Search

Oculomeningovascular amyloidosis is a variant of transthyretin (TTR) amyloidotic polyneuropathy, which is associated with blindness and brain ischemia, microhemorrages, and siderosis due to prominent production of the abnormal TTR in the eye and in the choroid plexuses. Tafamidis is a TTR stabilizer that is orally administered and, by interfering with amyloid fibril formation and deposition, is capable of slowing progression of TTR polyneuropathy and of early-stage cardiomyopathy. However, the ocular manifestations of amyloid deposition progressed despite tafamidis therapy in Val30Met TTR amyloidosis, and the effects of tafamidis on meningovascular amyloidosis are unknown. We observed failure of tafamidis to halt progression of oculomeningovascular amyloid deposition in a patient with familial Ala36Pro TTR amyloidosis. She received molecular diagnosis at age 24 and presented at age 26 with paresthesias of the lower limbs and bowel dysfunction. Echography showed minimal amyloid opacities in the corpus vitreum. Treatment with tafamidis meglumine was started. Sixteen months later, she complained of severe headache followed by left hemiparesthesias and numbness lasting 20 minutes. Magnetic resonance imaging showed multiple focal and diffuse hemosiderin deposits compatible with microbleeds and early siderosis. Echography showed a marked increase of "vitreal opacities." Our observation confirms that tafamidis fails in halting increase of vitreal amyloid deposits and indicates that it is presumably ineffective in preventing clinical onset due to progression of meningovascular amyloidosis. These failures may be due to the incapability of tafamidis to cross the blood-retina and blood-brain barriers. Therapeutic options targeting oculomeningovascular TTR amyloidoses in humans are required., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Superficial siderosis (SS) is characterized by hemosiderin deposition in the superficial layers of the central nervous system and can be seen during postmortem examination or with iron-sensitive magnetic resonance imaging techniques. The distribution of SS may predict the probable underlying cause. This study aimed to report the prevalence and natural history of SS in a population-based study., Methods: Brain magnetic resonance imaging scans from the MCSA (Mayo Clinic Study of Aging), a population-based study of residents 50 to 89 years of age in Olmsted County, Minnesota, were reviewed. Participants with imaging consistent with SS were identified from 2011 through 2016. An inverse probability weighting approach was used to convert our observed frequencies to population prevalence of SS. Additional data abstracted included amyloid positron emission tomography, Apolipoprotein E genotype, coexisting cerebral microbleeds, and extent of SS., Results: A total of 1412 participants had eligible magnetic resonance imaging scans. Two participants had infratentorial SS, restricted to the posterior fossa. Thirteen participants had cortical SS involving the cerebral convexities (7 focal and 6 disseminated). Only 3 of the participants with cortical SS (23%) also had cerebral microbleeds. The population prevalence of SS was 0.21% (95% confidence interval, 0-0.45) in those 50 to 69 years old and 1.43% (confidence interval, 0.53-2.34) in those over 69 years old. Apolipoprotein E ε2 allele was more common in those with SS (57.1% versus 15.0%; P <0.001). Compared with participants without SS, those with SS were also more likely to have a positive amyloid positron emission tomographic scan (76.9% versus 29.8%; P <0.001)., Conclusions: SS may be encountered in the general elderly population. The association with increased amyloid burden and Apolipoprotein E ε2 genotype supports cerebral amyloid angiopathy as the most common mechanism. Longitudinal follow-up is needed to evaluate the risk of subsequent hemorrhage in cases of incidentally discovered SS., (© 2017 American Heart Association, Inc.)

