Fatty acids platelets and oxidative markers following intravenous n-3 fatty acids administration in cystic fibrosis: An open pilot observational study.

BACKGROUND: An imbalance in the ratio of arachidonic acid and docosahexaenoic acid (DHA) was found in cystic fibrosis (CF) affected tissues and was suggested to promote inflammation. Several studies have shown that the long chain n-3 fatty acids reduced inflammatory activity while others have highlighted prooxidant activity of DHA at high concentrations. The aim of our study was to evaluate the effects of an intravenous fish-oil emulsion enriched with n-3 FA in patients with CF on plasma and platelet FA composition and peroxidation markers. METHODS: 13 patients with CF received one IV emulsion per week of 2 mL/kg fish-oil n-3 emulsion for 12 weeks. RESULTS: There was a significant increase in 20:5 n-3 and 22:6 n-3 platelet FA composition, no variation in 20:4 n-6, a decrease in n-9. There was no variation in plasma FA composition. Specific urinary markers of lipid peroxidation derived from n-3 and n-6 showed a very high level before infusion compared with usual values in healthy subjects which was not affected by treatment. A significant weight loss and a decrease in reduced glutathione were observed in adult patients. CONCLUSIONS: The intravenous administration of n-3 FA in CF patients induced a significant modification in platelet FA composition but no modification of oxidative markers. However, the weight loss and the decreased level in reduced glutathione observed in adult patients may suggest a potential deleterious activity for some patients. Further studies are necessary to determine the optimal dose and route for long chain FA administration required to reach a potential beneficial effect.     

Oral fish oil supplementation raises blood omega-3 levels and lowers C-reactive protein in haemodialysis patients--a pilot study.

BACKGROUND: We previously reported that haemodialysis patients have suboptimal blood levels of the cardioprotective omega-3 polyunsaturated fatty acids (n-3 PUFA) eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. In the present pilot study, we tested the hypothesis that supplementing haemodialysis patients for 12 weeks with the American Heart Association (AHA)-recommended fish oil dose would be well tolerated and efficacious in boosting blood n-3 PUFA levels and improving cardiovascular risk biomarkers. METHODS: Twenty-seven subjects were randomized in a 2 : 1 ratio to either 1.3 g of EPA + DHA daily or placebo. RESULTS: At baseline, 83% of subjects consumed inadequate dietary fish and had the following erythrocyte n-3 PUFA levels (mean +/- SD,% weight)-EPA: 0.3 +/- 0.2, DHA: 2.9 +/- 2.0, and ratio of n-6/n-3 PUFA: 4.2 +/- 1.3. Supplementation induced large increases in mean blood EPA and DHA levels (% increase, P-value vs placebo group): erythrocyte-EPA: +400%, P = 0.0018, DHA: +205%, P < 0.0001; plasma-EPA: +275%, P = 0.0003, DHA: +69%, P = 0.0352. Levels in the placebo group remained relatively unchanged. The omega-3 index, a value correlating with the level of cardioprotection, increased significantly in the fish oil group. A reduction in mean C-reactive protein levels (-3.3 +/- 8.1 mg/l, P = 0.0282) and a trend towards lower triglyceride levels (-24 +/- 74 mg/dl, P = 0.0783) were also observed in the active vs placebo group. Minimal side effects were noted. CONCLUSIONS: Our preliminary observations that the AHA-recommended fish oil dose is well tolerated, efficacious and may improve surrogate markers of cardiovascular disease in haemodialysis patients paves the way for larger clinical trials to confirm a clinical benefit.     

Fatty Acid Supplementation Improves Respiratory,Inflammatory and Nutritional Parameters in Adults with Cystic Fibrosis

