血色病肝脏铁过度沉着症1例

1.病例资料：患者，男，48岁。以“乏力、多饮、多尿、多食，伴消瘦4个月，加重1周”入院。既往有乙型肝炎和地中海贫血病史30年，无输血史，无血色病家族史，曾行“脾脏切除”治疗。查体：慢性贫血面容，全身皮肤黄染有散在色素沉着，巩膜黄染，双手肝掌，男性乳房发育；肼右肋下3cm，剑突下5cm，质硬；腹部未触及肿块。     

Hepatic iron overload in aceruloplasminaemia

We report the case of a 52 year old male with diabetes mellitus and long standing evidence of hepatic iron excess. Initially considered to have haemochromatosis, this patient was reevaluated when hepatic iron stores were found to be unaffected by a prolonged course of weekly phlebotomy. The development of neurological disease prompted diagnostic consideration of aceruloplasminaemia, which we confirmed by demonstration of a novel frameshift mutation in the ceruloplasmin gene. Our inability to resolve the patient's iron overload by regular phlebotomy is consistent with recent animal studies indicating an essential role for ceruloplasmin in cellular iron efflux. Evaluation of this case underscores the clinical relevance of aceruloplasminaemia in the differential diagnosis of hepatic iron overload and provides insight into the pathogenetic mechanisms of hepatocellular iron storage and efflux.     

Hepatic iron overload: diagnosis and quantification by noninvasive imaging

The diagnostic efficacy of magnetic resonance (MR) and computed tomography (CT) for detection and quantification of hepatic iron was assessed in a series of patients under investigation for clinical or biochemical evidence of hepatic iron overload. Thirty patients underwent MR imaging (SE 30,60/1000 or SE 30,60/2000) at 0.5 Tesla with calculation of hepatic T2 and liver to paraspinous muscle signal intensity ratios. Twenty-nine patients also had measurement of hepatic attenuation on noncontrast CT images. Results of these imaging studies were correlated in all patients with quantitative iron determination from liver biopsy specimens. The best predictor of liver iron among parameters studied was the ratio of the signal intensities of liver and paraspinous muscle (L/M) on a SE 60/1000 sequence. Both MR using L/M ratios and CT were sensitive methods for detection of severe degrees of hepatic iron overload with 100% of patients with hepatic iron on biopsy greater than 600 micrograms/100 mg liver dry weight detected on the basis of L/M less than 0.6 or CT attenuation greater than 70 Hounsfield units (HU). The MR parameter, however, was more specific than CT (100 vs 50%) and showed a higher degree of correlation with quantitated hepatic iron from biopsy. T2 measurements showed poor correlation with hepatic iron, due to difficulty in obtaining precise T2 measurements in vivo when the signal intensity is low. None of the parameters utilized was sensitive for detecting mild or moderate degrees of hepatic iron overload. We conclude that MR and CT are sensitive techniques for noninvasive detection of severe hepatic iron overload, with MR providing greater specificity than CT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differences in hypertension between blacks and whites: an overview

Hypertension is more prevalent and severe in urban black populations compared to whites, and is associated with a greater degree of target-organ damage for any given blood pressure level. In general, compared to whites, blacks respond well to diuretics and calcium channel blockers and less well to beta-blockers and ACE inhibitors. The exact mechanisms that contribute to differences in blood pressure between blacks and whites are still not fully understood, given the multi-factorial aetiology of essential hypertension. Various lines of evidence suggest black patients are more salt sensitive than whites, which is due to a tendency to retain sodium in the kidney. Inherent differences in ionic transport mechanisms, the renal epithelial sodium channel, the reninangiotensin-aldosterone system and vasoactive substances may be a partial explanation, but analysis is compounded by disparate socio-economic conditions between blacks and whites. At present, there is no complete explanation for these differences and further research is required.     

