Discontinuation of Car Seat Tolerance Screening and Postdischarge Adverse Outcomes in Infants Born Preterm.

OBJECTIVE: To study the association between discontinuing predischarge car seat tolerance screening (CSTS) with 30-day postdischarge adverse outcomes in infants born preterm. STUDY DESIGN: Retrospective cohort study involving all infants born preterm from 2010 through 2021 who survived to discharge to home in a 14-hospital integrated health care system. The exposure was discontinuation of CSTS. The primary outcome was a composite rate of death, 911 call-triggered transports, or readmissions associated with diagnostic codes of respiratory disorders, apnea, apparent life-threatening event, or brief resolved unexplained events within 30 days of discharge. Outcomes of infants born in the periods of CSTS and after discontinuation were compared. RESULTS: Twelve of 14 hospitals initially utilized CSTS and contributed patients to the CSTS period; 71.4% of neonatal intensive care unit (NICU) patients and 26.9% of non-NICU infants were screened. All hospitals participated in the discontinuation period; 0.1% was screened. Rates of the unadjusted primary outcome were 1.02% in infants in the CSTS period (n = 21 122) and 1.06% after discontinuation (n = 20 142) (P = .76). The aOR (95% CI) was 0.95 (0.75, 1.19). Statistically insignificant differences between periods were observed in components of the primary outcome, gestational age strata, NICU admission status groups, and other secondary analyses. CONCLUSIONS: Discontinuation of CSTS in a large integrated health care network was not associated with a change in 30-day postdischarge adverse outcomes. CSTS's value as a standard predischarge assessment deserves further evaluation.

Impact of the COVID-19 Pandemic on Fecal Immunochemical Testing, Colonoscopy Services, and Colorectal Neoplasia Detection in a Large United States Community-based Population.

BACKGROUND & AIMS: The COVID-19 pandemic has affected clinical services globally, including colorectal cancer (CRC) screening and diagnostic testing. We investigated the pandemic's impact on fecal immunochemical test (FIT) screening, colonoscopy utilization, and colorectal neoplasia detection across 21 medical centers in a large integrated health care organization. METHODS: We performed a retrospective cohort study in Kaiser Permanente Northern California patients ages 18 to 89 years in 2019 and 2020 and measured changes in the numbers of mailed, completed, and positive FITs; colonoscopies; and cases of colorectal neoplasia detected by colonoscopy in 2020 vs 2019. RESULTS: FIT kit mailings ceased in mid-March through April 2020 but then rebounded and there was an 8.7% increase in kits mailed compared with 2019. With the later mailing of FIT kits, there were 9.0% fewer FITs completed and 10.1% fewer positive tests in 2020 vs 2019. Colonoscopy volumes declined 79.4% in April 2020 compared with April 2019 but recovered to near pre-pandemic volumes in September through December, resulting in a 26.9% decline in total colonoscopies performed in 2020. The number of patients diagnosed by colonoscopy with CRC and advanced adenoma declined by 8.7% and 26.9%, respectively, in 2020 vs 2019. CONCLUSIONS: The pandemic led to fewer FIT screenings and colonoscopies in 2020 vs 2019; however, after the lifting of shelter-in-place orders, FIT screenings exceeded, and colonoscopy volumes nearly reached numbers from those same months in 2019. Overall, there was an 8.7% reduction in CRC cases diagnosed by colonoscopy in 2020. These data may help inform the development of strategies for CRC screening and diagnostic testing during future national emergencies.

A Comparative Analysis of Short-term Patient Outcomes After Laparoscopic Versus Robotic Rectal Surgery.