Introduction and aimsChronic inflammation plays a major role in lung deterioration in cystic fibrosis (CF) patients and anti-inflammatory strategies have beneficial effects. To study the changes seen after a oneyear course of low-dose dietary supplements with a mixture of fatty acids in adult patients with CF in chronic inflammation, pulmonary status (lung function, respiratory exacerbations and antibiotic consumption), quality of life and anthropometric parameters.Patients and methodSeventeen adult subjects with CF received 324mg of eicosapentaenoic, 216mg of docosahexaenoic, 480mg of linoleic and 258mg of gammalinolenic acid daily. We assessed inflammation markers, spirometry parameters, number and severity of respiratory exacerbations, antibiotic consumption, quality of life (St George's QoL), anthropometric parameters and serum phospholipid fatty acid composition.ResultsAt the end of the treatment period TNF alpha levels fell significantly and its soluble receptors (60 and 80) rose significantly. Levels of IgG and IgM anti-oxidised LDL antibodies fell significantly. Spirometry improved significantly. Annual respiratory exacerbations and days of antibiotic treatment fell significantly. The improvement in QoL was not significant. Serum levels of docosahexaenoic, total omega-3 and linoleic acid rose significantly and more favourable profiles were seen in monoenoic acids, arachidonic acid and the arachidonic/docosahexaenoic ratio. The fat-free mass and hand grip dynamometry improved significantly.ConclusionsLow-dose supplements of n-3 and gammalinolenic fatty acids over a long period (one year) appears to improve pulmonary status (lung function, respiratory exacerbations and antibiotic consumption), inflammatory and anthropometric parameters in adults with CF.     

Plasma and erythrocyte phospholipid fatty acids composition in Serbian hemodialyzed patients

Dyslipidemia is one of the possible risk factors for advanced atherosclerosis in patients with chronic renal failure. Abnormal phospholipid metabolism may play an important role in the progression of atherosclerosis in patients with renal failure. The aim of this study was to determine specific characteristics of plasma and erythrocyte phospholipid content and fatty acid composition in 37 patients with chronic renal failure on hemodialysis (HD). The results were compared with the characteristics of healthy subjects. Briefly, plasma triglyceride (p < 0.001), total cholesterol (p < 0.05), and total phospholipids (p < 0.01) levels were significantly higher and HDL-cholesterol level significantly lower (p < 0.01) in HD patients. Plasma phosphatidylcholine and phosphatidylethanolamine concentration were significantly higher (p < 0.001) in HD patients. The plasma phospholipid fatty acids composition indicated significantly (p < 0.01) higher level of oleic (18:1 n-9) and lower levels of eicopentaenoic (20:5 n-3 EPA) and docosahexaenoic (22:6 n-3 DHA) acids (p < 0.05). However, in HD patients, the relative concentration of plasma phospholipid n-6 polyunsaturated fatty acid (PUFA) was significantly lower (p < 0.05). The fatty acid composition of erythrocyte phospholipid in HD patients was modified with EPA and DHA levels significantly lowered (p < 0.05). Our results demonstrate an abnormal phospholipid metabolism and deficiency of n-3 PUFA in plasma and erythrocyte phospholipids in hemodialyzed patients.     

Specific Effects of γ-Linolenic,Eicosapentaenoic, and Docosahexaenoic Ethyl Esters on Bone Post-ovariectomy in Rats

Long chain polyunsaturated fatty acids (LCPUFAs) are involved in the regulation of bone metabolism. Increased dietary consumption of n-3, and possibly some n-6, LCPUFAs may limit postmenopausal bone loss. The aim of this study was to determine the effects on bone of specific fatty acids within the n-3 and n-6 LCPUFA families in ovariectomized (OVX) rats. Rats were OVX or sham-operated and fed either a control diet (OVX and sham) or a diet supplemented with 0.5 g/kg body weight/day of γ-linolenic (GLA), eicosapentaenoic (EPA), docosahexaenoic (DHA) ethyl esters or a mixture of all three (MIX) for 16 weeks. Bone mineral content (BMC), area, and density and plasma concentrations of insulin-like growth factor-I, vitamin D, selected biochemical markers of bone metabolism, and parathyroid hormone (PTH) were determined. The OVX-induced decrease in lumbar spine BMC was significantly attenuated by DHA but not by EPA or GLA supplementation or supplementation with a mixture of all three LCPUFAs. Endosteal circumferences of tibiae were significantly greater in DHA and EPA compared to OVX. Plasma C-terminal telopeptide of type I collagen and osteocalcin concentrations were not significantly different in the DHA group compared to OVX. Femur BMC decreased by a significantly greater amount in GLA than OVX, and final plasma PTH concentrations were significantly higher in GLA compared to all other groups. In conclusion, DHA ameliorated OVX-induced bone mineral loss. GLA exacerbated post-OVX bone mineral loss, possibly as a result of PTH-induced bone catabolism.     

