Traffic-related air pollution associations with cytokeratin-18, a marker of hepatocellular apoptosis, in an overweight and obese paediatric population.

INTRODUCTION: Traffic-related air pollution causes fatty liver, inflammation and fibrosis in animal models, but there have been few studies in humans. OBJECTIVES: To test the hypothesis that traffic-related air pollution causes non-alcoholic fatty liver disease (NAFLD) and increased markers for non-alcoholic steatohepatitis (NASH); and that NAFLD increases liver susceptibility to increased NASH risk. METHODS: Data collected prospectively from 74 overweight or obese children were obtained from the Yale Pediatric Obesity Clinic. Traffic-related air pollution was characterized as vehicle traffic volume on major roads within a 1 km residential buffer, and as residential nitrogen dioxide (NO2 ) exposure. Outcomes were hepatic fat fraction (HFF) measured by magnetic resonance imaging, liver enzymes using standard assays and plasma cytokeratin-18 (CK-18) by immunosorbent assays. RESULTS: Significant non-linear relationships with air pollution and CK-18 were found. Plasma CK-18 at follow-up increased from approximately 150 U/L to almost 200 U/L as residential traffic volume increased from 220 000 vehicle-km to 330 000 vehicle-km, after adjustment for baseline CK-18, age and gender. Among patients with NAFLD at baseline, CK-18 increased from 140 U/L to 200 U/L (a 1.5 standard deviation increase in CK-18) as NO2 increased from 8 to 10 ppb. CONCLUSIONS: Traffic-related air pollution was associated with CK-18. Effects were larger in children with pre-existing NAFLD at study entry.

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation.

Liver cancer is a major health-care concern and its oncogenic mechanisms are still largely unclear. Persistent hepatocyte cell death is a common feature among various chronic liver diseases, the blocking of which presents as logical treatment. Therefore, we aimed at investigating tumor development in mice with hepatocyte-specific Bid depletion--a BH3-only Bcl-2 family member that amplifies apoptotic death signals. Hepatocyte-specific conditional Bid-knockout mice (Bid(Δhep)) were injected with 25 mg/kg diethylnitrosamine (DEN) at 14 days of age, and liver tumorigenesis was investigated 9 months later. Additionally, different models of acute liver injury were used including: acute high-dose DEN challenge, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and carbon tetrachloride (CCL4) injection. Bid(Δhep) mice developed significantly fewer tumors, showed smaller maximal and average tumor size and reduced tumor incidence. In the acute DEN model, 48 h post injection we observed a significant reduction in liver injury in Bid(Δhep) animals, assessed via serum transaminases and liver histopathology. Furthermore, TNF-α, IL-1ß, cJUN and IL-6 mRNA expression was reduced. These findings were accompanied by reduced compensatory hepatocyte proliferation in Bid(Δhep) mice when compared with controls by immunohistochemistry for Ki67 and proliferating cell nuclear antigen 48 h after DEN injection. In the acute CCL4 model, Bid(Δhep) mice displayed reductions in liver injury and inflammation when compared with controls. No differences in liver injury and serum bilirubin levels were detected in Bid(Δhep) and Bid(flo/flo) mice fed with DDC, which induces bile duct injury and a ductular reaction. Our study demonstrates that in DEN-induced hepatocellular carcinoma, the inhibition of hepatocyte death pathways through Bid deletion protects animals from tumorigenesis. These results suggest that reducing hepatocyte cell death, liver inflammation and compensatory proliferation has a stronger beneficial effect than the potential side effect of enhancing tumor cell survival.

[Cytokeratin 18 as marker for non-invasive diagnosis and prognosis of acute and chronic liver diseases]. / Zytokeratin-18 als Marker zur nichtinvasiven Diagnostik und Prognose akuter und chronischer Lebererkrankungen.

