Identification and treatment of cystic fibrosis-related diabetes. A survey of current medical practice in the U.S.

OBJECTIVE: To describe physicians' attitudes and practices in screening for and treating abnormalities in glucose homeostasis in cystic fibrosis (CF) patients and to test the hypotheses that guidelines for screening for CF-related diabetes (CFRD) are not followed at most centers and that screening and treatment vary by the care provider's background. RESEARCH DESIGN AND METHODS: This cross-sectional survey included three groups of physicians: 1) 593 members of the Lawson Wilkins Pediatric Endocrine Society (LWPES), 2) 462 members of the pediatric assembly of the American Thoracic Society (ATS), and 3) 194 directors of cystic fibrosis centers (CFD). A mailed questionnaire was used for the survey. RESULTS: The overall response rate was 67%. Of these, 224 LWPES, 143 ATS, and 135 CFD physicians reported actively seeing CF patients. About two-thirds of CF physicians (ATS and CFD) reported routine screening for impaired glucose tolerance (IGT) in asymptomatic CF patients; a random glucose is most often used (60%), followed by HbA1c (50%), urine glucose (44%), fasting glucose (21%), and oral glucose tolerance test (2%). Only 40% of LWPES physicians reported intervening for stress-induced hyperglycemia, but 61% reported use of insulin for persistent IGT. Management of CFRD was similar for all groups; most physicians used insulin (91%). LWPES recommended more intensive glucose testing and nutritional guidelines than did ATS/CFD (P < 0.0001). LWPES reported less concern about risks of diabetes complications (P < 0.0001) and the importance of minimizing burdensome interventions (P < 0.01). All groups considered weight management a top priority. CONCLUSIONS: Screening for IGT is not routinely done in CF patients and screening tests vary. Greater agreement exists on methods of treating patients with persistent IGT or CFRD, although goals and aggressiveness of treatment vary with the provider's background. A consensus conference is recommended.

Birth size and risk of insulin-dependent diabetes mellitus (IDDM).

A case-control study was conducted to test the hypotheses that birth size is increased in infants who develop IDDM in childhood and that birth size differs by diagnosis age. Cases were non-Hispanic white (NHW) children randomly selected from the Colorado IDDM Registry (n = 221). Controls (n = 197) were NHW children frequency-matched to cases by age-group and gender. Self-administered questionnaires collected birth size and demographic data. There were no significant univariate differences in birth weight (cases 3303.0 g; controls, 3346.1 g; P = 0.40), birth length (cases, 50.8 cm; controls, 51.2 cm; P = 0.28), or ponderal index (cases, 2.52; controls, 2.49; P = 0.92). The case/control odds ratio (OR) controlling for gender, maternal education, and birth place was 1.0 (95% confidence interval (CI) 0.4, 2.5) for the highest category of birth weight compared to the lowest. There were no statistically significant case/control differences in ponderal index (highest to lowest category OR = 1.1; 95% CI 0.6, 2.0) or birth length (1 cm increase OR, 1.0; 95% CI 0.9, 1.2). Similarly, analysis by age-at-diagnosis groups revealed no significant differences, suggesting that birth size does not reveal prenatal diabetogenic influences.

Ethnic differences in human leukocyte antigen markers of susceptibility to IDDM.

OBJECTIVE: To determine whether genetic differences explain the lower risk of developing insulin-dependent diabetes mellitus (IDDM) for Hispanic versus non-Hispanic white children in Colorado. RESEARCH DESIGN AND METHODS: Hispanic (n = 62) and non-Hispanic white (n = 82) subjects with IDDM identified from the Colorado IDDM Registry and healthy, nondiabetic control subjects were recruited. Human leukocyte antigen (HLA) serologic typing and sequence-specific oligonucleotide typing of DQA1 and DQB1 alleles were performed. RESULTS: HLA and allele associations with IDDM were similar in both ethnic groups. HLA-DR3 and HLA-DR4 were more common in IDDM subjects in both ethnic groups. Subjects with DQBl alleles encoding aspartic acid (Asp) in position 57 were less likely to have IDDM, irrespective of ethnic background. HLA-DR3 was less common among Hispanic subjects than non-Hispanic white control subjects (4.4 vs. 17.5%, Hispanics vs. non-Hispanic whites, P = 0.04). CONCLUSIONS: These data suggest that the lower prevalence of HLA-DR3 in the Hispanic population, a pattern consistent with the presence of Amerindian admixture, may explain the lower rate of IDDM in the Hispanic population.

