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The Effect of Short Stature, Portal Hypertension, and Cholestasis on Growth Hormone Resistance in Children with Liver Disease¹

Departments of Medicine (R.I.G.H., J.S.J., J.P.M.) and Child Health (A.B., C.B.), King’s College School of Medicine and Dentistry, London, United Kingdom SE5 9PJ

Address all correspondence and requests for reprints to: Dr. John Miell, Department of Medicine, King’s College School of Medicine and Dentistry, Bessemer Road, London, United Kingdom SE5 9PJ.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Chronic liver disease is associated with GH resistance, which is characterized by high circulating GH and low insulin-like growth factor I (IGF-I) concentrations. Standard GH replacement has no effect on serum IGF-I in pediatric liver disease. The aims were to examine whether GH resistance can be overcome by supraphysiological GH and to determine whether GH resistance worsens with the progression of liver disease.

Thirty children, divided into five groups whose liver disease was at clinically different stages, were studied. They were given 0.2 IU/kg·day GH for 4 days and then 0.4 IU/kg·day for the next 4 days. Serum IGF-I and binding proteins (IGFBPs) were measured by immunoassay.

IGF-I was lower in all study groups than in normal controls. IGF-I, IGFBP-3, and acid-labile subunit rose in response to GH. The magnitude of the response reflected nutritional status and liver dysfunction; in particular, portal hypertension was associated with a poor IGF-I response. There was no change in IGFBP-2.

GH resistance begins early in the natural history of childhood liver disease and develops with the progression of liver disease, particularly with portal hypertension. It may be partially overcome by supraphysiological GH administration, but the effect becomes smaller with worsening liver disease.

	Introduction

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FAILURE of linear growth or malnutrition complicates chronic liver disease in children in about 50% of cases (1). Undernutrition is associated with frequent complications, hospitalization, and ultimately death, whereas impaired linear growth is a predictor of poor outcome after liver transplantation (2).

GH exerts the majority of its anabolic actions by the generation of the mitogenic polypeptide insulin-like growth factor I (IGF-I) (3). Although IGF-I is synthesized ubiquitously, most of the circulating IGF-I is derived from the liver (4). The bioavailability and bioactivity of IGF-I are regulated by a family of high affinity binding proteins (IGFBPs) and acid-labile subunit (ALS) (5). Chronic liver disease is associated with the development of GH resistance, which is characterized by high circulating GH and low IGF-I concentrations (6, 7). There are also marked abnormalities in the concentrations of circulating IGFBPs and ALS (8).

The management of children with liver disease remains a challenge. Although aggressive enteral feeding may improve growth, further treatments to promote anabolism are needed (9). GH has been used in a number of catabolic clinical settings to enhance nitrogen retention. GH receptors are present in reduced numbers on cirrhotic liver, but bind GH with an affinity similar to that in normal liver (10). In previous pediatric studies, standard GH replacement doses had no effect on serum IGF-I, leading to the conclusion that GH therapy was unlikely to have a role in childhood liver disease (11, 12). In contrast, GH administration to adult cirrhotics produced a sustained rise in IGF-I with up to 6 weeks of continuous treatment (13, 14, 15). This discrepancy may be explained by the severity of the liver disease at the time of GH administration and the greater intrinsic GH requirement of children.

The aims of the study were to examine whether GH resistance could be overcome by supraphysiological concentrations of GH and to examine whether GH resistance worsens with the progression of liver disease by studying five groups of children whose liver disease was at clinically different stages.

	Subjects and Methods

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Patients

Thirty prepubertal children (age, 4.3 ± 0.5 yr; range, 0.7–11.2 yr) were recruited into the study and divided into five age-matched groups: 1) children with biliary atresia after successful Kasai portoenterostomy (n = 7), 2) children with biliary atresia and short stature despite successful portoenterostomy (n = 4), 3) children with biliary atresia and significant portal hypertension (n = 6), 4) children with biliary atresia and significant cholestasis (n = 6), and 5) children with Alagille syndrome (n = 7).

