Plasma and muscle free carnitine deficiency due to renal Fanconi syndrome.

Plasma and urine free and acyl carnitine were measured in 19 children with nephropathic cystinosis and renal Fanconi syndrome. Each patient exhibited a deficiency of plasma free carnitine (mean 11.7 +/- 4.0 [SD] nmol/ml) compared with normal control values (42.0 +/- 9.0 nmol/ml) (P less than 0.001). Mean plasma acyl carnitine in the cystinotic subjects was normal. Four subjects with Fanconi syndrome but not cystinosis displayed the same abnormal pattern of plasma carnitine levels; controls with acidosis or a lysosomal storage disorder (Fabry disease), but not Fanconi syndrome, had entirely normal plasma carnitine levels. Two postrenal transplant subjects with cystinosis but without Fanconi syndrome also had normal plasma carnitine levels. Absolute amounts of urinary free carnitine were elevated in cystinotic individuals with Fanconi syndrome. In all 21 subjects with several different etiologies for the Fanconi syndrome, the mean fractional excretion of free carnitine (33%) as well as acyl carnitine (26%) greatly exceeded normal values (3 and 5%, respectively). Total free carnitine excretion in Fanconi syndrome patients correlated with total amino acid excretion (r = 0.76). Two cystinotic patients fasted for 24 h and one idiopathic Fanconi syndrome patient fasted for 5 h showed normal increases in plasma beta-hydroxybutyrate and acetoacetate, which suggested that hepatic fatty acid oxidation was intact despite very low plasma free carnitine levels. Muscle biopsies from two cystinotic subjects with Fanconi syndrome and plasma carnitine deficiency had 8.5 and 13.1 nmol free carnitine per milligram of noncollagen protein, respectively (normal controls, 22.3 and 17.1); total carnitines were 11.8 and 13.3 nmol/mg noncollagen protein (controls 33.5, 20.0). One biopsy revealed a mild increase in lipid droplets. The other showed mild myopathic features with variation in muscle fiber size, small vacuoles, and an increase in lipid droplets. In renal Fanconi syndrome, failure to reabsorb free and acyl carnitine results in a secondary plasma and muscle free carnitine deficiency.     

健康成人与肝脏疾病患者血浆肉毒碱的检测

目的建立成人总肉毒碱(TC)和游离肉毒碱(FC)的参考范围;检测肝病患者血浆TC和FC水平,并探讨其临床意义。方法采用循环酶法测定35例慢性病毒性肝炎、30例急性病毒性肝炎和30例肝硬化患者血浆TC和FC水平,同时测定200名健康成年人血浆TC和FC水平作为对照。结果健康成人TC为(56.5±9.6)μmol/L、FC为(46.6±8.2)μmol/L,其中男性TC为(57.5±8.5)μmol/L,女性TC为(55.6±10.5)μmol/L,两者之间差异无统计学意义(P>0.05),FC男性为(48.4±7.2)μmol/L,水平略高于女性(44.7±8.9)μmol/L。慢性病毒性肝炎患者的TC为(46.9±14.8)μmol/L、FC为(36.3±9.8)μmol/L,急性病毒性肝炎患者的TC为(44.4±14.2)μmol/L、FC为(35.4±13.0)μmol/L,均低于健康成年人(P<0.01);肝硬化患者TC和FC水平与健康组差异无统计学意义(P>0.05)。结论TC水平男女之间差异无统计学意义,FC男性水平略高于女性;女性肉毒碱有随年龄增加的趋势。肝病患者可发生肉毒碱代谢异常。     

Plasma lipid composition and LDL oxidation.

