Extrahepatic portal vein obstruction (EHPVO), leading to portal hypertension, is the most common cause of upper gastrointestinal bleeding in children in India (1,2). Patients present with splenomegaly or variceal bleeding. Hepatocellular functions have been reported to be normal. Radiologically, a portal or splenic vein block is seen or there is formation of a portal cavernoma around the block. Liver histology, apart from mild portal fibrosis, is normal (3). The etiology of the obstruction is not clear to date, though hypotheses forwarded have implicated umbilical sepsis, congenital portal vein malformations, dehydration, and hypercoagulable states (4,5).
It has been the clinical experience of physicians treating these patients that they have growth retardation. However, this has been objectively documented in only one study so far (6). There is no literature regarding the cause of growth retardation in this condition. Recent studies in patients with cirrhosis and portal hypertension, however, have documented growth hormone resistance (7,8).
We undertook a prospective study to document the growth and nutrition of a group of children with this disease who were under our care. We also carried out a preliminary study of growth hormone (GH) and insulin-like growth factor I (IGF-I) levels in our patients.
Thirty-three consecutive prepubertal children (23 boys and 10 girls) seen in the pediatric gastroenterology service of our hospital and diagnosed to have EHPVO were enrolled in the study. They were aged 1.5 to 12 years, with a median age of 7 years. Diagnosis of EHPVO was based on the history of upper gastrointestinal bleeding, presence of splenomegaly, endoscopic demonstration of esophageal varices, and the documentation of a block in the portal and/or splenic vein on ultrasonography. All the patients had normal liver function tests. None had edema or ascites. A mean of 4 episodes (range, 1-9) of upper gastrointestinal bleeding occurred per child before start of endoscopic sclerotherapy (EST). An average of 8 (range, 5-13) EST sessions, at intervals of 2-3 weeks, were needed to achieve variceal obliteration. During EST, 7 children had interval bleeding, all before the third EST session. Children were entered into the study after complete variceal obliteration, at least 3 months after their last bleed. At this stage, every child was documented to have normal hemoglobin and serum albumin.
General Clinical Workup
In addition to history relevant to portal hypertension, particular emphasis was given to symptoms of liver dysfunction, a review of systems for all causes of growth retardation, pubertal history, birth weight, and socioeconomic status. Detailed physical examination included a search for signs of undernutrition, vitamin and mineral deficiencies, dysmorphisms, pubertal status, and any organ system dysfunction, in addition to signs pertinent to portal hypertension.
Dietary history was taken from the mothers of the patients at the initial visit. At this time, they were given detailed instructions on filling out 3-day dietary recall pro forma, which served as the basis for intake calculations. Presence or absence of undernutrition was categorized based on weight for height.
Height was measured on a wall-mounted Holtain stadiometer by one of two trained observers throughout the study period. For children younger than 2 years of age, supine length was measured using a Holtain infantometer. Weight was taken on a beam balance with a minimal division of 100 g. Skinfold calipers were used for triceps and subscapular skinfold thickness measurements, which were converted into logarithmic scale for further calculations. Midarm muscle circumference (MAMC), an index of lean muscle mass, was calculated from midarm circumference (MAC) and triceps fold thickness (TT) using the equation: MAMC (cm) = MAC (cm) - (0.314 × TT in mm). Height and weight indices were expressed as standard deviation scores (z scores), calculated from reference data in well-nourished Indian children (9,10), to provide an index of deviation from national standards. However, these reference data did not include standards of weight for height, which was to be our basis for categorizing a child as undernourished or well nourished. Therefore, anthropometric indices of patients as well as controls were also converted into z scores using American reference data (11,12). Patients whose weight-for-height z score fell within 1 standard deviation of the mean of the weight-for-height z scores of the controls were categorized as being normally nourished at the present time. Differences in hormonal values between the patient and control groups were only evaluated in well-nourished patients.
