Safety and efficacy of treatment of pediatric cholesteryl ester storage disease with lovastatin.

The aim of this study was to prospectively assess the safety and efficacy of lovastatin in the treatment of cholesteryl ester storage disease in siblings who were ages 11.6 and 5 y at the beginning of treatment. Mean total and LDL cholesterol in the male proband, 7.40 and 5.68 mmol/L, respectively, on diet alone, fell 30% to 5.2 (p < or = 0.001) and 31% to 3.9 mmol/L (p < or = 0.001) on lovastatin 40 mg/d over 3.3 y, with simultaneous resolution of hepatosplenomegaly. In his sister, on lovastatin 20 mg/d for 1.5 y, total and LDL cholesterol fell, but not significantly; her hepatosplenomegaly was also reduced on treatment. Lovastatin was well tolerated without overt side effects or complications and without adverse changes in liver function tests or creatine phosphokinase. Normal and expected accretion of height and weight occurred during the treatment period for both children. Lovastatin appears to be a safe and effective treatment for pediatric cholesteryl ester storage disease.     

Effects of ursodeoxycholic acid therapy for liver disease associated with cystic fibrosis

The hydrophilic bile acid ursodeoxycholic acid (UDCA) has recently been shown to improve indexes of liver function in adult patients with various liver diseases. The clinical and biochemical responses to UDCA administration (10 to 15 mg/kg body weight per day) were therefore investigated in nine patients with cystic fibrosis and evidence of liver disease. All patients were receiving pancreatic enzymes and taurine supplementation. Liver function tests were done and serum bile acid concentrations and biliary bile acid composition were determined before and during UDCA therapy; fat balance studies and fecal bile acid excretion were carried out before and 6 months after UDCA treatment. After 2 months of bile acid therapy, biliary bile acid composition was enriched in UDCA from approximately 5% before treatment to 25%, at the expense of cholic and chenodeoxycholic acids, thus making the pool more hydrophilic. This enrichment is lower than that reported for adults with chronic liver diseases. Serum concentrations of UDCA increased significantly but variably. UDCA became the predominant fecal bile acid excreted (12% to 67%), indicating a variable absorption of the administered bile acid. Liver function improved in all patients after 2 to 6 months of therapy, although the degree of improvement (aspartate aminotransferase, -34%; alanine aminotransferase, -41%; gamma-glutamyltranspeptidase, -41% alkaline phosphatase, -19%) was lower than that observed in adults with chronic liver diseases. Mean coefficient of fat absorption and growth rate were, on average, unaffected by UDCA therapy, although an improvement was noted for three patients with greater severity of steatorrhea. The study indicates that UDCA can be used safely in this patient population but that higher doses of UDCA may be of greater benefit in the treatment of the liver disease associated with cystic fibrosis.     

Lovastatin therapy in receptor-negative homozygous familial hypercholesterolemia: lack of effect on low-density lipoprotein concentrations or turnover

To determine whether at least part of the fall in low density lipoprotein (LDL) levels during lovastatin therapy might be the result of a reduced secretion of lipoproteins by the liver, three children 6 to 9 years of age with receptor-negative homozygous familial hypercholesterolemia underwent treatment with lovastatin. These patients have no capacity to synthesize LDL receptors. During lovastatin therapy, at a dose of 2 mg/kg/day, there was no decrease in LDL-cholesterol levels, nor was the turnover rate of LDL affected by the drug. The only significant change was a 74% drop in very low-density lipoprotein during treatment. We conclude that lovastatin is not effective in treatment of receptor-negative homozygous familial hypercholesterolemia. The most likely mechanism of action for this drug is to increase LDL receptor activity.     