Prostate tissue and leukocyte levels of n-3 polyunsaturated fatty acids in men with benign prostate hyperplasia or prostate cancer

OBJECTIVE: To compare the levels of n-3 polyunsaturated fatty acids (PUFAs) in leukocytes and prostate tissue in men with prostate cancer or benign prostatic hyperplasia (BPH), as dietary intake of n-3 PUFAs has been linked to the risk of prostate cancer; the prostate-specific antigen (PSA) level was also compared to prostate tissue levels of n-3 PUFAs. PATIENTS AND METHODS: Prostate tissue was obtained and leukocytes isolated from 20 men with prostate cancer and 35 with BPH. The n-3 PUFAs alpha-linolenic acid (ALA), eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) were measured in prostate tissue and in peripheral blood leukocytes using gas chromatography. PSA levels were measured in all of the men. RESULTS: There was a strong positive correlation between EPA and DHA in leukocytes and in prostate tissue (EPA: r = 0.80, DHA: r = 0.53, both P < 0.001) in all the men, whereas there was no association between the content of ALA in leukocytes and in prostate tissue (r = -0.15). Men with BPH had similar levels of ALA in leukocytes and in prostate tissue, but men with prostate cancer had more ALA in prostate tissue than in leukocytes. The PSA level was significantly positively correlated with ALA level in prostate tissue (r = 0.42, P < 0.01) but there was no significant correlation between PSA level and EPA and DHA levels. There were no significant correlations between PSA level and n-3 PUFA levels in leukocytes. CONCLUSION: Dietary intake of the marine n-3 PUFAs reflected in EPA and DHA levels in leukocytes are also reflected in EPA and DHA levels in prostate tissue in men with and without prostate cancer. However, there is a discrepancy between the levels of ALA in leukocytes and in prostate tissue, with higher levels in men with prostate cancer. This is in accordance with the strong positive association between PSA and ALA levels in prostate tissue. This study therefore does not support the hypothesis that intake of marine n-3 PUFAs might protect against prostate cancer, but lends support to the deleterious role of ALA in the development of prostate cancer.     

Whole blood fatty acid analysis with micromethod in cystic fibrosis and pulmonary disease

ObjectivesTo assess fatty acid (FA) profiles in whole blood of 90 cystic fibrosis patients (CF) and 30 control subjects (C) and to correlate FA changes to the severity of respiratory disease.MethodsWhole blood FA were assessed by GC with a micromethod-based analysis.ResultsSaturated and monounsaturated FA are higher, whereas polyunsaturated FA are lower in CF versus C with reduction of total n-6 FA, 22:5n-3 and 22:6n-3 (DHA). The product of linoleic acid (LA) × DHA, proposed as a marker for the disease, is 30% lower in CF than in C. Correlations with the severity of the respiratory disease are present for different FA and for the LA × DHA product. There is a reduction of Δ5 desaturase activity in CF, greater in severe disease, suggesting a basic metabolic alteration.ConclusionsThe micromethod-based analysis of blood FA facilitates the assessment of the FA status while confirming alterations of FA profiles already reported in specific blood compartments of CF.     

Neuroprotective effect of docosahexaenoic acid-enriched phospholipids in experimental diabetic neuropathy

A deficiency in essential fatty acid metabolism has been widely reported in both human and animal diabetes. Fish oil supplementations (n-3 fatty acids), containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were less effective on diabetic neuropathy than (n-6) fatty acids. This partial effect of (n-3) fatty acids might be attributed to the presence of EPA, a competitor of arachidonic acid, which enhanced the diabetes-induced decrease of this fatty acid in serum and tissues. For determining whether a supplementation with DHA alone could prevent neuropathy in streptozotocin-induced diabetes, diabetic rats were given daily, by gavage, liposomes containing DHA phospholipids, at a dose of 60 mg/kg. Eight weeks of diabetes induced significant decreases in nerve conduction velocity (NCV), nerve blood flow (NBF), and sciatic nerve and erythrocyte (red blood cells [RBCs]) Na,K-ATPase activities. DHA phospholipids totally prevented the decrease in NCV and NBF observed during diabetes when compared with the nonsupplemented diabetic group. DHA phospholipids also prevented the Na,K-ATPase activity decrease in RBC but not in sciatic nerve. Moreover, DHA level in sciatic nerve membranes was correlated with NCV. These results demonstrate a protective effect of daily doses of DHA on experimental diabetic neuropathy. Thus, treatment with DHA phospholipids could be suitable for evaluation in clinical trials.     

