A Revised Classification of Primary Iron Overload Syndromes.

Background and Aims: The clinical introduction of hepcidin25 (Hep25) has led to a more detailed understanding of its relationship with ferroportin (FP) and divalent metal transporter1 in primary iron overload syndromes (PIOSs). In 2012, we proposed a classification of PIOSs based on the Hep25/FP system, which consists of prehepatic aceruloplasminemia, hepatic hemochromatosis (HC), and posthepatic FP disease (FP-D). However, in consideration of accumulated evidence on PIOSs, we aimed to renew the classification. Methods: We reviewed the 2012 classification and retrospectively renewed it according to new information on PIOSs. Results: Iron-loading anemia was included in PIOSs as a prehepatic form because of the newly discovered erythroferrone-induced suppression of Hep25, and the state of traditional FP-D was remodeled as the BIOIRON proposal. The key molecules responsible for prehepatic PIOSs are low transferrin saturation in aceruloplasminemia and increased erythroferrone production by erythroblasts in iron-loading anemia. Hepatic PIOSs comprise four genotypes of HC, in each of which the synthesis of Hep25 is inappropriately reduced in the liver. Hepatic Hep25 synthesis is adequate in posthepatic PIOSs; however, two mutant FP molecules may resist Hep25 differently, resulting in SLC40A1-HC and FP-D, respectively. PIOS phenotypes are diagnosed using laboratory tests, including circulating Hep25, followed by suitable treatments. Direct sequencing of the candidate genes may be outsourced to gene centers when needed. Laboratory kits for the prevalent mutations, such as C282Y, may be the first choice for a genetic analysis of HC in Caucasians. Conclusions: The revised classification may be useful worldwide.

Intravascular lymphoma masquerading as septic shock.

Intravascular lymphoma (IVL) is a rare type of extranodal lymphoma that selectively affects small blood vessels. We report a patient who presented with dyspnea and weight loss as well as refractory shock and multiple-organ dysfunction. The postmortem revealed disseminated involvement of an IVL but no evidence of infection.

A 10-year Follow-up Study of a Japanese Family with Ferroportin Disease A: Mild Iron Overload with Mild Hyperferritinemia Co-occurring with Hyperhepcidinemia May Be Benign.

This is a 10-year follow-up study of a family with ferroportin disease A. The proband, a 59-year-old man showed no noteworthy findings with the exception of an abnormal iron level. The proband's 90-year-old father showed reduced abilities in gait and cognition; however, with the exception of his iron level, his biochemistry results were almost normal. Brain imaging showed age-matched atrophy and iron deposition. In both patients, the serum levels of ferritin and hepcidin25, and liver computed tomography scores declined over a 10-year period. These changes were mainly due to a habitual change to a low-iron diet. The iron disorder in this family was not associated with major organ damage.

Phenotypes and Chronic Organ Damage May Be Different among Siblings with Wilson's Disease.

Background and Aims: Cloning of ATP7B provided evidence that Wilson's disease is a hepatic copper toxicosis with a variety of extrahepatic complications. Affected siblings with the same genetic background and exposure to similar environmental factors may be a good model for the study of genotype-phenotype correlation. Methods: Twenty-three affected siblings in 11 families were selected from a database. The first phenotypes were determined according to the international proposal. The final types of chronic organ damage were re-evaluated for life-long management. Results: Phenotypes were identical in 5 of the families and different in 6 of the families. The acute hepatic phenotype H1 was found in 3 younger siblings and 1 older sibling. All survived an acute episode of hemolysis with underlying chronic liver disease. One also presented complication with neurological disease. The neurological phenotype N1 with neuropsychiatric symptoms and hepatic disease was found in 2 aged siblings of 1 family, in an older sibling in 3 families and in the oldest sibling in 1 family. Phenotypes in siblings were mainly split by either H1 occurring in random order or age-dependent N1. Types of chronic organ damage were identical in 8 of the families and different in 3 of the families. The same combination of chronic liver disease was found in 6 families and chronic liver disease complicated with neurological disease in 2 families. Split organ damage in siblings was found when an older sibling was complicated by neurological disease. There was no reverse combination of a younger sibling being complicated by neurological disease in any of the families. Conclusion: Phenotype combinations of siblings were mainly modified by externally-induced hemolytic episodes, while chronic organ damage in siblings was split by age-dependent neurological complications.