BACKGROUND: The popularity of robot-assisted colorectal surgery has risen over recent years; however, patient-related advantages over laparoscopic surgery remain uncertain. OBJECTIVE: The goal of this study was to compare short-term patient outcomes following robotic and laparoscopic partial or complete rectal resections. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted at 5 large tertiary care Kaiser Permanente medical centers across Southern California. PATIENTS: There were 863 consecutive robotic and laparoscopic pelvic rectal surgeries, including low anterior resections, proctectomies with coloanal anastomosis, and abdominoperineal resections, performed between January 2010 and December 2019. MAIN OUTCOME MEASURES: Short-term patient outcomes, including postoperative length of hospital stay, emergency department returns, and 30-day readmissions, and mortality. RESULTS: A total of 458 surgical procedures were performed via robotic versus 405 via laparoscopic approaches. The robotic group had a higher proportion of male patients (57.4% vs 50.4%; p = 0.04) and a higher proportion of obese (27.1% vs 26.9%; p = 0.02) and overweight patients (36.9% vs 35.1%; p = 0.01). There was no difference in underlying comorbidities of diabetes or smoking, or in the rate of ileostomy creation. After adjusting for Charlson Comorbidity Index, no significant difference was found in emergency department returns between robotic and laparoscopic surgical patients ( p = 0.17). There were no significant outcome differences between the 2 groups with regards to length of stay during procedure, 30-day readmission, or death rates. LIMITATIONS: This study was limited by the lack of randomization in its design, selection of patients for surgical approach, and training and familiarity with robotic rectal surgery. CONCLUSIONS: This study shows length of stay during the procedure and postoperative 30-day readmission rates were generally similar between robotic and laparoscopic patients. Male patients and those with a higher BMI were more likely to have been operated via a robotic method. See Video Abstract at http://links.lww.com/DCR/B857 . UN ANLISIS COMPARATIVO DE LOS RESULTADOS A CORTO PLAZO DE LOS PACIENTES DESPUS DE LA CIRUGA RECTAL LAPAROSCPICA VERSUS LA ROBTICA: ANTECEDENTES:La popularidad de la cirugía colorrectal asistida por robot ha aumentado en los últimos años. Sin embargo, las ventajas relacionadas con el paciente siguen siendo inciertas sobre la cirugía laparoscópica.OBJETIVO:Nuestro objetivo era comparar los resultados de los pacientes a corto plazo después de resecciones rectales completas o parciales robóticas y laparoscópicas.DISEÑO:Este fue un estudio de cohorte retrospectivo.AJUSTE:El estudio se llevó a cabo en cinco grandes centros médicos de Kaiser Permanente de atención terciaria en el sur de California.PACIENTES:Se realizaron 863 cirugías robóticas y laparoscópicas rectales pélvicas consecutivas, incluidas resecciones anteriores bajas, proctectomías con anastomosis coloanal y resecciones abdominoperineales, realizadas entre enero de 2010 y diciembre de 2019.PRINCIPALES MEDIDAS DE RESULTADO:Resultados de los pacientes a corto plazo, incluida la duración de la estancia hospitalaria después del procedimiento, los retornos al departamento de emergencias y los reingresos y la mortalidad a los 30 días.RESULTADOS:Se realizaron un total de 458 procedimientos quirúrgicos a través del robot versus 405 con laparoscopia. El grupo robótico tuvo una mayor proporción de pacientes masculinos (57,4 vs 50,4%, p = 0,04) y una mayor proporción de pacientes obesos (27,1 vs 26,9%, p = 0,02) y con sobrepeso (36,9 vs 35,1%, p = 0,01). No hubo diferencia en las comorbilidades subyacentes de la diabetes y el tabaquismo, y en la tasa de creación de ileostomía. Después de ajustar por el índice de comorbilidad de Charlson, no se encontraron diferencias significativas en los retornos al servicio de urgencias entre los pacientes robóticos y laparoscópicos ( p = 0,17). No hubo diferencias significativas en los resultados entre los dos grupos con respecto a la duración de la estadía durante el procedimiento, las tasas de readmisión a los 30 días y las tasas de muerte.LIMITACIONES:Falta de aleatorización en el diseño del estudio, selección de pacientes para abordaje quirúrgico, capacitación y familiaridad con la cirugía rectal robótica.CONCLUSIONES:Este estudio muestra la duración de la estadía durante el procedimiento y las tasas de reingreso a los 30 días después del procedimiento fueron generalmente similares entre los pacientes robóticos y laparoscópicos. Los pacientes masculinos y aquellos con un índice de masa corporal más alto tenían más probabilidades de haber sido operados mediante un método robótico. Consulte Video Resumen en http://links.lww.com/DCR/B857 . (Traducción-Dr Yolanda Colorado ).

