Boneand Mineral, S(1990) 103-108 asevier

103

RAM 00246

Decreased

serum osteocalcin levels in patients with liver cirrhosis

Serum levels of osteocalcin (OC) have been found to be a specific biochemical parameter ofbane formation. We measured serum levels of osteocalcin, panthyroid hormone (PTH) and Vhydroqvitamin D (25(OH)D) in 49 patients with liver cinhosis, who are known to have no mcreased prevalence o: metb bolic bone disease, and i. matched control group (n = 35). Serum levels of OC were signi6cantly decreased in the patients with liver cirrhosis when compared to control subjects (PC O.Wl). Serum levets of 2XOH)D were decreased (P < OS”,,), whereas “ostatisti~at difference was &mdbetween tke senam levels of PM in the patientswith liver &rho& and thaw of the controts. In a ruwoup of 23 patients with cirrhosis of the liver and 34 control subject>. Abebane mineral content (BMC] ofthe mm-dnminant forearm war determined by single ptoton abaorptiometry. Ft%ICwas +qiFfantl~ Iwe~ :II. *‘I* ” . -li..-* rl__. with liver cirrhosis than the control subjects (P < 0.04). Our data demonstratevitamin D deficiency, decreased bone formation and a decreased BMC in patients wth liver cirrhosis.

Key words: Osteocalcin: Bone GLA protein; Lwer cirrhosis; Bone fcrmatmn; Bane densitometry

Patients with chronic liver disease are at increased risk to develop metabolic bone disease [l-4]. The etiology of the osteopathy of patients with chronic liver disease has not been clarified until now; among other EBCSCIvitamin D deficiency, steatarrhoea and calcium malabsorption have been suggested as possible patbogrtnetic factors [5,6]. Correspondence to: Dr P. PietsFhmann, Department gasse 13.1090 Vienna. Austria. 0169-60,90,M)3.5”~

of Medicme Ii, iTnwersny of Vienna, Gtinlue.

,990 Elsevier Ssier.m Publishers B.“. (BiomeduI

Divirion)

104

Osteocalcin (OC, also termed bone Gla protein) is a 49-amino acid bone matrix protein, which is released in the circulation and can be measured by radioimmunoassay [7]. Human OC contains three residues of y-carboxy glutamic acid, an amino acid, the synthesis of which is vitamin K dependent [8]. Serum levels of OC have been found to be a specific biochemical parameter of bone formation [9]. In order to gain further insights into bone metabolism in patients with chronic liver disease it was the aim of our study to estimate bone formation by measuring serum OC levels. In addition we determined serum levels of parathyroid hormone (PTH), Z-hy-

droxyvitamin D (25(OH)D) and the bone mineral content (BMC) in these patients.

Patients and Methods 49 patients with liver cirrhosis (33 males, 16 femabs) were studied. The diagnosis of liver cirrhosis .xas established by history, physical examination and biochemical tests. Histological studies of the liver were availabie in 18 patients. 35 patients had alcoholic cirrhosis, five patients had post-hepatitic cirrhosis (three after hepatitis B, two after hepatitis non-A-non-B), three patients had primary biliary cirrhosis and in six patients the cause of the cirrhosis was unknown. Thirteen patients were classi-

fied as stage A, 21 patients as stage B and 15 patients as stage C according to Child

WI. Clinical characteristics of the patients with liver cirrhosis are given in Table one. No patient received any medication known to inthence bone metaboliem, such as glucocorticoids, estrogens or fluorides. At the time of the present study no patient was actively drinking alcohol. Thirty-five healthy subjects (mean age 53 z 2 years; 24 males, 11 females) were studied as a control group. Serum levels of osteocalcin were determined by a radioimmunoassay manufactured by CIS International, Gif sur Yvette, France as described in detail earlier [ll]. Serum PTH was measured by a RIA with mid-region specificity using synthetic human PTH (43-68) as tracer and standard (Sorin Biomedica Saluggia, Italy). Serum 25(OH)D was measured by competitive binding protein assay after extraction and C1*purification (Radiochemical Center, Amersham, UK). All RIAs had Table 1

Clinical characteristics of the patients with liver cirrhosis (mean & SEM) rig< Knownduralionofdisease Prothrambinrime Bilirubin Alkalinephorphamre Aspanatcaminotranaferase Alanineaminotransferasr y_Glutamvltransferase

