Bone marrow fat content is correlated with hepatic fat content in paediatric non-alcoholic fatty liver disease.

AIM: To investigate the relationship between bone marrow fat content and hepatic fat content in children with known or suspected non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: This was an institutional review board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant, cross-sectional, prospective analysis of data collected between October 2010 to March 2013 in 125 children with known or suspected NAFLD. Written informed consent was obtained for same-day research magnetic resonance imaging (MRI) of the lumbar spine, liver, and abdominal adiposity. Lumbar spine bone marrow proton density fat fraction (PDFF) and hepatic PDFF were estimated using complex-based MRI (C-MRI) techniques and magnitude-based MRI (M-MRI), respectively. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SCAT) were quantified using high-resolution MRI. All images were acquired by two MRI technologists. Hepatic M-MRI images were analysed by an image analyst; all other images were analysed by a single investigator. The relationship between lumbar spine bone marrow PDFF and hepatic PDFF was assessed with and without adjusting for the presence of covariates using correlation and regression analysis. RESULTS: Lumbar spine bone marrow PDFF was positively associated with hepatic PDFF in children with known or suspected NAFLD prior to adjusting for covariates (r=0.33, p=0.0002). Lumbar spine bone marrow PDFF was positively associated with hepatic PDFF in children with known or suspected NAFLD (r=0.24, p=0.0079) after adjusting for age, sex, body mass index z-score, VAT, and SCAT in a multivariable regression analysis. CONCLUSION: Bone marrow fat content is positively associated with hepatic fat content in children with known or suspected NAFLD. Further research is needed to confirm these results and understand their clinical and biological implications.

Paediatric gastroenterology evaluation of overweight and obese children referred from primary care for suspected non-alcoholic fatty liver disease.

BACKGROUND: Screening overweight and obese children for non-alcoholic fatty liver disease (NAFLD) is recommended by paediatric and endocrinology societies. However, gastroenterology societies have called for more data before making a formal recommendation. AIM: To determine whether the detection of suspected NAFLD in overweight and obese children through screening in primary care and referral to paediatric gastroenterology resulted in a correct diagnosis of NAFLD. METHODS: Information generated in the clinical evaluation of 347 children identified with suspected NAFLD through screening in primary care and referral to paediatric gastroenterology was captured prospectively. Diagnostic outcomes were reported. The diagnostic performance of two times the upper limit of normal (ULN) for alanine aminotransferase (ALT) was assessed. RESULTS: Non-alcoholic fatty liver disease was diagnosed in 55% of children identified by screening and referral. Liver disease other than NAFLD was present in 18% of those referred. Autoimmune hepatitis was the most common alternative diagnosis. Children with NAFLD had significantly (P < 0.05) higher screening ALT (98 ± 95) than children with liver disease other than NAFLD (86 ± 74). Advanced fibrosis was present in 11% of children. For the diagnosis of NAFLD, screening ALT two times the clinical ULN had a sensitivity of 57% and a specificity of 71%. CONCLUSIONS: Screening of overweight and obese children in primary care for NAFLD with referral to paediatric gastroenterology has the potential to identify clinically relevant liver pathology. Consensus is needed on how to value the risk and rewards of screening and referral, to identify children with liver disease in the most appropriate manner.

Non-alcoholic fatty liver disease is associated with low bone mineral density in obese children.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Liver disease can be a cause of low bone mineral density. Whether or not NAFLD influences bone health is not known. AIM: To evaluate bone mineral density in obese children with and without NAFLD. METHODS: Thirty-eight children with biopsy-proven NAFLD were matched for age, gender, race, ethnicity, height and weight to children without evidence of liver disease from the National Health and Nutrition Examination Survey. Bone mineral density was measured by dual energy X-ray absorptiometry. Age and gender-specific bone mineral density Z-scores were calculated and compared between children with and without NAFLD. After controlling for age, gender, race, ethnicity and total per cent body fat, the relationship between bone mineral density and the severity of histology was analysed in children with NAFLD. RESULTS: Obese children with NAFLD had significantly (P < 0.0001) lower bone mineral density Z-scores (-1.98) than obese children without NAFLD (0.48). Forty-five per cent of children with NAFLD had low-bone mineral density for age, compared to none of the children without NAFLD (P < 0.0001). Among those children with NAFLD, children with NASH had a significantly (P < 0.05) lower bone mineral density Z-score (-2.37) than children with NAFLD who did not have NASH (-1.58). CONCLUSIONS: The NAFLD was associated with poor bone health in obese children. More severe disease was associated with lower bone mineralisation. Further studies are needed to evaluate the underlying mechanisms and consequences of poor bone mineralisation in children with NAFLD.

