Acta Med Scand 202: 221-224, 1977
The Hepatic Conversion of Vitamin D in Alcoholics with Varying Degrees of Liver Affection B. Lund, 0. H. Ssrensen, M. Hilden and B. Lund From Department of Medicine E , Frederiksberg Hospital, and the Department of Medicine, Hvidovre Hospital. Copenhagen, the Department of Medicine, Maribo. and the Department of Orthopaedic Surgery, Frederiksborg County Hospital, Hiliered, Denmark
ABSTRACT. The seasonal variations in circulating 25-hydroxycholecalciferol(25-HCC) were studied in 102 alcoholics with fatty liver disease without histologic signs of cirrhosis and in 35 patients with alcoholic cirrhosis. The mean levels were compared with those of normal persons. Alcoholics had generally lower 25-HCC values than the controls, particularly in the summer. This was primarily explained by insufficient diet and reduced exposure to sunshine. The ability of the liver to hydroxylate in the 25position was studied in three groups of alcoholics with 1) fatty liver disease without cirrhosis, 2) compensated cirrhosis, 3) severely incompensated liver cirrhosis. All three groups exhibited a significant increase in serum 25-HCC following the peroral administration of cholecalciferol at a dose of 1200 U daily for 7 days. Similar rises were seen 7 days after a single injection of loo00 U cholecalciferol. This indicates a normal intestinal absorption of vitamin D, even in advanced alcoholic liver disease, and i s inconsistent with a severely damaged 25-hydroxylation capacity in these patients. Osteomalacia due to impaired liver hydroxylation of vitamin D can hardly explain the increased fracture rate and the decreased bone mass, which have been described in alcoholics.
been reported in patients with chronic liver diseases. So far most interest has concentrated on patients with primary biliary cirrhosis, a rather rare disease. These patients often develop osteoporosis and osteomalacia due to malabsorption of calcium and vitamin D ( I , 9, 18, 21), or a defect in the hepatic metabolism of the vitamin (20). Liver affection in chronic alcoholism is on the other hand a much more common disease, but here the state of the skeleton and the metabolism of vitamin D have been less intensively studied. The results are furthermore controversial. Some studies show a decreased bone mass in alcoholics ( 3 , 4 , 13, 16). while others point at a normal skeleton in these patients (IS). Measurements of 25-HCC in alcoholics without cirrhosis have demonstrated normal (8) or low values (10). In one study (19), serum 25-HCC was low in female alcoholics without cirrhosis, but not in males. There seems to be general agreement. however, that 25-HCC is low when alcoholic cirrhosis has developed (8, 10, 11). The present study was undertaken to measure circulating 25-HCC in chronic alcoholics with I ) fatty liver disease without cirrhosis, 3) compensated cirrhosis, 3) cirrhosis with severe liver failure. The ability of the liver to hydroxylate in the 25-position was studied in these patients. Cholecalciferol was administered both by the oral and by the intramuscular route to exclude differences in intestinal absorption.
After absorption from the intestine or derivation by ultraviolet light irradiation from the skin precursor, cholecalciferol is hydroxylated in the liver to 25hydroxycholecalciferol (25-HCC), the major circulating form of the vitamin (14). This metabolite is further hydroxylated in the kidney to the most potent form of vitamin D known, 1,25-dihydroxyPATIENTS AND METHODS cholecalciferol (5). The liver thus has a central position in the metabolism of vitamin D, which might Circulating 25-HCC was measured in 102 patients with explain some of the bone abnormalities that have varying degrees of fatty liver disease, but without any
B . Lund et al.
221
80
.
70 . 60
)
40 . 50
::: 10
'
0
histological signs of cirrhosis, and in 35 patients with compensated alcoholic cirrhosis. The ultimate diagnosis was based in each case upon the histological changes in the liver biopsy. Seasonal changes throughout the year were studied in the fatty liver patients and compared with the results from 5% normal persons. The blood samples from the cirrhotic group were collected in May, September and December. To clarify whether low 25-HCC values were due to insufficient diet, malabsorption or inability of the liver to hydroxylate in the 25-position, cholecalciferol was given perorally or parenterally to groups of alcoholics with I ) fatty liver without cirrhosis, 2) compensated cirrhosis, 3) severely incompensated cirrhosis. Each group comprised 5-8 patients as shown in Figs. 3 and 4. The oral dose of cholecalciferol was 1200 U daily. Serum 25-HCC was measured before and after 7 days of treatment. The results were compared with the findings in 16 normal persons treated in a similar way. The parented dose was IOOOO LJ. given as one single intramuscular injection, with measurement of 25-HCC before and 7 days after the injection.
gj
5 9
Serum 25-HCC was measured by a competitive protein-binding assay according to Haddad and Chyu (6), with modifications in the extraction procedure and in the chromatographic step (12). Comparisons were made using Wilcoxon's rank sum test for paired and unpaired data.
RESULTS Fig. 1 illustrates the mean levels of 25-HCC in the fatty liver patients compared with normals. The values were slightly reduced in the former group, but the differences were only significant in the summer months. The 25-HCC values of the compensated cirrhotics were significantly lower than those in normals in the seasons studied (Fig. 2). Significant increases in the 25-HCC levels follow25-HCC
':iykf MAV
nglml
Normal Range
SEPT
60 .