Background: In patient with cerebral amyloid angiopathy (CAA) presenting with lobar hemorrhage (LH), magnetic resonance imaging (MRI) white matter hyperintensities (WMH) tend to be predominant in posterior regions with the "multiple subcortical spots" WMH pattern as the most frequent topographical WMH pattern. Our aim was to analyze WMH severity and topographical distribution in patients with cortical superficial siderosis (CSS)., Methods: We retrospectively analyzed MRIs from consecutive symptomatic isolated (i.e., without LH) CSS and LH-CAA (with or without associated CSS) patients. We analyzed baseline clinical characteristics including age, history of hypertension, diabetes, hypercholesterolemia, and pre-existing cognitive deficit. The presence of lobar microbleeds (MB) was scored on T2*. FLAIR (fluid-attenuated inversion recovery) WMH severity (using the Fazekas scale) and topographical distribution (using [slightly modified] earlier described WMH patterns) were analyzed and compared between both groups., Results: Twenty CSS and 63 LH-CAA patients were analyzed. Baseline clinical characteristics were similar between both groups, except for hypercholesterolemia less frequently present in the CSS group (P = .026). Lobar MB were significantly less frequently present in the CSS group (P < .01), and CSS was more frequently focal in the CSS group compared with LH-CAA patients with associated CSS (P = .03). Mean Fazekas scale was significantly lower in CSS patients (P = .011). WMH patterns did not differ between both groups, with the multiple subcortical spots pattern as the most frequently observed pattern., Conclusions: Relative severe WMH scores and similar topographical distribution in CSS patients argue for WMH as a CAA-related feature in these patients with isolated CSS, adding level of evidence that isolated CSS could correspond to early manifestations of CAA., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: To identify predictors of early lobar intracerebral hemorrhage (ICH) recurrence, defined as a new ICH within 6 months of the index event, in patients with cerebral amyloid angiopathy (CAA)., Methods: Participants were consecutive survivors (age ≥55 years) of spontaneous symptomatic probable or possible CAA-related lobar ICH according to the Boston criteria, drawn from an ongoing single-center cohort study. Neuroimaging markers ascertained in CT or MRI included focal (≤3 sulci) or disseminated (>3 sulci) cortical superficial siderosis (cSS), acute convexity subarachnoid hemorrhage (cSAH), cerebral microbleeds, white matter hyperintensities burden and location, and baseline ICH volume. Participants were followed prospectively for recurrent symptomatic ICH. Cox proportional hazards models were used to identify predictors of early recurrent ICH adjusting for potential confounders., Results: A total of 292 patients were enrolled. Twenty-one patients (7%) had early recurrent ICH. Of these, 24% had disseminated cSS on MRI and 19% had cSAH on CT scan. In univariable analysis, the presence of disseminated cSS, cSAH, and history of previous ICH were predictors of early recurrent ICH (p < 0.05 for all comparisons). After adjusting for age and history of previous ICH, disseminated cSS on MRI and cSAH on CT were independent predictors of early recurrent ICH (hazard ratio [HR] 3.92, 95% confidence interval [CI] 1.38-11.17, p = 0.011, and HR 3.48, 95% CI 1.13-10.73, p = 0.030, respectively)., Conclusions: Disseminated cSS on MRI and cSAH on CT are independent imaging markers of increased risk for early recurrent ICH. These markers may provide additional insights into the mechanisms of ICH recurrence in patients with CAA., (© 2016 American Academy of Neurology.)

Objectives: Estimating the prevalence of glutathione S-transferase gene polymorphism (GSTM1) null genotype among patients with beta thalassemia major (β-TM) in relation to myocardial status assessed by tissue Doppler and cardiac siderosis assessed by cardiac magnetic resonance imaging (MRI) T2*., Methods: Hundred patients with β-TM and 100 healthy controls were enrolled. Complete blood count (CBC), mean serum ferritin and GSTM1 genotyping, echocardiography, tissue Doppler, and cardiac MRI T2* were done., Results: Serum ferritin ranged from 1200 to 8000 ng/ml, and mean T2* value was 27.10 ± 11.20 ms. Of patients, 68 (68%) had no cardiac siderosis, while 24 (24%) with mild to moderate, and 8 (8%) with sever cardiac siderosis. T2* values were not correlated with serum ferritin (r = -0.09, P = 0.50). GSTM1 null genotype was prevalent in 46% of patients and 40% of controls (P = 0.69). Patients with null genotype had significantly shorter T2* (P = 0.001), higher left ventricular end-diastolic diameter (P = 0.002), and shorter ejection time (P = 0.005) with no significant relation to serum ferritin (P = 0.122). GSTM1 null genotype was the only predictor for cardiac iron overload (P = 0.002)., Discussion: Serum ferritin concentrations have been shown to correlate poorly with all stages of cardiac dysfunction. Low cardiac MRI T2* values occur in patients with β-TM despite good chelation therapy, suggesting a possible role of genetic factors in cardiac siderosis., Conclusion: GSTM1 null genotype is significantly associated with cardiac iron overload independent of serum ferritin in Egyptian patients with β-TM.