Children were defined as having short stature if their height SD score was below -1.5. Children were classified as having significant portal hypertension if there were signs of splenomegaly, esophageal varices, or reversed portal vein blood flow as determined by ultrasonography. Children were defined as having significant cholestasis if portoenterostomy failed to reestablish normal bile flow, and bilirubin remained above the normal range (<20 µmol/L). All children with significant cholestasis also had signs of portal hypertension.

Weight, height, midarm circumference, and triceps (TSF) and subscapular skinfold thickness (SSF) were measured as previously described (16).

The diagnosis of biliary atresia was made by the presence of biochemical evidence of cholestasis in the first few weeks of life and a liver biopsy showing the typical histological features. All diagnoses were confirmed at the time of portoenterostomy. The diagnosis of Alagille syndrome was made by the presence of cholestasis, typical histological features, and at least three characteristic extrahepatic manifestations.

All children underwent nutritional assessment by a trained pediatric dietitian to ensure they were consuming a diet that was adequate in both energy and protein. Target daily energy intake was 140% of the WHO recommended daily intake for weight, with 66% of the calories being provided by carbohydrates (17). Target protein intake was 4 g/kg BW. All children were given daily oral fat soluble vitamin supplements [750 µg retinol equivalents (vitamin A, 2500 U), 10 µg ergocalciferol (vitamin D, 400 U), 15 mg -tocopherol equivalents (vitamin E, 15 mg), and 1 mg vitamin K]. Fat-soluble vitamins were given parenterally if serum concentrations indicated such a need. No major change in diet was made in the 2 weeks before the study and during the study.

Fasting early morning blood samples were obtained from 20 age-matched normal children (age, 4.4 ± 0.8 yr), who were friends or normal siblings of the patients. All anthropometric indexes for control children lay within 2 SD of the mean for age and sex. All children had normal liver function and no diagnosed endocrine abnormality.

The study had the approval of the King’s College Hospital ethics committee, and written consent was obtained from the parents of all participants.

GH administration

Recombinant human GH (rhGH) was donated by Pharmacia-Upjohn (Milton Keynes, UK). rhGH (0.2 IU/kg·day) was administered daily for 4 days by a single sc injection. On the fifth day, the dose of rhGH was increased to 0.4 IU/kg·day for an additional 4 days. The injections were given to the children by a parent or local nurse after they had received instruction concerning administration.

Blood samples were taken before the first injection, on the fifth day before the injection on that day, and on the day after the last injection. Blood was centrifuged for 20 min at 2000 x g, and serum was separated and stored at -20 C until analysis.

Assays

Serum IGF-I and IGFBP-2 were measured by RIA, and IGFBP-3 was measured by immunoradiometric assay as previously described (7, 18). Serum ALS was measured by a commercially available enzyme linked immunosorbent assay according to the manufacturer’s instructions (Diagnostic Systems Laboratories, Inc., Webster TX). There was no detectable cross-reactivity with IGF-I, IGF-II, or IGFBP-1 to -6. The sensitivity of the assay was 70 µg/L. The interassay coefficient of variation was 8.5% at 2.2 mg/L and 8.9% at 30.1 mg/L, and the intraassay coefficient of variation was 6.1% at 1.65 mg/L and 3.9% at 2.2 mg/L.

Liver function tests and clotting time

Bilirubin (normal range, <20 µmol/L), aspartate aminotransferase (10–46 U/L), alkaline phosphatase (25–150 U/L), -glutamyl transferase (10–56 U/L), albumin (34–48/L), and international normalized prothrombin ratio (<1.3) were measured by automated standard clinical biochemical and hematological methods.

Statistical analysis

The SD scores were derived for all anthropometric data using population standards obtained from Tanner and Whitehouse (height, weight, TSF, and SSF) and from Frisancho (midarm circumference) (19, 20).