Low Rate of Perinatal Sepsis in Term Infants of Mothers with Chorioamnionitis.

OBJECTIVE: The risk of infection in infants of mothers with chorioamnionitis (CAM) may be lower than previously reported. This study's objective was to determine the incidence of intrapartum fever (IPF) and culture-positive early-onset bacterial neonatal infection (CPEOI) in the late preterm and term infants of mothers with or without CAM and to assess interhospital variation in neonatal infection management. STUDY DESIGN: This retrospective cohort study included mothers and newborns delivered at ≥35 weeks gestation at Kaiser Permanente Southern California Hospitals in 2010 (n = 31,112). Electronic medical and laboratory records from 13 medical centers were examined for maternal temperature, intrapartum, and neonatal antibiotic treatment. Rates for IPF, CAM, and CPEOI were estimated. Rates for starting neonatal antibiotics were calculated. RESULTS: The incidence of IPF was 9% and CAM 4%. The overall rate for CPEOI was 0.61/1,000 (95% confidence interval [CI] 0.34, 0.89/1,000). The rate of CPEOI was 4.0/1,000 (95% CI 0.50, 7.5/1,000) in infants born to mothers with CAM. The rate of beginning antibiotics for infants born to mothers with CAM ranged from 7 to 76% between nurseries. CONCLUSION: The rate of CPEOI in infants born to mothers with CAM is lower than previously reported. There is heterogeneity in initiation of neonatal antibiotics by neonatologists.

Sinonasal tract and nasopharyngeal adenoid cystic carcinoma: a clinicopathologic and immunophenotypic study of 86 cases.

Primary sinonasal tract and nasopharyngeal adenoid cystic carcinomas (STACC) are uncommon tumors that are frequently misclassified, resulting in inappropriate clinical management. Eighty-six cases of STACC included 45 females and 41 males, aged 12-91 years (mean 54.4 years). Patients presented most frequently with obstructive symptoms (n = 54), followed by epistaxis (n = 23), auditory symptoms (n = 12), nerve symptoms (n = 11), nasal discharge (n = 11), and/or visual symptoms (n = 10), present for a mean of 18.2 months. The tumors involved the nasal cavity alone (n = 25), nasopharynx alone (n = 13), maxillary sinus alone (n = 4), or a combination of the nasal cavity and paranasal sinuses (n = 44), with a mean size of 3.7 cm. Patients presented equally between low and high stage disease: stage I and II (n = 42) or stage III and IV (n = 44) disease. Histologically, the tumors were invasive (bone: n = 66; neural: n = 47; lymphovascular: n = 33), composed of a variety of growth patterns, including cribriform (n = 33), tubular (n = 16), and solid (n = 9), although frequently a combination of these patterns was seen within a single tumor. Pleomorphism was mild with an intermediate N:C ratio in cells containing hyperchromatic nuclei. Reduplicated basement membrane and glycosaminoglycan material was commonly seen. Necrosis (n = 16) and atypical mitotic figures (n = 11) were infrequently present. Pleomorphic adenoma was present in 9 cases; de-differentiation was seen in two patients. Immunohistochemical studies showed positive reactions for pan-cytokeratin, CK7, CK5/6, CAM5.2, and EMA, with myoepithelial reactivity with SMA, p63, calponin, S100 protein and SMMHC. CD117, CEA, GFAP and p16 were variably present. CK20 and HR HPV were negative. STACC needs to be considered in the differential diagnosis of most sinonasal malignancies, particularly poorly differentiated carcinoma, olfactory neuroblastoma and pleomorphic adenoma. Surgery (n = 82), often accompanied by radiation therapy (n = 36), was generally employed. A majority of patients developed a recurrence (n = 52) 2-144 months after initial presentation. Overall mean follow-up was 19.4 years (range 0.4-37.5 years): 46 patients died with disease (mean 6.4 years); 5 were alive with disease (mean 5.4 years), and 35 patients were either alive or had died of unrelated causes (mean 16.3 years). ACC of the SNT is uncommon. Recurrences are common. The following parameters, when present, suggest an increased incidence of either recurrence or dying with disease: mixed site of involvement, high stage disease (stage IV), skull base involvement, tumor recurrence, a solid histology, perineural invasion, bone invasion, and lymphovascular invasion.