Iron abnormalities in chronic liver disease may be the result of genetic diseases or secondary factors. The present study aimed to identify subjects with HFE-HH in order to describe the frequency of clinical manifestations, identify risk factors for iron elevation, and compare the iron profile of HFE-HH to other genotypes in liver disease patients. A total of 108 individuals with hepatic disease, transferrin saturation (TS) > 45%, and serum ferritin (SF) > 350 ng/mL were tested for HFE mutations. Two groups were characterized: C282Y/C282Y or C282Y/H63D genotypes (n = 16) were the HFE hereditary hemochromatosis (HFE-HH) group; and C282Y and H63D single heterozygotes, the H63D/H63D genotype, and wild-type were considered group 2 (n = 92). Nonalcoholic liver disease, alcoholism, and chronic hepatitis C were detected more frequently in group 2, whereas arthropathy, hepatocarcinoma, diabetes, and osteoporosis rates were significantly higher in the HFE-HH group. TS > 82%, SF > 2685 ng/mL, and serum iron > 178 μg/dL were the cutoffs for diagnosis of HFE-HH in patients with liver disease. Thus, in non-Caucasian populations with chronic liver disease, HFE-HH diagnosis is more predictable in those with iron levels higher than those proposed in current guidelines for the general population.

Objective: We sought to explore the mechanisms leading to cerebral amyloid angiopathy (CAA)-related cortical superficial siderosis (cSS) by examining its neuroimaging and genetic association with cerebral microbleeds (CMBs)., Methods: MRI scans of 84 subjects with probable or definite CAA participating in a longitudinal research study were graded for cSS presence and severity (focal, restricted to ≤ 3 sulci vs disseminated, ≥ 4 sulci), and CMB count. APOE ε variants were directly genotyped. We performed cross-sectional analysis comparing CMB counts and APOE ε2 and ε4 allele frequency between subjects with no, focal, or disseminated cSS., Results: cSS was present in 48% (n = 40) of the population. APOE ε2 was overrepresented among participants with focal (odds ratio [OR] 7.0, 95% confidence interval [CI] 1.7-29.3, p = 0.008) and disseminated (OR 11.5, 95% CI 2.8-46.2, p = 0.001) cSS relative to individuals without cSS. CMB counts decreased with increasing severity of cSS (median: 41, 38, and 15 for no cSS, focal cSS, and disseminated cSS, respectively, p = 0.09). The highest CMB count tertile was associated with APOE ε4 (OR 3.0, 95% CI 1.4-6.6, p = 0.006) relative to the lowest tertile., Conclusions: Among individuals with advanced CAA, cSS tends to occur in individuals with relatively lower CMB counts and with a distinct pattern of APOE genotypes. These results suggest that CAA-related cSS and CMBs may arise from distinct vasculopathic mechanisms., (© 2014 American Academy of Neurology.)

A 63-year-old woman with a past history of right subdural hematoma (SDH) at the age of 61 years was referred to our hospital under a suspicion of aceruloplasminemia (ACP). A neurological examination revealed very mild cognitive impairment and cerebellar ataxia. Blood chemistry data showed deficient ceruloplasmin (Cp), decreased copper, and increased ferritin. A nonsense mutation (c.2630G>A, p.Trp858Ter) was detected in the Cp gene. Brain magnetic resonance imaging (MRI) showed marked hypointensity at the surface of the cerebrum, cerebellum, and brainstem bilaterally, in addition to the bilateral basal ganglia, thalamus, and dentate nucleus, suggesting the coexistence of ACP and superficial siderosis (SS). The characteristics of SS in ACP have not been examined neuroradiologically or neuropathologically in great detail, while SDH and its curative surgery are known to cause SS. The distribution of the hypointensity areas on MRI was expanded bilaterally to the subtentorial areas of this patient, which was much more widespread than observed in typical SS after SDH. We speculate that the underlying ACP may expand the SS induced by SDH. Cp would accelerate iron export from the brain via the blood-cerebrospinal fluid (CSF) barrier, or CSF-brain barrier when excessive iron is loaded into the subarachnoid space., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Hepatic siderosis is common in patients with porphyria cutanea tarda (PCT). Mutations in the hereditary hemochromatosis (hh) gene (HFE) explain the siderosis in approximately 20% patients, suggesting that the remaining occurrences result from additional genetic and environmental factors. Two genes known to modify iron loading in hh are hepcidin (HAMP) and hemojuvelin (HJV). To determine if mutations in or expression of these genes influenced iron overload in PCT, we compared sequences of HAMP and HJV in 96 patients with PCT and 88 HFE C282Y homozygotes with marked hepatic iron overload. We also compared hepatic expression of these and other iron-related genes in a group of patients with PCT and hh. Two intronic polymorphisms in HJV were associated with elevated serum ferritin in HFE C282Y homozygotes. No exonic polymorphisms were identified. Sequencing of HAMP revealed exonic polymorphisms in 2 patients with PCT: heterozygosity for a G-->A transition (G71D substitution) in one and heterozygosity for an A-->G transition (K83R substitution) in the other. Hepatic HAMP expression in patients with PCT was significantly reduced, regardless of HFE genotype, when compared with patients with hh but without PCT with comparable iron overload. These data indicate that the hepatic siderosis associated with PCT likely results from dysregulated HAMP.