Early exposure to cow's milk and solid foods in infancy, genetic predisposition, and risk of IDDM.

Using a case-control study design, we examined the hypothesis that early exposure to cow's milk and solid foods increased the risk of IDDM. An infant diet history was collected from 164 IDDM subjects from the Colorado IDDM Registry with a mean birth year of 1973, and 145 nondiabetic population control subjects who were frequency matched to diabetic subjects on age, sex, and ethnicity. Early exposure was defined as exposure occurring before 3 mo of age. After controlling for ethnicity, birth order, and family income, more diabetic subjects were exposed early to cow's milk (OR 4.5, 95% CI 0.9-21.4) and solid foods (OR 2.5, CI 1.4-4.3) than control subjects. To examine this association while accounting for the genetic susceptibility to IDDM, we defined individuals as high and low risk by an HLA-DQB1 molecular marker. Early exposure to cow's milk was not associated with elevated risk for IDDM in low-risk individuals. Relative to unexposed low-risk individuals, early exposure to cow's milk was strongly associated in individuals with a high risK marker (OR 11.3, CI 1.2-102.0). Similar findings were observed for early exposure to solid foods. These data indicate that early exposure to cow's milk and solid foods may be associated with increased risk of IDDM. The inclusion of HLA-encoded risk in the analyses demonstrates the combined effect of genetic and environmental factors.

Nitrate levels in community drinking waters and risk of IDDM. An ecological analysis.

OBJECTIVE: To investigate whether higher IDDM incidence rates occurred in areas with high nitrate levels in their potable water supplies. RESEARCH DESIGN AND METHODS: Incidence rates for the 63 counties in Colorado were calculated using the Colorado IDDM Registry of children diagnosed < 18 yr of age between 1978 and 1988 (n = 1280). A weighted average of the nitrate levels from each water district within each county was calculated using data collected by the Colorado Department of Health between 1984 and 1988. RESULTS: The rs between nitrate levels and IDDM incidence was 0.26 (P = 0.03). After controlling for differences in ethnicity, counties with water nitrate levels in the third tertile (0.77-8.2 mg/L) had a significantly increased risk of IDDM compared with those in the first tertile (0.0-0.084 mg/L) (rp = 0.29, P = 0.02). CONCLUSIONS: This ecological analysis suggests that low-level nitrate exposure through drinking water may play a role in the etiology of IDDM, perhaps as a promoter through the generation of free radicals.

Clinical characteristics of IDDM in Hispanics and non-Hispanic whites. Little evidence of heterogeneity by ethnicity.

OBJECTIVE: To compare the clinical characteristics of IDDM in HD and NHWD subjects in order to evaluate potential heterogeneity of IDDM by ethnicity. RESEARCH DESIGN AND METHODS: HD subjects (n = 73) and NHWD subjects (n = 97) were recruited from the Colorado IDDM Registry. The registry included individuals who were Colorado residents, less than 18 yr old at diagnosis, placed on insulin within 2 wk of diagnosis, and had diabetes not secondary to other conditions. Residual beta-cell function was measured as the 1-h C-peptide response to a Sustacal challenge. RESULTS: HD subjects were similar to NHWD subjects in insulin dose, HbA1, HLA-DR antigens, ICAs, and family history of IDDM. HD subjects were more likely to have a family history of NIDDM than NHWD subjects (11 vs. 3%, P = 0.03). HD girls had higher C-peptide levels (0.27 vs. 0.11 nm/L [0.83 vs. 0.33 ng/ml], P = 0.01), BMI (22.7 vs. 20.9 kg/m2 P = 0.04), subscapular skinfold thickness (18.9 vs. 15.0 mm, P = 0.04), and WHR (0.81 vs. 0.77, P = 0.03) than NHWD females. After controlling for diabetes duration, BMI, sex, and family history of NIDDM, residual beta-cell function was associated significantly with Hispanic ethnicity, although the term accounted for just 3% of the overall variability in C-peptide levels. CONCLUSIONS: Little evidence of heterogeneity by ethnicity of IDDM patients in the Colorado IDDM Registry was found. Ethnic differences in C-peptide levels may be related to differences in body fat distribution in females rather than heterogeneity of the disease.

