A combined primary care residency in internal medicine and pediatrics.

The authors describe the development and evaluation of a primary care residency program encompassing both internal medicine and pediatrics. The combined residency is a four-year program of alternating six-month rotations in the two disciplines. One-fourth of the program is ambulatory medicine and includes training in a clinic for children and adults. Patient demographics are maintained for each resident, and an ambulatory-medicine-focused curriculum consisting of weekly conferences and self-directed independent study is used. The program is routinely evaluated and is highly rated by patients and residents. Factors critical to its success include emphasizing goals and experiences in outpatient versus inpatient care, developing an ambulatory practice to help support resident salaries, adequately preparing residents to take the board examinations in both disciplines, and providing a comprehensive primary care curriculum.

Gonadal function in patients with galactosaemia.

Gonadal function was followed in 26 females and 12 males with galactosaemia due to deficiency of the enzyme galactose-1-phosphate (Gal-1-P) uridyl transferase over a 4 year period. Gonadal function was normal in males, but all females except two had evidence of acquired ovarian failure. Twelve females with ovarian failure documented at the beginning of this study continued to have either primary or secondary amenorrhoea on follow-up. Five of six patients, who previously had normal gonadal function developed either hypergonadotrophic hypogonadism or an abnormal response to gonadotrophin-releasing hormone (LRH) indicative of acquired ovarian damage. Seven of eight female patients, 1-12 years of age, who were evaluated for the first time had an exaggerated release of gonadotrophins during LRH stimulation tests diagnostic of gonadal insufficiency. The pathogenesis of ovarian failure remains unknown, but it appears likely that galactose or Gal-1-P is toxic to the ovary. The source of galactose metabolites, which may begin to accumulate prenatally and continue to damage the gonad in the postnatal period, is likely to be derived from the diet and from the endogenous synthesis of Gal-1-P from glucose via a variety of metabolic pathways. The testis appears to be relatively resistant to the effects of abnormal galactose metabolism.

Carbohydrate intolerance in gonadal dysgenesis: evidence for insulin resistance and hyperglucagonemia.

To determine the pathogenesis of carbohydrate intolerance associated with gonadal dysgenesis, plasma glucose, insulin, glucagon, and growth hormone responses to oral glucose and intravenous tolbutamide, arginine and insulin were evaluated in 21 nonobese patients, 7-19 years old. Glucose intolerance was present in 9 of 21 nonobese patients (42.8%). Insulin levels, the area under the insulin curve after oral glucose and intravenous tolbutamide and the insulin to glucose ratio were significantly greater in patients than in controls (p less than 0.005). The decrease in plasma glucose following intravenous tolbutamide was significantly less in patients than in controls (p less than 0.05) despite insulin levels which were greater than in controls (p less than 0.05). After intravenous insulin, plasma glucose fell significantly less in patients than in controls (p less than 0.01). Plasma glucagon levels and the area under the glucagon curve after oral glucose and arginine infusion were significantly greater in patients than in controls (p less than 0.005 and p less than 0.01, respectively). The increase in glucagon after insulin-induced hypoglycemia was significantly less in patients than in controls (p less than 0.025). Fasting and stimulated growth hormone levels and the mean 24-hour growth hormone concentration were similar in patients and controls. These results indicate that glucose intolerance occurs frequently in gonadal dysgenesis and is associated with normal or increased insulin secretory responses. These abnormalities are probably due to insulin resistance and hyperglucagonemia. The decrease in insulin action does not appear to result from excessive growth hormone secretion or treatment with anabolic steroids or estrogen-progesterone medications.

Idiopathic leucine-sensitive hypoglycemia syndrome: insulin and glucagon responses and effects of diazoxide.

