Immediate pharmacotherapy intensification after cardiac resynchronization therapy: incidence, characteristics, and impact.

AIMS: Cardiac resynchronization therapy (CRT) is an established treatment for drug-refractory heart failure (HF) in patients with left bundle branch block (LBBB). Acute haemodynamic improvement after CRT implantation may enable the intensification of HF medication soon thereafter. Immediate pharmacotherapy intensification (IPI) after CRT implantation achieves a synergetic effect, possibly leading to a better prognosis. This study aimed to explore the incidence, characteristics, and impact of IPI on real-world outcomes among CRT recipients with a history of hospitalization for acute HF. METHODS AND RESULTS: This multicentre retrospective study enrolled CRT recipients with LBBB morphology, a QRS width ≥120 ms, a left ventricular ejection fraction ≤35%, and New York Heart Association II-IV HF symptoms. All patients had previous HF hospitalizations within the previous year and received guideline-directed medical therapy before CRT implantation. Patient baseline characteristics, including HF medication, were collected. IPI was defined as the intensification of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists within 30 days of CRT implantation. The primary endpoint was all-cause death or first hospitalization for HF; the secondary endpoint was all-cause death. We enrolled 194 patients (75% male; mean age, 65 ± 13 years; 78% with non-ischaemic cardiomyopathy). One hundred five (54%) patients received IPI. Patients who received IPI exhibited a significantly shorter QRS duration (159 ± 26 vs. 171 ± 32 ms; P = 0.004), higher estimated glomerular filtration rate (55.2 ± 20.0 vs. 47.8 ± 24.7 mL/min/1.73 m2 ; P = 0.022), and more dilated cardiomyopathy. During a median follow-up period of 29 months, 70 (36%) patients reached the primary endpoint and 42 (22%) patients died. Patients with IPI showed significantly better outcomes for the primary and secondary endpoints than patients without IPI. The volumetric responder ratio at 6 months after implantation was not significantly different between patients with and without IPI; however, patients who received IPI had reduced mortality even at 6 months after implantation. In the multivariate analysis, IPI was an independent predictor of the primary endpoint (hazard ratio, 0.51; 95% confidence interval, 0.27-0.97; P = 0.043). CONCLUSIONS: Immediate intensification of HF medication was achieved in 54% of CRT recipients and was significantly higher in patients without excessive QRS prolongation, preserved renal function, and dilated cardiomyopathy than others. In patients with LBBB morphology and QRS ≥ 120 ms, IPI was associated with a significantly better prognosis and fewer HF hospitalizations after CRT implantation than others.

Predictors of Recurrence after Catheter Ablation of Paroxysmal Atrial Fibrillation in Different Follow-Up Periods.

Background and objectives: Pulmonary vein (PV) reconnection is a major reason for recurrence after catheter ablation of paroxysmal atrial fibrillation (PAF). However, the timing of the recurrence varies between patients, and recurrence >1 year after ablation is not uncommon. We sought to elucidate the characteristics of atrial fibrillation (AF) that recurred in different follow-up periods. Materials and Methods: Study subjects comprised 151 consecutive patients undergoing initial catheter ablation of PAF. Left atrial volume index (LAVi) and atrial/brain natriuretic peptide (ANP/BNP) levels were systematically measured annually over 3 years until AF recurred. Results: Study subjects were classified into four groups: non-recurrence group (n = 84), and short-term- (within 1 year) (n = 30), mid-term- (1-3 years) (n = 26), and long-term-recurrence group (>3 years) (n = 11). The short-term-recurrence group was characterized by a higher prevalence of diabetes mellitus (hazard ratio 2.639 (95% confidence interval, 1.174-5.932), p = 0.019 by the Cox method), frequent AF episodes (≥1/week) before ablation (4.038 (1.545-10.557), p = 0.004), and higher BNP level at baseline (per 10 pg/mL) (1.054 (1.029-1.081), p < 0.0001). The mid-term-recurrence group was associated with higher BNP level (1.163 (1.070-1.265), p = 0.0004), larger LAVi (mL/m2) (1.033 (1.007-1.060), p = 0.013), and longer AF cycle length at baseline (per 10 ms) (1.194 (1.058-1.348), p = 0.004). In the long-term-recurrence group, the ANP and BNP levels were low throughout follow-up, as with those in the non-recurrence group, and AF cycle length was shorter (0.694 (0.522-0.924), p = 0.012) than those in the other recurrence groups. Conclusions: Distinct characteristics of AF were found according to the time to first recurrence after PAF ablation. The presence of secondary factors beyond PV reconnections could be considered as mechanisms for the recurrence of PAF in each follow-up period.