Low-density lipoprotein (LDL) oxidation in vivo depends on lipid composition and on plasma antioxidant status. The aim of our study was to investigate the relationship between plasma lipid composition and LDL oxidation and, in particular, to explore whether LDL-cholesterol/triglycerides ratio (LDL-C/TG) and LDL-cholesterol/high-density lipoprotein (HDL)-cholesterol ratio (LDL-C/HDL-C) can be used as predictive parameters of LDL oxidation in vivo. In 87 volunteers over a wide range of age plasma lipids and LDL oxidation were studied. Blood was collected after 12 h overnight fast. LDL oxidation was estimated by the level of conjugated diene (BDC) in the lipid fraction isolated from plasma after gradient ultra-centrifugation. The results were expressed as micromol/l (BDC/l) to evaluate the level of oxidized LDL, and as nmol of BDC for mg of LDL-cholesterol (BDC/LDL-C) for the evaluation of LDL oxidation degree. BDC/l correlated significantly with age, total and LDL-C, apolipoprotein B and TG, while BDC/LDL-C negatively correlated with total cholesterol, apolipoprotein B, LDL/TG and LDL/HDL ratios. Age of subjects significantly correlated with total and LDL-C and apolipoprotein B. TG have a significant inverse correlation with HDL-C. Our results support the hypothesis that among the several factors involved in LDL oxidation the most important determinants are LDL/TG. Plasma triglycerides appear to be very important even when circulating cholesterol levels are within normal limits. Moreover, we found that the LDL/HDL ratio is also very important with regard to the putative protective role of HDL against LDL oxidation in vivo. In conclusion, plasma lipid parameters must be evaluated not only for their absolute values but also for their mutual ratios as expression of plasma lipid homeostasis. Both LDL/TG and LDL/HDL ratios can be used as predictive parameters of in vivo LDL oxidation.     

健康成人与肝脏疾病患者血浆肉毒碱的检测

目的 建立成人总肉毒碱(TC)和游离肉毒碱(FC)的参考范围;检测肝病患者血浆TC和FC水平,并探讨其临床意义.方法采用循环酶法测定35例慢性病毒性肝炎、30例急性病毒性肝炎和30例肝硬化患者血浆TC和FC水平,同时测定200名健康成年人血浆TC和FC水平作为对照.结果健康成人TC为(56.5±9.6)μmol/L、FC为(46.6±8.2)μmol/L,其中男性TC为(57.5±8.5)μmol/L,女性TC为(55.6±10.5)μmol/L,两者之间差异无统计学意义(P》0.05),FC男性为(48.4±7.2)μmol/L,水平略高于女性(44.7±8.9)μmol/L.慢性病毒性肝炎患者的TC为(46.9±14.8)μmol/L、FC为(36.3±9.8)μmol/L,急性病毒性肝炎患者的TC为(44.4±14.2)μmol/L、FC为(35.4±13.0)μmol/L,均低于健康成年人(P《0.01);肝硬化患者TC和FC水平与健康组差异无统计学意义(P》0.05).结论 TC水平男女之间差异无统计学意义,FC男性水平略高于女性;女性肉毒碱有随年龄增加的趋势.肝病患者可发生肉毒碱代谢异常.     

Plasma carnitine levels in children with protein-calorie malnutrition before and after rehabilitation.

Plasma carnitine and albumin levels were measured in children suffering from protein-calorie malnutrition, before and after rehabilitation, and in apparently healthy controls. Both the constituents were lower in malnourished children and improved after treatment. Plasma carnitine showed significant positive correlation with plasma albumin.     

Plasma and urinary carnitine and acylcarnitines in chronic fatigue syndrome

Contradictory reports have suggested that serum free carnitine and acylcarnitine concentrations are decreased in patients with chronic fatigue syndrome (CFS) and that this is a cause of the muscle fatigue observed in these patients. Others have shown normal serum free carnitine and acylcarnitines in similar patients. We report here studies on free, total and esterified (acyl) carnitines in urine and blood plasma from UK patients with CFS and three control groups. Plasma and timed urine samples were obtained from 31 patients with CFS, 31 healthy controls, 15 patients with depression and 22 patients with rheumatoid arthritis. Samples were analysed using an established radioenzymatic procedure for total, free and esterified (acyl) carnitine. There were no significant differences in plasma or urinary total, free or esterified (acyl) carnitine between UK patients with CFS and the control groups or in renal excretion rates of these compounds. The data presented here show that, in the CFS patients studied, there are no significant abnormalities of free or esterified (acyl) carnitine. It is thus unlikely that abnormalities in carnitine homeostasis have any significant role in the aetiology of their chronic fatigue.     

Intrauterine growth restriction and fetal body composition.