Increase of serum lipoprotein (a) levels during growth hormone therapy in normal short children

We studied the effect of growth hormone (GH) therapy on serum lipoprotein levels and the atherogenic index in short children without GH deficiency. Fasting blood samples were collected from ten (eight males) normal, short, prepubertal children, aged 6–12 years, before, during a 1-year course of GH therapy (0.1 IU/Kg/day), and 3 months after the cessation of GH administration. An increase in serum lipoprotein(a) [Lp(a)] levels of (mean% ± SEM) 43 ± 14, 58 ± 18, 61 ± 17 above the baseline levels was noted at 3 months (P<0.05), 6 months (P<0.01), and 1-year (P<0.01) respectively after the beginning of GH administration. (ANOVA, P<0.01). An inverse relationship between baseline serum Lp(a) concentrations and the percentage increment in Lp(a) after 9 months of GH therapy (r=−0.65,P<0.05) was observed. GH therapy over a period of 1 year had no effect on plasma cholesterol, triglycerides, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein cholesterol [HDL-C] concentrations and the atherogenic index. Three months after the cessation of GH therapy, serum Lp(a) levels were not significantly different from the pre-treatment values. Conclusions Serum Lp(a) concentrations remained above pretreatment values during a 1-year period of GH treatment in short children without GH deficiency and declined shortly after cessation of therapy. Since GH therapy for short children without GH deficiency usually continues for several years, we suggest that serum Lp(a) levels should be determined and followed regularly in such children under prolonged GH therapy. Received: 11 February 1997 and in revised form: 10 June 1997 / Accepted: 6 July 1997     

Liver abnormalities during growth hormone treatment

BACKGROUND: Occasional and transient increase in liver enzymes is reported during growth hormone (GH) treatment in girls with Turner syndrome (TS). METHODS: Retrospectively, the specific role of GH treatment on liver and muscular enzymes was evaluated in 78 patients (48 boys; age range 4.0-20.8 years) affected by GH deficiency (GHD) who had been treated with GH for at least 1 year (range: 1-15 years). All patients had normal serum levels of liver and muscular enzymes before GH therapy was started. RESULTS: A clinically asymptomatic and mild increase in serum transaminase levels was observed in 6 of 78 patients with GHD during GH treatment; 3 (3.8%) of the patients showed an isolated, transitory and self-limiting increase in serum liver transaminase levels which was noticed 6 to 12 months after GH treatment was started, and normalized spontaneously within 3 to 6 months, without stopping the therapy. Three additional patients showed a transitory mild increase both in aspartate aminotransferase (AST) and creatine phosphokinase (CK) which also normalized spontaneously within 3 to 6 months. The increase in transaminase levels was not related to the brand of GH preparations nor to the dosage administered. CONCLUSIONS: A mild, transient, self-limiting increase in serum transaminase may occur during GH treatment. Concomitant determination of CK serum levels may quickly differentiate muscular from hepatic hypertransaminasemia. Except for persistent cases, this condition does not generally require further investigations.     

Increase of Serum Lipids and Serum Lipoproteins in Girls under Therapy with Estrogen and Norethisteron for Height Reduction

ABSTRACT. The effect of a combined treatment with ethinyl estradiol and norethisteron for height reduction on serum lipids and lipoproteins was investigated in 23 excessively tall girls (>97th percentile). Serum cholesterol, triglycerides, HDL-C and LDL-C were determined before and 3, 6, 9 and 12 months after the onset and 3 to 12 months after cessation of therapy. Treatment with ethinyl estradiol and norethisteron resulted in significant ( p <0.01) mean increases in serum cholesterol, triglycerides, HDL-C, and LDL-C of 20.6%, 95.5%, 23.6%, and 22.2% above pretreatment values, respectively. This increase occurred during the first 3 months of therapy and thereafter no further significant change was observed. After cessation of therapy elevated levels returned to pretreatment levels within 3 to 12 months in all but two patients. The results obtained suggest an influence of ethinyl estradiol and norethisteron on serum lipids and lipoproteins. Whether these reversible changes of serum lipids and lipoproteins are associated with an increased risk for developing atherosclerosis has to be evaluated in long term investigations.     

Clinical,biochemical and histological analysis of seven patients with cholesteryl ester storage disease

Lysosomal acid lipase (LAL) deficiency leads to two phenotypically different diseases: cholesteryl ester storage disease (CESD) and Wolman's disease. Lysosomal acid lipase hydrolyzes cholesteryl esters and triglycerides. Deficiency of LAL results in intralysosomal storage of cholesteryl esters and triglycerides. CESD has a chronic and benign course and is characterized by hepatomegaly and mild hypercholesterolemia. It leads to fibrosis (cirrhosis) and early atherosclerosis. This report presents the clinical, biochemical and microscopic data of seven patients with CESD followed up over 10 years. The physical development of all the study children remained within the normal range; 7 patients had hepatomegaly and 6 also had splenomegaly. Three patients had normal cholesterol, triglycerides and transaminases values; the other four had slightly elevated levels for these parameters. The activity of LAL in all patients was reduced to below 30% of the lower normal value. Histologically, cholesteryl crystals and lipid storage vacuoles in Kupffer cells were present in all examined patients except one. Accumulation of cholesteryl esters was visible on thin-layer chromatography of lipid extracts obtained from liver biopsies.     