Enteric-coated cysteamine for the treatment of paediatric non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a common cause of liver disease in children. Hepatic fat accumulation and oxidative stress contribute to its pathogenesis. Cysteamine bitartrate readily traverses cellular membranes and is a potent antioxidant. AIM: To evaluate the safety and efficacy of enteric-coated (EC) cysteamine in children with NAFLD. METHOD: Children, aged ≥10 y, meeting screening criteria with biopsy-proven NAFLD and serum ALT ≥60 IU/L, received twice-daily EC-cysteamine for 24 weeks. Monthly ALT, AST, body mass index (BMI) and gastrointestinal symptom scores were measured. Subjects with >50% reduction or normalisation of ALT achieved the primary endpoint. RESULTS: Of the 13 children enrolled (mean age 14.0 years), 11 completed EC-cysteamine therapy (mean dose 15.2 mg/kg/day) and were included in the final analysis. For these 11 subjects, the mean ALT levels at baseline and 24 weeks were 120.2 and 55 IU/L respectively (P = 0.002), and the AST levels were 60 and 36 IU/L respectively (P = 0.007). The primary endpoint was reached in 7 and normalisation (≤40 IU/L) of ALT in 5. After 24 week therapy, mean adiponectin levels increased (P = 0.009) and CK-18 fragment levels decreased (P = 0.013), insulin levels remained unchanged (P = 0.99). Mean leptin levels were decreased in responders (P = 0.044). Mean BMI was 34.5 at baseline and 34.2 kg/m(2) after treatment (P = 0.35). Mean symptom scores at baseline (1.1) and at 24 weeks (0.7) were similar. No major adverse events were reported. CONCLUSIONS: Enteric-coated cysteamine reduces ALT and AST levels in children with NAFLD without reduction in body mass index. Further studies will evaluate optimal cysteamine therapeutic dose and effect on liver histology in NAFLD (Clinicaltrials.gov protocol ID: 07-1699).

Symptoms and quality of life in obese children and adolescents with non-alcoholic fatty liver disease.

BACKGROUND: Data on the quality of life (QOL) of children with non-alcoholic fatty liver disease (NAFLD) are needed to estimate the true burden of illness in children with NAFLD. AIM: To characterize QOL and symptoms of children with NAFLD and to compare QOL in children with NAFLD with that in a sample of healthy children. METHODS: Quality of life and symptoms were assessed in children with biopsy-proven NAFLD enrolled in the NASH Clinical Research Network. PedsQL scores were compared with scores from healthy children. For children with NAFLD, between-group comparisons were made to test associations of demography, histological severity, symptoms and QOL. RESULTS: A total of 239 children (mean age 12.6 years) were studied. Children with NAFLD had worse total (72.8 vs. 83.8, P < 0.01), physical (77.2 vs. 87.5, P < 0.01) and psychosocial health (70.4 vs. 81.9, P < 0.01) scores compared with healthy children. QOL scores did not significantly differ by histological severity of NAFLD. Fatigue, trouble sleeping and sadness accounted for almost half of the variance in QOL scores. Impaired QOL was present in 39% of children with NAFLD. CONCLUSIONS: Children with NAFLD have a decrement in QOL. Symptoms were a major determinant of this impairment. Interventions are needed to restore and optimize QOL in children with NAFLD.