Effect of direct physician involvement on tobacco abstinence rates and other variables affecting participants of a freedom from tobacco class.

CONTEXT: Kaiser Permanente measures how often tobacco users are offered strategies to quit but not the success of such strategies. OBJECTIVE: To compare tobacco abstinence rates for participants of the Kaiser Permanente Riverside (California) Medical Center's Freedom from Tobacco Class in 2008, before direct physician involvement, and in 2009, after direct physician involvement, and to compare other variables affecting these rates. DESIGN: In a retrospective study, participants were divided into two groups based on year of participation. Data were collected using electronic medical records and phone interviews. MAIN OUTCOME MEASURES: Tobacco use status between both groups at 1, 3, 6, and 12 months after the classes started and within groups by sex, number of classes attended, medication received, and class teacher. RESULTS: The 12-month abstinence rates were 27% in 2008 and 33% in 2009 (p = 0.3). The abstinence rate for men improved from 23% to 38% (2008 vs 2009; p = 0.05), whereas for women it was 30% vs 27% (p = 0.7). Abstinence rates decreased over time for the group as a whole (p < 0.001). Attendance of 6 or more classes was associated with higher abstinence rates. There was no significant impact on abstinence rates due to age, body mass index, class teacher, or medications used. CONCLUSION: Direct physician involvement improved men's but not women's abstinence rates among class participants. The relapse rate was significant over the first year after the class. Further research is needed to study the difference between sexes and the factors affecting relapse.

Blunt head trauma in children in a community health care setting: outcomes and variables associated with the use of computed tomography.

OBJECTIVE: To evaluate the incidence of clinically important traumatic brain injury (ciTBI) in children presenting to a community hospital setting and identified factors associated with computed tomography (CT) use. STUDY DESIGN: Retrospective cohort study of consecutive children presenting with blunt head trauma to a community emergency department or clinic over 12 months. Logistic regression models were used to compare differences in characteristics between patients who received and did not receive CT scans. RESULTS: Of 1007 patients, 62% male, age 14 days-18 years (270 <2 years, 737 ≥2 years), 189 (18%) had CT scans, 2 (0.2%) showed evidence of ciTBI on CT, 13 (1.3%) hospitalized, and none required neurosurgical intervention or died. Factors associated with CT use in patients ≥2 years: history of vomiting (OR 4.08, 95% CI 2.08-7.99, P < .001), change in behavior (OR 2.83, 95% CI 1.63-4.91, P < .001), headache (OR 3.4, 95% CI 1.87-6.16, P < .001), loss of consciousness (OR 2.83, 95% CI 1.38-5.8, P = .004), and abnormal neurologic examination (OR 26.18, 95% CI 2.26-303.05, P = .009). Patients were more likely to receive CT scans in community emergency departments than clinics (OR 7.04, 95% CI 2.40-20.65, P = .002). CONCLUSION: Patients in our community hospital setting are at low risk of ciTBI. The clinical indicators used to determine the need for CT in patients with more significant mechanisms of injury to pediatric or academic centers may not apply to this group. Future studies are required to determine which clinical indications are significant in this setting.

Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management.

