Abnormal Blood Chemistry Data in Cushing’s Syndrome : Comparison with Those for Fatty Liver *.
TATSUO SATO, JUNICHI TAJIRI, TATSUYA SHIMADA RYOJI HIRAMATSU, AND TERUHISA UMEDA
Third Department of Internal Medicine, Kumamoto University Medical School, Kumamoto, 860
Abstract
It has been reported that fatty liver is not uncommon in Cushing’s syndrome. Biochemical data obtained from routine blood chemistry in 10 patients with Cushing’s syndrome were compared with those for 15 patients with histologically verified fatty liver. We found an absence of a decreased GOT/ GPT ratio, low normal choline esterase and increased lactic dehydrogenase activities together with lowered serum protein and albumin, and increased blood sugar and total cholesterol in Cushing’s syndrome when compared with those of fatty liver cases. These data and additional findings in liver histology obtained from one patient with Cushing’s syndrome due to adrenocortical car- cinoma indicated that fatty changes in the liver were not frequently encountered in Cushing’s syndrome. These abnormal biochemical data might be a way of distinguishing Cushing’s syndrome from fatty liver.
Multiple actions of steroid hormones are now well known, especially in protein, fat and glucose metabolism. On the other hand, the liver is thought to be the biggest meta- bolic factory in the body. In textbooks on both hepatology and endocrinology it has been reported that fatty liver is not uncom- mon in patients with Cushing’s syndrome. To our knowledge, the source of that men- tion was a report by Soffer et al. (1961) in which a histological study was carried out in 13 autopsied cases of Cushing’s syndrome.
The aspect that findings of postmortem ex- aminations might be quite different from those of antemortem studies led us to re- valuate the above report.
Clinically, patients with fatty liver showed some biochemical abnormalities characterized by a decreased ratio of GOT/GPT and in- creased lipids and choline esterase (ChE) levels. Moreover, these patients were fre- quently obese. Recently, it has been re- ported that more than 50 percent of patients with Cushing’s syndrome manifested general- ized obesity, not central obesity (Ross et al., 1982). These observations make it difficult to distinguish between Cushing’s syndrome and obese fatty liver cases in the office or at the bedside.
In this paper, we analyzed various bio-
chemical data in patients with Cushing’s syndrome and compared the values with those in fatty liver. We found that there were several abnormalities in routine labora- tory data in Cushing’s patients and these were different from those in fatty liver cases.
Materials and Methods
Ten patients with clinically, endocrinologically and surgically documented Cushing’s syndrome : 6 with bilateral adrenocortical hyperplasia, 3 with unilateral adenoma and one with multiple macro- nodular hyperplasia, were studied preoperatively.
Fifteen patients with fatty liver were the control group in whom the diagnosis was made by his- tological examinations of biopsy specimens via peritoneoscopy. All of the patients with Cushing’s syndrome were women and their ages ranged from 28 to 62 years with a mean of 40 years. Of 15 patients with fatty liver, 11 were men and 4 were women. Their mean age was 36 years. The body weight was more than 20 percent above their ideal weight in 9 cases. In these obese patients, Cushing’s syndrome was ruled out after deter- minations of urinary 17-OHCS and 17-KS and by dexamethasone suppression test.
Blood samples were taken at the time of hos- pital visits or in the morning following admission, usually 8 : 30 to 10: 30 am. without breakfast. Items of blood chemistry included serum total protein (TP), albumin (Alb), fasting blood sugar
T.P. (g/dl)
Alb. (g/dl)
FBS (mg/dl)
T. Chol. (mg/dl)
N.F. (mg/dl)
P<0.05
P<0.02
P<0.01
P<0.01
n.s.
8.0
200
O
O
00
300
400-
·
00
oo
7.0
·
5.0-
o
0
150
250-
300
o
0
oo
O
O
O
200
00
0
200
8
6.0-
4.0-
O
0
8
00
O
100
0
O
O
O
1
0
150
100
O
0
00
5.0
3.0
100
0
C
FL
C
FL
C
FL
C
FL
C
FL
(FBS), total cholesterol (T.Chol.), neutral fat (NF), phospholipid (PL), GOT, GPT, alkaline phos- phatase (Alp), leucine aminopeptidase (LAP), r- glutamyltranspeptidase (7-GTP), lactic dehydro- genase (LDH) and ChE. All of them were de- termined with autoanalyzers. The upper and lower normal limits of these parameters in our laboratory are represented in the following figures as shaded areas.