Serum cholesterol ester fatty acids in 7- and 13-month-old children in a prospective randomized trial of a low-saturated fat, low-cholesterol diet: the STRIP baby project

To evaluate changes that occur in serum cholesterol ester fatty acid composition during the transition from typical infant feeding to a more adult type of nutrition, this study compared the effects on serum cholesterol ester fatty acids of breast milk or formula at the age of 7 mo with effects caused by 6-mo dietary intervention in 137 children. The intervention [Special Turku coronary Risk factor Intervention Project for children (STRIP baby project)] aimed at a reduction of saturated fat intake to 10% of energy after the age of 1 y without purposefully influencing total fat intake. Nutrient intakes were calculated from 3-d food records. At the age of 7 mo, i.e. before dietary education began, milk type markedly influenced dietary and serum cholesterol ester fatty acid composition (mean serum cholesterol ester 16:0 in breastfed vs formula-fed infants, 13.7% vs 12.0%, respectively, p < 0.001; serum cholesterol ester 18:2n-6 50.6% vs 57.6%, p < 0.001). At the age of 13 mo the calculated fat intake of the intervention and control children differed markedly but serum cholesterol ester fatty acid compositions in all children resembled closely those measured in 7-mo-old breastfed infants, e.g. at the age of 13 mo the relative proportions of 18:2n-6 were 49.9% and 51.1% in previously formula-fed intervention and control children, respectively, and 50.3% and 50.1% in previously breastfed intervention and control children, respectively. In conclusion, serum cholesterol ester fatty acid composition reflected differences in dietary fat quality (breast milk or formula) at the age of 7 mo, whereas dietary intervention as applied in the STRIP baby project had only a minimal effect.     

Increase of serum lipids and serum lipoproteins in girls under therapy with estrogen and norethisteron for height reduction

The effect of a combined treatment with ethinyl estradiol and norethisteron for height reduction on serum lipids and lipoproteins was investigated in 23 excessively tall girls (greater than 97th percentile). Serum cholesterol, triglycerides, HDL-C and LDL-C were determined before and 3, 6, 9 and 12 months after the onset and 3 to 12 months after cessation of therapy. Treatment with ethinyl estradiol and norethisteron resulted in significant (p less than 0.01) mean increases in serum cholesterol, triglycerides, HDL-C, and LDL-C of 20.6%, 95.5%, 23.6%, and 22.2% above pretreatment values, respectively. This increase occurred during the first 3 months of therapy and thereafter no further significant change was observed. After cessation of therapy elevated levels returned to pretreatment levels within 3 to 12 months in all but two patients. The results obtained suggest an influence of ethinyl estradiol and norethisteron on serum lipids and lipoproteins. Whether these reversible changes of serum lipids and lipoproteins are associated with an increased risk for developing atherosclerosis has to be evaluated in long term investigations.     

Follow up study on children with dyslipidaemia detected by mass screening at 18 months of age: effect of 12 months dietary treatment

The present study was done to evaluate the effect of short-term dietary therapy on 148 dyslipidaemic children (24 familial hypercholesterolaemia, 105 non-familial hypercholesterolaemia and 19 hypertriglyceridaemia), detected by mass screening in children at 18 months of age. In the model diet used for treatment, 15% of the total calories were obtained from protein, 27% from fat and 57% from carbohydrate. Cholesterol intake was set at <200 mg/day and the ratio of polyunsaturated to saturated fatty acid (P/S ratio) was 1.2. When compared to the composition of the diet ingested by the dyslipidaemic children, only the P/S ratio changed from 0.7 to 1.2. During 12 months treatment, levels of total cholesterol, low density lipoproteins cholesterol and apoB decreased by 10%–15% in children with familial and non-familial hypercholesterolaemia. There was no significant change in the levels of high density lipoproteins. In 19 children with hypertriglyceridaemia, the intake of carbohydrate was limited to 55% of the total calories consumed and after 12 months of treatment, triglyceride levels reverted to normal. Throughout the study period, apprimately 70% of the children on this dietary therapy were seen in our clinics every 3–6 months and physical development was within normal ranges. These results, taken together, indicate that dietary therapy can be effective for correcting dyslipidaemia, even in young children.     

