The origin and spread of the HFE-C282Y haemochromatosis mutation.

The mutation responsible for most cases of genetic haemochromatosis in Europe (HFE C282Y) appears to have been originated as a unique event on a chromosome carrying HLA-A3 and -B7. It is often described as a "Celtic mutation"--originating in a Celtic population in central Europe and spreading west and north by population movement. It has also been suggested that Viking migrations were largely responsible for the distribution of this mutation. Two, initial estimates of the age of the mutation are compatible with either of these suggestions. Here we examine the evidence about HFE C282Y frequencies, extended haplotypes involving HLA-A and -B alleles, the validity of calculations of mutation age, selective advantage and current views on the relative importance of "demic-diffusion" (population migration) and "adoption-diffusion" (cultural change) in the neolithic transition in Europe and since then. We conclude that the HFE C282Y mutation occurred in mainland Europe before 4,000 BC.

Tumour necrosis factor alpha and its promoter polymorphisms' role in the phenotypic expression of hemochromatosis.

BACKGROUND: The majority of hemochromatosis patients are homozygous for the HFE-C282Y mutation. However, less than half of C282Y homozygous subjects identified by population screening studies actually develop the disease. The cytokine TNF-alpha is implicated in the regulation of iron metabolism at different levels. Our aim was to study the role of TNF-alpha and its promoter polymorphisms in the phenotypic expression of hemochromatosis in individuals with and without the C282Y mutation. METHODS: We studied 4 groups of 10 subjects each: (1) C282Y homozygotes without clinical hemochromatosis; (2) C282Y homozygotes with hemochromatosis; (3) secondary hemochromatosis (without C282Y mutation); and (4) controls. Groups were age-matched and sex-matched. Peripheral blood mononuclear cells (PBMC) were stimulated with lipopolysaccharide (LPS) and the release of TNF-alpha was measured. Additionally, the G/A polymorphisms at position -238 and -308 of the TNF-alpha, gene were determined by PCR and RFLP analysis in 178 hemochromatosis patients and 41 controls. RESULTS: TNF-alpha production from PBMC at 8 and 24 h after increasing concentrations of LPS stimulation were similar in the four groups. The prevalence of TNF-alpha polymorphisms was similar in patients and controls. The prevalences of cirrhosis, siderosis, median s-ferritin and median ALT values were similar in patients with and without the TNF-alpha polymorphisms. CONCLUSIONS: Neither TNF-alpha, released from PBMC nor the presence of TNF-alpha polymorphisms seem to be associated with disease manifestation in hemochromatosis.

Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection.

BACKGROUND/AIM: Previous studies have indicated that response to interferon therapy is inversely proportional to the amount of body iron stores. We have studied the relationship between serum ferritin, transferrin saturation, liver iron, presence of HFE-C282Y gene mutation and response to treatment in patients with chronic hepatitis C infection. METHODS: Two hundred and fifty-six naive, HCV-RNA positive patients (60% males, median age 38 years, range 21-70) were treated with interferon and ribavirin for 6 months. Iron indices and the presence of the C282Y mutation were measured. In 242 (94%) patients iron deposition were determined by Perls staining method. Patients with negative HCV-RNA at 6 months after the end of treatment were defined as sustained viral responders. RESULTS: Non-responders (n = 127) had significantly higher median s-ferritin values compared with sustained viral responders (130 microg/L vs. 75 microg/L P < 0.001). There was no difference in transferrin saturation among the two response groups. Only 23% (4/7) of patients with Perls grade 1 in liver biopsies responded to treatment vs. 54% (122/225) patients without iron deposition (P = 0.02), however, 10/13-non-responders had HCV genotype one. Two patients (0.8%) were homozygous for the C282Y mutation, 36 patients were heterozygous (14%). Among mutation carriers 26/38 achieved sustained response compared with 102/216 non-carriers (68% vs. 48%, P = 0.02). In a multivariate analysis s-ferritin (P = 0.030) and C282Y carrier status (P = 0.012) remained independent predict of sustained response. CONCLUSIONS: Raised s-ferritin values predicate non-response to interferon-ribavirin therapy in hepatitis C patients. Response rate in C282Y mutation carriers seems greater than in non-carriers.

HFE gene mutation (C282Y) and phenotypic expression among a hospitalised population in a high prevalence area of haemochromatosis.