Comparisons were made by means of an un- paired t-test, where a p value of 0.05 or less was considered as significant.
Histological studies of the liver were performed on one autopsied case who was a 25-year-old man and died of disseminated metastases of adreno- cortical cancer. This case was excluded from the present study because of multiple metastases to the liver.
Results
As shown in Fig. 1 and 2, TP and Alb levels were decreased in patients with Cushing’s syndrome when compared with those of control fatty liver cases. Seven of 10 patients with Cushing’s syndrome had TP values less than the normal range and 9 of them also showed low values of Alb under the lower normal limit. There was a significant difference in TP and Alb be- tween Cushing’s syndrome and fatty liver (6.3±0.5 vs 7.0±0.4 g/dl of TP; p<0.05 and 3.6±0.2 vs 4.3+0.4 g/dl of Alb; p< 0.02). FBS in Cushing’s syndrome was
GOT (U/I)
GPT (U/I)
Ch-E (U/I)
AIP (U/I)
7-GPT (U/I)
LDH (U/I)
n.s.
P<0.05
P<0.01
n.s.
n.s.
P<0.01
8
800
343
180
00
160
700
250
120
400-
140-
100
600
100-
8
200-
120
80
100
500
80
300-
1
8
150-
60
80
400
60
60
100-
40
300
·
40-
200-
40
20-
200
20-
50
20
0
0
C
FL
C
FL
100
C
FL
0
0
C
FL
100
C
FL
C
FL
significantly high when compared with that in fatty liver (115±31 vs 88±12 mg/dl; p<0.01). Serum T.Chol levels in Cushing’s syndrome and in fatty liver were 237±40.5 and 178±30.9 mg/dl, respectively. The dif- ference between the groups was also signifi- cant (p<0.01). However, the NF and PL values in Cushing’s syndrome corresponded closely with those of fatty liver.
Serum GOT and GPT levels in fatty liver distributed over wide ranges and the mean value for both enzymes were higher than those in Cushing’s syndrome. In GPT levels, there was a significant difference be- tween the two groups (31±20 in Cushing’s syndrome vs 92±60 u/l in fatty liver; p< 0.05). The ratio of GOT/GPT in Cushing’s syndrome and in fatty liver was 0.96±0.41
and 0.52+0.27, respectively. The difference between the groups was significant (p<0.01). ChE levels in both groups were mostly in the normal range, but the levels were sig- nificantly lower in Cushing’s syndrome than those in fatty liver (386±73 vs 513±104 u/1; p<0.01). Statstically, there was no signifi- cant difference between the Alp and LAP levels for the two groups. Although r-GTP levels in both groups showed wide distribu- tion and half of the Cushing’s patients had high 7-GTP, the difference between the two groups was not statistically significant. Ele- vated levels of LDH were also found in half of the Cushing’s patients. The mean LDH value in these patients was 256±78 compared with a vale of 180±39 u/1 in fatty liver cases (p<0.01). In addition, no
significant differences in the above bio- chemical parameters were found between fatty liver with and without obesity and between Cushing’s syndrome due to adreno- cortical hyperplasia and adenoma.
Fig. 3 is the liver morphology of a pa- tient who died of Cushing’s syndrome due to adrenocortical cancer with liver metastases. There was no fatty infiltration in the non- metastatic portion of his liver.
Discussion
As reported herein, we found that in Cushing’s syndrome TP and Alb were rela- tively low, while the mean values for FBS and T.Chol were higher than those for fatty liver. These changes might be the results of longstanding hypercortisolism in these pa- tients. There was no significant difference in GOT and GPT, but there were lowered ChE levels in Cushing’s syndrome. As mentioned before, a decreased ratio of GOT/GPT and elevated ChE activity were characteristic findings in fatty liver. However, no similar changes were noted in Cushing’s cases. In addition, we did not find any fatty infiltra- tion in the liver obtained from an autopsied case of Cushing’s syndrome. Soffer et al. (1961) reported that 6 patients with Cushing’s syndrome showed no abnormal changes on histological examinations of the liver, while a moderate fatty infiltration was found in 4 cases and an additional 3 had extensive fatty liver. However, these morphological findings were obtained from autopsied ma- terials and, thus, antemortem examinations may not reveal the same changes as post- mortem studies. Alpers et al. (1982) observed that the fatty liver occurred only in cases which received high doses of steroid hor- mones for long periods. It seemed likely that the concentrations of circulating steroid hormones in Cushing’s patients and in pa- tients that received therapeutical doses of the steroid were quite different. From these
observations, it was hard to accept the idea that in Cushing’s syndrome fatty liver was not uncommon.