Alzheimer's disease symptom severity in blacks and whites

OBJECTIVE: In order to determine whether there are racial differences in Alzheimer's Disease (AD) symptom severity and vascular comorbidities, we compared African-American (black) and Caucasian (white) patients with AD from similar socioeconomic backgrounds at the time the disease was first recognized. DESIGN: Cross-sectional observational study from a population-based dementia registry. PARTICIPANTS: Patients were enrolled from an HMO base population of 23,000 persons more than age 60 in Seattle, Washington. This study examines 453 subjects with probable AD (38 blacks (mean age 76.5, SD 6.4), and 415 whites (mean age 79.7, SD 6.7)). MEASUREMENTS: Measured were patient demographics, age at onset of AD, AD symptom duration, Mini-Mental State Exam (MMSE) score, Blessed Dementia Rating Scale, presence of psychiatric symptoms, and vascular comorbidities. RESULTS: Blacks had significantly lower mean cognitive scores (MMSE = 17.2, SD 5.6) compared with whites (MMSE = 20.2, SD 5.2, unpaired t test P < .01). The significant racial difference in MMSE scores persisted after controlling for education, duration of AD symptoms, age, and ADL impairment. Blacks and whites did not differ significantly regarding gender distribution, education level, income, or percent with early age of onset of AD. No statistically significant race-related differences were found in impairments in activities of daily living or symptoms of paranoia, hallucinations, or agitation. Blacks had significantly higher rates of hypertension (56%) compared with whites (34%) (Fisher's exact test, P = .013), but the rates of stroke and ischemic heart disease were similar. CONCLUSIONS: Despite uniform detection methods and controlling for reported duration of dementia symptoms, measured cognitive impairment is significantly more severe when AD is recognized in blacks compared with whites. The significantly higher prevalence of hypertension among black AD cases was not associated with excess cerebrovascular disease comorbidity. This study highlights a need for normative measurements of cognitive function in minority AD groups in order to distinguish differential cognitive symptom severity from possible measurement bias.     

Levels of mineralocorticoids in whites and blacks.

Blacks appear, on average, to retain more Na than whites. A higher production rate of mineralocorticoids could explain the greater Na retention in blacks. Although production of aldosterone has been shown to be lower in blacks, the level of another mineralocorticoid may be increased. Plasma levels of deoxycorticosterone and cortisol were measured in young whites (n=23; age=16.4+/-3.1[SD] years) and young blacks (n=25; age=13.8+/-1.3 years). Blacks had lower plasma levels of renin activity and aldosterone and lower urinary aldosterone excretion rates; thus, they appeared to be representative of blacks that retain additional Na. Plasma deoxycorticosterone levels were lower in blacks than in whites both at baseline (247+/-161 versus 381+/-270 pmol/L, P=0.048) and after stimulation with adrenocorticotropic hormone (822+/-294 versus 1127+/-628 pmol/L at 30 minutes, P=0.047; 925+/-366 versus 1440+/-834 pmol/L at 60 minutes, P=0.013). Cortisol levels were also lower in blacks at baseline (P=0.014) but were not significantly different from levels in whites after stimulation with adrenocorticotropic hormone. In a larger cohort of 407 whites (age=12.0+/-2.9 years) and 247 blacks (age=12.9+/-3.1 years), 18-hydroxycortisol excretion rates were also lower in blacks (P=0. 021). In conclusion, increased Na retention in blacks does not appear to be secondary to increased production of either aldosterone, deoxycorticosterone, cortisol, or 18-hydroxycortisol. A primary renal mechanism may mediate the increase in Na reabsorption in blacks.     

Hepatic mitochondrial malondialdehyde metabolism in rats with chronic iron overload

Peroxidative decomposition of mitochondrial membrane phospholipids with subsequent mitochondrial dysfunction is a postulated mechanism of liver cell injury in parenchymal iron overload. Malondialdehyde is formed when polyunsaturated fatty acids of membrane phospholipids undergo peroxidative decomposition, and it is metabolized by aldehyde dehydrogenase. We studied mitochondrial metabolism of malondialdehyde in rats with chronic dietary iron overload. Hepatic malondialdehyde concentrations were significantly increased in iron-loaded livers, and mitochondrial respiratory control ratios using glutamate as a substrate were decreased by 47% largely owing to reductions in state 3 respiration. When exogenous malondialdehyde was added to mitochondrial fractions, there was significantly less metabolism of malondialdehyde in mitochondria of iron-loaded livers as compared with controls. In addition, there was a 28% decrease in mitochondrial aldehyde dehydrogenase in iron-loaded livers but no change in cytosolic aldehyde dehydrogenase. Increased hepatic malondialdehyde in chronic iron overload may result from a combination of increased production and decreased metabolism of malondialdehyde, both of which may be due to iron-induced mitochondrial lipid peroxidation.     

