Abnormal Growth Hormone Dynamics in Chronic Liver Disease Do Not Depend on Severe Parenchymal Disease Samir N. Assaad,
Glenn R. Cunningham,
and Naguib A. Samaan
Abnormal basal serum levels of growth hormone IGH) and abnormal GH dynamics have been observed in patients with alcoholic cirrhosis (AC). To further characterize these abnormalities. patients with AC or schistosomal hepatic fibrosis (SHFI were evaluated. The former patients have parenchymal liver disease, portal hypertension, and portosystemic shunting. SHF. in contrast, is characterized by periportal fibrosis with minimal or no parenchymal cell disease, portal hypertension, and portosystemic shunting. We studied 20 patients with SHF and normal stature and 15 patients with AC. In these two groups of patients, basal serum GH was higher than normal (P < .Ol 1.A paradoxical increase in GH was observed during the oral glucose tolerance test (OGTT) in 55% of SHF and in 40% of AC patients. Significant GH elevation followed thyrotropin-releasing hormone (TRH) administration in 60% of SHF and 66% of AC patients, but not in normals. Serum nonsuppressible insulin-like activity (NSILA) and serum somatomedin C @m-C) levels were reduced significantly in both groups. In SHF patients, the paradoxical increase in GH during OGTT correlated inversely with Sm-C (r = -.6, P < .05). We conclude that (1) abnormal GH secretion occurs in both SHF and AC, (2) serum Sm-C and NSILA are diminished in both forms of liver disease, and (3) portosystemic shunting of blood appears to be the important pathology shared by both forms of liver disease. D 1990 by W.B. Saunders Company.
I
BASAL SERUM growth hormone (GH) levels and nonsuppression or a paradoxical rise after glucose administration have been described in patients with liver cirrhosis.‘-4 A significant increase in serum GH also was reported to occur in some cirrhotic persons, but not in normal people, after thyrotropin-releasing hormone (TRH) administration.“’ The pathogenesis of these abnormalities of GH secretion has not been elucidated fully. The theories are that they result from alterations in central neurotransmitters,’ from a.n effect produced by elevated estrogen levels,2,3 or from decreased serum albumin concentrations as a result of malnutrition.‘0 Somatomedins, which are believed to mediate many of the GH effects, were observed to be diminished in sera from subjects with chronic liver disease. This has been true where levels were measured by bioassay,“-‘3 radiorecep(RIA).” This decrease tor assay,j4 and radioimmunoassay may contribute, by the absence of negative feedback, to the increase in GH secretion in persons who have liver cirrhosis.” To determine whether parenchymal liver disease or portosystemic shunting are pathogenetic factors in the altered GH secretion and decreased somatomedin levels, we studied patients with two different forms of chronic liver disease. Schistosomal hepatic fibrosis (SHF) is characterized by periportal fibrosis, portal hypertension, portosystemic shunting, and minimal parenchymal involvement.‘6 In contrast, alcoholic cirrhosis (AC) is characterized by hepatic cell necrosis, regeneration nodules, portal hypertension, and portosystemic collaterals. The study also included a group of patients with SHF and short stature, an association previously iascribed to this type of liver disease.““9 To our knowledge, the cause of the growth retardation observed in these subjects has not been elucidated. NCREASED
PATIENTS We studied 30 patients with SHF and 15 patients with AC. Those with SHF had a documented past history of intestinal or urinary schistosomiasis or both, enlarged or shrunken liver, and signs of portal hypertension in the form of splenomegaly with or without esophageal varices. The diagnosis was confirmed by liver biopsy. The lobular pattern was preserved, and there was no evidence of liver cell Merabolism, Vol 39, No 4 (April), 1990: pp 349-356