Noninvasive Mapping of Premature Ventricular Contractions by Merging Magnetocardiography and Computed Tomography.

OBJECTIVES: This study aimed to develop a novel premature ventricular contraction (PVC) mapping method to predict PVC origins in whole ventricles by merging a magnetocardiography (MCG) image with a cardiac computed tomography (CT) image. BACKGROUND: MCG can noninvasively discriminate PVCs originating from the aortic sinus cusp from those originating from the right ventricular outflow tract. METHODS: This study was composed of 22 candidates referred for catheter ablation of idiopathic PVCs. MCG and CT were performed the same day before ablation. Estimated origins by MCG-CT imaging using the recursive null steering spatial filter algorithm were compared with origins determined by electroanatomic mapping (CARTO, Biosense Webster, Inc., Diamond Bar, California) during the ablation procedure. Radiopaque acrylic markers for the CT scan and coil markers generating a weak magnetic field during MCG measurements were used as reference markers to merge the 2 images 3-dimensionally. RESULTS: PVC origins were determined by endocardial and epicardial mapping and ablation results in 18 (86%) patients (right ventricular outflow tract in 10 patients, aortic sinus cusp in 2 patients, interventricular septum in 1 patient, near His bundle in 1 patient, right ventricular free wall in 1 patient, and left ventricular free wall in 3 patients). Estimated origins by MCG-CT imaging matched the origins determined during the procedure in 94% (17 of 18) of patients, whereas the electrocardiography algorithms were accurate in only 56% (10 of 18). Discrimination of an epicardium versus an endocardium or right- versus left-sided septum was successful in 3 of 4 patients (75%). CONCLUSIONS: The diagnostic accuracy of noninvasive MCG-CT mapping was high enough to allow clinical use to predict the site of PVC origins in the whole ventricles.

Tonsillectomy plus steroid pulse therapy is the most effective treatment in adult patients with C-Grade I IgA nephropathy, and the weight of the extracted palatine tonsils and Yamamoto scale have no significant correlation with the effects of this treatment.

OBJECTIVE: We studied patients who underwent tonsillectomy plus steroid pulse therapy (TSP) for immunoglobulin A nephropathy (IgAN), in order to investigate the clinical factors associated with a positive response to this treatment. METHODS: We analyzed 118 IgAN patients who underwent TSP. We collected patients' data retrospectively, including age, sex, blood pressure, onset of IgAN, pathological findings of a renal biopsy, serum concentration of creatinine, estimated glomerular filtration rate, serum concentration of protein, urinary protein, hematuria, past history of tonsillitis, the Yamamoto scale, the weight and pathological findings of the extracted palatine tonsils, and the presence or absence of anti-platelet drugs and renin-angiotensin system inhibitors (RAS-I) usage. This study included participants who were over 18 years of age, had undergone tonsillectomy within three months of steroid pulse therapy administered thrice, in whom renal biopsy was performed within a year before treatment, and with follow-up period of over 3 years. Clinical remission (CR) of urinary abnormalities was defined as remission of both proteinuria and hematuria: three consecutive negative results over a 6-month period, with a urinary sediment red blood cell count of <5/HPF, and a proteinuria qualitative reaction of (-) to (±). RESULTS: The CR rate of all cases was 56.8% and statistical significance was observed with respect to the C-Grade (P = 0.0003, P = 0.028) using both univariate and multivariate analysis. The CR rate of C-Grade І (73.4%) patients was significantly higher than that of C-Grade II patients (39.0%; P = 0.0004) and C-Grade III patients (30.8%; P = 0.003). We analyzed clinical factors in each C-Grade patient. No statistical significance was observed with respect to any of the factors using univariate analysis in C-Grade I patients. The weight of the extracted palatine tonsils and Yamamoto scale showed no statistical significance in every analysis. Fibrosis or hyalinization of the stroma of the palatine tonsils showed statistical significance (P = 0.026) only in the univariate analysis of C-Grade III patients. However, the patient number of C-Grade III was small. CONCLUSION: Our results indicate that TSP is mostly effective in patients with of C-Grade I IgAN and that the C-Grade reflects the clinical indication for TSP. The weight of the extracted palatine tonsils and Yamamoto scale did not show obvious correlations with the clinical effect of TSP.