Hepatic microsomal function in rats with chronic dietary iron overload

We determined whether alterations in hepatic microsomal function occur in association with iron-induced lipid peroxidation in vivo in rats with chronic dietary iron overload. In rats fed a 2.0% carbonyl iron diet for a period of 20 wk, there was no significant microsomal conjugated diene formation (evidence of microsomal lipid peroxidation) or difference in cytochrome P450 concentration found at mean (+/- SEM) hepatic iron concentrations of 1210 +/- 92 micrograms/g liver (wet wt) or 2730 +/- 100 micrograms/g. At a hepatic iron concentration of 4090 +/- 245 micrograms/g, however, there was significant conjugated diene formation (p less than 0.001) and a 56% decrease in the cytochrome P450 concentration (p less than 0.001). In rats fed a 2.5% carbonyl iron diet for 10 wk, achieving a liver iron concentration of 4820 +/- 420 micrograms/g, there was significant microsomal conjugated diene formation (p less than 0.001), a 35% reduction in cytochrome P450 (p less than 0.005), and a 16% reduction in aminopyrine demethylase activity (p less than 0.025), but only an 8% reduction in glucose-6-phosphatase activity (p = not significant). Finally, in rats fed a 3.0% iron-supplemented diet for 7 wk, achieving a liver iron concentration of 2730 +/- 205 micrograms/g, there was a 23% reduction in cytochrome P450 (p less than 0.025), a 28% reduction in cytochrome b5 (p less than 0.001), and a 47% increase in heme oxygenase activity (p less than 0.025) (heme oxygenase activity measured in this group only). We conclude that oral iron loading can produce microsomal lipid peroxidation in vivo that is associated with selective decreases in microsomal hemoprotein concentrations and cytochrome P450-dependent enzymes.     

Hepatic iron stores and markers of iron overload in alcoholics and patients with idiopathic hemochromatosis

Liver iron concentrations were determined in 60 alcoholics with liver disease of varying severity, 15 patients with untreated idiopathic hemochromatosis, and 16 control subjects with biliary tract disease. Mean liver iron concentrations (g/100 mg dry weight) were significantly greater in the alcoholics (156.4±7.8 (sem);P<0.05) and in patients with idiopathic hemochromatosis (2094.5±230.7;P<0.01) than in control subjects (53.0±7.0). Liver iron concentrations of >140 g/100 mg were found in 17 alcoholics (29%) and in all 15 patients with idiopathic hemochromatosis. Liver iron concentrations >1000 g/100 mg were found in all patients with idiopathic hemochromatosis but in none of the alcoholics. In the alcoholics no relationship existed between liver iron concentrations and the amount of alcohol consumed daily, the length of the drinking history, the amount of beverage iron consumed daily, or the severity of the liver disease. Serum ferritin concentrations reflected iron stores in patients with hemochromatosis and in alcoholics with minimal liver disease. However, in alcoholics with significant liver disease serum ferritin concentrations did not reflect iron stores accurately, although with normal values iron overload is unlikely. Serum iron concentration and percentage saturation of total iron-binding capacity were of little value in assessing iron status in either alcoholics or patients with hemochromatosis. Measurement of the liver iron concentration clearly differentiates between alcoholics with significant siderosis and patients with idiopathic hemochromatosis.R. W. Chapman was Watson-Smith Fellow of the Royal College of Physicians of London.     

Lipoprotein(a) at birth, in blacks and whites.

It has been shown that blacks have considerably higher concentrations than whites of lipoprotein(a) (Lp(a)), which has been identified as an independent risk factor for coronary heart disease, vein graft restenosis, and cerebrovascular disease. Smaller differences in Lp(a) concentrations have been noted between males and females. To examine whether gender and race differences are already detectable at birth, we examined Lp(a) concentrations in cord blood samples of 109 black (49 male and 60 female) and 123 white (67 male and 56 female) newborns. Maternal age, gestational age, fetal maturity indicators, weight, height and head circumference were analyzed as covariates. For race and sex combined, the mean Lp(a) concentration was 4.0 mg/dl (S.D. of 3.94 mg/dl), approximately 5-fold lower than that observed in adults. No statistically significant differences were found between race or gender groups. The cross-sectional examination of serum Lp(a) concentrations of 221 infants, children and adults showed a gradual increase in Lp(a) concentrations from birth to adult values by the second year of life. We conclude that the system responsible for the production and control of Lp(a) concentration is not yet mature--or has not yet been challenged--at birth.     