Plasma and Erythrocyte Phospholipid Fatty Acids Composition in Serbian Hemodialyzed Patients

Dyslipidemia is one of the possible risk factors for advanced atherosclerosis in patients with chronic renal failure. Abnormal phospholipid metabolism may play an important role in the progression of atherosclerosis in patients with renal failure. The aim of this study was to determine specific characteristics of plasma and erythrocyte phospholipid content and fatty acid composition in 37 patients with chronic renal failure on hemodialysis (HD). The results were compared with the characteristics of healthy subjects. Briefly, plasma triglyceride (p < 0.001), total cholesterol (p < 0.05), and total phospholipids (p < 0.01) levels were significantly higher and HDL-cholesterol level significantly lower (p < 0.01) in HD patients. Plasma phosphatidylcholine and phosphatidylethanolamine concentration were significantly higher (p < 0.001) in HD patients. The plasma phospholipid fatty acids composition indicated significantly (p < 0.01) higher level of oleic (18:1 n-9) and lower levels of eicopentaenoic (20:5 n-3 EPA) and docosahexaenoic (22:6 n-3 DHA) acids (p < 0.05). However, in HD patients, the relative concentration of plasma phospholipid n-6 polyunsaturated fatty acid (PUFA) was significantly lower (p < 0.05). The fatty acid composition of erythrocyte phospholipid in HD patients was modified with EPA and DHA levels significantly lowered (p < 0.05). Our results demonstrate an abnormal phospholipid metabolism and deficiency of n‐3 PUFA in plasma and erythrocyte phospholipids in hemodialyzed patients.     

Effects of n-3 fatty acids on renal function and renal prostaglandin E metabolism

The present study was performed to investigate the effects of dietary fish oil supplements on renal function and renal prostaglandin (PG) E metabolism. The usual "western" diet of 10 healthy volunteers (six female and 4 male) aged between 21 and 35 years was supplemented with 6 g/day of n-3 polyunsaturated fatty acids [3.6 g of eicosapentaenoic acid (EPA) and 2.4 g of docosahexaenoic acid (DHA)] for six weeks. Supine arterial blood pressure (BP) and heart rate (HR), renal hemodynamics, renal excretory function and urinary excretion of PGE2 and PGE3 were determined before and at the end of the fish oil supplementation period. No changes could be observed in BP and HR while renal plasma flow (RPF), determined as the clearance of PAH, significantly increased from 559 +/- 44 to 738 +/- 47 ml/min (P less than 0.001) with the fish oil supplements. This was associated with a decrease in renal vascular resistance from (8.11 +/- 0.54).10(-2) to (6.37 +/- 0.38).10(-2) mm Hg.min.ml-1 (P less than 0.01). Glomerular filtration rate (GFR), determined as the clearance of inulin, increased from 97 +/- 3 to 107 +/- 3 ml/min (P less than 0.01), resulting in a decrease in filtration fraction from an average of 0.19 +/- 0.01 to 0.15 +/- 0.01 (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Fatty acid levels and risk of asthma in young adults

BACKGROUND: There is current interest in the possible protective effect of long chain (n-3) fatty acids from fish in chronic lung diseases such as asthma. The aim of this community based cross sectional study was to determine whether plasma long chain (n-3) fatty acids, as a measure of dietary intake, differed between 1601 young adults with and without asthma. METHODS: Subjects of mean (SD) age 34.6 (7.1) years completed a detailed respiratory questionnaire, food frequency questionnaire, skin prick testing, and lung function tests including methacholine challenge test for bronchial hyperreactivity (BHR) and had venous blood taken for analysis of plasma fatty acids. Plasma fatty acid levels (%) were analysed using multiple logistic regression with alternative definitions of asthma and atopy as the outcomes. RESULTS: Atopy was not associated with any plasma fatty acid. The n-3 polyunsaturated fatty acids and n-6:n-3 ratio were not consistently associated with asthma or atopy. The n-6 polyunsaturated fatty acid dihomo gamma-linolenic acid (DHGLA) was positively associated with current asthma (OR=1.30, 95% CI 1.06 to 1.60), asthma (OR=1.34, 95% CI 1.13 to 1.60), and doctor diagnosed asthma (OR=1.25, 95% CI 1.06 to 1.48). CONCLUSION: Plasma n-3 fatty acids are not associated with a reduced risk of asthma or atopy among young adults. The association of DHGLA with asthma warrants further research to determine a cause-effect relationship.     