necrosis or regeneration. The portal tracts were filled with fibrous tissue and granulomas surrounding remnants of schistosoma eggs occasionally were seen. Serum globulin was elevated and serum albumin was decreased in most of these patients (mean + SD, 4.5 + 0.9 g/dL and 3.6 * 0.8 g/dL, respectively); mean serum bilirubin, serum aspartate transaminase, serum alanine transaminase, and prothrombin time were 0.35 + 0.15 mg/dL, 32 k 29 U/mL, 29 t 17 U/mL, and 12.2 + 0.7 seconds, respectively. Patients with SHF were divided into two groups. Group 1 included 20 patients of normal stature (18 of whom were males) who ranged in age from 20 to 43 years (mean, 25.5 years); four of these patients (patients no. 9, 12, 19, and 20, Table 1) had ascites. Their body mass indices ranged from 20.5 to 26.9 (mean, 23.3). Group 2 comprised IO males who had SHF and were of short stature. Their ages ranged from 16 to 30 years (mean, 19 years). They were below the third percentile in height (mean height, 148 cm; range, 126 to 154 cm) and their body mass indices ranged from 15.1 to 22.7 (mean, 18.5). Seven patients (patients no. 21 to 26 and no. 30) in group 2 had not undergone puberty. They had prepubertal levels of testosterone. One (patient no. 22) had ascites. None of the patients with SHF in either group had a history of alcoholic intake. and none had gynecomastia, palmar erythema, or spider angiomata. All patients had a normal free thyroxine index, except patient no. 29 in whom it was diminished slightly. The 15 men in group 3 had AC. The protocol for these studies was approved by the institutional review boards at Baylor College of Medicine and the Houston Veterans Administration Medical Cen-
From the Section of Endocrinology, Division of Medicine, The University of Texas M.D. Anderson Cancer Center, and the Department of Medicine, Veterans Administration Medical Center and Baylor College of Medicine, Houston, TX. Supported in part by Grant No. CA-2761 2-06 from the National Cancer Institute and the Nancy Carmichael Estate for Cancer Research. Dr Assaad was a Visiting Investigator from Alexandria University Medical School, Alexandria, Egypt and was supported by the Amideast Fundfor Educational and Training Support. Address reprint requests to Naguib A. Samaan, MD, PhD, Chief. Section of Endocrinology. Box 65, The University of Texas M.D. Anderson Cancer Center. 1515 Holcombe Blvd. Houston, TX 77030. o 1990 by W.B. Saunders Company. 00260495/90/3904-0004$3.00/0 349
ASSAAD. CUNNINGHAM,
350
Table 1. Serum Suppressible
AND SAMAAN
Insulin-like Activity (NSILA), Sm-C, end Serum GH Responses to an Oral Glucose Tolerance
Test in 30
Patients With SHF NSILA IU/mL)
Patient No:
Sm-C (U/mL)
GH (na/mL) Basal
30 min
60 min
90 min
120 ml”
412
2.26
6.9
3.4
2.3
2.1
529
0.29
6.7
5.3
3.8
1.9
2.8
155
0.6
2.6
2.4
8.2
5.4
3.2
183
0.31
10.5
11.4
3.3
5.9
255
0.92
8.4
3.4
1.9
1.7
3
276
0.38
1
1.4
141
1.52
2.2
1.9
6.5
4
2.7
8
126
0.46
2.1
2.3
1.3
9
216
0.19
6.2
18
33
21.5
9.2
10
292
0.28
3.8
11.4
58
39
11
306
0.31
5.3
2.9
12
248
0.21
5.3
31.4
13
288
0.29
1.5
1.4
1.4
1.6
1
14
177
0.9
1.6
1.7
1.8
2.1
2.1
15
456
0.58
1.4
25.5
9.4
4
16
310
0.78
4.9
7.5
4.7
4.9
17
446
0.78
1.7
9.8
6.8
2.1
1.2
18
338
0.25
2.5
5.4
3
2.5
4.1
19
384
0.3
20
285
0.21
10
5.8
16 9.7
1.4
8.8 IO
1.4 2.4
1.7
2
55
27.5
25 1.8 15
12.8
24.5
17.5
10.1
18.2
44
25
12.5
21
208
2.2
3.2
1.8
1.3
1.4
22
319
0.82
4.2
3.2
3.7
2.8
5.3
23
352
0.22
3.2
2
1.2
2.6
8.8
24
249
0.14
3.9
3.1
1.8
2.1
2.6
25
340
0.12
2.3
1.5
1.5
1.9
26
260
0.23
3.2
2.8
L
5.6
27
219
0.37
2.3
2.2
2.2
1.9
6.1
28
296
0.8
13.7
9.2
9.4
5.7
6.5
29
347
0.27
2
3
4.3
3
5.1
30
246
1.32
1.7
7.6
3.2
2.6
1.9
4.7 + 3.7
6.6 + 6.7