Cerebral cysticercosis: treatment with praziquantel

An infant with cerebral cysticercosis had marked clinical and radiographic improvement following treatment with praziquantel. Computed tomographic appearance and radioimmunoassay were helpful in establishing the diagnosis. Disappearance or size reduction of all active lesions were documented by computed tomography 6 months after praziquantel treatment. Simultaneous administration of dexamethasone during praziquantel treatment is essential to prevent reactive cerebral edema during treatment.     

Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis.

To evaluate the adverse effects associated with long-term methotrexate (MTX) therapy in children with juvenile rheumatoid arthritis, we conducted a retrospective review of 62 patients with polyarticular juvenile rheumatoid arthritis, treated from 84 to 296 weeks with MTX weekly. Pulmonary function testing was performed before MTX therapy on 46 patients older than 6 years of age; 26 patients had serial pulmonary function testing, and no abnormalities were detected. In all 62 patients, liver function (alanine aminotransferase and aspartate aminotransferase activity) was monitored every 3 months. Transient liver function abnormalities developed in nine patients during treatment. Twelve patients underwent percutaneous liver biopsies after receiving 815 to 2980 mg of MTX; none had fibrosis or cirrhosis. Macrocytic anemia developed in one child receiving simultaneous long-term trimethoprim-sulfamethoxazole therapy and resolved after the trimethoprim-sulfamethoxazole was discontinued. No stomatitis or rashes were observed. Six patients were able to discontinue MTX therapy when their disease remitted; 56 continue MTX therapy. No child permanently discontinued MTX therapy because of an adverse effect. These data suggest that MTX may be better tolerated in children with juvenile rheumatoid arthritis than in adults with rheumatoid arthritis.     

Hyperlipidemia and fatty acid composition in patients treated for type IA glycogen storage disease

Because glycogen storage disease type IA (GSD-IA) is characterized by recurrent episodes of hypoglycemia that promote a marked elevation in blood triglyceride levels, we evaluated plasma lipid levels in 12 patients with GSD-IA on a regular basis. Six of the 12 patients had plasma fatty acid composition measured; because of possible essential fatty acid deficiency, urinary prostaglandin excretion was also measured. All patients had triglyceride levels between 1440 and 6120 mg/dl (16.25 to 69.09 mmol/L) before treatment. After treatment to promote blood glucose levels of 75 to 85 mg/dl (4.2 to 4.7 mmol/L), triglyceride levels in each of 11 patients were between 189 +/- 31 (2.13 +/- 0.35 mmol/L) and 510 +/- 60 mg/dl (5.76 +/- 0.68 mmol/L). The lipoprotein fatty acid composition in six patients showed a substantial elevation in C16:0, C16:1 omega 7, and C18:1 omega 9, but no increase in C20:3 omega 9 (the fatty acid that characteristically increases in essential fatty acid deficiency). In addition, each of the six patients had normal 24-hour urinary excretion of prostaglandin. One patient, whose triglyceride levels remained elevated despite dietary treatment, was given either clofibrate, lovastatin, niacin, or fish oil. With the exception of lovastatin, these agents produced a decrease in triglyceride values for 1 to 2 months; however, by 3 months triglycerides reached pretreatment levels. Combined treatment with clofibrate and niacin resulted in a sustained decrease in plasma triglyceride levels for 4 months. The findings indicate that dietary management of GSD-IA is usually associated with improvements in triglyceride levels; however, patients maintain triglyceride values between 300 and 500 mg/dl (3.38 to 5.65 mmol/L). No patient had biochemical evidence of essential fatty acid deficiency.     

The usefulness of bone marrow aspiration in the diagnosis of Niemann-Pick disease type C in infantile liver disease.