Four children, treated with diazoxide for idiopathic leucine-sensitive (ILS) hypoglycemia of infancy, had follow-up studies at 2 to 10 yr of age to assess: (1) persistence of leucine sensitivity in later childhood. (2) pancreatic glucagon responses, and (3) the hormonal and glycemic effects of diazoxide therapy. On the third day after diazoxide therapy was stopped, the mean +/- S.E. baseline plasma glucose level (65.3 +/- 3.4 mg/dl) was significantly (P less than 0.005) lower than that of the controls (80.1 +/- 3.1 mg/dl). Corresponding mean plasma immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) values were higher than control values but the differences were not significant. After the oral administration of leucine (50 mg/kg) in the ILS children, the mean plasma IRI level rose from 15.2 +/- 4.1 to 59 +/- micro U/ml, the mean plasma glucose concentration fell to 36.0 +/- 3.3 mg/dl and the mean plasma IRG level rose from 196 +/- 16 to 261 +/- 41 pg/ml. These responses were significantly greater (P less than 0.05 to 0.005) than those of control children who received 150 mg/kg of leucine. Intravenous arginine administration caused similar changes in mean plasma glucose, IRI and IRG values in the ILS and control children. During diazoxide therapy in the ILS children, the baseline mean plasma glucose level (89.5 +/- 4.2 mg/dl) was significantly (P greater than 0.005) higher than without therapy. Corresponding mean plasma IRI and IRG values decreased with therapy but the differences were not significant. Diazoxide therapy blunted the changes induced by leucine administration in the ILS children but did not significantly change their response to arginine infusion. Our results indicate that marked sensitivity to leucine persists after infancy in the ILS children. Their IRG responses are appropriate to the stimuli, indicating that their pancreatic alpha cells do not share the abnormality of the beta cells. Diazoxide therapy increases baseline plasma glucose levels and inhibits IRI responses to leucine in ILS children, but it has little if any effect on IRG responses.

Hypergonadotropic hypogonadism in female patients with galactosemia.

We evaluated gonadal function in 18 female and eight male patients with galactosemia due to transferase deficiency; it was normal in the males, but 12 females had signs of hypergonadotropic hypogonadism. All female patients had a 46,XX karyotype, normal levels of thyroid hormone and prolactin, and no anti-ovarian antibodies. The biologic activity of urinary gonadotropins was normal. Ultrasonography of the pelvis revealed that ovarian tissue was diminished or absent. Total estrogens increased in one of two patients after administration of human menopausal gonadotropin. The frequency of hypergonadotropic hypogonadism was higher in females in whom dietary treatment for galactosemia was delayed. Clinical course and mean erythrocyte galactose-1-phosphate and urinary galactitol levels did not correlate with ovarian function. We conclude that female patients with galactosemia have a high incidence of ovarian failure due to acquired ovarian atrophy. Galactose or its metabolites may be toxic to the ovarian parenchyma, particularly during the immediate neonatal period.

Hyperthyroidism in children. A reevaluation of treatment.

The results of medical and surgical therapy were determined in 107 hyperthyroid children. After surgery, 85% of patients were rendered free of hyperthyroidism; however, 62% became hypothyroid. After medical treatment, 30% of patients were euthyroid and 2% became hypothyroid. The relapse rate, however, was higher after medical (22%) than after surgical (9%) therapy. Serious drug-related complications (arthritis-, hepatitis-, and collagen disease-like syndromes) occurred in 14% of patients. Complications occurred in 9% of surgically treated patients, but recurrent laryngeal nerve injury or permanent hypoparathyroidism did not occur. In medically treated patients, both a goiter size less than three times normal prior to treatment and a reduction in goiter size to less than two times normal at the completion of therapy correlated with a successful outcome.

Endocrine abnormalities in thalassemia major.

Endocrine function evaluations in 16 patients with beta-thalassemia indicate that hypogonadotropic hypogonadism, hypoparathyroidism, and reduced adrenocorticotropic hormone reserve occur frequently, whereas reduced growth hormone and thyroid reserve are less common manifestations. Hemosiderosis-induced damage of the endocrine glands seems to be the main cause for endocrine dysfunction in the patients studied.

Clinical, endocrinological, and enzymatic characterization of two patients with 5 alpha-reductase deficiency: evidence that a single enzyme is responsible for the 5 alpha-reduction of cortisol and testosterone.

