnew, J. E., Whelton, M. J., Sherlock, S. Lancet, 1968, i, 715. 2. Long, R. G., Meinhard, E., Skinner, R. K., Varghese, Z., Wills, M. R., Sherlock, S. Gut, 1978, 19, 85. 3. Frost, H. M. Calcif. Tissue Res. 1969, 3, 211. 4. Krawitt, E. L., Groundman, M. J., Mawer, E. B. Lancet, 1977, ii, 1246. 5. Whelton, M. J., Kehayglou, A. K., Agnew, J. E., Turnberg, L. A., Sherlock, S. Gut, 1971, 12, 978. 6. Pouchon, G., Kennan, A. L., De Luca, H. F. J. clin. Invest. 1969, 48, 2032. 7. Fraser, D. R., Kodicek, E. Nature, 1970, 228, 764. 8. Wagonfeld, J. B., Nemchausky, B. A., Bolt, M., Vander Horst, J., Boyer, J. L., Rosenberg, I. H. Lancet, 1976, i, 391.
reduced .8—10 Short
courses
of oral
or
parenteral vitamin
25(OH)D levels or improve skeletal demineralisation.8 However, the suggestion that impaired hepatic hydroxylation rather than malabsorption was the major factor underlying failure with conventional vitamin-D therapy in P.B.C.8 was not borne out in the most recent work.4 If vitamin D is given parenterally for long enough and in big enough doses (i.e., 100 000 i.u. monthly) patients with P.B.C. may attain 25 (OH)D levels in the normal range.9Moreover there is preliminary evidence that histological osteomalacia may be reversed with such treatment." Arnaud and associates have lately shown12 that 25(OH)D undergoes an enterohepatic circulation. One-third of an intravenous dose of 25(OH)D, was secreted into the duodenum in 24 h and a quarter of this amount was subsequently reabsorbed by the ileum. It is possible that cholestyramine, which is frequently prescribed for the relief of pruritus in primary biliary cirrhosis, and to which substances such as vitamin D are known to bind, may interfere with the enterohepatic circulation of 25(OH)D, thus depleting already limited body stores. 13,14 At present, there is little justification to recommend switching from the standard vitamin D preparation to expensive synthetic analogues such as locOHD3 or 25 (OH)Dy The results in Long’s paper2 suggest that the recommended parenteral prophylactic dose of 100 000 i.u. monthly may be insufficient, since many of his patients with osteomalacia were receiving that amount regularly. However, patient compliance is important and care should be taken that they actually receive the parenteral vitamin D prescribed. Furthermore, caution is necessary where patients are receiving agents such as cholestyramine which may bind vitamin D in the gut, or drugs known to induce hepatic microsomal enzymes such as spironolactone or phenobarbitone, both of which are prescribed to patients with P.B.c. (the former for fluid retention and the latter for pruritus). These agents impair the efficiency of vitamin D by conversion to nonbiologically active derivatives.15 In such patients the dose should be increased to 150 000 i.u. monthly. When response to parenteral vitamin D is assessed in a histologically proven case of osteomalacia, it is important to remember that radiological evidence of skeletal demineralisation will not be lessened if osteoporosis is also present. In cases which show no symptomatic or radiological response to vitamin D, a repeat bone biopsy may be indicated. If this reveals persistence of osteomalacia there is some evidence that synthetic analogues such as 25(OH)D38,11 may help. Finally, with respect to the treatment of osteoporosis in primary biliary cirrhosis, the aetiology of which remains obscure but is probably multifactorial, vitamin D in combination with calcium and fluoride may be worthy of trial. 16 These agents have some value in the treatment of postmenopausal osteoporosis, and this condition may well accompany primary biliary cirrhosis, most patients being of the right agegroup and sex. D do not increase
serum
9. Skinner, R. K., Long, R. G., Sherlock, S., Wills, M. R. ibid. 1977, i, 720. 10. Long, R. G., Skinner, R. K., Wills, M. R., Sherlock, S. ibi d. 1976, ii, 650. 11. Compston, J., Horton, L. W. L., Thompson, R. P. H. Gut (m the press). 12. Arnaud, S. B., Goldsmith, R. S., Lambert, P. W. Proc. Soc. exp. Biol. Med. 1975, 149, 570. 13. Thompson, W. G., Thompson, G. R. Gut, 10, 717. 14. Compston, J. E., Thompson, R. P. H. Lancet, 1977, i, 721. 15. Richens, A. in Anticonvulsant Drugs and Enzyme Induction (edited by A. Richens and F. Peter Woodford); p. 3. Amsterdam, 1976. 16. Jowsey, J., Riggs, B. L., Kelly, P. J. Am. J. Med. 1972, 53, 43.