57f 2years(range:25-82) 6f tyeZ?rS 622 2%(270%) 3.4 ?. 0.5 mgldl (O.O-1.0 mg/dl) 245* 16“/I (fo-170 U/l) 4s * 10u/l (O-20LJiIy 27 * 4 U/l (O-25Ufl)’ 167+ 28 U/l (O-MU/l)

-

105

Table 2 Serum levels of osteocalcin (OC), parathyroid hormone (FTH) and 25(0H)D in patients with liver cirrhosis (LC) and the control subjects (CO) (mean k SEM) LC OC

Fin 2SCOH)D

4.6 + 0.4 “g/ml

113.5+26.8pmoLl 7.5fZ.lneiml

co

-_

1.0 + 0.4 “g&d

69.1 + 5.9pmoln 14.5 * 1.2 “Plml

P c 0.001 n.9. PC 0.m

intraassay coefficients of variation in the useful range of the assays of less than 8% and interassay coefftcients of variation less than 14%. The minimal detectable concentration of OC was 0.2 &ml, that of pTH 20 pm&l, and that of 25(OH)D 1.5 q/ml. Routine blood chemistry, including liver function tests, plasma calcium and phosphorus levels, was measured by an American monitor parallel aualyser (Richmond, USA). The plasma calcium concentration was cerreeted accordiig to the formula of Husdan [12]. In 23 patients with liver cirrhosis (14 males, 9 :em&es; age 53 2 3 years; known duration of disease, 7 f 1 years) BMC was measured by single photon deusitometry with lx1 (NOW Gsteodensitometer GT 35) and calculated as the mean of six scans on the distal part of the non-dominant forearm. BMC is expressed iu arbitrary units, i.e., mass of bone mineral per unit length of bone. The reproducibibty oftbe method is f1.5%, obtained by repeated measurements performed by a single individual. BMC measurements of 34 normal subjects (mean age, 54 f 1 years; 20 males, 14 females) were included as a control group. The data are given as the mean * SEM. The Mann-Whitney U-test, anaIysis of variance and Pearson correlation coefficient were used for statistical analysis.

Serum levels of OC, PTH and Fi(GH)D in patients with liver drrhosis and control subjects are shown in Table 2. In patients withliver cirrhosis, serum GC levels were significantly decreased when compared to control subjects. Serum levels of PIT-I were slightly higher in patients with Livercirrh_..., o=i- however, rite difference was not statistically sipificant. Serum levels of 25(OH)D were significantly lower in patients with liver cirrhosis than in the control subjects. Plasma levels of corrected calcium were lower in the patients with liver cirrhosis than in the controi group (2.28 ? 0.02 vs. 2.44 + 0.02 mmov1; PC O.OtXN).Plasma phosphorus levels in the patieots and the controls were not statistically siguificaut (1.2+0.1vs.l.lfO.lmmoUi;n.s.). The patients with liver cirrhosis had a significantly decreased BMC when compared with the control subjects (39.6 + 2.5 vs. 49.5 -C2.3 U; P < 0.04) (Pig. 1). Serum OC levels and BMC were not statistically different when the patients witt

106

Fig. 1. Peripheral

o-

bone mineral content (BMC)

in c~ntml~(A) and patients with liver cirrhosis(a),

liver cirrhosis were subdivided according to Child stages A-C or the cause of liver disease (data not shown). In Ihe patients with liver cirrhosis a positive correlation of serum OC levels was found with the serum Z(OH)D levels (I = 0.62, P < 0.001) and plasma levels of corrected calcium (r. = 0.47; P < 0.03). No significant correlation between the serum OC levels and the PTH levels (r = 0.12; n.s.) or between BMC and serum OC levels (r = 0.37; n.s.) could be established. Furthermore, no significant correlation between the known duration of disease and serum OC levels (r = 0.06; as.) and BMC (r = 0.09; n.s.) could be found.