INTRODUCTION: Currently liver biopsy represents the gold standard to assess severity and fibrosis grade in liver diseases. Since this laborious, costly, and invasive procedure is associated with possible complications, non-invasive methods and biomarkers, which allow for an easy, reliable, and repeatable assessment of liver disease are warranted. Cytokeratin (CK) 18 is an intermediary filament protein, expressed in hepatocytes, which is proteolytically cleaved during liver damage. The resultant CK-18 fragments are released by hepatocytes and can be detected in serum. METHODS: A selective literature search in PubMed for original publications about the detection of CK-18 cell death markers in liver diseases was undertaken. RESULTS: Assessment of CK-18 cell death biomarkers allows for the early detection of liver damage in acute and chronic liver diseases. This is even feasible when transaminases are in the normal ranges. Detection of CK-18 biomarkers can also hint at disease activity and severity. For example, patients with non-alcoholic steatohepatitis exhibit elevated serum cell-death markers compared to those with simple steatosis. Furthermore, in patients with relevant fibrosis higher CK-18 values are found as compared to those with low fibrosis. In acute liver failure, cell death biomarkers may assist decision finding for the necessity of liver transplantation. DISCUSSION: Due to promising results of various studies, CK-18 cell death markers could be applied in clinical routine soon.

Recurrence of Disease Following Liver Transplantation: Nonalcoholic Steatohepatitis vs Hepatitis C Virus Infection.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is an increasing indication for orthotopic liver transplantation (OLT) in the United States and other countries. However, the incidence of disease recurrence and natural course following OLT remains incompletely understood. OBJECTIVE: To estimate the incidence of recurrent disease, outcome and identify risk factors associated with disease recurrence in patients undergoing OLT for NASH as compared to those undergoing OLT for HCV cirrhosis. METHODS: We identified all patients with end-stage liver disease secondary to NASH (n=53) or HCV (n=95) cirrhosis who underwent OLT at our institution between 1998 and 2005. Protocol liver biopsies were performed (Day 7, Month 4 and yearly) after OLT, and as clinically indicated. Kaplan-Meier survival analysis was performed to assess the fibrosis progression and survival. Cox regression analysis was performed to identify factors associated with disease recurrence. RESULTS: Five-year survival was 90.5% in NASH vs 88.4% in HCV group (p=0.97). The median (25%ile, 75%ile) follow-up to last available biopsy was 12.7 (5.9, 26.3) months, during which 17 (32%) of NASH patients developed persistent fatty infiltration in their graft, 8 (15%) of whom had accompanying histologic features of recurrent NASH. There was no difference in the prevalence of post-OLT steatosis between HCV and NASH patients after adjusting for time of histologic follow-up (p=0.33). Patients with HCV infection were more likely to develop hepatic fibrosis post-OLT than those with NASH (62.1% vs 18.9%, p<0.001). Multivariate analysis identified post-OLT diabetes (HR=2.0, 95% CI: 1.2-3.2, p=0.007) as an independent risk factor for fibrosis development. Additionally, NASH subjects who received steroids had a significantly higher risk of developing hepatic fibrosis post-OLT than NASH patients who did not receive steroids and all HCV subjects (p<0.001). CONCLUSION: Recurrence of steatosis post-OLT is common. Corticosteroid use may contribute to fibrosis progression in this population.

The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years.

OBJECTIVES: The long-term prognosis of non-alcoholic fatty liver disease (NAFLD) in children remains uncertain. We aimed at determining the long-term outcomes and survival of children with NAFLD. DESIGN: Retrospective longitudinal hospital-based cohort study. PATIENTS: Sixty-six children with NAFLD (mean age 13.9 (SD 3.9) years) were followed up for up to 20 years with a total of 409.6 person-years of follow-up. RESULTS: The metabolic syndrome was present in 19 (29%) children at the time of NAFLD diagnosis with 55 (83%) presenting with at least one feature of the metabolic syndrome including obesity, hypertension, dyslipidaemia and/or hyperglycaemia. Four children with baseline normal fasting glucose developed type 2 diabetes 4-11 years after NAFLD diagnosis. A total of 13 liver biopsies were obtained from five patients over a mean of 41.4 (SD 28.8) months showing progression of fibrosis stage in four children. During follow-up, two children died and two underwent liver transplantation for decompensated cirrhosis. The observed survival free of liver transplantation was significantly shorter in the NAFLD cohort as compared to the expected survival in the general United States population of the same age and sex (log-rank test, p<0.00001), with a standardised mortality ratio of 13.6 (95% confidence interval, 3.8 to 34.8). NAFLD recurred in the allograft in the two cases transplanted, with one patient progressing to cirrhosis and requiring re-transplantation. CONCLUSIONS: Children with NAFLD may develop end-stage liver disease with the consequent need for liver transplantation. NAFLD in children seen in a tertiary care centre may be associated with a significantly shorter survival as compared to the general population.