Review article: epidemiology, pathogenesis and potential treatments of paediatric non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of paediatric liver disease. Similar to NAFLD in adults, NAFLD in children is associated with obesity and insulin resistance and requires liver histology for diagnosis and staging. However, significant histological differences exist between adult and paediatric NAFLD to warrant caution in extrapolation of adult data. AIM: To review the available data on the epidemiology, pathogenesis, diagnosis and treatment of paediatric NAFLD. METHODS: Relevant articles were identified by Medline searches using the keywords: nonalcoholic fatty liver disease, steatohepatitis, obesity and children. RESULTS: The rise in childhood obesity has been accompanied by an increase in paediatric NAFLD. Age, gender and race/ethnicity are significant determinants of risk, and sex hormones, insulin sensitivity and adipocytokines are implicated in the pathogenesis of paediatric NAFLD. There is no consensus for treatment of NAFLD; however, data suggest that diet, exercise and some pharmacological therapies may be of benefit. CONCLUSIONS: To evaluate and effectively treat paediatric NAFLD, the pathophysiology and natural history of the disease should be clarified and non-invasive methods for screening, diagnosis, and longitudinal assessment developed. Randomized, controlled, double-blind trials of pharmacological therapies in children with biopsy-proven disease are necessary.

Underutilization of aspirin in hemodialysis patients for primary and secondary prevention of cardiovascular disease.

BACKGROUND: Patients on hemodialysis are at high risk for cardiovascular disease (CVD). Aspirin is an established therapy for primary and secondary prevention of CVD that may be underutilized in hemodialysis patients. To better understand the use of aspirin in hemodialysis patients, we examined the experience of an urban hemodialysis center. Guidelines for use as well as associated risks and benefits are reviewed. METHODS: Medical records for patients receiving hemodialysis treatment at our center (New York City, USA) in May 2004 were reviewed for aspirin use, presence of CVD, and potential contraindications to aspirin therapy. CVD was defined as a history of coronary artery disease, ischemic stroke, transient ischemic attack, or peripheral vascular disease. Potential contraindications to aspirin therapy included history of clinically significant bleeding or increased risk of bleeding, aspirin allergy and routine treatment with other anticoagulants. RESULTS: 176 patients were eligible for the study and 172 (98%) were included. Although 74 patients had a history of CVD, only 38 (51 %) of these were treated with aspirin. Among patients with a history of CVD who were not treated with aspirin, 19 (53%) had no identifiable contraindications to aspirin therapy for secondary prevention of CVD. Ninetyeight patients had no history of CVD, and 18 (18%) of these were treated with aspirin. Of patients without a history of CVD who were not treated with aspirin, 57 (71%) had no identifiable contraindications to aspirin therapy for primary prevention of CVD. CONCLUSIONS: Aspirin is underutilized in hemodialysis patients for the primary and secondary prevention of CVD. Given the high risk of CVD in hemodialysis patients, therapy with aspirin may be of significant benefit and prospective studies of aspirin therapy are needed.

A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis.

BACKGROUND: Children with non-alcoholic steatohepatitis are insulin-resistant and metformin has been proposed as a potential therapy. However, paediatric safety and efficacy data are absent. AIM: To test the hypothesis that metformin therapy will safely improve markers of liver disease in paediatric non-alcoholic steatohepatitis. METHODS: Single-arm open-label pilot study of metformin 500 mg twice daily for 24 weeks in non-diabetic children with biopsy-proven non-alcoholic steatohepatitis. RESULTS: Ten obese children (mean body mass index 30.4) enrolled and completed the trial. Mean alanine aminotransferase and aspartate aminotransferase (AST) improved significantly (P < 0.01) from baseline (184, 114 U/L) to end of treatment (98, 68 U/L). Alanine aminotransferase normalized in 40% and AST normalized in 50% of subjects. Children demonstrated significant improvements in liver fat measured by magnetic resonance spectroscopy (30-23%, P < 0.01); insulin sensitivity measured by quantitative insulin sensitivity check index (0.294-0.310, P < 0.05); and quality of life measured by pediatric quality of life inventory 4.0 (69-81, P < 0.01). CONCLUSION: Open-label treatment with metformin for 24 weeks was notable for improvement in liver chemistry, liver fat, insulin sensitivity and quality of life. A large randomized-controlled trial is needed to definitively determine the efficacy of metformin for paediatric non-alcoholic steatohepatitis.

Secondary focal segmental glomerulosclerosis in non-obese patients with increased muscle mass.

