Low temperature radioluminescence of LiF:Mg,Cu,P.

Low temperature radioluminescence spectra of LiF, variously co-doped with Mg, Cu and P, show highly unusual temperature dependencies which resemble thermoluminescence data. The signals include intense peaks and a relatively weak continuous background. One peak occurs below 30 K, together with a major peak near 125 K. The signals are highly sensitive to the dopants and slightly sensitive to X-ray dose rate. The role of donor acceptor pairs and the perturbations from intrinsic defects formed by ionisation can be used to describe all the observations. The 290 nm emission band is linked to H center annealing.

Screening blood donors for hereditary hemochromatosis: decision analysis model comparing genotyping to phenotyping.

OBJECTIVE: The identification of a gene for hereditary hemochromatosis in 69-100% of typical hemochromatosis patients has resulted in a genotypic test to identify persons with the typical missense mutation. Population screening by genotyping has the potential to reduce screening costs because of a high specificity of the genetic test. METHODS: Decision analysis techniques are used to compare the outcome, utility, and incremental cost savings of a plan to screen voluntary blood donors and their siblings for hemochromatosis using a genotypic test (C282Y mutation) with phenotypic tests (transferrin saturation, serum ferritin). RESULTS: Genotypic screening is less expensive than phenotypic screening only if the cost of the initial genetic test is less than $20. The screening program saves money (dominant strategy) if the cost of the initial genetic test is less than $28. Incremental cost saving declines as the cost of the gene test increases. At a gene test cost of $173, it costs $109,358 to identify a homozygote with potential life-threatening illness. Incremental cost saving also declines as the penetrance of the hemochromatosis gene in the population screened decreases. Phenotypic screening with confirmatory genetic testing results in a cost of $2,711 per homozygote with life-threatening complications. CONCLUSIONS: Population screening programs for hemochromatosis have the potential to save money. Optimal strategies for screening include initial testing for iron overload (phenotyping) with confirmatory genetic testing, or initial genetic testing if the test is less than $28.

Screening for hemochromatosis in children of homozygotes: prevalence and cost-effectiveness.

Although hereditary hemochromatosis is an autosomal recessive disease, most homozygotes are concerned with the genetic implications for their children. The optimal age for testing children and the cost implications of screening their children have not been clearly established. A clinical database consisting of 255 children from families with at least one homozygote is used to assess the prevalence of homozygotes among children of homozygous parents and to review the biochemical abnormalities and life-threatening symptoms in these young adults. Decision analysis is used to estimate the cost and utility of screening children of a homozygous parent. Eleven homozygotes were discovered among children of homozygotes. Only one male had a life-threatening event, cirrhosis. Decision analysis estimated cost saving of $12 per child screened ($ net present value) and a saving of 10 quality-adjusted days per child screened at age 10 years compared with not screening. If screening began at age 20 years, there is a cost saving of $65 per child screened. Sensitivity analysis showed that the major factors influencing cost savings were the cost of venesections, sensitivity and specificity of the screening tests, and prevalence of disease. Because the prevalence of hemochromatosis is higher in children of homozygotes than in the general population, screening with transferrin saturation and ferritin as early as age 10 years is recommended. Savings are augmented if the cost per venesection is eliminated by allowing hemochromatosis patients to become voluntary blood donors.

Screening blood donors for hereditary hemochromatosis: decision analysis model based on a 30-year database.