BACKGROUND: Population-based data on the demographics and clinical characteristics of patients with multiple unrelated drug class intolerances noted in their medical records are lacking. OBJECTIVES: To provide population-based drug "allergy" incidence rates and prevalence, and to identify individuals with multiple drug intolerance syndrome (MDIS) defined by 3 or more unrelated drug class "allergies," and to provide demographic and clinical information on MDIS cases. METHODS: Electronic medical record data from 2,375,424 Kaiser Permanente Southern California health plan members who had a health care visit and at least 11 months of health care coverage during 2009 were reviewed. Population-based drug "allergy" incidence rates and prevalence were determined for 23 unrelated medication classes. RESULTS: On January 1, 2009, 478,283 (20.1%) health plan members had at least one reported "allergy." Individuals with a history of at least 1 "allergy" and females, in general, reported higher population-based new "allergy" incidence rates. Multiple drug intolerance syndrome was present in 49,582 (2.1%). The MDIS cases were significantly older, 62.4 ± 16.1 years; heavier, body mass index 29.3 ± 7.1; and likely to be female, 84.9%, compared with average health plan members. They had high rates of health care utilization, medication usage, and new drug "allergy" incidence. They sought medical attention for common nonmorbid conditions. CONCLUSIONS: Multiple drug intolerance syndrome is in part iatrogenic. It is associated with overweight elderly women who have high rates of health care and medication usage. Urticarial syndromes only explain a small fraction of MDIS cases. Multiple drug intolerance syndrome is associated with anxiety, but not predominately with immunoglobulin E (IgE)-mediated allergy or life-threatening illness. Multiple drug intolerance syndrome can be managed by medication avoidance and judicious rechallenge.

Adverse reactions associated with therapeutic antibiotic use after penicillin skin testing.

BACKGROUND: There is little prospective data on the antibiotics prescribed and the adverse reactions associated with their use after penicillin skin testing. OBJECTIVE: Provide data on antibiotic use and new antibiotic "allergy" incidence after penicillin skin testing. METHODS: All patients who had penicillin skin testing at our Medical Center between 1-1-2000 and 12-31-2004 were followed through 12-31-2009. All therapeutic antibiotic use and all new "allergies" listed in their electronic medical records were reviewed. RESULTS: There were 1684 study subjects of whom 1191 (70.7%) were female. There were 118 (7.0%) positive to at least one penicillin skin test reagent and 3 (0.2%) were positive only to amoxicillin. The mean follow-up period was 4.5 ± 2.9 years. Subjects were exposed to a mean of 8.2 ± 10.5 therapeutic antibiotic courses during follow-up. The highest new antibiotic "allergy" incidence rates in skin test-negative subjects were noted for penicillins, 2.9%, and sulfonamides, 2.7%, p = 0.9097. Females had higher overall incidences of new antibiotic "allergy," independent of skin test result. Penicillin skin test-negative females treated with penicillin had a nonsignificantly higher new penicillin "allergy" incidence, 3.3% per course versus 1.9% for males, p = 0.0644. Cephalosporins had new antibiotic "allergy" incidence rates not significantly different from tetracyclines, quinolones, macrolides, clindamycin, metronidazole, nitrofurantoin, and other antibiotics. CONCLUSIONS: Females had higher new antibiotic "allergy" incidence rates. New "allergy" to cephalosporins occurred no more frequently than with non-beta-lactam-antibiotics, independent of skin test result. Sulfonamide antibiotics were associated with the higher rates of new antibiotic "allergy" than cephalosporins.

Economic burden of ventilator-associated pneumonia based on total resource utilization.