Background & Aims: Iron perturbations are frequently observed in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate a potential association of copper status with disturbances of iron homeostasis in NAFLD., Methods: We retrospectively studied 140 NAFLD patients and 25 control subjects. Biochemical and hepatic iron and copper parameters were analyzed. Hepatic expression of iron regulatory molecules was investigated in liver biopsy specimens by reverse-transcription polymerase chain reaction and Western blot analysis., Results: NAFLD patients had lower hepatic copper concentrations than control subjects (21.9 +/- 9.8 vs 29.6 +/- 5.1 microg/g; P = .002). NAFLD patients with low serum and liver copper concentrations presented with higher serum ferritin levels (606.7 +/- 265.8 vs 224.2 +/- 176.0 mg/L; P < .001), increased prevalence of siderosis in liver biopsy specimens (36/46 vs 10/47 patients; P < .001), and with elevated hepatic iron concentrations (1184.4 +/- 842.7 vs 319.9 +/- 451.3 microg/g; P = .020). Lower serum concentrations of the copper-dependent ferroxidase ceruloplasmin (21.7 +/- 4.1 vs 30.4 +/- 6.4 mg/dL; P < .001) and decreased liver ferroportin (FP-1; P = .009) messenger RNA expression were found in these patients compared with NAFLD patients with high liver or serum copper concentrations. Accordingly, in rats, a reduced dietary copper intake was paralleled by a decreased hepatic FP-1 protein expression., Conclusions: A significant proportion of NAFLD patients should be considered copper deficient. Our results indicate that copper status is linked to iron homeostasis in NAFLD, suggesting that low copper bioavailability causes increased hepatic iron stores via decreased FP-1 expression and ceruloplasmin ferroxidase activity thus blocking liver iron export in copper-deficient subjects.

Ferroportin disease is an autosomal dominant form of hemochromatosis associated with siderosis in cells of the mononuclear phagocyte system and, to varying degrees, in hepatocytes. Ferroportin was investigated as a candidate gene in two pedigrees with hyperferritinaemia and siderosis in mononuclear phagocytes. The entire ferroportin coding region was sequenced and hepatic iron concentration, histology and response to treatment were determined. The results were compared with previously reported cases. The A77D mutation was detected in patient 1, his father (patient 2) and his brother (patient 3), who had portal fibrosis. The V162del mutation was detected in patient 4, who developed anemia after the third weekly venesection. While the disease is rare, A77D and V162del are the most common ferroportin mutations in Caucasians. The spectrum of clinical expression of these two mutations was reviewed in all cases described to date. These mutations were associated with fibrosis in about a third of cases. For A77D and V162del, this analysis confirms that the threshold hepatic iron concentration for development of fibrosis may be higher than for classical hemochromatosis. These two mutations, which both decreased iron export in cell culture studies, give rise to similar patterns of clinical expression and morbidity, although the highest hepatic iron concentrations have been observed with A77D. It is important for clinicians to consider ferroportin disease in cases where there are features of iron overload unrelated to HFE, autosomal dominant inheritance and/or iron deposition in mononuclear phagocytes.

