L. Lyndon Key

The Effects of a High-protein, Low-fat, Ketogenic Diet on Adolescents With Morbid Obesity: Body Composition, Blood Chemistries, and Sleep Abnormalities

Objective. To evaluate the efficacy and metabolic impact of a high-protein, low-carbohydrate, low-fat ketogenic diet (K diet) in the treatment of morbidly obese adolescents with initial weights of >200% of ideal body weight. Methods. Six adolescents, aged 12 to 15 years, weighing an average of 147.8 kg (range, 120.6–198.6 kg) and having an average body mass index of 50.9 kg/m2 (39.8–63.0 kg/m2), consumed the K diet for 8 weeks. Daily intake consisted of 650 to 725 calories, which was substantively in the form of protein (80–100 g). The diet was very low in carbohydrates (25 g) and fat (25 g). This was followed by 12 weeks of the K diet plus two carbohydrates (30 g) per meal (K+2 diet). Main Outcome Measures. Anthropometric data and blood and urine were collected at enrollment, during week 1, and at 4-week intervals throughout the course of the study. Resting energy expenditure was measured by indirect calorimetry. Body composition was estimated using dual-energy x-ray absorptiometry, bioelectrical impedance analysis, and urinary creatinine excretion at enrollment and on completion of each phase of the diet. Nocturnal polysomnography and multiple sleep latency testing were conducted at baseline and repeated after an average weight loss of 18.7 kg to determine sleep architecture, frequency and duration of apneas, and daytime sleepiness. Results. Subjects lost 15.4 ± 1.4 kg (mean ± SEM) during the K diet and an additional 2.3 ± 2.9 kg during the K+2 diet. Body mass index decreased 5.6 ± 0.6 kg/m2during the K diet and an additional 1.1 ± 1.1 kg/m2during the K+2 diet. Body composition studies indicated that weight was lost equally from all areas of the body and was predominantly fat. Dual-energy x-ray absorptiometry showed a decrease from 51.1% ± 2.1% body fat to 44.2% ± 2.9% during the K diet and then to 41.6% ± 4.5% during the K+2 diet. Lean body mass was not significantly affected. Weight loss was accompanied by a reduction in resting energy expenditure of 5.2 ± 1.8 kcal/kg of fat-free mass per day. Blood chemistries remained normal throughout the study and included a decrease in serum cholesterol from 162 ± 12 to 121 ± 8 mg/dL in the initial 4 weeks of the K diet. An increase in calcium excretion was accompanied by a decrease in total-body bone mineral content. A paucity of rapid eye movement sleep and excessive slow-wave sleep were seen in all subjects at enrollment. Weight loss led to an increase in rapid eye movement sleep (P < .02) and a decrease in slow-wave sleep (P < .01) to near normal levels. Conclusions. The K diet can be used effectively for rapid weight loss in adolescents with morbid obesity. Loss in lean body mass is blunted, blood chemistries remain normal, and sleep abnormalities significantly decrease with weight loss.

Combination Macrophage-Colony Stimulating Factor and Interferon-γ Administration Ameliorates the Osteopetrotic Condition in Microphthalmic (mi/mi) Mice

ABSTRACT: Malignant osteopetrosis is a fatal congenital bone disorder characterized by defective osteoclastic function. Death frequently occurs within the first decade of life. The precise molecular defect(s) that causes osteopetrosis is not known. The possibility that osteoclasts, like macrophages, are controlled by interactions with cytokines suggests that these agents may provide a means of increasing osteoclastic function. Macrophage-colony stimulating factor (M-CSF), a cytokine known to enhance macrophage and osteoclast generation, and recombinant human interferon-γ (rIFN), a cytokine known to stimulate superoxide generation by white cells, were administered to microphthalmic (mi/mi) mice in an attempt to improve the osteopetrotic condition. Each cytokine was administered separately and in combination to neonatal mi/mi mice for 7 consecutive d. Bone turnover, osteoclast numbers, superoxide generation by white cells, and hematocrit were assessed. rIFN, M-CSF, and a combination of the cytokines stimulates oxygen-derived free radical production by white cells and increased bone resorption. rIFN resulted in a reduction in the number of osteoclasts. This reduction in number was ameliorated by M-CSF. M-CSF alone and in combination with rIFN resulted in improved hematopoietic function, increased weight gain, and increased physical activity of the affected mutants.

Response to growth hormone in children with chondrodysplasia

Theoretic concerns exist that children with chondrodysplasia will not grow in response to growth hormone (GH) therapy because of an inability of the abnormal growth cartilage to respond. Experience to date, however, suggests that there is an increase in growth velocity, especially during the first year of treatment, which may be beneficial. Growth has increased during the early phases of GH therapy in both patients with achondroplasia and patients with hypochondroplasia. Fourteen patients with achondroplasia in the National Cooperative Growth Study have been treated with an average dose of GH of 0.317 mg/kg per week for an average of 2.6 years and have gained an average of 0.7 SD in height. Twenty patients with hypochondroplasia in the National Cooperative Growth Study have been treated with an average dose of GH of 0.317 mg/kg per week for an average of 2.6 years and have gained an average of 0.7 SD in height. These data suggest that the abnormal growth cartilage in patients with chondrodysplasia responds to GH therapy. The effect on final height cannot be predicted with the currently available data.