BACKGROUND & AIMS: The high prevalence, morbidity, premature death, and benefit of early diagnosis and treatment make hemochromatosis a prime target for screening in the white population. Decision analysis techniques were used to compare the outcome, utility, and incremental cost savings of a plan to screen voluntary blood donors for hemochromatosis. METHODS: The screening strategy includes sequential testing of serum unsaturated iron-binding capacity, serum transferrin saturation, serum ferritin, and either hepatic iron index or venesections to measure exchangeable body iron. Estimates of prevalence, asymptomatic intervals, probabilities of life-threatening clinical complications, symptom-specific life expectancy, and sensitivity and specificity of screening tests are based on our database of 170 hemochromatosis homozygotes and the published literature. RESULTS: The screening strategy led to an incremental increase in utility of 0.84 quality-adjusted life days with an incremental cost savings of $3.19 per blood donor screened. When the potential of identifying asymptomatic homozygous siblings was included, these values increased to 1.18 quality-adjusted life days and $12.57 per person screened. Screening remained a dominant strategy given a prevalence of hemochromatosis of > 0.0026 or an initial screening test cost of < $8. CONCLUSIONS: Screening blood donors for hemochromatosis has the potential to improve overall societal health status and decrease third-party payer health care costs over the long-term.

Hepatic morphology and iron quantitation in perinatal hemochromatosis. Comparison with a large perinatal control population, including cases with chronic liver disease.

We compared hepatic morphology, hepatocellular siderosis, extrahepatic parenchymal siderosis, and (by chemical assay of liver and spleen) the amount of elemental iron and copper in 12 cases of perinatal hemochromatosis (PH) with 119 perinatal controls. Controls were subgrouped according to diagnoses based on clinical and autopsy findings; 37 had chronic liver disease, either hepatic fibrosis (17) or cirrhosis (20). Graded semiquantitatively, hepatocellular siderosis varied widely among controls, and some showed more than PH cases. By chemical assay, total hepatic iron in PH cases was not significantly greater than in any control group except the preterm. Therefore, our findings do not support an etiological role for iron in PH. Its distinctive hepatic morphology seems related to onset of liver disease during fetal life, when periportal hepatocytes normally contain hemosiderin (as in 71 of 82 controls without chronic liver disease). Environmental agents (such as hypoxia, virus, drug) that could damage a fetal liver would usually damage other fetal organs as well. They would be unlikely to recur in a subsequent pregnancy and thereby account for PH occurring in siblings. In initiating PH, therefore, putative environmental agents may need to interact with a factor or factors intrinsic to the developing fetal liver.

Rate of iron reaccumulation following iron depletion in hereditary hemochromatosis. Implications for venesection therapy.

Although venesection therapy is well established for the initial depletion of iron stores in hereditary hemochromatosis, the frequency of subsequent therapy has not been clearly defined. In this study, 21 homozygotes (16 male, five female; mean age of 58, with a range of 26 to 77 years) who had completed initial venesection therapy were followed without further venesections for a mean of 4.0 years (range of 1 to 10.4 years) with iron reaccumulation assessed by annual serum ferritin concentration. Over the follow-up period, the mean rise in serum ferritin was 99 (micrograms/l)/year (range of 1.2 to 241 micrograms/l). The mean interval for the ferritin to become elevated above the normal range in 10 patients was 3.8 years. Eleven of 21 patients required no further venesection therapy over the follow-up interval. There was no significant correlation between the annual rate of ferritin increase and the age or amount of iron removed by prior venesections. These data demonstrate that monitoring body iron stores annually and the selective use of venesections if iron stores reaccumulate is a safe alternative to lifelong venesections every 2-4 months. Many homozygotes will not require reinitiation of venesection therapy for > 4 years. Annual monitoring of body iron stores with reinstitution of weekly venesection when the serum ferritin exceeds the upper limit of normal was a safe alternative to long-term maintenance venesection.

Clinical presentation of hemochromatosis: a changing scene.