BACKGROUND: Secondary focal segmental glomerulosclerosis (FSGS) is a pattern of glomerular injury mediated by hyperfiltration and other adaptive structural-functional responses. We describe 3 non-obese patients with elevated body mass index (BMI) owing to increased muscle mass who had renal biopsy findings favoring a form of secondary FSGS. METHODS: Clinical and pathologic data were obtained on 3 patients with 1) renal biopsy findings of focal segmental and/or global glomerulosclerosis with glomerulomegaly; 2) BMI > or = 30; 3) body fat percentage < 20%; 4) "highly muscular" appearance, and 5) proteinuria > or = 1 g/d without nephrotic syndrome. 24-hour urine creatinine excretion was used to estimate lean body mass and percentage body fat. RESULTS: The 3 patients were males (age 38 - 48 years) employed in jobs requiring strenuous physical activity. BMIs ranged from 30.4 - 32.1 kg/m2 with body fat percentages of 12.9 - 16.8%. Creatinine clearances at time of biopsy ranged from 113 - 208 ml/min. Renal biopsies showed focal segmental and/or global glomerulosclerosis affecting a minority of glomeruli with glomerular hypertrophy and minimal (mean 15%) foot process effacement. Treatments included angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or weight loss. Over a mean follow-up time of 24.3 months, serum creatinine remained stable and proteinuria decreased in all patients. CONCLUSIONS: Non-obese patients with increased BMI due to elevated muscle mass are at risk of developing a secondary form of FSGS that resembles obesity-related glomerulopathy.

Decision analysis for the cost-effective management of recurrent colorectal cancer.

OBJECTIVE: To determine whether the use of [(18)F]2-fluoro-2-deoxyglucose positron emission tomography (FDG PET) in addition to computed axial tomography (CT) is helpful in managing recurrent colorectal cancer (CRC). SUMMARY BACKGROUND DATA: There is no consensus on a management algorithm for CRC. However, when recurrence is suspected, CT is generally used for further evaluation and staging of disease. METHODS: The authors used decision trees based on theoretical models to assess the cost-effectiveness of a CT + FDG PET strategy for the diagnosis and management of recurrent CRC compared with a CT-alone strategy. These theoretical models focus on patients with hepatic recurrence who are potentially curable through surgical hepatic resection. The population entering the decision trees consisted of patients with CRC who had undergone surgical resection of their primary CRC and who were suspected of having recurrence based on elevated levels of carcinoembryonic antigen. RESULTS: The CT + FDG PET strategy was found to be cost-effective for managing patients with elevated carcinoembryonic antigen levels who were candidates for hepatic resection. The CT + FDG PET strategy was higher in mean cost by $429 per patient but resulted in an increase in the mean life expectancy of 9.527 days per patient. CONCLUSIONS: These results show, through rigorous decision tree analysis, the potential cost-effectiveness of FDG PET in the management of recurrent CRC. The decision trees can be used to model various features of the management of recurrent CRC, including the cost-effectiveness of other newly emerging technologies.

Economic evaluation studies in nuclear medicine: a methodological review of the literature.

BACKGROUND: The growing need for evaluation of the utility of new nuclear medicine technologies has spawned a few economic studies ranging from preliminary indications of cost savings to complete decision analysis models incorporating costs and quality of life. The objective of the current study was to evaluate the methodological quality of economic analyses of nuclear medicine procedures which targeted cost-effectiveness or cost-utility issues published in the medical literature during the years 1985-1999. METHODS: A computerized literature search was used to identify original investigations from the medical literature which included an economic analysis of a nuclear medicine procedure. Each economic analysis article was evaluated by two independent reviewers for adherence to ten accepted methodological criteria. RESULTS: Of the 29 articles meeting the search criteria, only six (21%) conformed to all ten methodological criteria. CONCLUSIONS: Published economic analyses of nuclear medicine procedures usually do not meet accepted methodological standards and could be significantly improved to achieve overall better quality relative to similar analyses in the literature from other medical fields. Continued improvement in the number and quality of economic studies is critically needed for the future competitiveness of nuclear medicine studies.

A review of the literature for whole-body FDG PET in the management of patients with melanoma.