6.9 + 9.4
6.3 ? 5.8
1.93 + 0.52
1.77 + 0.57
1.72 ? 0.53
Glenn R. Cunningham,
and Naguib A. Samaan
Abnormal basal serum levels of growth hormone IGH) and abnormal GH dynamics have been observed in patients with alcoholic cirrhosis (AC). To further characterize these abnormalities. patients with AC or schistosomal hepatic fibrosis (SHFI were evaluated. The former patients have parenchymal liver disease, portal hypertension, and portosystemic shunting. SHF. in contrast, is characterized by periportal fibrosis with minimal or no parenchymal cell disease, portal hypertension, and portosystemic shunting. We studied 20 patients with SHF and normal stature and 15 patients with AC. In these two groups of patients, basal serum GH was higher than normal (P < .Ol 1.A paradoxical increase in GH was observed during the oral glucose tolerance test (OGTT) in 55% of SHF and in 40% of AC patients. Significant GH elevation followed thyrotropin-releasing hormone (TRH) administration in 60% of SHF and 66% of AC patients, but not in normals. Serum nonsuppressible insulin-like activity (NSILA) and serum somatomedin C @m-C) levels were reduced significantly in both groups. In SHF patients, the paradoxical increase in GH during OGTT correlated inversely with Sm-C (r = -.6, P < .05). We conclude that (1) abnormal GH secretion occurs in both SHF and AC, (2) serum Sm-C and NSILA are diminished in both forms of liver disease, and (3) portosystemic shunting of blood appears to be the important pathology shared by both forms of liver disease. D 1990 by W.B. Saunders Company.
I
BASAL SERUM growth hormone (GH) levels and nonsuppression or a paradoxical rise after glucose administration have been described in patients with liver cirrhosis.‘-4 A significant increase in serum GH also was reported to occur in some cirrhotic persons, but not in normal people, after thyrotropin-releasing hormone (TRH) administration.“’ The pathogenesis of these abnormalities of GH secretion has not been elucidated fully. The theories are that they result from alterations in central neurotransmitters,’ from a.n effect produced by elevated estrogen levels,2,3 or from decreased serum albumin concentrations as a result of malnutrition.‘0 Somatomedins, which are believed to mediate many of the GH effects, were observed to be diminished in sera from subjects with chronic liver disease. This has been true where levels were measured by bioassay,“-‘3 radiorecep(RIA).” This decrease tor assay,j4 and radioimmunoassay may contribute, by the absence of negative feedback, to the increase in GH secretion in persons who have liver cirrhosis.” To determine whether parenchymal liver disease or portosystemic shunting are pathogenetic factors in the altered GH secretion and decreased somatomedin levels, we studied patients with two different forms of chronic liver disease. Schistosomal hepatic fibrosis (SHF) is characterized by periportal fibrosis, portal hypertension, portosystemic shunting, and minimal parenchymal involvement.‘6 In contrast, alcoholic cirrhosis (AC) is characterized by hepatic cell necrosis, regeneration nodules, portal hypertension, and portosystemic collaterals. The study also included a group of patients with SHF and short stature, an association previously iascribed to this type of liver disease.““9 To our knowledge, the cause of the growth retardation observed in these subjects has not been elucidated. NCREASED
PATIENTS We studied 30 patients with SHF and 15 patients with AC. Those with SHF had a documented past history of intestinal or urinary schistosomiasis or both, enlarged or shrunken liver, and signs of portal hypertension in the form of splenomegaly with or without esophageal varices. The diagnosis was confirmed by liver biopsy. The lobular pattern was preserved, and there was no evidence of liver cell Merabolism, Vol 39, No 4 (April), 1990: pp 349-356