The aim of the present study was to describe the histopathologic features of hepatic iron accumulation in patients with chronic hepatitis C (CH-C) infection, the relation between HFE mutations and hepatic iron location and among iron distribution, HFE, and hepatic damage. We studied 206 patients with CH-C infection. Of 101 patients with hemosiderin deposits, 90.1% had iron deposits in hepatocytes (alone or with sinusoidal and/or portal involvement). The hepatic iron score increased significantly as iron accumulation involved sinusoidal and portal tract compartments and according to HFE genotypes. Severe fibrosis and cirrhosis were associated more markedly with the presence of hemosiderin iron in the 3 hepatic compartments, HFE mutations, and high alcohol intake. We suggest that part of the iron accumulation in CH-C infection derives from increased iron absorption and release from storage cells and that the amount and distribution of hepatic iron deposits is related to hepatic damage. HFE mutations favor both processes, but other factors, genetic or acquired, are involved.

The mystery surrounding the apparent lack of iron within the macrophages of individuals with hereditary hemochromatosis, a condition of excessive uptake of dietary iron, has yet to be fully explained. We have suggested that iron deficiency of macrophages in people with hereditary hemochromatosis mutations is associated with increased resistance to infection by Yersinia and other intracellular pathogens, a selection pressure resulting in unusually high current population frequencies of hereditary hemochromatosis mutations. Such selection pressure has been called Epidemic Pathogenic Selection (EPS). In support of the theory of EPS, a considerable number of virulent species of bacteria multiply mainly in iron-rich macrophages of their mammalian hosts. Among these fastidious pathogens are strains of Chlamydia, Coxiella, Francisella, Legionella, Mycobacterium, Salmonella and Yersinia. Iron deficiency of macrophages of persons with hereditary hemochromatosis gene mutations may result in increased resistance to members of these bacterial pathogens. People with genes that result in hereditary hemochromatosis may be protected against coronary artery disease associated with Chlamydia and Coxiella infection in the absence of iron overload. In the clinical setting, when a patient appears to be iron deficient, the reason for this should be carefully evaluated. Iron supplementation may adversely affect the health of individuals who have mounted an acute phase response to infection, injury or stress, or who carry genes predisposing them to iron overload disorders.

Background & Aims: Iron overload is observed frequently in chronic liver disease, and some studies have suggested that chronic iron overload may contribute to the pathogenesis of hepatocellular carcinoma (HCC). Heterozygosity for hereditary hemochromatosis (HH) is associated with increased body iron stores. The discovery of the HH gene HFE has enabled identification of the heterozygote status. The aim of this study was to evaluate if heterozygosity for HH is a risk factor for HCC., Methods: The C282Y and the H63D mutation of the HFE gene were analyzed in 137 patients with HCC and no history of HH, 107 patients with cirrhosis without HCC and 126 healthy controls. Hepatic iron content was measured by using a semiquantitative histologic score., Results: Seventeen of 137 HCC patients (12.4%) were C282Y heterozygote, compared with only 4 of 107 (3.7%) cirrhotic patients without HCC and 6 of 126 (4.8%) healthy controls (P < 0.05). The frequency of the H63D mutation showed no significant differences. C282Y heterozygote HCC patients had significantly higher levels of serum ferritin and transferrin saturation than C282Y wild-type patients (793 +/- 122 vs. 355 +/- 23 ng/mL, and 42.3% +/- 7.3% vs. 29.2% +/- 1.7%, respectively), and significantly higher iron deposition in HCC as well as in nontumorous liver tissue., Conclusions: The C282Y heterozygous genotype is significantly more common in HCC patients and is associated with significantly increased intrahepatic iron deposition and systemic iron stores. These results suggest that C282Y heterozygosity plays a role in liver iron deposition and could contribute to hepatocarcinogenesis via the accumulation of potentially carcinogenic iron. These findings may have implications for HCC screening and prevention strategies.