Electrophysiological relation between the superior vena cava and right superior pulmonary vein in patients with paroxysmal atrial fibrillation.

INTRODUCTION: The superior vena cava (SVC) is a main source of nonpulmonary vein (PV) ectopies initiating atrial fibrillation (AF). Empiric SVC isolation may improve rhythm outcomes after catheter ablation of AF. Because the SVC passes immediately adjacent to the right superior PV (RSPV), an electrophysiological relation could be present between the two structures. The present study aimed to estimate the interrelation between the SVC and RSPV by evaluating arrhythmogenic activities observed during catheter ablation of AF. METHODS AND RESULTS: Study subjects comprised 121 consecutive patients referred for catheter ablation of paroxysmal AF. Isoproterenol infusion was used to induce ectopies and AF. Patients were divided into two groups depending on the presence of arrhythmogenic SVC: arrhythmogenic-SVC (A-SVC) and nonarrhythmogenic SVC (Non-A-SVC) groups. The prevalence of females was higher and body surface area was smaller in the A-SVC group (N = 22) than Non-A-SVC group (N = 99). Arrhythmogenic activities were observed in 60 (49%) RSPVs, 24 (20%) right inferior PVs, 72 (59%) left superior PVs, and 31 (25%) left inferior PVs. Arrhythmogenic RSPVs were more prevalent in the A-SVC group than Non-A-SVC group (86% vs. 41%, P = 0.0001), whereas these prevalences in the other three PVs were not different between groups (P >0.3). In multivariable analysis, arrhythmogenic RSPV was the only independent predictor of arrhythmogenicity of the SVC (OR, 8.53; 95% CI 2.31-31.46; P = 0.001). CONCLUSIONS: An electrophysiological interrelation may be present between the SVC and RSPV in patients with paroxysmal AF. Semiempiric SVC isolation limited to patients with an arrhythmogenic RSPV may be a more efficient treatment strategy.

Iron overload patients with unknown etiology from national survey in Japan.

Transfusion is believed to be the main cause of iron overload in Japan. A nationwide survey on post-transfusional iron overload subsequently led to the establishment of guidelines for iron chelation therapy in this country. To date, however, detailed clinical information on the entire iron overload population in Japan has not been fully investigated. In the present study, we obtained and studied detailed clinical information on the iron overload patient population in Japan. Of 1109 iron overload cases, 93.1% were considered to have occurred post-transfusion. There were, however, 76 cases of iron overload of unknown origin, which suggest that many clinicians in Japan may encounter some difficulty in correctly diagnosing and treating iron overload. Further clinical data were obtained for 32 cases of iron overload of unknown origin; median of serum ferritin was 1860.5 ng/mL. As occurs in post-transfusional iron overload, liver dysfunction was found to be as high as 95.7% when serum ferritin levels exceeded 1000 ng/mL in these patients. Gene mutation analysis of the iron metabolism-related genes in 27 cases of iron overload with unknown etiology revealed mutations in the gene coding hemojuvelin, transferrin receptor 2, and ferroportin; this indicates that although rare, hereditary hemochromatosis does occur in Japan.

A Single Amino Acid Mutation Converts (R)-5-Diphosphomevalonate Decarboxylase into a Kinase.