Developmental spectrum of children with congenital osteopetrosis

This study reports on the developmental status of 23 children, ranging in age from 2 weeks to 11 years, with the severe form of autosomal recessive osteopetrosis. Results revealed widely scattered cognitive, adaptive, and language scores and delayed gross motor skills.

Osteopetrosis. The pharmaco-physiologic basis of therapy.

Medical treatments of osteopetrosis have attempted to improve hematologic function, reduce the osteosclerotic condition, and/or improve immune function. Prednisone therapy has improved hematologic function in some patients, but has not resulted in a reduction in bone mass. Calcium deficient diets have limited further sclerosis in some patients. High-dose calcitriol and parathormone infusions have stimulated osteoclastic activity. In some patients, high-dose calcitriol has resulted in clinical improvement. Newer treatments, such as interferon gamma and macrophage colony stimulating factor, may alter the osteoclastic and immune defects by stimulating cellular formation and function. These therapies, alone or in combination, ameliorate but do not cure the osteopetrotic condition.

A Ketogenic Very Low Calorie Diet (VLCD) in the Treatment of Children with NIDDM |[dagger]| 500

A form of early-onset diabetes, with persistent C-peptide production and negative islet cell antibodies has been reported with increasing frequency in various ethnic groups throughout the US. While insulin is often an essential part of the initial therapy of these patients, the clinical manifestations of this disease eventually become more characteristic of NIDDM. Prolonged insulin therapy may increase the risks of weight gain and progressive insulin resistance. We evaluated the use of a ketogenic very low calorie diet (VLCD) in the treatment of NIDDM in 10 African-American children (mean age 13.9±2.3 years). Patients were admitted to the General Clinical Research Center for 3-5 days, and consumed 7-800 calories daily. The ketogenic VLCD was high in protein (1.5 grams per kg of lean body mass), and contained less than 30 grams each of fat and carbohydrate. At study entry, patients had a mean BMI of 44.4±2.5 (SEM), and a HgbA1c of 8.8±0.8%. Prior to starting the diet, 5/10 were treated with insulin (mean dose = 0.49±0.20 unit/kg/day) and 3/10 were taking metformin and/or acarbose. Insulin and oral agents were weaned as preprandial blood sugars fell below 80 mg/dl, and all patients were able to discontinue medications within three days of instituting the VLCD. Upon follow-up, 1-3 months later, all but one had sustained weight loss on this diet, and 7/10 had lost more than 5 kg. Overall, BMI fell to 41.5±2.3 (p=0.02), while HgbA1c dropped to 7.6±0.9%(p<0.005), off of all pharmacologic therapies. Systolic blood pressure also declined from 133.5±3.0 to 120.5±3.0 mmHg (p=0.01).

GROWTH HORMONE THERAPY IN TRACHEOMALACIA

Growth hormone may be involved in normal cartilage production. Two patients with GH deficient states were treated with GH. Both patients, one with panhypopituitarism (patient 1) and another with pseudohypoparathyroidism (patient 2) presented with severe tracheomalacia. Both patients required tracheostomy. Patient 1 had his tracheostomy at age 3 years and 9 years later, despite numerous ENT procedures to reduce granulation tissue, could not be extubated due to collapse of the tracheal cartilage. Patient 1 was treated for hypothyroidism and hypoadrenalism. An insulin-glucagon test showed no GH values greater than 2 ng/ml (Hybritech IRMA). At one month of life, patient 2 had a tracheostomy and was diagnosed with pseudohypoparathyroidism with no significant rise in phosphate excretion, cyclic-AMP, or calcium (urinary or serum ionized) after PTH administration. This patient had a low IGF-1 and IBP-3. Patient 1 was treated with GH at a dose of 0.05 mg/kg/dose SC 6X per week; patient 2 at a dose of 0.1 mg/kg/day SC (the higher dose due to resistance to peptide hormones), each for six months. After treatment, the tracheal cartilage had become more firm, allowing extubation in both patients. This experience suggests a role for GH in the development of tracheal cartilage.