BACKGROUND: Niemann-Pick disease type C (NPC) is a fatal, autosomal recessive lysosomal storage disease which may present in infancy with cholestatic jaundice and/or hepatosplenomegaly. In cholestatic patients with splenomegaly, a bone marrow aspirate has been advocated as a relatively accessible tissue to demonstrate storage phenomena. Typically in patients with NPC, macrophages with abnormal cholesterol storage, so called foam cells, can be detected in the bone marrow. AIM: To review our experience of bone marrow aspiration in children with NPC presenting with infantile liver disease. METHODS: A retrospective analysis of 11 consecutive children (8 males) from Birmingham Children's Hospital with NPC presenting with infantile liver disease was undertaken. The diagnosis of NPC was confirmed in all cases by demonstrating undetectable or low rates of cholesterol esterification and positive filipin staining for free cholesterol in cultured fibroblasts. RESULTS: The median age at presentation was 1.5 months (range 0.5-10). Bone marrow aspirates showed storage cells in only 7/11 cases. Bone marrow aspirates which had storage cells were undertaken at a median age of 11 months while those with no storage cells were undertaken at median age 2.3 months. The overall sensitivity of bone marrow aspirates for detecting storage cells in children presenting with infantile liver disease was 64%; however, for children who had bone marrow aspirates in the first year of life it was only 57%. CONCLUSIONS: The sensitivity of bone marrow aspirate for the diagnosis of NPC disease in patients presenting with infantile liver disease was lower than previously reported. Where NPC is suspected clinically, definitive investigations should be undertaken promptly. There is a need to develop sensitive screening methods for NPC in children presenting with infantile liver disease.     

Dextrothyroxine treatment of phosphorylase-kinase deficiency glycogenosis in four boys.

Four boys, aged 2 years 5 months to 3 years 7 months, with large hepatomegaly due to phosphorylase-kinase deficiency glycogenosis, were given a trial of sodium dextrothyroxine (D-T4) at a mean dose of 0.165 mg/kg/day for an average period of 6 months. Phosphorylase-kinase was undetectable in the haemolysates of erythrocytes (3 patients) or in the liver (one patient) before, and still undetectable in the haemolysates of the four patients during treatment, thus pointing to X-linked phosphorylase-kinase deficiency glycogen storage disease (GSD IXb). D-T4 administration resulted in complete normalization of liver size, decrease of serum GOT (p less than 0.02), GPT (p less than 0.05) and triglycerides (p less than 0.01) to normal values, as well as correction of mild asymptomatic hypoglycemia (p less than 0.01). As long as the outcome of type IXb glycogenosis in adult life remains undefined, dextrothyroxine therapy seems an effective means of reducing liver size and correcting part of the biochemical abnormalities of the disease.     

Cholesterol ester storage disease: clinical, biochemical, and pathological studies of four new cases

Cholesterol ester storage disease (CESD) is infrequent in children. Four new cases in two nonrelated families are presented. Acid lipase deficiency in the leukocytes of the patients and reduced activity (50%) in those of parents were demonstrated. Clinical manifestations varied from neonatal cholestasis to asymptomatic hepatomegaly. Hepatic histology showed lipid vacuoles and cholesterol ester storage in hepatocytes and Kupffer cells. Increased levels of cholesterol and hepatomegaly were the first findings. There is as yet no specific treatment for CESD; however, the early detection of cases would make possible the timely control of complications.     

Failure of ursodeoxycholic acid to dissolve radiolucent gallstones in patients with cystic fibrosis

Ursodeoxycholic acid has been used widely to dissolve cholesterol gallstones and more recently was shown to improve clinical symptoms and biochemical indices in different chronic liver diseases, including that associated with cystic fibrosis. We treated 10 cystic fibrosis patients (5 males, 5 females, age range 2–22 years) with pancreatic insufficiency and normal liver function with ursodeoxycholic acid 15–20 mg/kg/day. Seven patients had radiolucent gallstones (in 3 cases associated with biliary sludge) and 3 had sludge; all were asymptomatic. Before treatment, the gallbladder was well opacified in oral cholecystogram. The gallbladder was scanned by ultrasound in similar conditions and by the same operator before administration of ursodeoxycholic acid and after a median period of treatment of 16 months (range 11–32 months). During treatment, all patients remained asymptomatic and the relative proportion of ursodeoxycholic acid in duodenal bile increased from 4.7 ± 3.2% at baseline to 34.7 ± 8.6%. Complete or partial dissolution of gallstones was never observed and the maximum diameter of stones increased from a mean of 6.1 ± 3.4 to 8.0 ± 5.3 mm; in one case the development of biliary sludge occurred during bile acid therapy. Sludge disappeared in 1 of the 6 patients who initially had it, while in 2 cases its volume increased. We conclude that ursadeokycholic acid is not effective in most CF patients with gallstones, probably because cholesterol is not the main component of stone or sludge.     