The biosynthesis of isopentenyl diphosphate, a fundamental precursor for isoprenoids, via the mevalonate pathway is completed by diphosphomevalonate decarboxylase. This enzyme catalyzes the formation of isopentenyl diphosphate through the ATP-dependent phosphorylation of the 3-hydroxyl group of (R)-5-diphosphomevalonate followed by decarboxylation coupled with the elimination of the 3-phosphate group. In this reaction, a conserved aspartate residue has been proposed to be involved in the phosphorylation step as the general base catalyst that abstracts a proton from the 3-hydroxyl group. In this study, the catalytic mechanism of this rare type of decarboxylase is re-investigated by structural and mutagenic studies on the enzyme from a thermoacidophilic archaeon Sulfolobus solfataricus The crystal structures of the archaeal enzyme in complex with (R)-5-diphosphomevalonate and adenosine 5'-O-(3-thio)triphosphate or with (R)-5-diphosphomevalonate and ADP are newly solved, and theoretical analysis based on the structure suggests the inability of proton abstraction by the conserved aspartate residue, Asp-281. Site-directed mutagenesis on Asp-281 creates mutants that only show diphosphomevalonate 3-kinase activity, demonstrating that the residue is required in the process of phosphate elimination/decarboxylation, rather than in the preceding phosphorylation step. These results enable discussion of the catalytic roles of the aspartate residue and provide clear proof of the involvement of a long predicted intermediate, (R)-3-phospho-5-diphosphomevalonate, in the reaction of the enzyme.

PIEZO1 gene mutation in a Japanese family with hereditary high phosphatidylcholine hemolytic anemia and hemochromatosis-induced diabetes mellitus.

Hereditary xerocytosis (HX) or dehydrated hereditary stomatocytosis (DHS) [OMIM 194380], in which PIEZO1 gene mutation has recently been identified, is difficult to diagnose. We report here the discovery of a PIEZO1 gene mutation in a Japanese family (father, daughter, and son) who were previously diagnosed with hereditary high phosphatidylcholine hemolytic anemia (HPCHA). All of the affected family members had non-spherocytic hemolytic anemia associated with severe hemochromatosis-related diabetes mellitus. Although the causative correlation between HPCHA and PIEZO1-gene mutated HX/DHS remains to be clarified, our findings raise an important question as to whether any of the HPCHA cases previously diagnosed in Japan may have in fact been the form of hemolytic anemia known as HX/DHS with PIEZO1 gene mutation.

In Vivo Formation of the Protein Disulfide Bond That Enhances the Thermostability of Diphosphomevalonate Decarboxylase, an Intracellular Enzyme from the Hyperthermophilic Archaeon Sulfolobus solfataricus.

UNLABELLED: In the present study, the crystal structure of recombinant diphosphomevalonate decarboxylase from the hyperthermophilic archaeon Sulfolobus solfataricus was solved as the first example of an archaeal and thermophile-derived diphosphomevalonate decarboxylase. The enzyme forms a homodimer, as expected for most eukaryotic and bacterial orthologs. Interestingly, the subunits of the homodimer are connected via an intersubunit disulfide bond, which presumably formed during the purification process of the recombinant enzyme expressed in Escherichia coli. When mutagenesis replaced the disulfide-forming cysteine residue with serine, however, the thermostability of the enzyme was significantly lowered. In the presence of ß-mercaptoethanol at a concentration where the disulfide bond was completely reduced, the wild-type enzyme was less stable to heat. Moreover, Western blot analysis combined with nonreducing SDS-PAGE of the whole cells of S. solfataricus proved that the disulfide bond was predominantly formed in the cells. These results suggest that the disulfide bond is required for the cytosolic enzyme to acquire further thermostability and to exert activity at the growth temperature of S. solfataricus. IMPORTANCE: This study is the first report to describe the crystal structures of archaeal diphosphomevalonate decarboxylase, an enzyme involved in the classical mevalonate pathway. A stability-conferring intersubunit disulfide bond is a remarkable feature that is not found in eukaryotic and bacterial orthologs. The evidence that the disulfide bond also is formed in S. solfataricus cells suggests its physiological importance.