DIIussion Our data demonstrate decreased serum OC levels, decreased 9MC and low 25(OH)D levels in patients with liver cirrhosis. The finding of a decreased peripheral BMC in our patients with liver cirrhosis is in accordance with data in the Iiterature on patients with alcoholic cirrhosis or chrooic cholestatic liver disease [13,14] and addsevidence that osteopenia is frequent in patients with chronic liver disease. Serum levels of osteocalcin have been demonstrated to reflect the de llovo synthesis of OC by the osteoblasts and thus to be a parameter of bone formation. In diseases with increased bone formation, such as in primaly hyperparathyroidism or hyperthyroid&, serum levels of OC are increased [7,15], whereas reduced bone fonnation present in hypothyroidism or in patients receiving glucocorticoids is associated with decreased serum OC levels [15,16]. In postmenopausal osteoporosis serum

107 OC !cvels have been shown to correlate very closely with histomorphometric parameters of bone forma&n [S]. The decreased serum OC levels in our :a!ienrs with liver cirrhosis thus give evidence that bone format& is reduced in this disorder. Consequently, bone disease in patients with liver cirrhosis might he due, at least in part, to a decreased osteoblastic activity. Our data are in line with Fonseca and co-workers who found decreased OC levels in patients with primary biliary cirrhosis [17]. In a very recently published study Diamond and co-workers demonstrated decreased serum OC levels in patients with alcoholic and cholestatic liver disease [IS]. In their study Diamond et al. included both patients with liver cirrhosis and non-cirrhotics; no direct cmnparisoo of OC levels in cirrhotics and control objects are presented. Ethanol and gluwcorticoid treatment has been found to decrease bone formation [15,19,20]. As the majority of Diamond’s patients with alcoholic liver disease were actively drinking and eight out of the 20 patients with cholestatic liver disease received glucocorticoids, factors other than chronic !iver disease itself might have contribuled to the decreawd X levels observed in the study. In our study semm levels of 25(OH)D were decreased in patients with liver cirrhosis whereas, in accordance with data in the literature 1211 no statistical difference was found between the serum !cvds of ITII aod ihose of the conlrols. In most srudies vitamin D deficiency has been described in cholestatic or alcoholic liver cirrhosis [6,22,23]; however scme authors found normal vitamin D levels in patients with primary biliary cirrhosis [24,25]. Vitamin D deficiency in patients with liver cirrhosis might be due to a combination of factors including a decreased sun expo sure, a deficient dietary vitamin D intake, malabsorption and a defective hydroxylation of vitamin D in the liver [22]. In the patients with liver cirrhosis serum OC levels correlated positively with 25(OH)D and serum calcium levels; however, we did not find a significant correlation between serum OC levels and serum ITH levels. In osteoblast culture systems 1,25(OH),D, has been found to stimulate OC synthesis [26]. In our study, 25(OH)D, but not 1,25(OH),D levelswere measured; however, the serum levels of 25(OH)D are the main circ!datizg form of vitamin and represent the body stores of vitamin D [27j. Thus it seems possible that vitamin D deficiency, among other factors, may contribute to a decreased osteoblastic activity in patients with liver cirrhosis.

1 Atkmson M. Nordin KC, Sb;:!o: 5. M;!;L;;.qxio: ;t:d 50-a z-^“- in prolonged obstructive “. .u.ur jaundice. Quart I Med 1955;99:229-312. 2 Dibble JB, Sheridan P. Hampshire R, et 81. Osreomalacia, wamin D defiaeq and cholesasis in chronic iiverdiseasc. Quart1 Mcd 1982;51:89-103. 3 Summerskill W, Kelly 5’1. Osteoporosis with fractwes in anzcteric nnbotis: obse~au~n~ supplemented bymieroradiographicevaluationofbone. Proc MayoClio 1%.+38:162-174. 4 Paterson CR, Losowske MS. The bones in chronic liver disease. Sand J Gmuwnraol 1%7;2:293-300. 5 Calcium and chronic liver disease. Lancet1987;ii:1065-1066. 6 BengoaJM, Sittin MD, Meredith S, Kelly SE. Shah. N, Bakter AL, Rosenberg IH. lnrestinal c&a-