Paired Student’s t test was used to determine the significance of differences in mean IGF-I and IGFBPs at the different time points. Comparison between groups was performed by ANOVA; when P < 0.05, the calculation was completed with Fisher’s least significant difference test. Results are given as the mean ± SEM.

The correlations between serum IGF-I and IGFBPs and measures of liver dysfunction and anthropometry were determined by simple regression analysis.

	Results

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Clinical characteristics

Table 1 gives the clinical and biochemical characteristics of the groups. In all groups of children with biliary atresia, except those with short stature, skinfold thickness SD scores were significantly lower than height or weight SD scores. In the Alagille group, skinfold thickness SD scores were higher than height or weight SD scores.

Baseline serum IGF-I was significantly lower in all study groups compared with that in normal controls (Table 2). Serum IGF-I was significantly lower in the cholestatic group than in the successful Kasai group. Serum IGF-I in the other three groups lay between the values in the cholestatic and successful Kasai groups. Baseline serum IGFBP-2 was significantly higher in all study groups compared with normal control levels. The highest values were found in the Alagille group, which were significantly higher than those in other groups. Baseline serum IGFBP-3 was significantly lower in the portal hypertension, cholestatic, and short stature groups compared with those in the normal controls, successful Kasai group, and Alagille group. Baseline serum ALS was significantly lower in the portal hypertension, cholestatic, short stature, and Alagille groups compared with those in the normal controls and successful Kasai group.

Effect of GH administration

After 4 days of GH treatment (0.2 IU/kg·day), serum IGF-I and IGFBP-3 rose significantly in the successful Kasai and cholestatic groups (Fig. 1). There was no significant change in IGF-I and IGFBP-3 in the other groups. Serum IGF-I and IGFBP-3 in the successful Kasai group rose to concentrations significantly higher than control values. After 4 days, serum IGF-I and IGFBP-3 in the short stature, portal hypertension, and Alagille groups was not significantly different from control values. In contrast, serum IGF-I and IGFBP-3 in the cholestatic group remained below control values. There were marked individual differences in the IGF-I and IGFBP-3 responses to GH (Fig. 1).

View larger version (23K): [in this window] [in a new window]   Figure 1. Upper panel, Change in serum IGF-I, determined by RIA, according to group in response to 0.2 IU/kg·day GH for 4 days and 0.4 IU/kg·day GH for an additional 4 days. The individual serum IGF-I response is shown together with the mean ± SEM of each group. Middle panel, Change in serum IGFBP-3, determined by immunoradiometric assay. The individual serum IGFBP-3 response is shown together with mean ± SEM of each group. Lower panel, Change in serum ALS, determined by enzyme-linked immunosorbent assay. The individual serum ALS response is shown together with mean ± SEM of each group.

There was no change in serum IGFBP-2 in response to either dose of GH (day 8 IGFBP-2: successful Kasai, 1.09 ± 0.13 mg/L; short stature, 1.27 ± 0.01 mg/L; portal hypertension, 1.11 ± 0.08 mg/L; cholestatic, 1.15 ± 0.04 mg/L; Alagille, 1.25 ± 0.09 mg/L).

There was no significant rise in serum ALS after 4 days of GH. After 8 days, serum ALS was significantly greater than baseline in the successful Kasai and Alagille groups (Fig. 1).