OBJECTIVES: To characterize the current economic burden of ventilator-associated pneumonia (VAP) and to determine which services increase the cost of VAP in North American hospitals. DESIGN AND SETTING: We performed a retrospective, matched cohort analysis of mechanically ventilated patients enrolled in the North American Silver-Coated Endotracheal Tube (NASCENT) study, a prospective, randomized study conducted from 2002 to 2006 in 54 medical centers, including 45 teaching institutions (83.3%). METHODS: Case patients with microbiologically confirmed VAP (n = 30)were identified from 542 study participants with claims data and were matched by use of a primary diagnostic code, and subsequently by the Acute Physiology and Chronic Health Evaluation II score, to control patients without VAP (n = 90). Costs were estimated by applying hospital-specific cost-to-charge ratios based on all-payer inpatient costs associated with VAP diagnosis-related groups. RESULTS: Median total charges per patient were $198,200 for case patients and $96,540 for matched control patients (P < .001); corresponding median hospital costs were $76,730 for case patients and $41,250 for control patients (P = .001). After adjusting for diagnosis-related group payments, median losses to hospitals were $32,140 for case patients and $19,360 for control patients (P = .151). The median duration of intubation was longer for case patients than for control patients (10.1 days vs 4.7 days; P < .001), as were the median duration of intensive care unit stay (18.5 days vs 8.0 days; P < .001) and the median duration of hospitalization (26.5 days vs 14.0 days; P < .001). Examples of services likely to be directly related to VAP and having higher median costs for case patients were hospital care (P < .05) and respiratory therapy (P < .05). CONCLUSIONS: VAP was associated with increased hospital costs, longer duration of hospital stay, and a higher number of hospital services being affected, which underscores the need for bundled measures to prevent VAP. TRIAL REGISTRATION: NASCENT study ClinicalTrials.gov Identifier: NCT00148642.

Prevalence of coronary heart disease associated with HFE mutations in adults attending a health appraisal center.

PURPOSE: Mutations of the HFE gene that cause hereditary hemochromatosis may be associated with an increased risk of cardiovascular disease. We examined the relation between two HFE mutations (C282Y and H63D), indicators of iron homeostasis, and the prevalence of coronary heart disease in a large population of white adults. SUBJECTS AND METHODS: We conducted a cross-sectional study of 30,916 white adults aged 25 to 98 years who attended a health appraisal center and underwent screening for HFE mutations. Coronary heart disease and cardiovascular risk factors were ascertained by questionnaire and medical records. RESULTS: Overall, 12% (1798/15,362) of men and 7% (1074/15,554) of women had a history of coronary heart disease. Of 10 HFE genotypes tested (five genotypes by sex), only men with the C282Y/H63D genotype (compound heterozygotes) had a significantly higher prevalence of coronary heart disease compared with men with no HFE mutations (odds ratio = 1.6; 95% confidence interval: 1.1 to 2.4; P = 0.01) after adjusting for cardiovascular risk factors. Elevated serum ferritin levels (>250 ng/mL) were associated with a lower prevalence of coronary heart disease in men (10% [255/2209] vs. 12% [1515/12,461] in controls, P = 0.008), which was not significant after adjusting for use of aspirin and anticoagulants. There were no significant associations between elevated transferrin saturation in either men or women, or between elevated serum ferritin levels or HFE mutations in women, and the prevalence of coronary heart disease. CONCLUSION: The results do not support a consistent association between HFE mutations or serum iron indicators and the prevalence of coronary heart disease.

Prevalence of hemochromatosis-related symptoms among individuals with mutations in the HFE gene.

OBJECTIVE: To determine the prevalence of hemochromatosis-related symptoms in homozygotes for the HFE mutation C282Y compared with controls without HFE mutations identified through a large screening program of subjects attending a health appraisal center. SUBJECTS AND METHODS: Presence of symptoms commonly associated with clinical hemochromatosis was ascertained by self-report on a written questionnaire among C282Y homozygotes and HFE wild-type subjects of white or Hispanic ethnicity identified from screening 41,599 adult subjects between March 1999 and August 2001. A subset of C282Y homozygotes and wild-type subjects identified from 12,756 subjects attending the center in the final year of the study completed a standardized double-blind interview with a physician regarding the presence, duration, and severity of a larger set of symptoms. Prevalence of symptoms among C282Y homozygotes and wild-type controls ascertained by written questionnaire and interview were compared by chi2 analysis or Fisher exact test. Symptoms among subjects with other combinations of the C282Y and H63D HFE mutations were also assessed by questionnaire. RESULTS: The 124 C282Y homozygotes who filled out the written questionnaire and the 17 C282Y homozygotes who completed the physician double-blind interview reported no significantly higher rates of arthritis or joint pain, abdominal pain, arrhythmias, darkening of skin, or other symptoms traditionally associated with hemochromatosis compared with the 22,429 wild-type controls who filled out the written questionnaire and 29 wild-type controls who completed the double-blind interview. The only symptom reported more frequently by C282Y homozygotes was loss of body hair, reported by 5 C282Y/C282Y female subjects compared with 1 wild-type male subject (P=.02) in the physician interview. Symptoms among subjects with other HFE genotypes were similar to symptoms of wild-type subjects. CONCLUSIONS: Results of this study indicate that many of the symptoms associated with hemochromatosis are common among HFE wild types and that clinical penetrance of the C282Y/C282Y genotype in regard to these symptoms is low.