Alterations in immune response and PPAR/LXR regulation in cystic fibrosis macrophages

BackgroundCystic fibrosis (CF) is characterized by an excessive inflammatory response in epithelial cells and macrophages. In CF mice, lung inflammation can be abrogated by oral treatment with docosahexaenoic acid (DHA). Since PPARs and LXRs are important regulators of inflammation and fatty acid metabolism in macrophages, we hypothesized that these pathways are dysregulated in CF macrophages and are corrected with DHA treatment.MethodsPeritoneal macrophages were obtained from wild type and cftr^−/− mice. LPS induced cytokine secretion and NFκB activity were analyzed with and without oral DHA treatment. The expression and activity of PPARα,γ, δ and LXRα were analyzed by RT-PCR and EMSA.ResultsLPS induced TNFα and IL-6 secretion and NFκB p65 activity were increased in CF macrophages. This was associated with low basal PPARγ expression and attenuated LPS induced induction of PPARδ, LXRα and ABCA1. DHA pretreatment in vivo decreased TNFα secretion and p65 activity, and increased PPARα and γ expression and function. The effects of DHA could be reproduced by PPAR agonists and blocked by a PPARα antagonist.ConclusionImpaired regulation of nuclear receptors may contribute to the abnormal LPS induced signaling in CF macrophages and is reversed by DHA.     

A pilot study on the safety and efficacy of a novel antioxidant rich formulation in patients with cystic fibrosis.

BACKGROUND: Pancreatic insufficiency and a diminished bile acid pool cause malabsorption of important essential nutrients and other dietary components in cystic fibrosis (CF). Of particular significance is the malabsorption of fat-soluble antioxidants such as carotenoids, tocopherols and coenzyme Q(10) (CoQ(10)). Despite supplementation, CF patients are often deficient in these compounds, resulting in increased oxidative stress, which may contribute to adverse health effects. This pilot study was designed to evaluate the safety of a novel micellar formulation (CF-1) of fat-soluble nutrients and antioxidants and to determine its efficacy in improving plasma levels of these compounds and reducing inflammatory markers in induced sputum. METHODS: Ten CF subjects, ages 8 to 45 years old, were given orally 10 ml of the CF-1 formulation daily for 56 days after a 21-day washout period in which subjects stopped supplemental vitamin use except for a standard multivitamin. Plasma obtained at -3, 0 (baseline), 1, 2, 4, and 8 weeks was assayed for beta-carotene, gamma-tocopherol, retinol, and CoQ(10) as well as for safety parameters (comprehensive metabolic panel and complete blood count). In addition, pulmonary function was measured and induced sputum was assayed for markers of inflammation and quantitative bacterial counts both prior and during dosing. RESULTS: No serious adverse effects, laboratory abnormalities or elevated nutrient levels (above normal) were identified as related to CF-1. Supplementation with CF-1 significantly increased beta-carotene levels at all dosing time points when compared to screening and baseline. In addition, gamma-tocopherol and CoQ(10) significantly increased from baseline in all subjects. Induced sputum myeloperoxidase significantly decreased and there was a trend toward decreases in PMN elastase and total cell counts with CF-1. There was a significant inverse correlation between the antioxidant levels and induced sputum changes in IL-8 and total neutrophils. Lung function and sputum bacterial counts were unchanged. CONCLUSION: The novel CF-1 formulation safely and effectively increased plasma levels of important fat-soluble nutrients and antioxidants. In addition, improvements in antioxidant plasma levels were associated with reductions in airway inflammation in CF patients.     