The final serum IGF-I correlated positively with height SD score (r = 0.4; P = 0.02), weight SD score (r = 0.43; P = 0.02), skinfold thickness SD score (TSF: r = 0.4; P = 0.03; SSF: r = 0.47; P = 0.01), midarm circumference SD score (r = 0.61; P = 0.001), and albumin (r = 0.64; P = 0.0002) and negatively with serum bilirubin (r = -0.37; P = 0.04) and -glutamyl transferase (r = -0.51; P = 0.004). The final serum IGFBP-3 correlated positively with skinfold thickness SD score (TSF: r = 0.46; P = 0.01; SSF: r = 0.51; P = 0.005), and albumin (r = 0.78; P = 0.0001) and negatively with serum bilirubin (r = -0.41; P = 0.03), International Normalisto Ratio (r = -0.59; P = 0.001) and -glutamyl transferase (r = 0.49; P = 0.007). The final serum ALS correlated positively with weight SD score (r = 0.38; P = 0.04), skinfold thickness SD score (TSF: r = 0.42; P = 0.02; SSF: r = 0.48; P = 0.01), midarm circumference SD score (r = 0.52; P = 0.007), and albumin (r = 0.64; P = 0.0002) and negatively with serum aspartate transaminase (r = -0.5; P = 0.006) and -glutamyl transferase (r = -0.48; P = 0.009). The percent increase in serum IGF-I, IGFBP-3, and ALS did not correlate with anthropometric indexes or measures of liver dysfunction. The correlations were unaffected if the children with Alagille syndrome were excluded.

Adverse side-effects

One child withdrew from the study after 4 days because he refused to have any more blood tests. Two children became pyrexial (39.0 and 38.7 C) during the second half of the study. The fever resolved spontaneously within 48 h of stopping GH. No source of sepsis was found. No headaches or peripheral edema were reported.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This is the largest study in which children with liver disease have been given GH. It shows that children with chronic liver disease respond to larger doses of GH than those used for GH replacement therapy by increasing their serum IGF-I and IGFBP-3, and the magnitude of the response reflects their current nutritional status and liver function. There is a differential response of IGF-I and IGFBP-3, and portal hypertension appears to have a particularly deleterious effect on the IGF-I response. Children with Alagille syndrome behave differently from children with biliary atresia.

A successful Kasai portoenterostomy halts the progression of liver dysfunction caused by biliary atresia and reverses the jaundice in 70–90% of children operated on under 8 weeks of age (21). However, the diagnosis is often delayed, such that many children present late, and only 40% survive jaundice free and untransplanted into adulthood (22). Portal hypertension occurs in most children whose operation is delayed beyond 8 weeks of life, and fibrosis and biliary cirrhosis may affect parts of the liver where bile drainage is not achieved despite a successful operation. Four groups of children with biliary atresia representing increasing severity of liver disease were studied. Children with an uncomplicated, successful portoenterostomy account for 20–30% of children with biliary atresia, whereas children with short stature comprise a much smaller proportion. In the latter group, all anthropometric parameters are proportionately low. Children with severe portal hypertension develop skeletal muscle wasting and abdominal distension from hepatosplenomegaly. Portoenterostomy is unsuccessful in approximately 30–40% of infants. These children progress to hepatic failure within the first 2 yr of life and often require liver transplantation in infancy.

Despite normal growth and liver function, baseline IGF-I in the successful Kasai group was lower than that in age-matched controls. However, this group responded well to GH with marked IGF-I, IGFBP-3, and ALS production. The IGF-I response was comparable to the changes reported previously in the investigation of children with short stature (23). Children with short stature despite successful portoenterostomy had low serum IGF-I and IGFBP-3 levels, which responded well to both GH doses, bringing concentrations up to control values. However, the ALS response was less than that in the successful Kasai group. IGF-I concentrations were unchanged in the portal hypertension group despite increases in IGFBP-3. The physiological significance of this differential response is unclear, but may result in reduced IGF-I bioavailability. The underlying mechanism may involve the impaired hepatic delivery of other factors, such as insulin, which are required for normal IGF-I production (24).