OBJECTIVE: To assess the differences in fetal body compartments between fetuses with normal growth and those with reduced intrauterine growth, during the third trimester, through ultrasonographic determination of subcutaneous tissue thickness (SCTT). METHODS: Twenty-eight patients were enrolled into this case control study carried out at 30-31 weeks' gestation. Two study groups were matched for maternal age and pregestational body mass index: controls (n = 14) and intrauterine growth-restricted (IUGR) fetuses (n = 14). Routine ultrasound-derived biometric parameters (head circumference, abdominal circumference, femur length and humerus length) were measured. Additionally, the mid-arm fat mass and lean mass (MAFM and MALM), the mid-thigh fat mass and lean mass (MTFM and MTLM), the abdominal fat mass (AFM) and the subscapular fat mass (SSFM) were measured. The Mann-Whitney U-test and Student's t-test were used to compare the two groups. RESULTS: The abdominal circumference and the humerus were significantly smaller in IUGR fetuses than in controls. Most of the SCTT values were different in the two groups. The SSFM (3.6 +/- 1.1 vs. 2.6 +/- 0.7 mm; P = 0.011), the AFM (5.1 +/- 0.7 vs. 4 +/- 1 mm; P = 0.01), the MAFM (3.5 +/- 0.9 vs. 2.2 +/- 0.8 cm2; P < 0.01) and MALM (2.1 +/- 0.4 vs. 1.7 +/- 0.5 cm2; P = 0.029) were all significantly greater in fetuses with normal development compared to those with growth restriction. CONCLUSIONS: During the third trimester, SCTT (with the exception of MTFM and MTLM) is reduced in fetuses with IUGR. Furthermore, MALM is lower in growth-restricted fetuses, confirming that the parameters measured in this study are affected in IUGR fetuses. Our findings indicate that specific changes in fetal body compartments occur as a result of chronic metabolic impairment.     

Effect of body size and body composition on survival in peritoneal dialysis patients.

BACKGROUND: Using 24-hour urinary creatinine excretion as a measure of muscle mass, we examined whether body composition influences the survival of incident peritoneal dialysis (PD) patients. We hypothesized that patients with high body mass index (BMI) and low muscle mass might be considered to have high levels of body fat. METHODS: Using serum creatinines and creatinine clearances reported on Medical Evidence Form 2728, 24-hour urinary creatinine was calculated in 10 140 incident PD patients with normal (18.5 - 24.9 kg/m2) or high (> or = 25 kg/m2) BMI. Patients were classified as low and normal/high muscle mass groups based on the 25th percentile of 24-hour urinary creatinine (0.64 g/day). RESULTS: In multivariable parametric survival models, compared to the normal BMI-normal/high muscle mass patients, high BMI-normal/high muscle mass patients had lower hazard of all-cause [hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.83 - 0.97] and cardiovascular (HR 0.88, 95% CI 0.79 - 0.97) death; high BMI patients with low muscle mass had higher hazard of all-cause (HR 1.29, 95% CI 1.17 - 1.42) and cardiovascular (HR 1.21, 95% CI 1.06 - 1.39) death. CONCLUSION: Both body size and body composition influence survival of incident PD patients. As incident PD patients with high BMI and normal or high muscle mass have the best survival, PD patients should be encouraged to gain muscle mass rather than fat mass.     

Abnormalities of body composition in peritoneal dialysis patients.

OBJECTIVES: Body composition changes occur in peritoneal dialysis (PD) due to abnormalities in nutrition and hydration. We investigated abnormalities of nutrition and hydration in PD patients compared with healthy controls by measurement of total body potassium (TBK) and body water compartments. DESIGN: Cross-sectional comparison study. METHODS: We measured TBK--an indicator of body cell mass--by whole body counting, total body water (TBW) by deuterium oxide dilution, and extracellular water (ECW) by bromide dilution in 29 PD patients and 32 controls. RESULTS: The absolute mean value of TBK for PD patients was not significantly lower than in controls. The ratios of observed TBK to predicted TBK from prediction formulas were compared. Equations used were those of Boddy, Bruce, Burkinshaw, and Ellis and our own equation derived from a local control database (Leeds). Observed/predicted ratios of TBK were significantly less in PD than in control subjects for all equations. Water volumes did not differ between PD and control groups. Observed/predicted ratios for TBK in PD patients correlated with serum potassium (Boddy r = 0.355, p = 0.06; Bruce r = 0.411, p < 0.05; Burkinshaw r = 0.457, p < 0.01; Leeds r = 0.412, p < or = 0.05; Ellis r = 0.356, p = 0.06) and tended to correlate with serum albumin (Bruce r = 0.343, p = 0.07; Burkinshaw r = 0.421, p < 0.05; Leeds r = 0.357, p = 0.06; Ellis r = 0.310, p = NS). There was no relationship with serum potassium in controls. Serum albumin in PD correlated with TBK (r = 0.445, p < 0.02), TBK/height (r = 0.419, p < 0.05), TBK/weight (r = 0.554, p = 0.002), and TBK/TBW (r = 0.586, p = 0.0001). Extracellular water/intracellular water (ECW/ICW) was inversely related to TBK (r = -0.455, p < 0.02 in PD; r = -0.387, p < 0.05 in controls) and to TBK/height (r = -0.446, p < 0.02 in PD; r = -0.411, p = 0.02 in controls). TBK/weight reduced with age in PD (r = -0.445, p < 0.02), as did TBK/TBW in PD (r = -0.463, p < 0.02). ECW/ICW tended to increase with age in PD (r = 0.351, p = 0.06). CONCLUSIONS: Observed/predicted ratio of TBK is reduced in PD patients relative to healthy controls, indicating reduced body cell mass. Serum albumin and potassium reflect TBK indices in PD. Body water volumes did not differ between PD and controls, implying no overall abnormality in hydration in the PD group. However, ECW is relatively increased compared to ICW with decreasing TBK indices, suggesting relative ECW expansion with reduction in body cell mass.     

Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport.

The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-[methyl-3H]carnitine was administered intravenously to six normal subjects, one patient with primary muscle carnitine deficiency (MCD), and four patients with primary systemic carnitine deficiency (SCD). Specific radioactivity was followed in plasma for 28 d. A three-compartment model (extracellular fluid, muscle, and "other tissues") was adopted. Rate constants, fluxes, pool sizes, and turnover times were calculated. Results of these calculations indicated reduced transport of carnitine into muscle in both forms of primary carnitine deficiency. However, in SCD, the reduced rate of carnitine transport was attributed to reduced plasma carnitine concentration. In MCD, the results are consistent with an intrinsic defect in the transport process. Abnormal fluctuations of the plasma carnitine, but of a different form, occurred in MCD and SCD. The significance of these are unclear, but in SCD they suggest abnormal regulation of the muscle/plasma carnitine concentration gradient. In 8 of 11 subjects, carnitine excretion was less than dietary carnitine intake. Carnitine excretion rates calculated by kinetic compartmental analysis were higher than corresponding rates measured directly, indicating degradation of carnitine. However, we found no radioactive metabolites of L-[methyl-3H]carnitine in urine. These observations suggest that dietary carnitine was metabolized in the gastrointestinal tract.     

Plasma carnitine levels in liver cirrhosis: relationship with nutritional status and liver damage

The plasma level of carnitine, a co-factor involved in many metabolic reactions, is high in alcoholic liver cirrhosis, due to an increased amount of esterified carnitine. To determine if this alteration is linked to alcoholic liver disease or to liver cirrhosis per se. total carnitine, free carnitine, total esterified carnitine, short chain acylcarnitine and long chain acylcarnitine were measured in 41 patients suffering from liver cirrhosis of different aetiology and severity. In 19 of these patients, acetylcarnitine was also measured. Moreover, multivariate analysis was performed to assess the association of carnitine plasma levels with nutritional and liver disease indices. Of the nutritional indices (creatinine/height ratio, mid upper arm muscle circumference and triceps skinfold) only triceps skinfold appeared to be weakly correlated with carnitine (with long chain acylcarnitine). Significantly high levels of acetylcarnitine, short chain acylcarnitine, total esterified carnitine and total carnitine were found in cirrhotics independently of the aetiology of cirrhosis, even though a trend towards higher levels of acetylcarnitine was evident in heavy drinkers. Direct correlations of gamma-glutamyltransferase with acetylcarnitine, acetylcarnitine/free carnitine, short chain acylcarnitine/free carnitine and total esterified carnitine/free carnitine were found. Carnitine plasma levels did not differ in the three Pugh-Child's classes; however, a trend towards higher levels of acetylcarnitine was found in Pugh-Child's class C. In conclusion, the high levels of acetylcarnitine, short chain acylcarnitine, total esterified carnitine and total carnitine found in cirrhosis were linked to liver disease. Alcohol abuse seemed only to be an exacerbating factor.     

Plasma beta-N-acetylhexosaminidase isoenzyme composition and temperature conversion factors

Using the chromogenic substrate 3,3'-dichlorophenylsulfonphthaleinyl-N-acetyl-beta-D-glucosaminide for the activity determination of plasma beta-N-acetylhexosaminidase (Hex), the temperature conversion factors (TCF) offer a highly significant positive correlation with the relative proportion of Hex B isoenzyme (P< 0.001). The calculation of TCF 37 degrees/25 degrees C allows the isoenzyme composition of Hex to be determined quickly and cheaply. The results may be superimposed over those obtained in a previously described method based on the calculation of the enzyme's activation energy using four temperatures. However, the use of TCF 37 degrees/30 degrees C does not appear to comply with the required demands.     