Secondary hyperparathyroidism and bone turnover in elderly blacks and whites

This study was undertaken to describe the prevalence of secondary hyperparathyroidism in African-American and Caucasian participants in the Boston Low-Income Elderly Osteoporosis Study and to examine and compare associations of hyperparathyroidism with biochemical markers of bone turnover and bone density in the two racial groups. Serum osteocalcin and serum cross-linked N-telopeptides of type I collagen, and calcaneal bone mineral density were measured in February or March in 255 men and women, 64 yr of age and older. Subjects were categorized as normal or as having hyperparathyroidism, based on a serum PTH concentration below or above the top of the normal range (6.9 pmol/liter), respectively. The prevalence of hyperparathyroidism was 38% in the 144 black subjects and 20% in the 111 white subjects. Serum osteocalcin and cross-linked N-telopeptides of type I collagen were significantly higher in both black and white hyperparathyroid subjects (P < 0.05), and the hyperparathyroid-related difference in osteocalcin was greater among black than white subjects. Hyperparathyroidism was significantly associated with reduced heel bone mineral density in blacks (P = 0.008) but not in whites. This study provides evidence that secondary hyperparathyroidism is prevalent in elderly adults, both black and white, and that it should not be viewed as a benign condition in either group. Recent public health efforts to promote higher calcium and vitamin D intakes, targeted predominantly to older Caucasians, should also be directed to older African-Americans.     

Hepatic mitochondrial oxidative metabolism in rats with chronic dietary iron overload

We examined the effects of chronic dietary iron overload on hepatic mitochondrial oxidative metabolism. Experimental iron overload was produced by feeding rats a chow diet supplemented with carbonyl iron over a 7-week period. Biochemical and histologic evaluations of liver tissue confirmed moderate degrees of hepatic parenchymal iron overload. Electron microscopy showed no abnormalities in hepatic mitochondrial ultrastructure in blocks of tissue or in mitochondrial fractions from iron-loaded liver. Studies of mitochondrial oxidative metabolism revealed a consistent and progressive decrease in state 3 (ADP-stimulated) respiration and in respiratory control ratios at hepatic iron concentrations above 1,000 micrograms per gm for all three substrates studied, glutamate, beta-hydroxybutyrate and succinate. Changes in state 4 (ADP-limited) respiration and ADP/O ratios were not progressive with increasing hepatic iron concentrations. At hepatic iron concentrations at which there were decreases in state 3 respiration and respiratory control ratios, there was also evidence of lipid-conjugated diene formation, indicative of mitochondrial lipid peroxidation. There were no changes in mitochondrial function when iron as either ferritin or hemosiderin or as a combination of ferritin, hemosiderin and ferric nitrilotriacetate was added in vitro to normal liver homogenates. Use of density gradient centrifugation to reduce iron and lysosomal contamination of mitochondrial fractions failed to prevent the reduction in mitochondrial function. We conclude that moderate degrees of chronic hepatic iron overload in vivo result in an inhibitory defect in the mitochondrial electron transport chain as evidenced by a decrease in state 3 respiration and respiratory control ratios.     

Alpha2-adrenergic receptor-induced vascular constriction in blacks and whites

Black Americans have a reduced hypotensive response to the alpha2-adrenergic receptor agonist clonidine compared with whites, despite similar central sympathoinhibition. This reduced hypotensive response might be explained by greater postsynaptic vascular alpha2-adrenergic receptor vasoconstrictive response. However, clonidine has a low alpha2/alpha1 selectivity ratio. Therefore, to determine the role of altered alpha2-adrenergic receptor vascular sensitivity in ethnic differences in vascular response, we compared local vascular responses with the highly selective alpha2-adrenergic receptor agonist dexmedetomidine in healthy black (n=18) and white (n=19) subjects. Increasing doses of dexmedetomidine (0.001 to 1000 ng/min) were infused into a dorsal hand vein, and the local response was measured with a linear variable differential transformer. Dexmedetomidine caused pronounced venoconstriction, with an average (+/-SD) maximum response of 74.5+/-17.72% but with no difference between blacks and whites. There was substantial intersubject variability in the sensitivity to dexmedetomidine; the dose resulting in 50% (ED50) of maximum vasoconstriction ranged from 0.08 ng/min to 256 ng/min. The geometric mean ED50 was 2.28 ng/min (95% CI, 0.02 to 271.6 ng/min) in blacks and 1.58 ng/min (95% CI, 0.11 to 24.55 ng/min) in whites (P=0.59). Our data indicate that alpha2-adrenergic receptor-induced venoconstriction is similar in blacks and whites. These findings do not support the hypothesis that altered alpha2-adrenergic receptor sensitivity is the explanation for the decreased blood pressure response to systemic administration of clonidine in blacks. The response to dexmedetomidine provides a model that will allow further study of the regulation of alpha2-adrenergic receptor-mediated vascular responses     