Establishment of Bone Marrow Stromal Cell Cultures and Permanent Clonal Stromal Cell Lines from Osteopetrotic (mi/mi) and Steel Mutant (Sl/Sld) Mice: Studies of Bone Resorption by Engrafted Hemopoietic Stem Cells In Vitro

The cellular defect in osteopetrosis is unknown. The disorder has been cured by total body irradiation and marrow transplantation in the mi/mi mouse mutant. The etiology has been presumed due to a defect in the ability the marrow stem cells to differentiate into normally functioning osteoclasts. Data are not available to prove that replacing only the osteoclast precursor (an unidentified cell) will cure the disorder. To test whether marrow stromal cells may be responsible for the cure and transmission of this disorder, we found that C57BL/6J marrow cultures contain elements capable of degrading or resorbing 45Ca radiolabelled bone particles (60±5.2% of bone added to the culture). Uncloned and cloned marrow stromal cell lines can be engrafted with stem cells from continuous C57BL/6J mouse spleen cultures and bone is degraded or resorbed by these cultures at a level equal to whole long-term marrow cultures (59 ± 6.2%). Uncloned stromal cells from 6–8 week old osteopetrotic mi/mi mutants were engrafted with nonadherent cells (containing stem cells) from continuous spleen cell cultures of C57BL/6J, mi/+ heterozygote and mi/mi mice. The release of 45Ca from bone particles added was 2.2 ± .08% with each stem cell source. In contrast, cultures of C57BL/6J stromal cells engrafted with mi/mi non-adherent spleen cells showed 45Ca release 96% of normal. In cultures of C57BL/6 stromal cells alone, 45Ca release from bone was not higher than background 45Ca release in the absence of cells. Permanent clonal marrow stromal cell lines were substituted for primary uncloned stromal cell cultures. Clones derived from mi/mi mice blocked stem cell mediated 45Ca resorption compared to clonal lines from mi/+, steel mutation Sl/Sld, or control WCB6F1 (+/+) mice. These data suggest that marrow cells from mi/mi mice may be involved in the reduction of osteoclast function seen in this mutant and provide a focus for studying the role of marrow stroma in the genesis of osteopetrosis.

33 BROMOCRIPTINE USED TO TREAT GIGANTISM IN A TWENTY-THREE MONTH OLD CHILD

Bromocriptine (1.25 mg BID) was administered orally to a 23 year old asymptomatic female with accelerated growth and a parasellar tumor (tissue type unknown). Other forms of therapy were refused. Length increased from 76 to 95 cm (22 cm/yr) and weight increased from 10 to 16.25 kg between ages 13 and 23 months. Bone age was 2 years at a chronological age of 18 months. Somatomedin C level was 4.3 U/ml (n=2: normal 0.8 to 2.2 U/ml). Thirteen growth hormone values during overnight monitoring averaged 4.7 ng/ml, range 1.8 to 7.9 ng/ml. Suppression to 5.0 ng/ml was seen during an OGTT. Other neuroendocrine functions were normal. No evidence of isosexual precocity was noted. Somatomedin C levels were 3.2, 2.6, 2.5, 2.4, and 2.2 U/ml on days 1 to 5 of therapy, 2.5 U/ml at 14 days and 2.7 U/ml at 56 days. Length increased from 95 to 97 cm (4.8 cm/yr) during the first 5 months of therapy. CT scan at 5 months shows no change in tumor size. The patient remains asymptomatic.The decrease in levels of somatomedin C associated with a reduction in the growth rate may have resulted from decreased GH production; however, other effects of bromocriptine, such as blocking the peripheral action of somatomedins may be involved.

155 A REDUCTION IN CRANIAL SCLEROSIS DURING CALCITRIOL THERAPY IN A PATIENT WITH CRANIOMETAPEYSEAL DYSPLASIA

A 1 month old male presented with a left facial nerve palsy, hepatosplenomegaly, and sclerosis of long bones and the base of the skull. The original diagnosis of osteopetrosis was revised to craniometaphyseal dysplaisa (CMD) based on mandibular sclerosis and normal density of the vetebrae. by 2 months of age, hepatosplenomegaly had resolved, but the base of the skull had become more sclerotic and there was no improvement of facial nerve function. Parameters from an iliac crest biopsy included: trabecular bone volume, 15.1% (25±3%); osteoclast surface area, 2.6% (1.1±0.3%); and osteoclast number/mm trabecular bone surface, 0.37 (0.12±0.02). All these parameters differ significanly from childhood norms (±SD). Osteoblastic parameters were normal. The patient was begun on high dose (1.5 mcg/kg/d) calcitriol (Hoffmann-La-Roche) and a low calcium (15 mg/kg/d) diet (Ross Laboratories). After 7 months of therapy, the facial nerve palsy had improved. Raiographs of the base of the skull demonstrated decreased density. A CT demonstrated increased size of optic foramina and internal auditory canals. A reapeat iliac crest biopsy showed decreased osteoclast number and increased trabecular bone volume.In CMD, sclerosis of the cranium has increased throughout early childhood in all reported cases. In our patient, high dose calcitriol reversed the cranial sclerosis without stimulating excessive bone loss from other, less sclerotic bones.