Clinical varieties of carnitine and carnitine palmitoyltransferase deficiency

Several clinical entities are associated with disorders of fatty acid oxidation or transfer across the inner mitochondrial membrane. Over 40 cases of the primary carnitine deficiency syndrome have been reported to date and various subtypes have been characterized. This represents a large clinical spectrum. The deficiency of carnitine in muscle is at the basis of a syndrome characterized by muscle weakness and lipid storage myopathy. The systemic form of carnitine deficiency is more generalized and includes recurrent episodes of hepatic encephalopathy as well as lipid storage in muscle, liver and heart. In one subtype, hypoglycemia upon fasting and cardiomyopathy are found. There are also several causes of secondary carnitine deficiency states which are either acquired or associated with inborn errors of metabolism (organic acidurias, defects of acyl-CoA dehydrogenases). Clinically, Carnitine palmitoyltransferase (CPT) deficiency is a rather homogeneous syndrome presenting with recurrent episodes of myoglobinuria provoked by fasting or prolonged exercise. The only exception is an infantile variety associated with severe hypoglycemia and hepatic CPT deficiency. Using malonyl-CoA, a specific inhibitor of CPT-I, we had suggestions in five adult patients with myoglobinuria that CPT-II is lacking in muscle, liver and platelets while CPT-I is above the control level. The enzyme abnormality seems partial and limited to CPT-II or to its binding to the inner mitochondrial membrane.     

Plasma adiponectin and leptin levels,body composition,and glucose utilization in adult women with wide ranges of age and obesity

OBJECTIVE: The purpose of this study was to determine the relationships between plasma adiponectin and leptin levels, total and central obesity, and glucose utilization across the adult age span. RESEARCH DESIGN AND METHODS: We studied 148 women aged 18-81 years with a BMI range of 17.2-44.3 kg/m(2). Total percent body fat was determined by dual-energy X-ray absorptiometry and abdominal fat by computed tomography. Glucose tolerance in non-type 2 diabetic volunteers was determined with an oral glucose tolerance test. Glucose utilization (M) was measured during the last 60 min of hyperinsulinemic-euglycemic clamps (240 pmol x m(-2) x min(-1)). Plasma adiponectin levels were measured by radioimmunoassay. The women were separated into three age-groups: young, middle, and old (<40, 40-59, and >or=60 years, respectively), as well as by glucose tolerance status. RESULTS: Adiponectin concentrations did not differ by age-groups. There were significant age effects for BMI, percent body fat, visceral fat, subcutaneous abdominal fat, VO(2max), and M. Adiponectin levels were lower in the prediabetic women (n = 18) than in the normal glucose-tolerant women (n = 108) and the women with type 2 diabetes (n = 22) (both P < 0.05). Univariate correlations revealed significant negative relationships between plasma adiponectin levels and BMI, percent body fat, visceral fat, subcutaneous abdominal fat, fasting leptin, and fasting insulin and positive relationship with M (all P < 0.05). In a multiple stepwise regression model to predict adiponectin, only M remained in the model at P < 0.001. Multivariate analyses revealed a significant relation for M as a function of adiponectin, insulin, and VO(2max). CONCLUSIONS: The data suggest that plasma adiponectin does not change with age but levels are negatively associated with percent body fat, visceral fat, subcutaneous abdominal fat, insulin, and leptin levels in women. Adiponectin is positively associated with M across the age span in women.     

Dietary intake and body composition of Japanese ulcerative colitis patients in remission.

The purpose of this pilot study (N=26) was to investigate dietary intake and body composition and problems associated with dietary intake (such as unnecessary dietary restriction) in Japanese patients in remission from ulcerative colitis. Findings revealed the macronutrient intake and dietary fiber (absolute amount) were lower than the national average in men, but this may have been due to differences in the methods used to measure dietary intake. Although the fat intake (%E) of ulcerative colitis patients in this study was similar to that of the Japanese population, it differed greatly from that of people in Western countries. No significant differences in weight, height, or body mass index were found when comparing the sample of individuals living with ulcerative colitis with the general Japanese population. Seventeen patients (65.4%) reported being cautious about what they ate even though in remission, and 6 patients were even more cautious about what they ate now than they had been in the past. The authors suggest further research to clarify the problems that unnecessary dietary restriction cause for ulcerative colitis patients who are in remission.