Another finding of the present study was that Cushing’s patients showed several abnormal data in routine laboratory tests. We found that half of the patients had elevated 7-GTP, but this was not statisti- cally significant when compared with that of fatty liver cases. However, serum LDH was significantly higher in Cushing’s syndrome than in fatty liver. Yoshiba et al. (1980) studied 19 patients treated with glucocorti- coids and found that 10 of them (53%) had elevated 7-GTP. They postulated that the elevated 7-GTP might result from the enzyme induction by the steroid hormone rather than cholestasis because of normal Alp levels. The discrepancy between their findings and ours might be due to different concentrations of glucocorticoid in plasma because therapeutic doses were much higher than the endogenous steroid hormone in Cushing’s syndrome mentioned before. We also found that serum Alp and LAP levels in Cushing’s syndrome and in fatty liver were in the normal range. Takaishi et al. (1977) reported an elevated serum LDH in 16 of 20 patients with Cushing’s syndrome (80%). Since the elevated LDH was parallel to urinary 17-OHCS output, they suggested that the increased glucocorticoid secretion resulted in the elevation of LDH by some undetermined mechanism. In the present study, we also found increased LDH in Cushing’s syndrome, but only in 50 percent of the patients. Such a different frequency might be due to differences in the stage of the illness in their patients and ours. Al- though we examined isozyme patterns of LDH in only 4 patients with Cushing’s syndrome, all of them showed a normal pattern. In other words, neither increased muscular nor hepatic isozyme was found. Further study should be necessary.
Previously, we reported that patients with Cushing’s syndrome frequently showed
increased numbers of platelets, relatively elevated 7-GTP and LDH, and significantly lowered creatine phosphokinase activity when compared with those with simple obesity (Sato et al., 1984). These abnormal data obtained in the previous study and the present study might be of value in screening Cushing’s syndrome in the office or at the bedside.
In summary, our findings indicated that fatty liver was not frequently encountered in most patients with Cushing’s syndrome because the blood chemistry data including GOT/GPT ratio, ChE, TP, Alb, FBS and T.Chol levels were noticeably different from those for fatty liver.
References
Alpers, D. H. and S. M. Sabesin (1982). Fatty liver. In: Diseases of the liver. Edited by
L. Schiff and E. R. Schiff, 5th Ed. J. B. Lip- pincott Co, Philadelphia, p-839.
Ross, E. J. and D. C. Linch (1982). Cushing’s syndrome-Killing disease; Discriminatory val- ues of signs and symptoms aiding early diag- nosis. Lancet 2, 646-649.
Sato, T., R. Hiramatsu, T. Iwaoka, Y. Fujii, T. Shimada and T. Umeda (1984). Changes in platelets, serum lactic dehydrogenase, 7-gluta- myltranspeptidase, choline esterase and creatine phosphokinase levels in patients with Cushing’s syndrome. Tohoku J. exp. Med., 144, 195-200.
Soffer, L. J., A. Iannaccone and J. L. Gabrilove (1961). Cushing’s syndrome, A study of fifty patients. Amer. J. Med., 30, 129-146.
Takaishi, M., Y. Ozawa, T. Shimizu and Y. Shishiba (1977). Elevated serum lactic de- hydrogenase activity in patients with Cushing’s syndrome. Endocrinol. Japon., 24, 381-384.
Yoshiba, M., K. Fujihara, T. Sakai, Y. Okada, G. Toda, H. Suzuki, H. Oka and T. Oda (1980). An elevated serum 7-GTP activity in patients treated with steroid hormone. Acta Hepatol. Japon., 21, 1077 (Japanese).