At baseline, hemogram and serum chemistry including liver functions and serum proteins were performed. A fasting serum sample was taken at 8 AM for assay of GH and IGF-I. GH was assayed by polyclonal double antibody commercial RIA kits from Diagnostic Products Corporation, U.S.A. Acid ethanol-extracted IGF-I was measured by a commercial IRMA assay from Diagnostic Systems Laboratories, U.S.A. IGF-I levels are age- and sex-dependent, therefore the IGF-I values were expressed as standard deviation scores from reference data published by Diagnostic Systems Laboratories.
Thirty-five age- and sex-matched, prepubertal, well-nourished healthy controls, drawn from among the patients' siblings, were similarly evaluated. Controls weighed at least 80% of the 50th percentile of weight for age of National Centre for Health Statistics (NCHS) standards, as per norms of the Indian Academy of Pediatrics.
The mean of the z scores obtained for anthropometric indices and IGF-I values for patients were compared with that of controls. GH levels, which do not vary with age, were compared as mean of the whole patient group versus the control group. Student's t-test was used to test for statistically significant differences between groups for the anthropometric parameters. The values of GH and IGF-I z scores, whose distributions were not normal, were tested by nonparametric analysis (Wilcoxon rank sum test). Categorical variables were tested by the chi square test.
Informed consent was taken from patients of all subjects, and assent from the older subjects themselves, for participating in the study. Approval of the institutional ethics committee was taken before commencing the study.
All patients included in the study had normal hemoglobin levels, as well as normal liver functions including serum protein. When compared with reference data derived from well-nourished Indian children, 18 of the 33 patients (54.5%) were below the 5th percentile in height, compared to 2 of 35 controls (5.7%, p < 0.0001). Patients (mean height z score, -1.46 ± 1.37) were significantly shorter than controls (mean height z score, -0.56 ± 0.71, p < 0.001). Fourteen of the thirty-three patients (42.4%) were also below the 5th percentile for weight, versus 2 of 35 controls (5.7%, p < 0.01). Therefore, weight-for-height standard deviation scores were derived for all patients and controls.
The mean of the z scores of weight for height of the control group was -0.60 ± 0.73, using NCHS reference standards. Twenty-two patients had weight-for-height z scores greater than -1.33 (i.e., within 1 SD of that of the controls). The percent weight for height (i.e., weight of the child divided by the 50th percentile NCHS reference weight for height) was greater than 89% in all these 22 patients. These were categorized as having normal current nutritional status. Eight patients had z scores between 1 and 2 standard deviations of that of the controls, whereas the remaining three had a weight-for-height z score more than 2 standard deviations below that of the controls.
Comparison of anthropometry and hormone (GH and IGF-I) levels was carried out between 22 well-nourished patients and 35 controls (Table 1). Height z scores (using NCHS reference standards) were significantly lower in patients than in controls (p < 0.01). MAMC, an index of lean muscle mass, was lower in the patient group than the control group (p < 0.0001). Height and MAMC z scores had a positive correlation (r = 0.63, p < 0.01). In contrast, triceps skinfold thickness z scores, evaluated in 20 patients and 22 controls, were not significantly different in the 2 groups. GH was significantly elevated (p < 0.01) and IGF-I z scores were significantly lower (p < 0.001) in the patient group.
Reliable dietary evaluation was possible in only 21 of the 33 patients. The mean caloric intake was 84 calories per kilogram.