Several methods have been used to develop rodent models with the hepatic manifestations of porphyria cutanea tarda (PCT). Acute iron administration or mutations of the hemochromatosis gene (Hfe) have been used to generate hepatic siderosis, a nearly uniform finding in PCT. Heterozygosity for a null mutation at the uroporphyrinogen decarboxylase (Uro-D+/-) locus has been developed to mimic familial PCT in humans. This study examines the interplay of these 2 genetic risk factors and their influence, alone and combined with polychlorinated-biphenyl exposure. Neither an Hfe-null mutation nor iron-dextran administration alone or in combination with polychlorinated biphenyl exposure was porphyrinogenic in a 3-week model using mice wild-type at the Uro-D locus. Homozygosity for an Hfe-null mutation significantly elevated hepatic iron but not to the extent seen with parenteral iron-dextran administration. Homozygosity for an Hfe-null mutation but not iron-dextran administration was porphyrinogenic in animals heterozygous for the Uro-D mutation. Polychlorinated biphenyls were also porphyrinogenic in these animals. Uroporphyria in Uro-D+/- animals was exacerbated by combinations of the homozygous Hfe-null mutation and polychlorinated biphenyls and iron-dextran and polychlorinated biphenyls. In all cases in which uroporphyria developed, a greater degree of experimental uroporphyria was seen in female animals. All elevated hepatic uroporphyrin concentrations were accompanied by depressed uroporphyrinogen decarboxylase activity and the presence of a factor in cytosol that inhibits recombinant human uroporphyrinogen decarboxylase. In conclusion, the expression of the uroporphyric phenotype, dependent on the susceptibility imparted by a genetic mutation, provides a uniquely facile model for dissecting the molecular pathogenesis of the disease.

Non hemochromatotic liver siderosis often present an heterogeneous iron distribution, but histological scoring of iron overload are validated only in case of genetic hemochromatosis, where iron is homogeneously distributed. The aim of this work was to study the improvement of histological scoring by introducing a coefficient of heterogeneity in cases of heterogeneous liver siderosis. Thus, on 254 liver biopsies with siderosis were determined: i) the histologic total iron score (TIS) as previously described; ii) the coefficient of heterogeneity, leading to corrected TIS (corTIS); iii) the liver iron content (LIC). Liver siderosis was homogeneously distributed in 160 biopsies and heterogeneously distributed in 94. Correlation between histological scoring and LIC, in the group with heterogeneous liver siderosis, was improved by the use of the coefficient of heterogeneity. This coefficient leads to accurately quantify all liver siderosis.

Background/aims: Liver fibrosis and cirrhosis represent common pathological findings in humans with iron overload. This study was undertaken to assess whether in vivo targeting of iron to liver parenchymal or nonparenchymal cells would differently affect collagen gene activity., Methods: Rats were treated with an iron diet or intramuscular injections of iron dextran, and in situ hybridization analyses on liver samples were performed., Results: These iron treatments determined parenchymal or reticuloendothelial cell iron overload, respectively. The typical distribution of iron into different liver cells was documented by histochemistry and confirmed by in situ hybridization analysis with a ferritin L complementary RNA probe. In iron-fed rats, in situ hybridization analysis identified a signal for collagen type I messenger RNA into nonparenchymal cells in zones I and II. In rats with nonparenchymal cell iron overload, no activation of collagen gene expression was detected into or near iron-laden nonparenchymal cells. These findings were also confirmed by quantitative Northern blot analysis., Conclusions: The results of this study indicate that, regardless of the total hepatic iron burden, selective localization of iron into liver cells (i.e., parenchymal cells) is required for the activation of collagen gene during long-term iron overload in rodents.

The present investigation evaluated the serum transferrin receptor concentration in subjects with nontransfusional iron overload who were identified in two separate studies on the basis of a serum ferritin level above 400 micrograms/L. Subjects with preclinical hereditary hemochromatosis were evaluated in the first study and those with the African form of iron overload in the second. In the first study, hereditary hemochromatosis was identified in 14 white men on the basis of a persistent elevation in transferrin saturation above 55%. The serum receptor concentration was elevated above the upper cut-off of 8.5 mg/L in two of the subjects, but the mean receptor of 6.1 +/- 1.4 mg/L (mean +/- 2 SE) did not differ significantly from the normal mean for this assay of 5.6 +/- 0.3 mg/L. In the same study, 60 control subjects with secondary iron overload were identified on the basis of a serum ferritin persistently above 400 micrograms/L, with a normal serum C-reactive protein concentration but with a transferrin saturation < 55%. Three of these subjects had an elevated serum receptor concentration but the mean value of 5.5 +/- 0.4 mg/L did not differ from normals nor from subjects with hemochromatosis. In the second study, 49 black Africans with iron overload were divided into those with or without an elevated transferrin saturation. The mean serum receptor concentration of 5.0 +/- 0.8 mg/L and 4.5 +/- 0.4 mg/L, respectively, did not differ statistically. It was concluded that there is no evidence of generalized dysregulation of the transferrin receptor in hemochromatosis or African siderosis.