Health care utilization and costs by metabolic syndrome risk factors.

BACKGROUND: This study compared prevalent health utilization and costs for persons with and without metabolic syndrome and investigated the independent associations of the various factors that make up metabolic syndrome. METHODS: Subjects were enrollees of three health plans who had all clinical measurements (blood pressure, fasting plasma glucose, body mass index, triglycerides, and high-density lipoprotein cholesterol) necessary to determine metabolic syndrome risk factors over the 2-year study period (n = 170,648). We used clinical values, International Classification of Diseases, Ninth Revision (ICD-9) diagnoses, and medication dispensings to identify risk factors. We report unadjusted mean annual utilization and modeled mean annual costs adjusting for age, sex, and co-morbidity. RESULTS: Subjects with metabolic syndrome (n = 98,091) had higher utilization and costs compared to subjects with no metabolic syndrome (n = 72,557) overall, and when stratified by diabetes (P < 0.001). Average annual total costs between subjects with metabolic syndrome versus no metabolic syndrome differed by a magnitude of 1.6 overall ($5,732 vs. $3,581), and a magnitude of 1.3 when stratified by diabetes (diabetes, $7,896 vs. $6,038; no diabetes, $4,476 vs. $3,422). Overall, total costs increased by an average of 24% per additional risk factor (P < 0.001). Costs and utilization differed by risk factor clusters, but the more prevalent clusters were not necessarily the most costly. Costs for subjects with diabetes plus weight risk, dyslipidemia, and hypertension were almost double the costs for subjects with prediabetes plus similar risk factors ($8,067 vs. $4,638). CONCLUSIONS: Metabolic syndrome, number of risk factors, and specific combinations of risk factors are markers for high utilization and costs among patients receiving medical care. Diabetes and certain risk clusters are major drivers of utilization and costs.

Harnessing stakeholder perspectives to improve the care of osteoporosis after a fracture.

UNLABELLED: This study used in-depth interviews and focus groups to evaluate osteoporosis care after a fracture. Patients (eligible women aged 67 who sustained a clinical fracture(s)), clinicians, and staff stated that an outreach program facilitated osteoporosis care management, but more-tailored education and support and increased participation of orthopedic specialists appear necessary. INTRODUCTION: Osteoporosis treatment reduces fracture risk, but screening and treatment are underutilized, even after a fracture has occurred. This study evaluated key stakeholder perspectives about the care of osteoporosis after a fracture. METHODS: Participants were from a nonprofit health maintenance organization in the United States: eligible women members aged 67 or older who sustained a clinical fracture(s) (n = 10), quality and other health care managers (n = 20), primary care providers (n = 9), and orthopedic clinicians and staff (n = 28); total n = 67. In-depth interviews and focus groups elicited participant perspectives on an outreach program to patients and clinicians and other facilitators and barriers to care. Interviews and focus group sessions were transcribed and content-analyzed. RESULTS: Patients, clinicians, and staff stated that outreach facilitated osteoporosis care management, but important patient barriers remained. Patient knowledge gaps and fatalism were common. Providers stated that management needed to begin earlier, and longer-term patient support was necessary to address adherence. Orthopedic clinicians and staff expressed lack of confidence in their osteoporosis management but willingness to encourage treatment. CONCLUSIONS: Although an outreach program assisted with the management of osteoporosis after a fracture, more-tailored education and support and increased participation of orthopedic specialists appear necessary to maximize osteoporosis management.