No effects of n-3 fatty acid supplementation on serum total testosterone levels in older men: the Alpha Omega Trial

The intake of the n-3 fatty acids alpha-linolenic acid (ALA), acid (EPA) and docosahexaenoic acid (DHA) has been related to testosterone levels in epidemiological analyses. The aim of this study was to assess whether the n-3 fatty acids affects testosterone levels in post-myocardial infarction (MI) patients, who are at risk of testosterone deficiency. In a double-blind, placebo-controlled trial of low-dose supplementation of n-3 fatty acids, we included 1850 male post-MI patients aged 60-80?years who participated in the Alpha Omega Trial. Patients were randomly allocated to margarines that provided 400?mg/day of EPA-DHA (n?=?453), 2?mg/day of ALA (n?=?467), EPA-DHA plus ALA (n?=?458), or placebo (n?=?472). Serum testosterone levels were assessed at baseline and after 41?months using whole day blood samples obtained at the subjects' home or at the hospital. Subjects were on average age of 68.4 (SD 5.3) years old and had baseline mean serum total testosterone of 14.8 (SD 5.6)?nmol/L. The four randomized groups did not differ for baseline characteristics. ALA, EPA-DHA, and EPA-DHA plus ALA supplementation did not affect serum total testosterone compared to placebo. Moreover, n-3 fatty acid supplementation did not affect the risk of incident testosterone deficiency (n?=?76 with total testosterone <8.0?nmol/L). We conclude that n-3 fatty acids supplementation did not affect serum total testosterone in men who had had a MI.     

Lung transplantation in cystic fibrosis normalizes essential fatty acid profiles

BackgroundCystic fibrosis (CF) can be a devastating disease. Disorders in essential fatty acid state are increasingly reported and various supplementation trials have been performed in an attempt to improve outcomes. However, the mechanisms leading to these disturbances remain elusive.We wanted to investigate the role of the diseased CF lung on fatty acid profiles.MethodsWe compared fatty acid profiles in patients with CF after lung transplantation (n = 11) to age-matched healthy controls and homozygous F508del patients (n = 22 each).ResultsCompared to healthy controls, in patients with CF, there are decreased levels of docosahexaenoic, linoleic and arachidonic acid and increased levels of mead acid. In patients that underwent a lung transplantation, levels of docosahexaenoic, linoleic and arachidonic acid were normal. Mead acid did not decrease significantly.ConclusionsThe diseased CFTR deficient lung is a major determinant in the disturbed fatty acid profile in CF.     

The role of fish oil/omega-3 fatty acids in the treatment of IgA nephropathy

Beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) have been reported in recent epidemiologic studies and randomized clinical trials in a variety of cardiovascular and autoimmune diseases. Fish and marine oils are the most abundant and convenient sources of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the two major n-3 fatty acids that serve as substrates for cyclooxygenase and lipoxygenase pathways leading to less potent inflammatory mediators than those produced through the n-6 PUFA substrate, arachidonic acid. N-3 PUFA can also suppress inflammatory and/or immunologic responses through eicosanoid-independent mechanisms. Although the pathophysiology of IgA nephropathy is incompletely understood, it is likely that n-3 PUFA prevents renal disease progression by interfering with a number of effector pathways triggered by mesangial immune-complex deposition. In addition, potential targets of n-3 PUFA relevant to renal disease progression could be similar to those involved in preventing the development and progression of cardiovascular disease by lowering blood pressure, reducing serum lipid levels, decreasing vascular resistance, or preventing thrombosis. In IgA nephropathy, efficacy of n-3 PUFA contained in fish oil supplements has been tested with varying results. The largest randomized clinical trial performed by our collaborative group provided strong evidence that treatment for 2 years with a daily dose of 1.8 g of EPA and 1.2 g of DHA slowed the progression of renal disease in high-risk patients. These benefits persisted after 6.4 years of follow up. With safety, composition, and dosing convenience in mind, we can recommend two products that are available as pharmaceutical-grade fish-oil concentrates, Omacor (Pronova Biocare, Oslo, Norway) and Coromega (European Reference Botanical Laboratories, Carlsbad, CA).     