Although many studies have examined the regulation of transferrin, transferrin receptor and ferritin subunit gene expression in experimental systems, no molecular biological data in humans have been documented to date. In this study we simultaneously analyzed the hepatic content of transferrin, transferrin receptor and heavy and light ferritin subunit messenger RNAs in tissue samples obtained from subjects with normal iron balance and patients with primary or secondary iron overload. Steady-state levels of transferrin messenger RNA were not depressed by iron overload. On the contrary, they were increased (p less than 0.001) in patients with severe hepatic siderosis (liver iron content greater than 200 mumol/gm dry wt) as compared with the control group. This indicates that, as already suggested by our previous data in experimental siderosis, iron maintains the ability to induce transferrin gene activity even when cellular iron content is significantly increased. Transferrin receptor gene expression was found to respond in the same manner to any cause of iron-tissue load, regardless of the cause. In fact, a lower signal for transferrin receptor messenger RNA was consistently detected in iron-overloaded patients vs. control subjects, particularly in patients with thalassemia major and idiopathic hemochromatosis (p less than 0.001). Ferritin light-subunit messenger RNA accumulation was significantly increased in those patients with severe siderosis (idiopathic hemochromatosis and thalassemia major = liver iron between 200 and 600 mumol/gm dry wt). The fact that no significant change in hepatic ferritin heavy-subunit gene expression was detected in iron-loaded patients confirms preferential production of light-subunit--enriched ferritins in long-term iron overload.(ABSTRACT TRUNCATED AT 250 WORDS)

Three children of a mother with biopsy-confirmed posttransfusional hepatitis of undetermined etiology (non-A, non-B hepatitis) died in utero or in infancy. All had liver disease of intrauterine onset. The two liveborn children died of the consequences of severe hepatic insufficiency manifest at birth and met clinicopathologic criteria for neonatal hemochromatosis. Although hepatic architecture in the stillborn fetus was markedly disordered, with hepatocyte giant cell transformation, extrahepatic siderosis was not present and hepatic siderosis was minimal. These findings indicate that in some cases of neonatal hemochromatosis, extrahepatic siderosis may be caused by hepatic injury rather than primarily due to excessive transport of iron from mother to fetus and support speculation that in some instances an infective agent may be responsible.

With regard to disturbances of the iron metabolism, porphyria cutanea tarda (PCT) is most frequently accompanied by liver siderosis. In 74 out of 88 patients suffering from PCT (84%), we found histochemical evidence of liver siderosis. These patients showed a significantly higher incidence of HLA A3--which has been proved to be associated with hemochromatosis--than those without liver siderosis (39.2% vs. 7.1%). With part of the PCT patients, disorders of the iron metabolism related to the HLA system (A3) might contribute to the manifestation of the disease. We discuss PCT as the result of the combined action of several predisposing genetic markers and exogenic factors.

We studied iron overloading and HLA genotype in two families with overt forms of idiopathic haemochromatosis in two successive generations. In each family the spouse of the patient with overt haemochromatosis in the first generation had clinical and laboratory signs of moderate iron overload and a HLA haplotype A3, B14 and A3, B7 respectively--which is frequently associated with the haemochromatosis gene. This specific HLA haplotype had been transmitted to the second generation patient with overt disease, which thus could be considered as having received a haemochromatosis gene from each parent. Although the finding of cases of overt disease in successive generation firstly suggests a dominant transmission the genetical analysis of these families lead to further strong argument in favour of recessive inheritance of idiopathic haemochromatosis.

Subnormal activity of hepatic uroporphyrinogen decarboxylase is responsible for the derangement of porphyrin biosynthesis in both sporadic and familial porphyria cutanea tarda, but the enzymatic defect is not clinically expressed in the absence of hepatic siderosis. The pedigree study described here offers support for the hypothesis that a single allele for HLA-linked hereditary hemochromatosis is responsible for the hepatic siderosis in sporadic porphyria cutanea tarda. A two-locus causation model for sporadic porphyria cutanea tarda might explain both the observed incidence of overt cases and the rarity of multiple affected individuals within a pedigree.