Biochemical staging of the chronic hepatic lesions of Wilson disease.

BACKGROUND: Copper toxicity steadily affects the livers of patients with Wilson disease. However, the toxic effect of copper on serum aspartate and alanine aminotransferase levels remains to be clarified as a prerequisite for diagnostic tests. The clinical records of 33 cases were analyzed to clarify the natural history of Wilson disease. Phenotypes were simplified into hepatic, acute, and neurologic. The bio-low stage of both enzymes was less than 40 IU/L, the bio-moderate stage was intermediate between 40 and 200 IU/L, and the bio-high stage was more than 200 IU/L of either or both enzymes. Rebounded enzyme levels at the recovery period from anemia were presumed to be the chronic baselines when pre-anemic enzyme levels were not available in the acute phenotype. We investigated whether these enzyme levels may provide information useful for screening patients. The natural history of chronic Wilson disease consisted of the first increasing and second decreasing phases. The clinical courses of a 4-year-old boy and 12-year-old girl were representative of the 2 phases, respectively. All but one patient were in the decreasing phase. Negative correlations were obtained between age and enzyme level in the decreasing phase. The hepatic phenotype may be a prototype found throughout the 2 phases, and acute and neurologic phenotypes may be major complications in the bio-moderate and bio-low stages of the decreasing phase, respectively. Biochemical staging may provide a better understanding of Wilson disease when combined with phenotypes. Bio-high stage patients should be referred to a medical center for diagnosis.

Prognosis of myocardial infarction with left ventricular dysfunction in the coronary revascularization era.Subanalysis of the Japanese Coronary Artery Disease (JCAD) Study.

BACKGROUND: Indications of implantable cardioverter-defibrillator (ICD) for patients with an old myocardial infarction (OMI) and left ventricular dysfunction (LVD) were expanded in Western countries after the results of MADIT II. However, the prognosis of OMI patients with LVD and the merits of prophylactic implantation of ICD, based on evidence in Japan, have not yet been clarified. This subanalysis of the Japanese Coronary Artery Disease (JCAD) Study focused on MADIT II-compatible patients to clarify the prognosis of OMI patients with LVD in Japan. METHODS AND RESULTS: Consecutive 6,868 OMI patients were prospectively followed up for 3 years or until clinical events occurred. 291 patients had left ventricular ejection fraction (LVEF) ≤30%. Clinical events, congestive heart failure, cardiopulmonary arrest on arrival and vascular events were significantly more frequent in patients with LVEF ≤30% than in those with better LVEF. In the LVEF ≤30% group, cardiopulmonary arrest on arrival comprised 33% of all-cause deaths, and the survival curves at 2 years of the LVEF ≤30% group were almost compatible with those of the MADIT II ICD group. CONCLUSIONS: In this subanalysis, LVD was less frequent than in Western countries. The annual death rate in JCAD was better than for the MADIT II ICD group. The prophylactic use of ICD seemed to be less effective than in Western countries but still expected to be useful for OMI patients with LVD in Japan.

(R)-mevalonate 3-phosphate is an intermediate of the mevalonate pathway in Thermoplasma acidophilum.

The lack of a few conserved enzymes in the classical mevalonate pathway and the widespread existence of isopentenyl phosphate kinase suggest the presence of a partly modified mevalonate pathway in most archaea and in some bacteria. In the pathway, (R)-mevalonate 5-phosphate is thought to be metabolized to isopentenyl diphosphate via isopentenyl phosphate. The long anticipated enzyme that catalyzes the reaction from (R)-mevalonate 5-phosphate to isopentenyl phosphate was recently identified in a Cloroflexi bacterium, Roseiflexus castenholzii, and in a halophilic archaeon, Haloferax volcanii. However, our trial to convert the intermediates of the classical and modified mevalonate pathways into isopentenyl diphosphate using cell-free extract from a thermophilic archaeon Thermoplasma acidophilum implied that the branch point intermediate of these known pathways, i.e. (R)-mevalonate 5-phosphate, is unlikely to be the precursor of isoprenoid. Through the process of characterizing the recombinant homologs of mevalonate pathway-related enzymes from the archaeon, a distant homolog of diphosphomevalonate decarboxylase was found to catalyze the phosphorylation of (R)-mevalonate to yield (R)-mevalonate 3-phosphate. The product could be converted into isopentenyl phosphate, probably through (R)-mevalonate 3,5-bisphosphate, by the action of unidentified T. acidophilum enzymes fractionated by anion-exchange chromatography. These findings demonstrate the presence of a third alternative "Thermoplasma-type" mevalonate pathway, which involves (R)-mevalonate 3-phosphotransferase and probably both (R)-mevalonate 3-phosphate 5-phosphotransferase and (R)-mevalonate 3,5-bisphosphate decarboxylase, in addition to isopentenyl phosphate kinase.