Hemorrhage associated with vitamin C deficiency in surgical patients

BACKGROUND: Diffuse hemorrhage in surgical patients with normal coagulation parameters may be caused by vitamin C deficiency and is rapidly reversed by vitamin C replacement. METHODS: Patients treated on a surgical service were entered into a clinical registry over a 12-month period if they experienced diffuse hemorrhage in the face of normal coagulation parameters and a plasma ascorbic acid level < 0.6 mg/dL (normal 0.6-2.0 mg/dL). Oral vitamin C replacement was administered after determination of plasma ascorbic acid level. Response to therapy, including subsequent bleeding events, need for blood transfusions, and demographic data including social and dietary history were retrospectively reviewed from hospital and outpatient clinic records. RESULTS: Twelve patients with bleeding diatheses and low plasma ascorbic acid levels were identified. Plasma ascorbic acid levels were 0.1 to 0.5 mg/dL (mean, 0.3 mg/dL). There were 6 men and 6 women; age ranged from 46 to 90 years (mean, 78 years). Coagulation parameters were normal in all patients. Diffuse postoperative bleeding from nonsurgical causes was evident in 10 of 12 patients. Four patients, 2 of whom had operations, presented with chronic recurrent blood loss from the gastrointestinal tract. Each patient received 250 to 1000 mg of vitamin C replacement daily. Within 24 hours of vitamin C administration, there was no further evidence of clinical bleeding nor need for subsequent blood transfusions in any patient. CONCLUSIONS: Vitamin C deficiency should be included in the differential diagnosis of nonspecific bleeding in surgical patients. Prolonged hospitalization, severe illness, and poor diet create vitamin C deficiency with significant clinical consequences. Oral vitamin C replacement rapidly reverses the effects of this disorder.     

Association of alpha(1)-antichymotrypsin deficiency with milder lung disease in patients with cystic fibrosis

BACKGROUND: Cystic fibrosis (CF) is characterised by an excess of free proteinases that destroy lung tissue. Despite this, previous studies have shown that patients with CF with a mild deficiency variant of the proteinase inhibitor alpha(1)-antitrypsin have less, rather than more, severe pulmonary disease. Alpha(1)-antichymotrypsin is another important serine proteinase inhibitor that protects the lung against proteolytic attack, and point mutations in the alpha(1)-antichymotrypsin gene that result in plasma deficiency are associated with chronic obstructive pulmonary disease. METHODS: The effect of alpha(1)-antichymotrypsin deficiency and the -15 alpha(1)-antichymotrypsin signal peptide genotype on lung function was assessed in patients with CF. RESULTS: One hundred and fifty seven patients with CF were screened and 10 were identified with a plasma deficiency of alpha(1)-antichymotrypsin (plasma concentration <0.2 g/l). In a multivariate analysis these individuals had significantly less severe lung disease than those who had normal or raised levels of alpha(1)-antichymotrypsin: forced expiratory volume in one second (FEV(1)) 69.9% predicted versus 53. 2% predicted (p=0.04) and chest radiographic score of 7.2 versus 9.7 (p=0.03) for those with and without alpha(1)-antichymotrypsin deficiency, respectively. The -15 signal peptide genotype did not affect plasma levels, but the -15 Ala/Ala signal peptide genotype was over-represented in individuals with CF compared with healthy blood donor controls. CONCLUSION: These data indicate that deficiency of alpha(1)-antichymotrypsin is associated with less severe pulmonary disease in patients with CF, and support our previous observations that mild genetic deficiency of a proteinase inhibitor is associated with an improved outcome.     

Osteoporosis and osteopenia in adults and adolescents with cystic fibrosis: prevalence and associated factors

BACKGROUND: Patients with cystic fibrosis (CF) have many risk factors for reduced bone mineral density (BMD). The aim of this study was to determine the prevalence of osteoporosis and osteopenia in a large cross section of patients and to identify risk factors. METHODS: All patients attending the regional centre were invited to participate in the study. Bone mineral density was measured at the lumbar spine, femoral neck, and for total body with a Lunar DPX-L densitometer. Multiple indices of disease severity were investigated, and liver and thyroid function, blood calcium, phosphate, 25-OH vitamin D, follicle stimulating and luteinising hormone, oestradiol, and testosterone levels were measured. Patients completed a four day prospective dietary diary. Exercise was assessed by a seven day activity recall questionnaire. Sexual development and treatment histories were obtained. The relationship between all these variables and BMD measurements was analysed. RESULTS: Sixty six percent of 114 patients assessed had osteopenia or osteoporosis. The Shwachman-Kulczycki (SK) clinical score (higher score = less severe disease) correlated significantly with BMD at the lumbar spine and femoral neck, and with total body BMD (p<0.001). There was a predicted increase of 0.0032 g/cm(2) in lumbar spine BMD for every unit increase in the SK score. Oral steroid use was significantly associated with reduced BMD at the lumbar spine (p = 0.017) and femoral neck (p = 0.027). CONCLUSIONS: Osteopenia and osteoporosis are common findings in a heterogeneous population of adults with CF. Patients at most risk are those with severe disease and those who have used corticosteroids.