PURPOSE: To investigate the changing modes of clinical presentation and diagnosis in 93 patients with familial hemochromatosis and to compare the results with other reports from 1935 to the present. PATIENTS AND METHODS: The presenting features and the frequency of signs and symptoms were analyzed in 93 homozygotes from 56 families. RESULTS: Hemochromatosis was detected by chance in 40% of the 56 probands. Abdominal pain (16%), joint pains (11%), and weakness (9%) were prominent features that brought the patient to the physician. Although 38% of the male patients had loss of libido and impotence, these were not identified as presenting features. Features of liver disease (84%), arthritis (11%), and diabetes (2%) led the physician to the diagnosis. Impotence and testicular atrophy were notable, by their absence, in alerting physicians to the presence of hemochromatosis. Screening of family members led to the detection of 37 homozygotes, of whom 46% were asymptomatic. Among this group, arthropathy and gonadal failure were the most common symptoms. The classic triad of hepatomegaly, diabetes, and pigmentation was present in only 8% of patients. Clinical features were rare in patients with less than 5 g of exchangeable body iron and invariably present in those with more than 16 g. CONCLUSION: The presenting clinical features of hemochromatosis have changed since the original description of the disease in 1935. Family studies have led to the earlier discovery of more homozygous women and earlier detection with less iron loading and, as a result, fewer signs and symptoms.

Abnormalities in iron metabolism in multiple sclerosis.

High iron concentrations have been reported in the brains of multiple sclerosis victims. To determine if there are abnormalities in general iron metabolism indicative of iron overload in MS, measurements of transferrin saturation, serum ferritin and red cell ferritin in 31 female and 18 male patients were compared to the results in 49 age- and sex-matched healthy controls. Compared to controls, mean serum ferritin in MS was high, whereas transferrin saturation and red cell ferritin were similar. High values in one or more individual test results were observed in eleven MS patients. They were prevalent in patients who required bilateral assistance to walk or were confined to a chair, and appeared to be related to the severity of the disease. An investigation was made into the relationship of the high serum ferritin values in MS to the HLA-A3 histocompatibility antigen, a marker of the hemochromatosis gene which is prevalent in MS. A statistically significant interaction was not found between serum ferritin and the presence of HLA-A3.

Ferritin release by mononuclear cells in hereditary hemochromatosis.

An anomaly of the iron-loading disorder hereditary hemochromatosis is that bone marrow iron stores remain low until later stages of the disease. The possibility that this may be related to a disorder of reticuloendothelial ferritin metabolism was examined by studying ferritin release from mononuclear cells. Ferritin release was measured in peripheral blood mononuclear cells from four patients with hemochromatosis who had not received treatment, from six patients with hemochromatosis who had received treatment, and from 10 age- and gender-matched controls by using a modified hemolytic plaque assay. Ferritin release from the hemochromatotic cells was enhanced when compared with that of controls, and added iron stimulated ferritin release to a comparable degree in both groups. Enhanced ferritin release above matched control values was found both in cells from patients with hemochromatosis with partial phlebotomy who had high serum ferritin values and in cells from patients with hemochromatosis with full phlebotomy who had normal serum ferritin values. The increased ferritin release observed in these studies may signify abnormal reticuloendothelial iron metabolism in hemochromatosis.

Perinatal hemochromatosis. Clinical, morphologic, and quantitative iron studies.

Three sibling and two isolated-case perinates (4 newborn, 1 stillborn) died with siderotic cirrhosis and widespread parenchymal siderosis, the latter similar to that seen in both hereditary and secondary hemochromatosis. Reticuloendothelial siderosis was absent, as occurs in primary hemochromatosis. Studies of iron metabolism were performed antemortem in two of the siblings and ante-, post- and internatally in their mother, who showed hyperferremia antenatally. The only finding in the affected family suggestive of hereditary hemochromatosis was the commonly associated HLA haplotype (A3, B7) in the mother and an infant. Liver morphology, including immunocytochemistry and ultrastructure, was similar in the 5 infants and suggested that liver disease commenced as massive necrosis in midfetal life. Histologic grading and chemical assays for iron and copper on liver and spleen of the 5 index cases were compared with 26 controls; placentas were compared with 12 control placentas. Hepatic iron concentration, but not hepatic copper concentration, was significantly increased in index cases, compared with controls. Hepatic iron to copper ratio was significantly increased in index cases, compared with controls, but this ratio was unaltered in spleen and placenta. Total hepatic iron, but not total hepatic copper, was significantly increased in index cases, compared with a subgroup of 11 controls of low gestational age, similar to the fetal stage when liver disease commenced in utero. The results suggest that, irrespective of the fetal liver disease being genetic or acquired, hepatic iron overload was directly involved in pathogenesis.