BACKGROUND: A review and meta-analysis of the literature on the use of 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in the detection of recurrent melanoma was conducted. The goals were to evaluate the quality of data reporting and to determine the overall values for the sensitivity and specificity of whole body FDG PET and management changes. METHODS: Guidelines to evaluate reporting within articles were formulated based on the United States medical payer source criteria for assessing studies reporting information on the utilization of new medical technology. A meta-analysis was conducted using methodology described in the peer reviewed literature. RESULTS: Our MEDLINE PLUS search resulted in a universe of 89 total articles. Within these 89, 19 were categorized in our targeted content area of which 13 were selected for analysis in our targeted subset, with the remaining 70 covering 24 different related content areas. Five of 13 (38%) articles in the target subset reported data which was adequate for incorporation into modeling objectives based on PET sensitivity and specificity values, with 1 of 13 (8%) in the same target subset reporting data adequate for modeling based on change-in-management data. Through a meta-analysis of the 13 target articles we determined, within a 95% confidence level, an overall sensitivity of 92% (95% confidence level 88.41%-95.82%) and an overall specificity of 90% (95% confidence level 83.26%-96.05%) as calculated by number of lesions, for FDG PET detecting recurrent melanoma throughout the whole body. Furthermore, limited data available for change-in-management suggests an overall FDG PET directed change-in-management value of 22%. CONCLUSIONS: Our review suggests that improvements can be made to more effectively report the results of these FDG PET studies. The overall values determined through the meta-analysis indicate the potential benefits of using FDG PET as a diagnostic/management tool. Furthermore, these values should prove useful to assessing the cost effectiveness of utilizing FDG PET in the management of recurrent melanoma.

Decision analysis for the cost effectiveness of sestamibi scintimammography in minimizing unnecessary biopsies.

BACKGROUND: The purpose of this study was to assess if breast cancer screening using sestamibi scintimammography (SSMM) in conjunction with mammography (MM) is cost effective in avoiding biopsies in healthy patients. METHODS: Quantitative decision tree sensitivity analysis was used to compare the conventional MM alone strategy (strategy A) with two decision strategies for screening with SSMM; SSMM after an indeterminate mammogram (strategy B) or SSMM after both a positive and an indeterminate mammogram (strategy C). Cost effectiveness was measured by calculating the expected cost per patient and the average life expectancy per patient for baseline values as well as over a range of values for all of the variables of each strategy. RESULTS: Based on Medicare reimbursement values, strategies B and C showed a cost savings of $9 and $20 per patient respectively as compared to strategy A. This translates into respective savings of $189 and $420 million per year assuming 21 million females undergo screening each year. Strategies B and C did however have a loss of mean life expectancy of 0.000178 and 0.000222 years respectively as compared to strategy A due to interval progression of breast cancer in a small number of women. Strategies B and C significantly lowered the number of biopsies performed on healthy patients in the screening population by 750,063 and 1,557,915 biopsies respectively as compared to strategy A. CONCLUSIONS: These results quantitatively verify the potential utility of using SSMM in avoiding unnecessary biopsies.

Autonomic performance and dehydroepiandrosterone sulfate levels in HIV-1-infected individuals: relationship to TH1 and TH2 cytokine profile.

BACKGROUND: Products of immune activation, including cytokines and lipid membrane derivatives, have been implicated in the pathogenesis of the neurologic sequelae, including autonomic dysfunction, associated with human immunodeficiency virus 1 (HIV-1) infection. In animal models, autonomic and endocrine dysfunction are associated with an altered cytokine profile. OBJECTIVES: To investigate the relationship between markers of immune activation (beta(2)-microglobulin), HIV-1 disease progression (CD4(+) cell count and viral load), and autonomic nervous system performance and to assess the relationship between autonomic performance, plasma levels of dehydroepiandrosterone sulfate (DHEAS), and T(H)1 and T(H)2 cytokine profile. METHODS: Thirty-one HIV-1-infected individuals and 22 HIV-1-negative controls were evaluated with a comprehensive neurologic, neuropsychological, and autonomic examination. Interleukin 4 and interferon gamma were measured by enzyme-linked immunosorbent assay in the supernatant of stimulated peripheral blood mononuclear cells. RESULTS: A composite measure of autonomic performance (AZ score) was significantly lower (worse autonomic function) in patients compared with controls (P=.04). A lower AZ score was associated with higher beta(2)-microglobulin serum levels and a lower CD4(+) cell count. Interleukin 4 levels were significantly inversely associated with AZ score (P=.01), whereas interferon gamma levels were significantly positively associated with DHEAS levels (P=.04). CONCLUSIONS: Our data show significant associations between markers of immune activation and disease progression and a composite measure of autonomic function in HIV-1-infected individuals. In addition, they suggest that poor autonomic function and low DHEAS plasma levels tend to be associated with an unbalanced cytokine profile.