Predictors of target organ damage in hypertensive blacks and whites

The purpose of this study was to evaluate the association of the insulin resistance syndrome with both blood pressure and target organ damage in blacks and whites with essential hypertension. Eighty-two black and 63 white French Canadian patients were studied. None had diabetes, and antihypertensive medications had been discontinued for >/=1 week. Measurements included 24-hour blood pressure monitoring, fasting plasma lipids, insulin sensitivity determined with the Bergman minimal model, echocardiogram, microalbumin excretion, and inulin and lithium clearances. Compared with the white French Canadians, black patients had an attenuated nighttime reduction in blood pressure (P<0.02), increased cardiac dimensions (P<0.001), greater microalbumin excretion (P<0.05), increased inulin clearance (indicative of glomerular hyperfiltration; P<0.001), and decreased lithium clearance (indicative of increased sodium reabsorption in the proximal tubule; P<0.001). Blood pressure levels were not related to insulin resistance; although in blacks, the nighttime reduction in systolic blood pressure was inversely related to fasting plasma insulin (r=-0.18, P<0.04). In a stepwise multivariate analysis (including blood pressure levels and components of the insulin resistance syndrome as independent variables), race was the strongest predictor of left ventricular mass (r=0.53, P<0.000), relative wall thickness (r=0.49, P<0.000), and both inulin (r=0.53, P<0.000) and lithium (r=0.41, P<0.000) clearances. Nighttime systolic blood pressure was also a significant determinant of concentric left ventricular hypertrophy (r=0.37, P<0.000). In blacks, microalbumin excretion was related to insulin resistance. These observations are consistent with the hypothesis that there is a genetic contribution to cardiac hypertrophy, glomerular hyperfiltration, and sodium retention in blacks with essential hypertension.     

Similar prevalence of renovascular hypertension in selected blacks and whites

Renovascular hypertension is a potentially curable form of high blood pressure that is thought to be extremely rare among blacks. We demonstrate, however, that in a clinically selected population, the prevalence of renovascular hypertension is similar in blacks and whites. We prospectively evaluated 167 hypertensive subjects who had one or more clinical features known to be associated with renovascular hypertension. All subjects had captopril-stimulated peripheral renin measurements and conventional renal arteriography. All significant renal artery stenoses (greater than 50% luminal narrowing) were treated with percutaneous transluminal angioplasty or surgery. Renovascular hypertension was diagnosed if there was a blood pressure response to interventional therapy, according to the criteria established by the Cooperative Study of Renovascular Hypertension. Of the total group evaluated, 24% (39 of 167) had renal artery stenosis and 14% (23 of 167) had renovascular hypertension. Renal artery stenosis or occlusion was found in 27% (26 of 97) of whites and 19% (13 of 67) of blacks (p = 0.27). Renovascular hypertension was diagnosed in 18% (17 of 97) of whites and 9% (6 of 67) of blacks evaluated (p = 0.25). Renovascular hypertension was associated with severe or refractory hypertension and with smoking, but there were no racial differences in these associations. Blacks with renovascular hypertension tended to have low captopril-stimulated peripheral renin activity. We conclude that blacks with clinical features suggestive of renovascular hypertension should be evaluated with angiography. Captopril-stimulated plasma renin may not be useful in detecting blacks with renovascular hypertension, but this and other potential screening tests require further evaluation.     

Correlates of postural hypotension in a community sample of elderly blacks and whites

Postural hypotension is thought to be prevalent among the elderly, but few community-based studies of this condition have been conducted. In addition, little is known about postural hypotension in blacks despite well documented racial differences in hypertension and stroke. Data on 659 elderly (greater than or equal to 60 years of age) participants in a survey of two rural, biracial townships were analyzed to describe the frequency and correlates of postural hypotension. Twelve percent of the 659 adults experienced a drop of 10 mmHg or greater in systolic blood pressure on going from sitting to standing (supine measures were not available). This degree of postural hypotension was twice as common for whites as for blacks (14.5% vs 7.5%, P = 0.01). Postural hypotension was associated with elevated sitting blood pressure and showed positive but statistically non-significant relationships with anti-hypertensive medications and leanness. The association between race and postural hypotension persisted after adjusting for these and other risk factors (OR = 2.2, 95% CI:1.2,4.0).