Usefulness of erythrocyte ferritin analysis in hereditary hemochromatosis.

A study was carried out to determine the usefulness of erythrocyte ferritin analysis in identifying homozygotes and heterozygotes in families affected with hereditary hemochromatosis, an autosomal recessive disorder. To select the subjects the genotypes of 60 people from 26 affected families were determined by HLA-A and HLA-B haplotyping. In addition, data for 12 homozygotes for whom erythrocyte ferritin values were available from the literature were included. Likelihood analysis was used to evaluate the diagnostic value of erythrocyte ferritin analysis alone and in combination with serum ferritin testing. An erythrocyte ferritin value of 150 ag/cell or higher combined with a serum ferritin level above the 90th percentile indicated homozygosity, whereas a value of less than 150 ag/cell and a serum ferritin level at or below the 90th percentile indicated that homozygosity could be ruled out with a high degree of confidence. The probability of heterozygosity rose to 92% when the erythrocyte ferritin value was between 29 and 149 ag/cell and to 98% when this result was combined with a serum ferritin level at or below the 90th percentile. Erythrocyte ferritin analysis in combination with serum ferritin testing is useful for identifying homozygotes and a proportion of heterozygotes in families affected with hemochromatosis.

Transferrin receptors in the human gastrointestinal tract. Relationship to body iron stores.

Fluorescently labeled antibodies were used to identify transferrin receptors and mucosal transferrin in human gastrointestinal biopsy sections. Transferrin receptors were evident in the villous epithelium and the crypt areas of duodenum, ileum, and colon, predominantly in the basal-lateral area. In 7 subjects with low iron stores, the intensity of duodenal villous staining for receptor, on a scale of 0-4, was 2.1 +/- 0.3 (mean +/- SD). This value was significantly higher than the value in 13 subjects with normal iron stores (1.1 +/- 0.4). In 5 patients with hereditary hemochromatosis, duodenal transferrin receptor staining was not significantly different from that in the subjects with normal iron stores. Transferrin staining was found in the apical cytoplasm of epithelial cells in the duodenum, ileum, and colon, but observer assessment was not sufficiently reproducible to make a quantitative analysis. Our results suggest that iron deficiency is accompanied by an increase in transferrin receptors in duodenal absorptive cells, and the genetic lesion in hemochromatosis does not involve an increase in transferrin receptors in the intestinal mucosa compared with subjects with normal iron stores.

Zinc absorption in inflammatory bowel disease.

Zinc absorption was measured in 29 patients with inflammatory bowel disease and a wide spectrum of disease activity to determine its relationship to disease activity, general nutritional state, and zinc status. Patients with severe disease requiring either supplementary oral or parenteral nutrition were excluded. The mean 65ZnCl2 absorption, in the patients, determined using a 65Zn and 51Cr stool-counting test, 45 +/- 17% (SD), was significantly lower than the values, 54 +/- 16%, in 30 healthy controls, P less than 0.05. Low 65ZnCl2 absorption was related to undernutrition, but not to disease activity in the absence of undernutrition or to zinc status estimated by leukocyte zinc measurements. Mean plasma zinc or leukocyte zinc concentrations in patients did not differ significantly from controls, and only two patients with moderate disease had leukocyte zinc values below the 5th percentile of normal. In another group of nine patients with inflammatory bowel disease of mild-to-moderate severity and minimal nutritional impairment, 65Zn absorption from an extrinsically labeled turkey test meal was 31 +/- 10% compared to 33 +/- 7% in 17 healthy controls, P greater than 0.1. Thus, impairment in 65ZnCl2 absorption in the patients selected for this study was only evident in undernourished persons with moderate or severe disease activity, but biochemical evidence of zinc deficiency was uncommon, and clinical features of zinc depletion were not encountered.