Effect of lifestyle modifications on blood pressure by race, sex, hypertension status, and age.

Recommendations for control of high blood pressure (BP) emphasize lifestyle modification, including weight loss, reduced sodium intake, increased physical activity, and limited alcohol consumption. The Dietary Approaches to Stop Hypertension (DASH) dietary pattern also lowers BP. The PREMIER randomized trial tested multicomponent lifestyle interventions on BP in demographic and clinical subgroups. Participants with above-optimal BP through stage 1 hypertension were randomized to an Advice Only group or one of two behavioural interventions that implement established recommendations (Est) or established recommendations plus DASH diet (Est plus DASH). The primary outcome was change in systolic BP at 6 months. The study population was 810 individuals with an average age of 50 years, 62% women, 34% African American (AA), 95% overweight/obese, and 38% hypertensive. Participants in all the three groups made lifestyle changes. Mean net reductions in systolic (S) BP in the Est intervention were 1.2 mmHg in AA women, 6.0 in AA men, 4.5 in non-AA women, and 4.2 in non-AA men. The mean effects of the Est Plus DASH intervention were 2.1, 4.6, 4.2, and 5.7 mmHg in the four race-sex subgroups, respectively. BP changes were consistently greater in hypertensives than in nonhypertensives, although interaction tests were nonsignificant. The Est intervention caused statistically significant BP reductions in individuals over and under age 50. The Est Plus DASH intervention lowered BP in both age groups, and significantly more so in older individuals. In conclusion, diverse groups of people can adopt multiple lifestyle changes that can lead to improved BP control and reduced CVD risk.

Breast cancer outcomes among older women: HMO, fee-for-service, and delivery system comparisons.

OBJECTIVE: To analyze the relationship of health insurance status and delivery systems to breast cancer outcomes--stage at diagnosis, treatment selected, survival--focusing on comparisons among women aged 65 or more having Medicare alone, Medicare/Medicaid, or Medicare with group model HMO, non-group model HMO, or private fee-for-service (FFS) supplement. DESIGN: Retrospectively defined cohort from Sacramento, Calif, regional cancer registry. SETTING: Thirteen-county region in northern California with mature managed care market. PATIENTS: Female invasive breast cancer patients aged 65 or more (N = 1,146), diagnosed 1987-1993. MEASUREMENTS AND MAIN RESULTS: Health insurance was determined from hospital records. Outcomes were analyzed with multivariate regression models, controlling for age, ethnicity, time, and SES measures. Stage I diagnosis was more likely among group model HMO patients than among private FFS insured (odds ratio [OR], 1.42; 95% confidence interval [CI], 0.84 to 2.40). Stage I tumors were significantly less likely for Medicaid patients (OR, 0.50; 95% CI, 0.31 to 0.82). Use of breast-conserving surgery plus radiation (BCS+) varied significantly by hospital type (including HMO-owned and various-sized community hospitals) and time. Survival of patients with private FFS, group-, and non-group model HMO insurance was not significantly different, but was for those with Medicaid or Medicare alone. CONCLUSIONS: This study sheds new light on the relationship of insurance to stage and survival among older breast cancer patients, highlighting the importance of distinguishing types of HMOs and types of FFS plans. These outcomes do not differ significantly between women with Medicare who are in HMOs and those with private FFS supplemental insurance. However, patients with Medicare/Medicaid or Medicare alone are at risk for poorer outcomes.

The relationship of HMOs, health insurance, and delivery systems to breast cancer outcomes.