Two siblings with 46,XY male pseudohermapthroditism were demonstrated to have the phenotype characteristic of 5 alpha-reductase deficiency, namely normal testes and male Wolffian duct derivatives (epididymis, vas deferens, and seminal vesicle) terminating in a blind-ending vagina. Clitoromegaly was present at birth and increased further at the time of expected puberty. The diagnosis of 5 alpha-reductase deficiency was confirmed by demonstration of male levels of testosterone and testosterone precursors before and after hCG administration, elevated plasma testosterone to dihydrotestosterone and urinary etiocholanolone to androsterone ratios, and by in vitro studies indicating 5 alpha-reductase enzyme deficiency in the epididymis of one patient. Studies of control and mutant epididymal microsomes indicated that a single enzyme is responsible in the normal person for the 5 alpha-reduction of testosterone and cortisol (and probably other delta 4-3-ketosteroids as well) and that 5 alpha-reductase activity is undetectable for all substrates examined in the mutant. This finding explains why the formation of 5 alpha-reduced glucocorticoids is also defective in the disorder.

Scintigraphic abnormalities in glycogen storage disease.

Fifteen patients with glycogen-storage disease type 1 (von Gierke's disease) were evaluated by serial scintigraphy, with a clearly recognizable pattern of an enlarged liver with diminished radionuclide accumulation, splenomegaly with considerably increased uptake and renomegaly. In seven of these patients with GSD-1 scintigraphy demonstrated focal defects of varying size. Small or stable defects suggest benign hepatic adenomata, whereas malignant change occurred in growing large lesions. The potential malignant end-point of hepatic-cell carcinoma in GSD-1 warrants careful serial liver scintigraphy with scintiangiography on a routine basis.

Pathologic and immune factors in thyroid disease.

Thyroid glands from 33 children with hyperthyroidism and nine with juvenile lymphocytic thyroiditis were examined histologically and for IgG, IgA, IgM, and C3 by immunofluorescent staining. There was no significant difference between glands with JLT and those with hyperthyroidism in the degree of lymphoid infiltration or lymphoid follicle formation. In thyroiditis there was no correlation between the degree of histologic abnormalities and the presence of immunofluorescent staining for IgG, IgM, or IgA. In hyperthyroidism there was a correlation between the degree of histologic abnormalities and the presence of IgG. In both groups of patients LI and LFF were distinctly more severe in glands positive for C3. Postsurgical hypothyroidism correlated with LI but not with LFF, IgG, or C3.

Cadaver renal transplantation in children with cystinosis.

Five children with end-stage renal disease resulting from cystinosis received seven cadaver renal allografts. Four recipients have functioning grafts eight to 55 months after receiving the transplant and one recipient lost two grafts at 17 and 26 months after the transplant. There was no florid recurrence of the Fanconi syndrome although proximal renal tubular dysfunction developed in two patients, in one in association with chronic rejection and in one without apparent etiology. Free cystine content of white blood cells, cultured skin fibroblasts and allograft tissue was significantly increased. Cystine crystals were observed in the mesangium of two grafts and in the interstitial tissue of all grafts; however, no cystine crystals were found in the tubules. The location of the cystine crystals, as well as the fact that the highest free level of cystine of allograft tissue was observed in the graft undergoing chronic rejection. led to the hypothesis that recipient cells infiltrating the graft were the source of cystine deposition. The data indicate that successful cadaveric transplantation does not correct the primary metabolic defect in cystinosis, thereby explaining the persistence of the extrarenal clinical manifestations, such as photophobia and hypothyroidism, after renal transplantation in cystinosis.

Surgical treatment of hyperthyroidism in children.

During the past ten years, subtotal thyroidectomy for hyperthyroidism was performed upon 43 children at Childrens Hospital of Los Angeles. There were no deaths, no recurrent laryngeal nerve injuries and no permanent hypoparathyroidism. During the one to ten year follow-up period, one patient had recurrent hyperthyroidism develop and was treated with 131I. Twenty-five patients are hypothyroid and require thyroid supplement; 14 are euthyroid and receiv no medication. Postoperative thyroid function did not correlate well with gland remnant size, degree of fibrosis or the extent of lymphoid follicle formation. Lymphocytic infiltration was more severe in patients who had hypothyroidism develop postoperatively. Transient hypocalcemia developed in 22 patients. The effectiveness and safety of the surgical treatment for hyperthyroidism in children is reaffirmed, and it is advocated for consideration over 131I or prolonged medical therapy.