Relationship of body iron stores to levels of serum ferritin, serum iron, unsaturated iron binding capacity and transferrin saturation in patients with iron storage disease.

None of the methods for assessing total body iron burden in patients with hemochromatosis is satisfactory. Although it is commonly believed that a relationship exists between serum ferritin levels and total iron burden, the extent of this relationship has not previously been documented. In the present investigation we measured the total body iron burden of 88 patients with putative hemochromatosis, 54 of whom were homozygotes for the 845G-->A (C282Y) mutation. The total body iron stores were estimated from the volume of red cells removed during therapeutic phlebotomy corrected for an estimated 2 mg/day dietary iron absorbed during the phlebotomy period; the amount of storage iron was compared to the serum ferritin, serum iron, unsaturated iron binding capacity, and transferrin saturation before the beginning of phlebotomy. The serum ferritin proved to be the best predictor of body iron stores. The correlation between all of the analytes and the body iron burden was greater in patients homozygous for the C282Y mutation than in those who were not, including the compound heterozygotes for C282Y and H63D. The body iron burden tended to be greater in patients homozygous for the C282Y mutation than the other patients at any other given ferritin level. We conclude that the serum ferritin level does provide some information regarding total iron burden but even in the case of C282Y homozygotes, the correlation is not very strong.

Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA.

BACKGROUND: There has been much interest in screening populations for disease-associated mutations. A favoured candidate has been the HFE gene, mutations of which are the most common cause of haemochromatosis in the European population. About five people in 1000 are homozygotes for the 845G-->A mutation, but little is known of how many have mutation-caused clinical manifestations. METHODS: We screened 41038 individuals attending a health appraisal clinic in the USA for the 845G--> A and 187C-->G HFE mutations, and analysed laboratory data and data on signs and symptoms of haemochromatosis as elicited by questionnaire. FINDINGS: The most common symptoms of haemochromatosis, including poor general health, diabetes, arthropathies, arrhythmias, impotence, and skin pigmentation were no more prevalent among the 152 identified homozygotes than among the controls. The age distribution of homozygotes and compound heterozygotes did not differ significantly from that of controls: there was no measurable loss of such individuals from the population during ageing. However, there was a significantly increased prevalence of a history of hepatitis or "liver trouble" among homozygotes and in the proportion of homozygotes with increased concentrations of serum aspartate aminotransferase and collagen IV; these changes were not related to iron burden or to age. Only one of the 152 homozygotes had signs and symptoms that would suggest a diagnosis of haemochromatosis. INTERPRETATION: The normal age distribution of people with the haemochromatosis genotype, and the lack of symptoms in patients of all ages, indicate that the penetrance of hereditary haemochromatosis is much lower than generally thought. The clinical penetrance of a disorder is an essential consideration in screening for genetic disease; disorders with low penetrance are more expensive candidates for screening than disorders with high penetrance. Our best estimate is that less than 1% of homozygotes develop frank clinical haemochromatosis.

Penetrance of hemochromatosis.

We undertook a three-year screening program for mutations of the HFE gene among 41,000 subjects attending the Kaiser Permanente Health Appraisal Center in San Diego, California. Our results show that the C282Y and H63D mutations of the HFE gene associated with hemochromatosis have measurable and consistent effects on iron indicators and are associated with liver disorders, but have no measurable effect on other iron overload-related symptoms and life-expectancy. The very low clinical penetrance of the HFE mutations must be taken into account in calculating cost/benefit and risk/benefit ratios in screening for hemochromatosis.