Smokers with IDDM experience excess morbidity. The Colorado IDDM Registry.

OBJECTIVE--To determine whether there is an association between smoking and the self-reported morbidity of people with IDDM and to evaluate the nature of a possible interaction between smoking and IDDM in increasing the risk of morbidity among smokers with IDDM. RESEARCH DESIGN AND METHODS--Subjects were non-Hispanic whites aged 18-28 yr who participated in the Colorado IDDM Registry Follow-up Survey (case subjects, n = 24) or the 1985 NHIS (control subjects, n = 5876). Assessments of self-reported morbidity included any hospitalization in the past year; bed days, sick days, and limited-activity days in the past 2 wk; and ratings of poor health. The criteria outlined by Saracci were used to determine whether smoking was associated with greater morbidity among IDDM case compared to control subjects (smoking by IDDM interaction). RESULTS--Age- and sex-adjusted ORs, estimated from logistic regression, showed that people with IDDM reported excess morbidity compared with control subjects, regardless of smoking status. Smokers with IDDM reported morbidity 3-10 times as often as nonsmoking control subjects and were 2-3 times more likely to report morbidity than nonsmokers with IDDM. The smoking by IDDM interaction was more than multiplicative for all morbidity measures. Fifty to 75% of excess morbidity in young smokers with IDDM over simple additive effects was related to the interaction between smoking and IDDM. CONCLUSIONS--There was excess reported morbidity among people with IDDM who smoked, greater than that expected from the combined effects of smoking and IDDM. Smoking cessation in young people with IDDM may alleviate some of this excess, but more study is needed to determine whether smoking serves as an indicator of poor IDDM care practices or has a physiological impact that compounds the morbidity experienced by people with IDDM.

Incidence of insulin-dependent diabetes mellitus in Colorado.

We examined the incidence of insulin-dependent diabetes mellitus in children 0-17 years of age in Colorado from 1978 to 1988. Cases were ascertained from a statewide registry based on physician surveillance. A total of 1,376 children were diagnosed during this interval in a population averaging 860,000 children. The degree of ascertainment was estimated to be 93.3%. The age-adjusted incidence rate of insulin-dependent diabetes mellitus was 14.8/100,000 person-years. The rate was lower in individuals of Spanish origin (Hispanics) (8.7/100,000 person-years) compared with non-Hispanic individuals (15.5/100,000 person-years) (incidence rate ratio = 0.6, 95% confidence interval = 0.4-0.8). Incidence rates were higher in winter and lower in summer for children 5-17 years old. Children diagnosed before the age of 5 years showed no significant seasonal pattern, although peak incidences were observed in autumn and spring. No temporal trend in diabetes incidence was observed overall or by ethnic group. The increasing insulin-dependent diabetes incidence reported by registries in Europe during this time period was not observed in Colorado.

Accuracy of a filter paper method for measuring glycosylated hemoglobin.

OBJECTIVE: To compare glycosylated hemoglobin (GH) results obtained by filter paper fingerstick collection and mailed for assay by affinity chromatography with results from a venous sample assayed by ion-exchange chromatography (HbA1) in a local laboratory. RESEARCH DESIGN AND METHODS: Fifty-eight volunteer subjects with insulin-dependent diabetes mellitus (IDDM), aged 5-24 yr, included patients at a referral-based IDDM clinic and subjects in an ongoing research study. We obtained two blood samples from each subject. One was collected by fingerstick onto filter paper, the other by venipuncture into a vacutainer. We sent filter paper samples to the Diabetes Research Laboratory (Univ. of Missouri, Columbia, MO) for analysis. Vacutainer samples were sent to the Clinical Chemistry Department of the Clinical Laboratory, University of Colorado Health Sciences Center. RESULTS: Results were highly correlated (r = 0.89, P = 0.0001). Fifty-nine percent were classified identically when results were normalized to SD units and grouped to suggest levels of clinical concern. CONCLUSIONS: The filter paper method is a convenient, accurate measure of glycosylated hemoglobin in young people with IDDM. It should be considered a credible alternative research and clinical tool.