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.

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.

Potential of the international scoring system for the diagnosis of Wilson disease to differentiate Japanese patients who need anti-copper treatment.

AIM: Patients with Wilson disease show complex clinical features. Accurate diagnosis at the initial clinical manifestation is important for patients to receive effective treatment with anti-copper agents. In this study, we assessed whether the international scoring system for the diagnosis of Wilson disease is a reliable tool for screening Japanese patients with primary copper toxicosis requiring anti-copper treatment. METHODS: Twenty-three Japanese patients suspected of Wilson disease were enrolled in this study. We performed long-range polymerase chain reaction to detect ATP7B mutations in this series. Finally, we retrospectively assessed the reliability of using a diagnostic score of 4 or more points as the cut-off for this scoring system. RESULTS: Ten patients were homozygous or compound heterozygous for ATP7B mutations including a novel mutation of 3837 bp deletion including 3 exons. The mutation would have been missed by the traditional analysis. Six patients were heterozygous for ATP7B mutations. Three of these six patients had additional diagnostic points. The other three patients were diagnosed as carriers of a mutant gene based on their low scores. One of the seven patients free from ATP7B mutation was affected by copper toxicosis. Though the score was 3 points based on increased urinary copper and copper-positive cirrhosis, anti-copper treatment promptly improved liver failure, which was likely due to idiopathic copper toxicosis. CONCLUSION: The international scoring system for diagnosis of Wilson disease is a fairly reliable tool for screening Japanese patients who need anti-copper treatment. Caution is needed for patients with possible idiopathic copper toxicosis because the maximal score is 4 points.

Patients with chronic hepatitis C may be more sensitive to iron hepatotoxicity than patients with HFE-hemochromatosis.

AIM: In chronic hepatitis C, iron might play an important role as a hepatotoxic co-factor. Therefore, venesection, a standard treatment for hemochromatosis, has been proposed as an alternative for patients who respond poorly to anti-viral therapy. To improve our understanding of iron-induced hepatotoxicity, we compared the responses to venesection between patients with chronic hepatitis C and those with HFE-hemochromatosis. METHODS: Fourteen Japanese patients with chronic hepatitis C and eight Italian patients with HFE-hemochromatosis underwent repeated venesection with a serum ferritin endpoint of 20 and 50 ng/mL, respectively. Serum iron indices and liver function tests were measured in pre- and post treatment blood samples from each patient. Body iron stores were calculated using the removed blood volume. RESULTS: In both patients with hepatitis and hemochromatosis, serum ferritin, aminotransferase and hepcidin 25 were reduced after venesection. The serum aminotransferase activity, but not the serum ferritin level, was predictive of effective iron removal treatment. Hepcidin regulation was set at an inappropriately low level in hemochromatosis patients (11.1 ± 9.2 ng/mL), but not so in hepatitis patients (30.7 ± 14.5 ng/mL). Inversely, the estimated body iron stores of hemochromatosis patients were 5,960 ± 2,750 mg, while those of hepatitis patients were 730 ± 560 mg. Judging from the liver enzyme reduction ratio, patients with hepatitis seemed to be more sensitive to iron hepatotoxicity than hemochromatosis patients. CONCLUSION: Even though the threshold of iron hepatotoxicity and benefit of its removal differ between patients with chronic hepatitis C and those with HFE-hemochromatosis, venesection is a valid choice of treatment to reduce liver disease activity in both diseases.

Preliminary study of spontaneous hepatitis in Long-Evans Cinnamon rats: a blood exchange may improve fetal hepatitis.