DEC 40
60 50 40 30
"
20 10 n v
151'70 P
The Hepatic Conversion of Vitamin D in Alcoholics with Varying Degrees of Liver Affection B. Lund, 0. H. Ssrensen, M. Hilden and B. Lund From Department of Medicine E , Frederiksberg Hospital, and the Department of Medicine, Hvidovre Hospital. Copenhagen, the Department of Medicine, Maribo. and the Department of Orthopaedic Surgery, Frederiksborg County Hospital, Hiliered, Denmark
ABSTRACT. The seasonal variations in circulating 25-hydroxycholecalciferol(25-HCC) were studied in 102 alcoholics with fatty liver disease without histologic signs of cirrhosis and in 35 patients with alcoholic cirrhosis. The mean levels were compared with those of normal persons. Alcoholics had generally lower 25-HCC values than the controls, particularly in the summer. This was primarily explained by insufficient diet and reduced exposure to sunshine. The ability of the liver to hydroxylate in the 25position was studied in three groups of alcoholics with 1) fatty liver disease without cirrhosis, 2) compensated cirrhosis, 3) severely incompensated liver cirrhosis. All three groups exhibited a significant increase in serum 25-HCC following the peroral administration of cholecalciferol at a dose of 1200 U daily for 7 days. Similar rises were seen 7 days after a single injection of loo00 U cholecalciferol. This indicates a normal intestinal absorption of vitamin D, even in advanced alcoholic liver disease, and i s inconsistent with a severely damaged 25-hydroxylation capacity in these patients. Osteomalacia due to impaired liver hydroxylation of vitamin D can hardly explain the increased fracture rate and the decreased bone mass, which have been described in alcoholics.
been reported in patients with chronic liver diseases. So far most interest has concentrated on patients with primary biliary cirrhosis, a rather rare disease. These patients often develop osteoporosis and osteomalacia due to malabsorption of calcium and vitamin D ( I , 9, 18, 21), or a defect in the hepatic metabolism of the vitamin (20). Liver affection in chronic alcoholism is on the other hand a much more common disease, but here the state of the skeleton and the metabolism of vitamin D have been less intensively studied. The results are furthermore controversial. Some studies show a decreased bone mass in alcoholics ( 3 , 4 , 13, 16). while others point at a normal skeleton in these patients (IS). Measurements of 25-HCC in alcoholics without cirrhosis have demonstrated normal (8) or low values (10). In one study (19), serum 25-HCC was low in female alcoholics without cirrhosis, but not in males. There seems to be general agreement. however, that 25-HCC is low when alcoholic cirrhosis has developed (8, 10, 11). The present study was undertaken to measure circulating 25-HCC in chronic alcoholics with I ) fatty liver disease without cirrhosis, 3) compensated cirrhosis, 3) cirrhosis with severe liver failure. The ability of the liver to hydroxylate in the 25-position was studied in these patients. Cholecalciferol was administered both by the oral and by the intramuscular route to exclude differences in intestinal absorption.
After absorption from the intestine or derivation by ultraviolet light irradiation from the skin precursor, cholecalciferol is hydroxylated in the liver to 25hydroxycholecalciferol (25-HCC), the major circulating form of the vitamin (14). This metabolite is further hydroxylated in the kidney to the most potent form of vitamin D known, 1,25-dihydroxyPATIENTS AND METHODS cholecalciferol (5). The liver thus has a central position in the metabolism of vitamin D, which might Circulating 25-HCC was measured in 102 patients with explain some of the bone abnormalities that have varying degrees of fatty liver disease, but without any
B . Lund et al.
221
80
.
70 . 60
)
40 . 50
::: 10
'
0
histological signs of cirrhosis, and in 35 patients with compensated alcoholic cirrhosis. The ultimate diagnosis was based in each case upon the histological changes in the liver biopsy. Seasonal changes throughout the year were studied in the fatty liver patients and compared with the results from 5% normal persons. The blood samples from the cirrhotic group were collected in May, September and December. To clarify whether low 25-HCC values were due to insufficient diet, malabsorption or inability of the liver to hydroxylate in the 25-position, cholecalciferol was given perorally or parenterally to groups of alcoholics with I ) fatty liver without cirrhosis, 2) compensated cirrhosis, 3) severely incompensated cirrhosis. Each group comprised 5-8 patients as shown in Figs. 3 and 4. The oral dose of cholecalciferol was 1200 U daily. Serum 25-HCC was measured before and after 7 days of treatment. The results were compared with the findings in 16 normal persons treated in a similar way. The parented dose was IOOOO LJ. given as one single intramuscular injection, with measurement of 25-HCC before and 7 days after the injection.
gj
5 9
Serum 25-HCC was measured by a competitive protein-binding assay according to Haddad and Chyu (6), with modifications in the extraction procedure and in the chromatographic step (12). Comparisons were made using Wilcoxon's rank sum test for paired and unpaired data.
RESULTS Fig. 1 illustrates the mean levels of 25-HCC in the fatty liver patients compared with normals. The values were slightly reduced in the former group, but the differences were only significant in the summer months. The 25-HCC values of the compensated cirrhotics were significantly lower than those in normals in the seasons studied (Fig. 2). Significant increases in the 25-HCC levels follow25-HCC
':iykf MAV
nglml
Normal Range
SEPT
60 .
DEC 40
60 50 40 30
"
20 10 n v
151'70 P