108 urnabsorplionandvitamin D status in chronic cholestatic liver disease. Hepatology 1984;4:261-265. 7 Price PA, Parthcmorc JG, Deftor U, Nishimoto SK. New biochemical marker for bone metabolism. J Ciin Invert 1980:878-883. 8 Gallop PM, Lian JB, Hauschka PV. Carboxylated calcium binding proteins and vitamin K. N Engl 1 tvied 1980;30i:14?&1466. 9 Brown JP, Malaval L. Chapuy MC, Delmas PD, Edouard C, Meunier PJ. Serum bone GLA-protein: a specific marker for bone formation in posrmcnopausal osteoporosis. Lancet 1984;i:lWl-1093. 10 Child CG Ill, TurcorteJG. Surgeryandponal hypeneosion.In: Child CG HI, ed. Theliverandportal hypertension. Phiiadelphia: W.B. SaundenCo., 1964,50. 11 Pierscbmann P, Wolorzcruk W, Panzer S, Kyde P, Smolen J. Decreased serum ostcocakin levels in phenpmcoumcn-treated patients. 1 Clin Endoninal Metab 1988;66:3071-1074. 12 Thomas L. Labor and Diagnose. MarburgiLahn: Med. Verlagsgesellschaft 2nd Edn. 1984:249. 13 Morbarhan SA, Russell RM, Raker RR, Pomer DB, Iber FL, Miller P. Metabolic bone disease in alcoholic cirrhosis: a comparison of the effect al vitamin D,, 25.hydroxyvitamin D or supportive treatment. Am Assoc Study Liver Uis 1984;4:266-273. 14 Srellon AJ, Davis A, Compston I. Williams R. Osteoporosis in chronic cholestatic liver disease. clue* I Med 1985;N.w Scrics 57;223:783-790. 15 Lukcrt BP, Higgins JC, Staskopf MM. Serum ostcocalcin is increased in patients with hypertbyroidism and dscreaxd in patients receiving glucocordcoids. J Clin Endocrinol Meab 1985;62:1056. 16 Voneda M, Takatsuki K. Yamauehi K, Oiso Y, Kumkawa M. Kawakuta A, Izuchi K. Tanaka H, Kozawa0. MiruaY, NagasakaA, Ohyama T,TomiaA. lnfluenceofthyroidfunctioninserum bone Gla protein. Endocrinol Jpn 1988;35(1),121-129. 17 Fonseca V, Epstein 0, Gill DS, Menon RK, Thomas M, McIntyre N, Dandona P. Hyperparathymidirm and low serum osteacalcin despite vitamin D replacement in primary biliary cirrhosis. J Clin Endocrinol Metab 1987;64:873-877. 18 DiamondTH, Stiel D, Lunzer MC, Oowall D, Eckstein RP,PosenS. Hepaticosteodyrtmphy. Static sod liy~lamic butte histomorphometry in 80 patients aith chronic liver disease. Gastmenrerolagy 1989;96:213-221. 19 Rico H. Cabranes IA. Cab&o I. Gdmez-Castresana F, Hemandez ER. Low serum osteocalcin in acute alcohol intaxicarion: a direct toxic effect of alcohol on osteoblasts. Bone Mineral 1987;2:221-225. 20 Diamond T. S&IO. Lunzer M, Wilkinson M, Posen S. Ethanol reduces bane formation and may cause osteoporosis. Am J Med 1989.86~282-288. 21 Long RG, Meinhard E. Skinner RK, Varghese 2, Wills MR, Scherlock S. Clinical, biochemical and histological studies of osteomalacia, osteoporosis and pamthyroid function in chronic liver disease. GUI 1978:19:85-90. 22 Hepner GW, Roginsky M, Fai Moo M Abnormal vitamin metabolism in padentswitb cirrhosis. Dig Dis 1976:.X:527-532. 23 Long iiG. Wi!!s MR. Skinner RK, et al. Serum 25.bydroxyvitamic.D in alcoholics with varying degreer of liver affection. Acta Med Sized 1977202:221-224. 24 Madoff DS, Kaplan MN, Neer RM. et al. Osteoparosiris primary biliary cirrhosis. Effects of 2.5.hydroxyvilamin-D,treatment. Gastmenterolo8y 1982;83:!?-102. 25 Kaplan MM, Goldberg MJ, Matloff DS, et al. Effect of2.5.hydroxyvitammD,on vifamin D metabo. lites in Primary biliarycirrhosir. Gastroentemlo8y 1981;81:681-685. 26 Price PA, Bankol Sa. 1,25!OH)& increased synthesis of the vitamin K dependent protein by osteacarcomacellr. J BiolChem 198:255:116&!. 27 Trei KS, Wabner HW, Offord KP, Melton W III, Kuman R, Riggs BL. Effect of aging on vitamin D stores and bone density in women. Calcif Tissue In1 1987,740:241-243.

Decreased serum osteocalcin levels in patients with liver cirrhosis.

Serum levels of osteocalcin (OC) have been found to be a specific biochemical parameter of bone formation. We measured serum levels of osteocalcin, pa...
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