Zinc metabolism in patients on maintenance hemodialysis.

Recent studies have focused attention on the possible role of zinc depletion in the pathogenesis of uremic symptoms such as dysgeusia and impotence. The present studies were undertaken to evaluate the prevalence of zinc deficiency and abnormalities of zinc metabolism in patients with end-stage renal disease. A total of 43 stable chronic hemodialysis patients were screened for evidence of zinc deficiency by measurement of fasting predialysis leukocyte and plasma zinc. The results were compared with those from 30 healthy volunteers. Seventeen of these 43 patients had 65Zn absorption measured, and in 9 the rate of disappearance of 65Zn from the body was also measured. The results were compared with those obtained in 20 healthy controls. The nutritional status of these 17 patients was estimated by global nutritional assessment and calculation of the Quetelet index while 9 of 17 had dietary zinc intake calculated from a diet history. The mean plasma zinc level was lower in the hemodialysis patients (11.7 +/- 2.3 mumol/l vs. 13.3 +/- 2.9 mumol/l in controls; p less than 0.05). The mean leukocyte zinc level was 0.81 +/- 0.27 mumol/g dry weight in dialysis patients and 0.81 +/- 0.22 mumol/g in controls (p greater than 0.2). The mean 65Zn absorption in the patients was 49 +/- 14% and in controls 53 +/- 12% (p greater than 0.2). Mean turnover of body 65Zn was 0.47 +/- 0.11%/day in patients and 0.43 +/- 0.18%/day in controls (p greater than 0.1). The mean 65Zn half-life was 154 +/- 29 days in patients and 187 +/- 75 days in controls (p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Management of adenocarcinoma in a columnar-lined esophagus.

Of 89 patients diagnosed between 1973 and 1983 as having at least 3 cm of columnar-lined esophagus, 22 were found to have adenocarcinoma. There was no difference in sex ratio, smoking, or the use of alcohol between the benign and adenocarcinoma groups. The patients with adenocarcinoma were older (63 years versus 57 years) and had a higher frequency of dysphagia (64% versus 46%), gastrointestinal bleeding (36% versus 24%), extended columnar-lined esophagus (94% versus 28%), and epithelial dysplasia (68% versus 10%). Heartburn was less frequent in the adenocarcinoma group (59% versus 79%), but when it occurred, it was of longer duration (mean, 18.8 years versus 10.9 years). In 2 patients, progression from benign columnar-lined esophagus to early adenocarcinoma was observed. Of the patients with adenocarcinoma, 2 received palliative treatment without resection and died four and nine months later. Six underwent partial esophagogastrectomy with 1 postoperative death. Four had residual columnar-lined esophagus at the resection margins. In one of them, stricture developed and in one, anastomotic recurrence of adenocarcinoma; 1-year survival was 50%. Fourteen patients underwent total thoracic esophagectomy with no operative deaths, strictures, or anastomotic recurrences; 1-year survival was 5 of 6. Surgical staging revealed that 63% had transmural spread and 55%, lymph node involvement.(ABSTRACT TRUNCATED AT 250 WORDS)

Low serum 25-hydroxyvitamin D in hereditary hemochromatosis: relation to iron status.