In this study of children with EHPVO, we have confirmed the presence of growth retardation not attributable to anemia, undernutrition, or deranged liver functions. The widely accepted anthropometric index of active undernutrition or “wasting” is weight for height. Our patients, who fulfilled sufficiently stringent criteria for normal nutrition based on weight for height, were significantly shorter than healthy controls from the same families. The anthropometric findings in our patients are consistent with a state of diminished growth hormone action. Anabolic action by GH on muscle growth leads to increased lean muscle mass, whereas its lipolytic effect results in decreased adiposity. Thus, lack of growth hormone action would lead to short stature, decreased midarm muscle circumference (an index of lean muscle mass), and preserved or increased skinfold thickness as seen in our patients. Two prospective studies on similar groups of patients have been reported previously. The patients reported by Sarin et al., like ours, were significantly shorter than the controls (6). However, their definition of normal percent weight for height was 80% rather than the generally used cutoff of 90%. The mean daily caloric intake of the control and patient groups, whose mean age was 8.4 years, was reported to be 55 cal/kg and 61 cal/kg, respectively. Thus, it is possible that some patients showed the effects of undernutrition as well as the disease. Hormonal studies were not performed in this study.
In contrast, the second study did not report growth retardation in their patients (13). Instead, they noted an increased growth velocity after shunt surgery. However, the authors did not mention the height standard deviation score of the patient group, either before or after surgery. Shunt surgery had been performed as the primary treatment for their bleed in most of their patients, unlike ours who were stabilized by sclerotherapy. The high postoperative growth velocity noticed in a subset of their patients was not quantitated. Thus, the reasons for possible differences between their observations and those of ours as well as Sarin et al. are not clear.
The pattern of elevated basal GH and decreased IGF-I in patients as compared to controls suggests a state of diminished GH action. The ideal test for spontaneous GH secretion is an integrated 24-hour profile. However, numerous studies have been able to document elevated basal GH levels in GH-resistant states like undernutrition (14), anorexia nervosa (15), and portal hypertension (8), though GH levels seen in classic GH insensitivity syndrome are usually (though not invariably) higher than those obtained in our patients. Since IGF-I levels are highly correlated with nutrition, and undernutrition is always a possibility in any chronic disease, care must be taken to exclude any possibility of undernutrition before interpreting IGF-I values. The patients whose hormonal data were compared with controls all had weight for height greater than 89% of expected by NCHS standards. Although chronic undernutrition in the past could also account for the same anthropometric features as found in our patients, the biochemical features found would not be explained by this.
GH resistance has been documented in previous studies on adults with portal hypertension caused by cirrhosis (7,8) as well as in children with chronic liver disease with or without portal hypertension (16). Assaad et al. have documented elevated basal GH in portal hypertension without parenchymal liver damage, which occurs in schistosomiasis (17). Moller et al., in a study of 22 patients with cirrhosis and portal hypertension, documented low IGF-I levels in the presence of raised basal GH (8). This was accompanied by low levels of IGF-binding protein (IGFBP) 3 and high levels of IGFBPI. The authors suggested that the high IGFBPI could result from the insulin resistance known to exist in cirrhotic patients (18,19). In a study of 9 children with chronic liver disease, Bucuvalas et al. documented short stature, preserved subutaneous skinfolds, low IGF-I values, and preserved insulin sensitivity in the presence of elevated integrated GH levels, suggesting resistance to the growth-promoting, lipolytic, and diabetogenic effects of GH (16).
The cause of GH resistance in our patients remains to be studied. EHPVO has been shown to result in diminished portal blood flow to the liver (20). Diminished portal blood supply has been demonstrated in cirrhotic patients to result in decreased insulin delivery to the liver (21). Thus, via the known inverse regulation of IGFBPI production by insulin, IGF-I action can be decreased. Additionally, studies on an animal model of portal vein ligation have shown poor hepatic growth as well as decreased mitochondrial function during the phase of decreased hepatic blood flow (22). GH receptor defects or impairments downstream of the receptor may thus be the cause.
In conclusion, we have confirmed that portal vein obstruction in children leads to growth retardation. Decreased lean muscle mass, preserved subcutaneous fat, and low IGF-I levels in the presence of high basal GH levels suggest a state of GH resistance. Alternative tests of GH secretion would be helpful in future studies. Further studies are necessary to elucidate the site and mechanism of the resistance.
Acknowledgment: The authors thank Ramesh Kumar for technical assistance A. B. Prajapati for secretarial assistance.
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