reduced .8—10 Short
courses
of oral
or
parenteral vitamin
25(OH)D levels or improve skeletal demineralisation.8 However, the suggestion that impaired hepatic hydroxylation rather than malabsorption was the major factor underlying failure with conventional vitamin-D therapy in P.B.C.8 was not borne out in the most recent work.4 If vitamin D is given parenterally for long enough and in big enough doses (i.e., 100 000 i.u. monthly) patients with P.B.C. may attain 25 (OH)D levels in the normal range.9Moreover there is preliminary evidence that histological osteomalacia may be reversed with such treatment." Arnaud and associates have lately shown12 that 25(OH)D undergoes an enterohepatic circulation. One-third of an intravenous dose of 25(OH)D, was secreted into the duodenum in 24 h and a quarter of this amount was subsequently reabsorbed by the ileum. It is possible that cholestyramine, which is frequently prescribed for the relief of pruritus in primary biliary cirrhosis, and to which substances such as vitamin D are known to bind, may interfere with the enterohepatic circulation of 25(OH)D, thus depleting already limited body stores. 13,14 At present, there is little justification to recommend switching from the standard vitamin D preparation to expensive synthetic analogues such as locOHD3 or 25 (OH)Dy The results in Long’s paper2 suggest that the recommended parenteral prophylactic dose of 100 000 i.u. monthly may be insufficient, since many of his patients with osteomalacia were receiving that amount regularly. However, patient compliance is important and care should be taken that they actually receive the parenteral vitamin D prescribed. Furthermore, caution is necessary where patients are receiving agents such as cholestyramine which may bind vitamin D in the gut, or drugs known to induce hepatic microsomal enzymes such as spironolactone or phenobarbitone, both of which are prescribed to patients with P.B.c. (the former for fluid retention and the latter for pruritus). These agents impair the efficiency of vitamin D by conversion to nonbiologically active derivatives.15 In such patients the dose should be increased to 150 000 i.u. monthly. When response to parenteral vitamin D is assessed in a histologically proven case of osteomalacia, it is important to remember that radiological evidence of skeletal demineralisation will not be lessened if osteoporosis is also present. In cases which show no symptomatic or radiological response to vitamin D, a repeat bone biopsy may be indicated. If this reveals persistence of osteomalacia there is some evidence that synthetic analogues such as 25(OH)D38,11 may help. Finally, with respect to the treatment of osteoporosis in primary biliary cirrhosis, the aetiology of which remains obscure but is probably multifactorial, vitamin D in combination with calcium and fluoride may be worthy of trial. 16 These agents have some value in the treatment of postmenopausal osteoporosis, and this condition may well accompany primary biliary cirrhosis, most patients being of the right agegroup and sex. D do not increase
serum
9. Skinner, R. K., Long, R. G., Sherlock, S., Wills, M. R. ibid. 1977, i, 720. 10. Long, R. G., Skinner, R. K., Wills, M. R., Sherlock, S. ibi d. 1976, ii, 650. 11. Compston, J., Horton, L. W. L., Thompson, R. P. H. Gut (m the press). 12. Arnaud, S. B., Goldsmith, R. S., Lambert, P. W. Proc. Soc. exp. Biol. Med. 1975, 149, 570. 13. Thompson, W. G., Thompson, G. R. Gut, 10, 717. 14. Compston, J. E., Thompson, R. P. H. Lancet, 1977, i, 721. 15. Richens, A. in Anticonvulsant Drugs and Enzyme Induction (edited by A. Richens and F. Peter Woodford); p. 3. Amsterdam, 1976. 16. Jowsey, J., Riggs, B. L., Kelly, P. J. Am. J. Med. 1972, 53, 43.