BACKGROUND: The current climate of anger and frustration with managed care has heightened interest in the quality of health care provided by managed-care plans, particularly health maintenance organizations (HMOs). This breast cancer outcomes study, investigating relationships of health insurance and delivery systems to stage at diagnosis, treatment selected, and survival, is based in a heavily penetrated, highly competitive HMO market. METHODS: Data for 1,788 residents of northern California younger than 65 years of age at diagnosis (1987-1993) were provided by a population-based cancer registry. Patient insurance included fee-for-service (FFS), group-model HMO, nongroup HMO, publicly insured, and uninsured. Diagnosis and treatment occurred in 73 hospitals (large, medium/moderately small, or very small community, rural, teaching, or HMO-owned hospitals). Regression models examined relationships of insurance and hospital type to 3 outcomes (stage, treatment, and survival), controlling for age, ethnicity, education, neighborhood occupational class, and time period. RESULTS: Early diagnosis was as likely for group-model and nongroup-model HMO-insured patients as for the private FFS-insured patients. In 1987-1990, HMO-owned hospitals were leaders in treating 46% of early-stage breast cancers with breast-conserving surgery plus radiation (BCS+); by 1991-1993, the most significant increases in BCS+ use occurred at teaching and large community hospitals. Survival of group-model HMO, nongroup-model HMO, and FFS patients was not significantly different. Publicly insured/uninsured patients had more stage III/IV disease (OR=2.01, P = 0.006) and greater all-cause mortality (risk ratio 1.46, P = 0.015). CONCLUSIONS: Group-model and nongroup-model HMO patients are similar to FFS-insured patients in stage at diagnosis and survival outcomes. Treatment selection is related to hospital type rather than insurance coverage.

In vivo renal vascular and tubular function in experimental hypercholesterolemia.

Hypercholesterolemia (HC) is often associated with impaired peripheral and coronary vascular responses to endothelium-dependent vasodilators, which are probably due to low bioavailability of nitric oxide. To examine the effect of HC on renal vascular and tubular function, 22 domestic pigs were studied after being fed a 12-week normal (n=11) or HC (n=11) diet. Renal regional perfusion and intratubular contrast media concentration in each nephron segment (representing fluid reabsorption) were quantified in vivo with electron-beam computed tomography before and after a suprarenal infusion of either acetylcholine (6 pigs of each diet) or sodium nitroprusside (SNP; 5 pigs of each diet). An increase in cortical perfusion, observed in normal pigs with acetylcholine (+35+/-6%, P=0. 002) and SNP (+12+/-4%, P=0.005), was blunted in the HC group (+8. 8+/-4.0, P=0.01, and -4.6+/-4.0%, P=0.1, respectively, P=0.003 and P=0.005 compared with normal) as was an increase in medullary perfusion (+58+/-21 in normal versus +24+/-11% in HC, P=0.04). A decrease in the intratubular contrast media concentration in the distal tubule and collecting duct of normal pigs was observed in all tubular segments (and was significantly enhanced in the proximal tubule and Henle's loop) in the HC group, which was associated with increased sodium excretion. The tubular and renal excretory responses to SNP were similar between the groups. In conclusion, early experimental HC in the pig attenuates renal perfusion response to both endothelium-dependent and -independent vasodilators possibly because of decreased bioavailability or decreased vascular responsiveness to nitric oxide. This vascular impairment may play a role in maladjusted renovascular responses and contribute to renal damage in later stages of atherosclerosis.

Low back pain: predictors of absenteeism, residual symptoms, functional impairment, and medical costs in Oregon workers' compensation recipients.