necrosis or regeneration. The portal tracts were filled with fibrous tissue and granulomas surrounding remnants of schistosoma eggs occasionally were seen. Serum globulin was elevated and serum albumin was decreased in most of these patients (mean + SD, 4.5 + 0.9 g/dL and 3.6 * 0.8 g/dL, respectively); mean serum bilirubin, serum aspartate transaminase, serum alanine transaminase, and prothrombin time were 0.35 + 0.15 mg/dL, 32 k 29 U/mL, 29 t 17 U/mL, and 12.2 + 0.7 seconds, respectively. Patients with SHF were divided into two groups. Group 1 included 20 patients of normal stature (18 of whom were males) who ranged in age from 20 to 43 years (mean, 25.5 years); four of these patients (patients no. 9, 12, 19, and 20, Table 1) had ascites. Their body mass indices ranged from 20.5 to 26.9 (mean, 23.3). Group 2 comprised IO males who had SHF and were of short stature. Their ages ranged from 16 to 30 years (mean, 19 years). They were below the third percentile in height (mean height, 148 cm; range, 126 to 154 cm) and their body mass indices ranged from 15.1 to 22.7 (mean, 18.5). Seven patients (patients no. 21 to 26 and no. 30) in group 2 had not undergone puberty. They had prepubertal levels of testosterone. One (patient no. 22) had ascites. None of the patients with SHF in either group had a history of alcoholic intake. and none had gynecomastia, palmar erythema, or spider angiomata. All patients had a normal free thyroxine index, except patient no. 29 in whom it was diminished slightly. The 15 men in group 3 had AC. The protocol for these studies was approved by the institutional review boards at Baylor College of Medicine and the Houston Veterans Administration Medical Cen-
From the Section of Endocrinology, Division of Medicine, The University of Texas M.D. Anderson Cancer Center, and the Department of Medicine, Veterans Administration Medical Center and Baylor College of Medicine, Houston, TX. Supported in part by Grant No. CA-2761 2-06 from the National Cancer Institute and the Nancy Carmichael Estate for Cancer Research. Dr Assaad was a Visiting Investigator from Alexandria University Medical School, Alexandria, Egypt and was supported by the Amideast Fundfor Educational and Training Support. Address reprint requests to Naguib A. Samaan, MD, PhD, Chief. Section of Endocrinology. Box 65, The University of Texas M.D. Anderson Cancer Center. 1515 Holcombe Blvd. Houston, TX 77030. o 1990 by W.B. Saunders Company. 00260495/90/3904-0004$3.00/0 349
ASSAAD. CUNNINGHAM,
350
Table 1. Serum Suppressible
AND SAMAAN
Insulin-like Activity (NSILA), Sm-C, end Serum GH Responses to an Oral Glucose Tolerance
Test in 30
Patients With SHF NSILA IU/mL)
Patient No:
Sm-C (U/mL)
GH (na/mL) Basal
30 min
60 min
90 min
120 ml”
412
2.26
6.9
3.4
2.3
2.1
529
0.29
6.7
5.3
3.8
1.9
2.8
155
0.6
2.6
2.4
8.2
5.4
3.2
183
0.31
10.5
11.4
3.3
5.9
255
0.92
8.4
3.4
1.9
1.7
3
276
0.38
1
1.4
141
1.52
2.2
1.9
6.5
4
2.7
8
126
0.46
2.1
2.3
1.3
9
216
0.19
6.2
18
33
21.5
9.2
10
292
0.28
3.8
11.4
58
39
11
306
0.31
5.3
2.9
12
248
0.21
5.3
31.4
13
288
0.29
1.5
1.4
1.4
1.6
1
14
177
0.9
1.6
1.7
1.8
2.1
2.1
15
456
0.58
1.4
25.5
9.4
4
16
310
0.78
4.9
7.5
4.7
4.9
17
446
0.78
1.7
9.8
6.8
2.1
1.2
18
338
0.25
2.5
5.4
3
2.5
4.1
19
384
0.3
20
285
0.21
10
5.8
16 9.7
1.4
8.8 IO
1.4 2.4
1.7
2
55
27.5
25 1.8 15
12.8
24.5
17.5
10.1
18.2
44
25
12.5
21
208
2.2
3.2
1.8
1.3
1.4
22
319
0.82
4.2
3.2
3.7
2.8
5.3
23
352
0.22
3.2
2
1.2
2.6
8.8
24
249
0.14
3.9
3.1
1.8
2.1
2.6
25
340
0.12
2.3
1.5
1.5
1.9
26
260
0.23
3.2
2.8
L
5.6
27
219
0.37
2.3
2.2
2.2
1.9
6.1
28
296
0.8
13.7
9.2
9.4
5.7
6.5
29
347
0.27
2
3
4.3
3
5.1
30
246
1.32
1.7
7.6
3.2
2.6
1.9
4.7 + 3.7
6.6 + 6.7
6.9 + 9.4
6.3 ? 5.8
1.93 + 0.52
1.77 + 0.57
1.72 ? 0.53