Long-Evans Cinnamon rats are a Wilson disease model highly susceptible to fulminant hepatitis around the age of 20 weeks, and hepatoma over the age of one year. Although prophylaxis has been established for the otherwise fatal hepatitis, effective treatment remains unknown. A blood exchange was tested to determine whether the prognosis of spontaneous hepatitis could be modified in icteric female rats. When bilirubinuria appeared, the rats immediately underwent surgery. Rats under anesthesia were first cannulated into the right atrium via the carotid vein, followed by 2.5 mL of blood exchange with heparinized fresh blood from Long-Evans agouti rats. Treated rats and controls were then observed for 2 months. Compared to the 50% mortality of untreated rats, all icteric rats that received a blood exchange survived the acute episode. We confirmed that Wilson disease animals are highly susceptible to acute hepatitis and show a poor prognosis. However, a single blood exchange improved spontaneous hepatitis in this animal model. This would serve as a first step for establishing a treatment for fatal hepatitis in animals. A blood exchange may improve fulminant hepatitis of Wilson disease model rats.

Current state of Wilson disease patients in central Japan.

OBJECTIVE: This study evaluated the current state of patients with Wilson disease in central Japan. PATIENTS AND METHODS: Between 1999 and 2007, 30 patients were diagnosed as having Wilson disease with an International Diagnostic Score of 4 or more. The phenotypes, genotypes and post-diagnostic courses of these patients were analyzed. RESULTS: Twenty-six patients had ATP7B mutations responsible for Wilson disease. Four patients had a single mutant chromosome. There were 2 major mutations of 2333 G>T and 2871 delC (40%), and 6 novel mutations (13%) in our patients. The first clinical manifestation was the hepatic form in 22, neurological form in 5, and hemolysis in 3 patients. The hepatic form was diagnosed around the age of 13 years, followed by neurological complication with a time lag of 9 years. Thus, some patients, especially patients with the neurological form, did not undergo early diagnostic tests including ATP7B analysis. During the post-diagnosis period, 3 patients were hospitalized for recurrent liver disease, and 2 patients committed suicide. One female patient died from acute hepatic failure associated with encephalopathy after fertilization therapy, while 2 male patients recovered from encephalopathy-free, prolonged hepatic failure after noncompliance with drug therapy. The King's Scores for liver transplantation were below the cut-off in both cases. CONCLUSION: To minimize delayed diagnosis, ceruloplasmin determination and ATP7B analysis may be recommended to patients showing hepatic damage of unknown etiology. At gene diagnosis, appropriate management of patients including compliance education and emotional care to prevent suicide might be important.

Prevalence and clinical characterization of patients with acute hepatitis B induced by lamivudine-resistant strains.

BACKGROUND AND AIMS: Acute hepatitis caused by lamivudine (LMV)-resistant strains has not been reported, and the clinical impact of LMV-resistant strains on acute hepatitis is not known. The aim of this study was to investigate the molecular and clinical characteristics of patients with acute hepatitis B caused by LMV-resistant strains. METHODS: Forty-five patients with acute hepatitis B were studied. Hepatitis B virus (HBV) subgenotypes and LMV-resistance mutations were determined by direct sequencing of the preS and polymerase regions, respectively. RESULTS: HBV subgenotypes A2 (n = 18), B1 (n = 1), B2 (n = 3), B3 (n = 2), C1 (n = 1), C2 (n = 19) and C6 (n = 1) were detected in patients with acute hepatitis. LMV-resistance mutations were detected in two patients. LMV-resistance mutations (L180M, M204I) were detected in a patient with subgenotype C2 who had acute self-limited hepatitis. The other patient with LMV-resistance mutations (L180M, M204V) was infected with subgenotype A2 and had severe hepatitis. CONCLUSION: LMV-resistant strains are rare, but they are starting to be found in patients with acute hepatitis B. Surveillance for detecting drug-resistant HBV strains would be important for clinical practice.