Increasing trend of outpatient management of children with newly diagnosed IDDM. Colorado IDDM Registry, 1978-1988.

OBJECTIVE: To examine the management of newly diagnosed insulin-dependent diabetes mellitus (IDDM) in Colorado over time and to determine the prevalence of outpatient care at IDDM diagnosis on a statewide basis. RESEARCH DESIGN AND METHODS: The Colorado IDDM Registry was used to assess medical care at the diagnosis of IDDM in 1182 patients less than 18 yr of age between 1978 and 1988. RESULTS: Twenty-three percent of children with IDDM in Colorado reported never being hospitalized during the diagnosis period. Treatment of IDDM at diagnosis (outpatient vs. inpatient) did not differ by age, sex, or ethnicity/race. Patients living in rural counties were less likely to have been treated as outpatients at diagnosis than those living in urban counties. Physicians at specialized diabetes clinics (e.g., The Barbara Davis Center for Childhood Diabetes and The Childrens Hospital) were more likely to treat newly diagnosed children in an outpatient setting than physicians not affiliated with these clinics. The proportion of patients receiving only outpatient care at IDDM diagnosis increased from 6% in 1978 to 35% in 1988. This increase can be attributed to three factors: 1) an increase in the number of Colorado children diagnosed at The Barbara Davis Center, where outpatient care is strongly advocated; 2) a change in treatment practices at The Childrens Hospital away from routine hospitalization at onset; and 3) a steady increase in outpatient care for newly diagnosed diabetic children by physicians who were not affiliated with the aforementioned specialized diabetes clinics. CONCLUSIONS: The relatively new practice of outpatient care at diagnosis of IDDM increased between 1978 and 1988 in Colorado, in both specialized diabetes clinics and physicians' practices not affiliated with specialized clinics.

Colorado IDDM Registry. Incidence and validation of IDDM in children aged 0-17 yr.

The purpose of this study was to determine the incidence of insulin-dependent diabetes mellitus (IDDM) among children aged 0-17 yr for age, sex, season, and urban and rural residence of onset in Colorado. Retrospective registration of new-onset cases was conducted from 1978 to 1980, and then prospective registration continued through 1983 with the use of physician reporting with hospital validation. The annual incidence of IDDM was 15.2/100,000 per year (95% confidence interval [CI] 14.1, 16.3), with little difference between the sexes. The highest incidence was in the 10- to 14-yr age-group for both sexes. There was a seasonal peak of winter onset in those aged 10-17 yr, with similar patterns between sex and ethnic groups. No temporal trend over the 6 yr was seen, although an excess of cases was seen for 15- to 17-yr-old boys in 1980-1982. Rates were similar for urban and rural areas of the state. Case ascertainment was estimated to be 93.2% complete (95% CI 91.5, 95.5). Incidence was similar in Colorado to other populations in the United States at similar latitudes. These data serve as a baseline for evaluation of changes in incidence over time, by region, and for the identification of possible outbreaks.

Colorado IDDM Registry: lower incidence of IDDM in Hispanics. Comparison of disease characteristics and care patterns in biethnic population.

The Colorado IDDM Registry identifies newly diagnosed cases of insulin-dependent diabetes mellitus (IDDM) throughout the state. Hispanics in Colorado are a racial mixture of American Indian and White populations. Because American Indians have a low risk of IDDM, and differing frequencies of HLA antigens and haplotypes are reported for Hispanics and non-Hispanics, we compared incidence rates and disease characteristics. Eligible participants were less than 18 yr of age and Colorado residents at time of diagnosis, diagnosed between 1 January 1978 and 31 December 1983, and on insulin within 2 wk of diagnosis. Subjects were reported by their physicians, and statewide validation of reporting was conducted through review of hospital discharge indexes. Incidence rates for Hispanics (n = 76) were significantly lower than those for non-Hispanics (n = 628), although 95% confidence intervals overlapped for children aged 10-17 yr. Age-adjusted rates were significantly lower in Hispanic than non-Hispanic males, whereas age-adjusted rates for females did not differ. The cumulative risk of IDDM was less for Hispanic males aged 0-17 yr than for non-Hispanic males (P less than .001); cumulative risk among females was males (P less than .001); cumulative risk among females was not different (P = .10). Clinical onset characteristics and medical care at diagnosis were similar. After diagnosis, hospitalizations per 100 person-yr appeared higher in Hispanics, but ketoacidosis and insulin reactions per 100 person-yr were similar. Difference in rate of hospitalizations may have been due to lower response rates among older non-Hispanics.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced risk of IDDM among breast-fed children. The Colorado IDDM Registry.