The usefulness of bone marrow aspiration in the diagnosis of Niemann-Pick disease type C in infantile liver disease

Background

Niemann–Pick disease type C (NPC) is a fatal, autosomal recessive lysosomal storage disease which may present in infancy with cholestatic jaundice and/or hepatosplenomegaly. In cholestatic patients with splenomegaly, a bone marrow aspirate has been advocated as a relatively accessible tissue to demonstrate storage phenomena. Typically in patients with NPC, macrophages with abnormal cholesterol storage, so called foam cells, can be detected in the bone marrow.

Aim

To review our experience of bone marrow aspiration in children with NPC presenting with infantile liver disease.

Methods

A retrospective analysis of 11 consecutive children (8 males) from Birmingham Children''s Hospital with NPC presenting with infantile liver disease was undertaken. The diagnosis of NPC was confirmed in all cases by demonstrating undetectable or low rates of cholesterol esterification and positive filipin staining for free cholesterol in cultured fibroblasts.

Results

The median age at presentation was 1.5 months (range 0.5–10). Bone marrow aspirates showed storage cells in only 7/11 cases. Bone marrow aspirates which had storage cells were undertaken at a median age of 11 months while those with no storage cells were undertaken at median age 2.3 months. The overall sensitivity of bone marrow aspirates for detecting storage cells in children presenting with infantile liver disease was 64%; however, for children who had bone marrow aspirates in the first year of life it was only 57%.

Conclusions

The sensitivity of bone marrow aspirate for the diagnosis of NPC disease in patients presenting with infantile liver disease was lower than previously reported. Where NPC is suspected clinically, definitive investigations should be undertaken promptly. There is a need to develop sensitive screening methods for NPC in children presenting with infantile liver disease.     

Neonatal intrahepatic cholestasis with hepatic siderosis and steatosis

Abstract Neonatal intrahepatic cholestasis is a heterogeneous disease of undetermined cause. There is an unreported subset of idiopathic neonatal intrahepatic cholestasis with an unusual histological combination of hepatic siderosis and macrovesicular steatosis. The patients were a 34-day-old female and a 39-day-old male with normal birth weights. Their mothers had received oral iron supplement4–6 weeks before delivery. The patients had obstructive jaundice noticed at the well-baby clinic at 1 month of life. They had high levels of serum galactose and tyrosine, hyperferritinemia. Urinary organic acid and bile acid analyses were negative, and galactose-1-phosphate uridyltransferase activity in red cells was normal. Liver biopsies showed diffuse iron deposits and macrovesicular fat. By substituting formula milk with lactose-free milk, the patients responded, and had normal biochemical tests within 5 months of life. Follow-up biopsies, at the age of 12 months, showed mild residual fibrosis without iron or fat deposits. They are both well at 3 and 6 years of age, respectively, without biochemical liver dysfunction and neurologic impairment. Prenatal iron-overload might contribute to the pathogenesis of the disease, but further studies are needed to confirm the assumption.     

Early increases in concentrations of total, LDL, and HDL cholesterol in HIV-infected children following new exposure to antiretroviral therapy

Antiretroviral therapy (ART) is associated with dyslipidemia and cardiovascular disease in adults infected with HIV. For children perinatally infected with HIV, ART exposure is lifelong and early-onset dyslipidemia could have significant long-term effects. We examined cholesterol levels in children during the first year after exposure to a new ART regimen (initiation or switch). In 52 children, total cholesterol increased by 30.5 and 43 mg/dL at 6 and 12 months, respectively (P < 0.001). Low-density lipoprotein cholesterol made the largest contribution, but high-density lipoprotein cholesterol also increased within months of therapy alteration. Early identification of these children and intervention could mediate potential increased risk for future cardiovascular disease.