A male patient with ferroportin disease B and a female patient with iron overload similar to ferroportin disease B.

Reticuloendothelial iron overload is associated with secondary hemochromatosis including repeated transfusions and iron over-supplementation. Ferroportin disease B is a severe subtype of hereditary iron overload syndrome with an activated reticuloendothelial system. The iron exporter ferroportin may be insensitive to hepcidin 25 in this subtype. However, the interactions between the hepcidin-ferroportin system and modifiers of reticuloendothelial iron overload have not yet been elucidated. We describe two patients with iron overload conditions that were compatible with ferroportin disease B, but their genetic backgrounds and habitual states differed. Both patients had diabetes, periportal fibrosis with severe iron deposits in their hepatocytes and Kupffer cells, and adequate levels of circulating hepcidin 25. However, the first patient was heterozygous for a mutation in the FP gene and free from the acquired factors of iron overload, while the second patient was a heavy drinker with a heterozygous mutation in the TFR2 gene and no mutations in the FP gene. The first patient was the second reported case of ferroportin disease B in Japan. Our study on these 2 patients suggests that liver fibrosis associated with compound iron overload of reticuloendothelial cells and hepatocytes may occur via multi-etiological backgrounds.

Various copper and iron overload patterns in the livers of patients with Wilson disease and idiopathic copper toxicosis.

Wilson disease (WD) is a major type of primary copper toxicosis associated with hypoceruloplasminemia, while idiopathic copper toxicosis (ICT) is a minor type characterized by normoceruloplasminemia. Because ceruloplasmin is the major circulating ferroxidase, iron metabolism may be affected in patients with WD. Biopsied liver specimens obtained from patients with primary copper toxicosis were fixed with glutaraldehyde solution and embedded in epoxy resin. Ultrathin sections that had or had not been stained with uranyl acetate solution were examined under an electron microscope equipped with an energy dispersive X-ray analyzer. A 7-year-old boy with WD was free from any metal overloading at the pre-treatment stage. Pre-treatment liver specimens of another 16 patients showed a variety of copper and iron overload patterns, from isolated copper to evenly distributed combined overloading. A 19-year-old female patient was free from any metal overloading after 7 years of treatment. Post-treatment overloading in another 6 patients ranged between evenly distributed combined patterns and isolated iron patterns. All patients had hypoceruloplasminemia throughout treatment periods. A patient with normoceruloplasminemic ICT continued to display isolated copper overloading after 2.5 years of treatment. In conclusion, these observations support the hypothesis that iron accumulates in patients with hypoceruloplasminemia.

Association of puppies' behavioral reaction at five months of age assessed by questionnaire with their later 'Distraction' at 15 months of age, an important behavioral trait for guide dog qualification.

Guide dogs help visually impaired persons both physically and psychologically. More than half of all candidate dogs do not qualify, mainly for behavioral reasons. Improved training efficacy is desirable, and earlier prediction of qualification-related traits would be beneficial. In a previous study, we identified 'Distraction', assessed during the training period, as an important behavioral trait for judging the qualification of guide dogs at the Japan Guide Dog Association. As a second step, we aimed to develop an index that can predict during the puppy period. In this study, candidate guide dogs, 5-month-old Labrador retrievers, were assessed by puppy raisers using a newly developed questionnaire that consisted of 20 items. The same dogs were assessed later, at 15 months, by trainers to determine 'Distraction'. In principal components analysis, nine items, including excitability toward strangers, initiative while out for a walk, and exploration, composed the first principal component (PC1). When we compared PC1 points with 'Distraction' points, the two categories were positively correlated (n=110, r(s)=0.31, P=0.0009). Although the accuracy of the questionnaire should be increased, the results of the present study suggest that it may be possible to assess and predict 'Distraction', which is associated with disqualification for guide dogs, early in the puppy-raising period.