Under normal conditions, vitamin D absorbed from the diet or synthesized in the skin is transported to the liver where it undergoes hydroxylation. The purpose of this study was to determine whether excess hepatic iron affects this process and the subsequent production of 1,25-dihydroxyvitamin D (1,25-[OH]2D) in the kidney. Mean serum 25-hydroxyvitamin D (25-OHD) concentrations in untreated hereditary hemochromatosis were 13 +/- 6 (SD) in 9 patients with cirrhosis, 13 +/- 6 in 5 patients with hepatic fibrosis, and 22 +/- 6 in 10 patients with normal hepatic architecture aside from siderosis and were significantly lower than the levels found in 24 controls matched for age, sex, and season, p less than 0.05. The mean serum 25-OHD levels in the two groups with hemochromatosis and hepatic damage were significantly lower than the value in the group with normal hepatic architecture, p less than 0.05. Serum 25-OHD levels in individual patients were inversely related to the size of body iron stores as measured by exchangeable body iron, r = -0.64, or serum ferritin, r = -0.47, p less than 0.05. In 15 patients removal of excess body iron by venesection therapy produced a significant increase in the mean serum 25-OHD from 20 ng/ml to 30 ng/ml, p less than 0.05. In contrast, mean serum 1,25-[OH]2D levels were similar in iron-loaded and control subjects, indicating that the regulation of this metabolite was intact in patients with hemochromatosis. The results reveal that the low serum 25-OHD concentration in patients with hemochromatosis is directly related to the extent of iron loading and it is improved by venesection therapy.

Zinc absorption and leukocyte zinc in alcoholic and nonalcoholic cirrhosis.

To determine if malabsorption of zinc contributes to the zinc deficiency found in cirrhosis, the absorption of an oral dose of ZnCl2, labeled with 65Zn and a nonabsorbed marker 51CrCl3, was determined from the ratio of these isotopes in a stool specimen. Average 65Zn absorption in 25 alcoholic cirrhotics, 37 +/- 17% (SD), was low compared to 55 +/- 16% in 31 healthy volunteer controls (P less than 0.01). In contrast, mean 65Zn absorption, 47 +/- 11%, in 11 nonalcoholic cirrhotics was not significantly different from the average result in healthy controls. Low 65Zn absorption was accompanied by low leukocyte zinc in a subgroup of alcoholic cirrhotics with ascites and/or ascites and encephalopathy, but not in the subgroup in which these clinical features were absent. Thus, low zinc absorption contributes to zinc deficiency in decompensated alcoholic cirrhosis. The failure to find similar abnormalities in nonalcoholic cirrhosis suggests that the long-standing consumption of alcoholic beverages contributes to the malabsorption of zinc.

Dual-isotope method for determination of human zinc absorption: the use of a test meal of turkey meat.

The percentage of 65Zn taken up (absorbed) from extrinsically labeled turkey meat was calculated from the amounts of 65Zn and a nonabsorbed 51Cr marker present in the body or in a single stool specimen after 1-2 d. 51CrCl3 proved to be a suitable marker for unabsorbed 65Zn and so the early determination of 65Zn absorption was possible. With stool counting, 65Zn absorption data from first stool samples after 1-2 d were accurate as judged by correlation with the amount of 65Zn in the body 7-10 d later (retention); results from subsequent stools gave lower absorption values due to the early excretion of some absorbed 65Zn. The dual-isotope method gave reproducible results when four successive tests of zinc absorption were carried out in a group of six subjects. The average (mean +/- SD) 65Zn absorption from turkey meals containing 31 mumol (2 mg) and 46 mumol (3 mg) of zinc was 39 +/- 8% and 29 +/- 6%, respectively, measured by stool counting; 65Zn absorption and retention correlated well in both studies. A series of different beverages was given in place of water with the turkey meal. Orange juice significantly reduced 65Zn absorption and milk also showed this tendency, but tea, whiskey, wine or beer had no significant effect on the absorption of 65Zn from the turkey meal. In groups of subjects the mean ratio of 65Zn absorption from extrinsically labeled turkey meat on two occasions (1.06) was not significantly different from that of the absorption of extrinsic to intrinsic 65Zn labels (1.16). The dual-isotope technique with either stool or body counting is suitable for the rapid determination of 65Zn absorption from extrinsically labeled turkey within 2 d.