Transmission, natural history, and treatment of hepatitis C virus infection in the pediatric population.

Compared with the adult population, hepatitis C virus infection may differ in the pediatric age group with respect to transmission, course, and response to treatment. The prevalence of hepatitis C in children is between 0.05% and 0.4%. The major mode of acquisition has shifted from parenteral transmission to maternal-infant transmission. However, the actual rate of maternal-infant transmission is low. The natural history of hepatitis C in children is not well characterized, although the available information suggests a milder disease than in adults. In the eight studies of treatment with interferon for hepatitis C in children, the incidence of a complete sustained response varied from 0 to 45%. No pediatric studies have evaluated quality of life or the effect of treatment on the development of cirrhosis and hepatocellular carcinoma. Children may respond better to treatment than adults. We recommend that children with hepatitis C are considered for treatment only as part of a controlled clinical trial.

A meta-analysis of the literature for whole-body FDG PET detection of recurrent colorectal cancer.

UNLABELLED: A meta-analysis of the literature for the use of FDG PET in the detection of recurrent colorectal cancer (CRC) was conducted to evaluate the quality of the reported studies. Overall values for the sensitivity and specificity of whole-body FDG PET and an overall FDG PET-directed percentage change in management were also determined through this analysis. METHODS: Guidelines to evaluate the articles were formulated on the basis of the U.S. medical payer source criteria for assessing studies that report information on usage of new medical technology. A metaanalysis was conducted using methodology described in the peer-reviewed literature. RESULTS: On the basis of the guidelines established for our review, the availability of necessary information for assessing the reliability of the FDG PET data for diagnosing recurrent CRC was less than ideal. Through a meta-analysis of 11 articles, we determined, within a 95% confidence level, an overall sensitivity of 97% (95% confidence level, 95%-99%) and an overall specificity of 76% (95% confidence level, 64%-88%) for FDG PET detecting recurrent CRC throughout the whole body. Furthermore, through pooling of the change-in-management data, an overall FDG PET-directed change in management was calculated to be 29% (95% confidence level, 25%-34%). CONCLUSION: Our review suggests that improvements can be made to more effectively report the results of these FDG PET studies. The overall values determined through the meta-analysis indicate the potential benefits of using FDG PET as a diagnostic or management tool. Furthermore, these values should prove to be useful to assess the cost-effectiveness of using FDG PET in the management of patients with recurrent CRC.

Clozapine-induced agranulocytosis. Incidence and risk factors in the United States.

BACKGROUND: Clozapine is an atypical antipsychotic agent that is more effective than standard neuroleptic drugs in the treatment of patients with refractory schizophrenia. Unlike classic neuroleptic agents, clozapine is not associated with the development of acute extrapyramidal symptoms or tardive dyskinesia. The main factor limiting its use is the risk of potentially fatal agranulocytosis, estimated to occur in 1 to 2 percent of treated patients. After clozapine was approved by the Food and Drug Administration, it became available for marketing in the United States in February 1990 only as part of a special surveillance system (the Clozaril Patient Management System, or CPMS), in which a weekly white-cell count was required for the patient to receive a supply of the drug. METHODS: We evaluated the CPMS data for February 1990 through April 1991 by survival analysis to determine the incidence of agranulocytosis and the effects of potential risk factors such as age and sex. Data were available for 11,555 patients who received clozapine during the period after marketing began. RESULTS: Agranulocytosis developed in 73 patients, resulting in death from infectious complications in 2 patients. Episodes of agranulocytosis occurred in 61 patients within three months after they began treatment. The cumulative incidence of this side effect was 0.80 percent (95 percent confidence interval, 0.61 to 0.99) at 1 year and 0.91 percent (95 percent confidence interval, 0.62 to 1.20) at 1 1/2 years. The risk of agranulocytosis increased with age and was higher among women. CONCLUSIONS: The occurrence of agranulocytosis is a substantial hazard of the administration of clozapine, but this hazard can be reduced by monitoring the white-cell count. The increasing risk of agranulocytosis with age and the reduced incidence after the first six months of treatment provide additional guidelines for the prescription and monitoring of clozapine treatment in the future.