Clinicopathological study of Japanese patients with genetic iron overload syndromes.

In addition to hemochromatosis, aceruloplasminemia and ferroportin disease may be complicated by iron-induced multiple organ damage. Therefore, clinicopathological features should be evaluated in a wider range of genetic iron disorders. This study included 16 Japanese patients with genetic iron overload syndromes. The responsible genes were CP in four, HAMP in one, HJV in three, TFR2 in five, and SLC40A1 in three patients. No phenotype dissociation was observed in patients with the CP, TFR2, or HAMP genotypes. Two of the three patients with the HJV genotype displayed classic hemochromatosis instead of the juvenile type. Patients with the SLC40A1 genotype were affected by mild iron overload (ferroportin A) or severe iron overload (ferroportin B). Transferrin saturation was unusually low in aceruloplasminemia patients. All patients, except those with ferroportin disease, displayed low serum hepcidin-25 levels. Liver pathology showed phenotype-specific changes; isolated parenchymal iron loading in aceruloplasminemia, periportal fibrosis associated with heavy iron overload in both parenchymal and Kupffer cells of ferroportin B, and parenchyma-dominant iron-loading cirrhosis in hemochromatosis. In contrast, diabetes occurred in all phenotypes of aceruloplasminemia, hemochromatosis, and ferroportin disease B. In conclusion, clinicopathological features were partially characterized in Japanese patients with genetic iron overload syndromes.

Liver structures of a patient with idiopathic copper toxicosis.

This is the first report describing the liver structures of a Japanese patient with idiopathic copper toxicosis, which should be differentiated from hepatolenticular degeneration of Wilson disease. An 11-year-old Japanese boy presented with ascites associated with biochemical liver damage. Involvement of hepatitis virus was ruled out by laboratory tests. Because urinary copper excretion was increased, Wilson disease was highly suspected, but the serum level of ceruloplasmin was normal, and Kayser-Fleischer rings were not detected by slit lamp examination. Brain images were within normal limits. ATP7B analysis was negative for mutations. Liver specimen showed cirrhosis associated with chronic active hepatitis. Almost all hepatocytes were positive for orcein-stained granules. Mallory bodies were found in some hepatocytes. Fatty change was minimal, and there were no glycogenated nuclei in the parenchyma. Combined regimens of trientine and zinc for 6 months improved the decompensated state of liver function. After 2.5 years of treatment, a second liver biopsy was performed. The post-treatment liver showed complete disappearance of portal inflammation and remarkable decrease in cuprothionein granules. Mallory bodies disappeared from the parenchyma. An abundance of hepatocellular Mallory bodies and heavy copper loading limited to the liver may be specific to idiopathic copper toxicosis.

Identification of a novel mutation in the HAMP gene that causes non-detectable hepcidin molecules in a Japanese male patient with juvenile hemochromatosis.

Hepcidin is an iron-regulatory hepatic peptide hormone encoded by the HAMP gene that downregulates iron export from enterocytes and macrophages into the blood plasma. In this study, we identified a novel mutation in the HAMP gene of a 58-year-old Japanese male patient with hemochromatosis. By direct sequencing of the five hereditary hemochromatosis-related genes, HFE, HAMP, HJV, TFR2, and SLC40A1, the previously unreported p.R75X mutation was identified, and the patient was found to be homozygous for the mutation. No other potentially pathogenic mutations were detected. In an LC-MS/MS analysis, hepcidin molecules were not detected in the patient's serum or urine. These results indicate that the p.R75X mutation causes iron overload by impairing the hepcidin system.