The hypothesis that breast-feeding can provide protection against the development of insulin-dependent diabetes mellitus (IDDM) and would, therefore, be less common among subjects with IDDM was tested with a retrospective design. Cases (n = 268) were selected from the Colorado IDDM Registry and the Barbara Davis Center for Childhood Diabetes (Denver, CO). Two control groups were recruited, one from physicians' practices throughout Colorado (n = 291) and the second through random-digit dialing from the Denver area (n = 188). Cases were less likely to have been breast-fed than controls after adjustment for birth year, maternal age, maternal education, family income, race, and sex [adjusted odds ratio (OR) = 0.70; 95% confidence interval (CI) = 0.50-0.97]. This finding was consistent for both control groups and by birth-year intervals. A greater decrease in risk of IDDM was seen among subjects who had been breast-fed to an older age (for breast-feeding duration of greater than or equal to 12 mo, adjusted OR = 0.54, 95% CI = 0.27-1.08). The amount of IDDM that might be explained by breast-feeding habits (population percentage attributable risk) ranged from 2 to 26%, varying according to the breast-feeding prevalence reported in other studies. Replication of this work in different populations, controlled for the strong secular trends in breast-feeding habits, is critical before the hypothesis of protection is accepted.

Microinvasive carcinoma of the cervix.

One hundred seventy-seven patients with squamous cell carcinoma that invaded the cervical stroma to a depth of 5.0 mm or less were the subjects of this investigation. Fifty-one patients were treated primarily by vaginal hysterectomy, 42 by total abdominal hysterectomy, and 84 by radical hysterectomy with pelvic lymphadenectomy. In 52 patients with lesions that invaded the cervical stroma to a depth of 3.0 mm or less, 984 lymph nodes were examined and none contained metastatic tumor. Conversely, lymph node metastases were present in three of 32 patients with lesions that had stromal invasion of 3.1 to 5.0 mm. After therapy, all patients were followed up from 2 to 14 years, and none was lost to follow-up. Among 145 patients with lesions that invaded the stroma to a depth of 3.0 mm or less, only two developed recurrences, both of which were intraepithelial. Among the 32 cases of carcinoma that invaded the stroma 3.1 to 5.0 mm, there were three invasive recurrences, and two deaths.

Carcinoembryonic antigen in carcinoma of the uterine cervix: antigen distribution in primary and metastatic tumors.

Immunohistochemical staining for carcinoembryonic antigen (CEA) was performed on primary tumors and regional lymph nodes from 100 patients undergoing radical hysterectomies and pelvic lymphadenectomies for invasive carcinoma of the uterine cervix. Antigen staining was present in 82% of keratinizing squamous carcinomas as compared with 50% in nonkeratinizing tumors. Seventeen patients with CEA-producing cervical cancer had regional lymph nodes metastases, all of which stained positively for CEA. Conversely, antigen could not be detected in lymph nodal metastases from primary tumors devoid of CEA. The pattern and intensity of CEA staining in primary tumors and their metastases were similar in all cases. Antigen was present in highest concentrations in the cytoplasm and tumor cell membrane of all tissues examined and isolated nuclear staining was absent. The clinical implications of these findings are discussed.

Biochemical markers in the plasma and tumors of patients with gynecologic malignancies.