Commensurate with their poor biochemical and nutritional states, the children with significant cholestasis had low IGF-I, IGFBP-3, and ALS concentrations in keeping with the findings in previous studies (6, 7). Although the percent increases in IGF-I and IGFBP-3 were similar to those in the successful Kasai and short stature group, the final IGF-I and IGFBP-3 concentrations remained below normal. There was individual variation in the response to GH within this group. Portal hypertension is also a feature of this group, and it appeared that the response to GH was poorer in those children with the worst portal hypertension. The effect of GH (0.27 IU/kg·day) has previously been studied in five cholestatic and malnourished children with progressive liver disease after portoenterostomy (12). In contrast to the current study, only one child showed an increase in IGF-I and IGFBP-3. The difference between the two studies may relate to the younger age of Bucuvalas’s patients. As GH does not regulate normal growth until the second year of life, it may be unreasonable to expect GH to have an effect in infants with chronic liver disease (25).

As it is well recognized that serum IGF-I and IGFBPs are regulated by nutritional intake (4), it is possible that variations in diet were partly responsible for the differences between the groups. However, this effect is likely to be small, as each child was assessed to ensure that they were consuming a diet that was adequate in both protein and energy.

Two doses were used to examine whether there was a graded response in pediatric liver disease. Although IGF-I concentrations were higher after the higher GH dose, the extra gain was statistically insignificant. In contrast, IGFBP-3 continued to rise during the second half of the study, resulting in a possibly disadvantageous fall in the IGF-I to IGFBP-3 molar ratio after the higher GH dose.

Growth-retarded children with Alagille syndrome have been reported to be insensitive to GH (11). However, the dose used was 0.13 IU/kg·day for 3 days, and this may explain the difference between the two studies. Similar to the findings in Bucuvalas’s study and in contrast to results in growth-retarded children with biliary atresia, children with Alagille syndrome had normal baseline IGFBP-3 concentrations. The hepatic production of IGFBP-3 has been localized to Kupffer cells, in contrast to IGF-I and other IGFBPs, which are synthesized in parenchymal hepatocytes (26). In biliary atresia, cirrhosis may lead to Kupffer cell activation and altered function. In contrast, cirrhosis occurs in as few as 20% of children with Alagille syndrome. The maintenance of normal Kupffer cell function in Alagille syndrome may explain the difference in IGFBP-3 concentrations between the two diagnoses. The response to GH of the children with Alagille syndrome was heterogeneous, and these differences were not wholly explained by differences in age, hepatic function, or nutritional status, suggesting that there are other unidentified factors that affect GH responsiveness.

It was surprising that GH had no effect on IGFBP-2 concentrations, as serum IGFBP-2 is suppressed by GH in healthy subjects (27). This suggests that factors associated with pediatric liver disease, such as circulating cytokines, may be responsible for the increased IGFBP-2, and these cannot be overcome by GH treatment in the short term.

It is unclear how these findings could be translated into a clinically beneficial effect in children with chronic liver disease, as it is unknown whether the short term increases in IGF-I and IGFBP-3 could be maintained over the longer term and whether the changes would effect an anabolic response. The direct effects of GH on growth plate and muscle have not been studied and may contribute to an anabolic response even in the sickest patients. There were individual variations in IGF-I response, as has been found in short normal children, and the full potential benefit of GH treatment for these children will require longer term studies.

In conclusion, this study has shown that the GH resistance in pediatric liver disease can be partially overcome by GH doses higher than those normally used for GH replacement, although the effect was less with increasing severity of liver disease. The study provides evidence that GH resistance worsens with the progression of liver disease.

	Acknowledgments

 
We thank Pharmacia-Upjohn for providing the GH; Giorgina Mieli-Vergani, King’s College Hospital, for allowing us to study her patients; and Dr. Paul Cheeseman for his assistance with preparation of the serum.

	Footnotes

 
¹ This work was supported by the Children’s Liver Disease Foundation (Project Grant NL 1729).

² Medical Research Council Training Fellow.

³ Supported by the Wellcome Trust.

Received February 22, 1999.

Revised May 19, 1999.

Accepted June 21, 1999.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Holt, R. I. G. Articles by Miell, J. P. Search for Related Content PubMed PubMed Citation Articles by Holt, R. I. G. Articles by Miell, J. P. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Bile Duct Diseases Liver Diseases