BACKGROUND: Wide variations in disability duration and magnitude have been noted among recipients of workers' compensation for low back pain. Findings from recent studies have indicated that inclusion of a broad array of variables (i.e., physical, occupation, social, economic) is needed to understand differences in workers' responses to occupational low back pain. METHODS: Workers' compensation and questionnaire data from 340 Oregon workers with low back claims were merged to develop multivariate models predicting: (1) absenteeism days, (2) residual symptoms, (3) functional impairment, and (4) medical costs. RESULTS: Forty-two percent of the variation in low back symptoms was explained by: discontinuing physical fitness activities post-injury (beta = -.419), self-reported low energy/high fatigue (beta = -.227), poorer general health (beta = .137), and attorney involvement in claim (beta = .117), (adjusted R2 = .418, p < 0.001). Survival curves revealed significantly longer claim durations among workers who discontinued physical fitness activities post-injury, compared with workers who did not; these differences remained significant even after controlling for severity of the initial injury. CONCLUSION: Continuation of physical fitness activities during the recovery process was found to be a significant predictor in three of four regression models, providing evidence on behalf of a relationship between fitness and positive health outcomes. However, it was not possible to clearly differentiate pre-morbid from post-injury fitness, nor to determine if this relationship was due to a therapeutic effect on the back, the general restorative benefits of remaining active, or represents a proxy variable for workers' self-care efforts during recovery.

Prevention of work-related disability.

INTRODUCTION: The cost of work-related injury is large and is rising in many states. Managed care providers are being asked to assist with solutions, particularly in the area of facilitating return to work. Kaiser Permanente of the Northwest responded by developing the Kaiser on-the-job program, which includes processes to facilitate the primary, secondary, and tertiary prevention of work-related disability. METHODS: This paper describes the role that managed care can play in the prevention of work-related disability through consultation, training, immunization programs, and targeted screening and case management interventions. A quality and case management system is described, which gives physicians feedback on modified work and time-off authorization by diagnosis. RESULTS: The results demonstrate statistically significant decreasing physician-authorized average time loss for low back cases from 1991 through 1995 (17.8 disability days per case in 1991 and 15 per case in 1995, P = .01). According to Oregon State Accident Insurance Fund (SAIF Corporation) data, the Kaiser on-the-job average total claims cost was reduced 33% for disabling cases as compared to two other health care organizations (P = .002). CONCLUSION: The methods utilized here to prevent work-related disability appear effective. They are relevant to many managed care program models and their efforts to improve workplace health and productivity.

Prevention of work-related disability.

The authors, reporting from Kaiser Permanente, describe a new program that may be helpful to other managed care providers in preventing workplace injury and minimizing disability after injury.

Managed occupational health care in an HMO.

This paper describes the efforts of an HMO to improve its delivery of occupational health services. Customer needs identification, occupational health structure, data systems, case management, clinical guidelines, and quality management are outlined. Our experience suggests that high-quality occupational health services can be integrated into managed care systems thereby offering cost-effective care to large numbers of workers. Comparing 1991 to 1995, physician authorization of total disability days was reduced 17.9% per disability case (p < .0001). Based on July 1994 to June 1995 Oregon State Accident Insurance Fund (SAIF Corporation) data, HMO average total claim cost was $916/claim representing respectively, a 21% and a 20% reduced cost compared to two PPO model programs (MCO 00 and MCO 01). Patient satisfaction data indicated that 90% of patients were satisfied or very satisfied with the physician they saw. The savings appear to be due to cost-effective treatment and rapid return to work.

Occupational injuries among urban recyclers.

In this article, we describe the emergence of urban recycling as a new trade and discuss the new pattern of injuries among its practitioners. We conducted a retrospective chart review and convenience survey at an urban homeless health center. We found a high prevalence of severe, costly injuries, many of which are amenable to prevention. Lacerations, infections, needle sticks, and blunt trauma are all common in this group. Some cases are extremely expensive or even lethal. We conclude that a new trade and a new pattern of injuries associated with it have emerged around recycling.

New insights into the pathophysiology of renovascular hypertension.

In recent years, the pathophysiology of renovascular hypertension has been reviewed, and the classic concept that activation of the renin-angiotensin system is solely responsible for the development and maintenance of renovascular hypertension has been challenged. In fact, experimental evidence indicates that other systems, such as the lipoxygenase pathway, may have a more critical role in the long-term maintenance of high blood pressure after renal artery stenosis. Herein we discuss the intrarenal mechanisms that control pressure-induced natriuresis under physiologic conditions and the role of the kidney in the pathophysiology of renovascular hypertension.