Tumor markers in gynecologic malignancies can be classified generally as oncofetal proteins, carcino-placental proteins, and more specific tumor-associated antigens. Carcinoembryonic antigen (CEA) is most effective as a tumor marker in mucinous adenocarcinomas of the endocervix and ovary and in keratinizing squamous cell carcinomas of the cervix. In contrast, the use of alphafetoprotein (AFP) in gynecologic cancer is limited to patients with germ cell tumors of the ovary and specifically endodermal sinus tumors. The beta subunit of human chorionic gonadotropin (beta-hCG) remains an exemplary tumor marker for trophoblastic malignancies and may be useful in selected patients with epithelial carcinomas of the ovary. Plasma levels of these antigens are generally related to total tumor burden (tumor antigen concentration x extent of disease)). Although the lack of specificity of these markers has limited their use in the diagnosis of gynecologic malignancies, they have been effective as a means of monitoring disease status in patients whose tumors contain high antigen concentrations. More specific tumor-associated antigens have been described in ovarian cervical cancers, but their clinical efficacy remains to be demonstrated in large numbers of patients. Immunohistochemical staining of tissue specimens identifies patients whose tumors contain high antigen concentrations and who therefore should benefit most from serial plasma determinations following therapy. Potential future uses of biochemical markers include radioimmunodetection procedures using radiolabelled antibodies to tumor-associated antigens and antigen-directed chemotherapy.

Multiple biochemical markers in patients with gynecologic malignancies.

Plasma levels of carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), and human chorionic gonadotropin (hCG) were measured in 253 patients with gynecologic malignancies and in 317 patients with benign gynecologic diseases. Plasma concentrations of each of these antigens were elevated in a significantly (p less than 0.001) greater number of patients with invasive gynecologic cancers than in the control population. Carcinoembryonic antigen was the most commonly elevated marker, followed by AFP and hCG. Prior to therapy, over 85% of patients with ovarian or cervical cancer had elevated plasma levels of one or more antigens. Specifically, CEA was most often elevated in patients with mucinous adenocarcinomas of the ovary and endocervix. Alpha-fetoprotein was most often increased in patients with germ cell or stromal tumors of the ovary and in patients with large-cell nonkeratinizing cervical cancers. In contrast, hCG concentrations were highest in patients with serious cystadenocarcinomas of the ovary and in patients with keratinizing squamous cell carcinomas of the cervix. Plasma antigen levels were directly related to tumor differentiation and stage of disease, and generally returned to normal eight to 12 weeks following therapy. Effective plasma and tumor antigen screening during initial evaluation of patients with gynecologic tumors should help to identify the most appropriate antigen for immunodetection procedures and for serial plasma determinations following therapy.

Therapeutic implications of patterns of recurrence in cancer of the uterine cervix.

Five hundred twenty-six patients with invasive cervical cancer, treated at the University of Kentucky from 1964 to 1976, were followed 2--12 years after therapy. One hundred and sixty patients (31%) developed tumor recurrence. Recurrent cancer was noted with 1 year after therapy in 58% of patients and within 2 years of treatment in 76% of patients. Only 6% of patients with recurrent cervical cancer survived 3 or more years. Stage of disease, cell type, lesion size, and the presence of lymph vascular space invasion by tumor cells were all shown to be prognostically significant. The addition of extrafascial hysterectomy to radiation therapy significantly decreased the incidence of recurrence in stage IB cervical tumors 5 cm or more in diameter. Analysis of this data suggests that radical hysterectomy and pelvic lymphadenectomy is as effective as irradiation only in the treatment of large cell squamous carcinomas 2 cm or less in diameter.

Carcinoembryonic antigen in carcinoma of the uterine cervix. 2. Tissue localization and correlation with plasma antigen concentration.

Immunoperoxidase staining for carcinoembryonic antigen (CEA) was performed on the tumors of 241 patients with invasive carcinoma of the cervix. Positive tissue staining indicative of a CEA concentration of at least 3 microgram/gm was present in 154 tumors (63%) as opposed to 0 of 30 specimens of normal cervix (p less than .001). Plasma CEA values were obtained at the time of tissue staining on all patients. Plasma CEA concentration was related more directly to total tumor burden (tumor CEA content x extent of disease) than to tumor CEA concentration alone. Progressively rising plasma CEA levels predicted recurrent disease in over 80% of patients whose tumors stained positively for CEA. In contrast, serial plasma CEA values correlated positively with clinical disease status in only 28% of patients whose tumors were devoid of CEA. Immunoperoxidase staining of tissue specimens identifies those patients whose tumors contain high levels of CEA and who therefore should benefit most from subsequent plasma antigen determinations.