BACKGROUND: Previous studies have shown that up to 0.5% of the Caucasian population is homozygous for the HFE gene C282Y mutation. High prevalence values have been reported in Northern Europe. To what extent the presence of this mutation is associated with overt clinical haemochromatosis is unclear. AIM: To determine the prevalence of the C282Y allele in a hospitalised population of an acute medical department, and study the phenotypic expression in the homozygotes. METHODS: Blood samples were obtained from 2027 hospitalised patients; 1900 Caucasians and 127 non-Caucasians. Serum iron, transferrin, and ferritin were measured at admission. The presence of the HFE gene mutation was determined by polymerase chain reaction based analysis. Follow up fasting blood samples were obtained from patients homozygous for the mutation. RESULTS: Fourteen of the 1900 Caucasian subjects (0.74%) were homozygous and 224 (11.8%) were heterozygous for the C282Y mutation, including 32 subjects (1.7%) who were compound heterozygous for the C282Y and H63D mutations. Ten of 14 (71%) homozygous patients displayed mild to moderate biochemical expression of haemochromatosis with a serum ferritin level <550 microg/l, two (14%) patients were "non expressing", and two of five in whom liver biopsies were carried out had cirrhosis, including one with advanced hepatocellular carcinoma. CONCLUSIONS: The prevalence of C282Y homozygosity in a hospitalised population was 0.74%. However, the majority of homozygous patients displayed mild to moderate biochemical expression. C282Y mutation screening may detect individuals that do not develop haemochromatosis. Transferrin saturation and ferritin, which are used as first line screening in haemochromatosis, may be highly unreliable in the presence of an inflammatory process.

The clinical expression of hemochromatosis in Oslo, Norway. Excessive oral iron intake may lead to secondary hemochromatosis even in HFE C282Y mutation negative subjects.

BACKGROUND: The prevalence of hereditary hemochromatosis in Norway is one of the highest reported in the world. However, the clinical presentation in patients with hemochromatosis in Norway seems to be different compared with recent studies elsewhere. The aim of this study was to investigate patients with hemochromatosis in one community hospital in Norway and to study the prevalence of the C282Y mutation. METHODS: One hundred and twenty patients were consecutively admitted to one medical department in Oslo. Serum transferrin and ferritin concentrations were measured in all patients, and a percutaneous liver biopsy was obtained in 108 of 120 (90%) patients. Stainable iron (Perls stain) in hepatocytes was graded from 0 to 4+ and fibrosis from 1 to 4. Genotyping for the C282Y and H63D mutation in the HFE gene was performed by PCR-RFLP. RESULTS: Forty-eight (40%) of the patients suffered from tiredness and astenia and 29 (24%) had typical arthropathy. Only 5 of 105 (4.5%) had biopsy confirmed cirrhosis and 5 had diabetes mellitus. Patients referred from a blood bank had significantly less symptoms and signs compared with other patients. Twenty-one of 120 (17.5%) patients were C282Y mutation negative. Seventeen (81%) of these patients (16 women and 1 man) had a history of extensive oral iron intake lasting from 5 to 50 years. When excluding those with extensive oral iron intake (n = 17), 92 of 103 (89%) were homozygous for the C282Y mutation, 7 (7%) were heterozygous including 3 compound heterozygous and 4 (4%) were mutation negative. CONCLUSIONS: Only a minority of our patients with hemochromatosis had a far advanced disease at the time of diagnosis (less than 5% had cirrhosis) and hemochromatosis in a majority of the C282Y mutation negative patients was associated with excessive oral iron intake for several years.

High prevalence of the hemochromatosis-associated Cys282Tyr HFE gene mutation in a healthy Norwegian population in the city of Oslo, and its phenotypic expression.

BACKGROUND: Previous studies have shown that 5%-10% of white subjects are heterozygous for the HFE gene C282Y mutation, which is associated with hemochromatosis. The aim of our study was to determine the prevalence of heterozygosity and homozygosity for the C282Y HFE gene mutation and its phenotypic expression in a group of healthy Norwegians. METHODS: Fasting blood samples were obtained from 505 unrelated hospital employees. Serum iron, transferrin, and serum ferritin were measured. Transferrin saturation was calculated. The presence of HFE gene mutation was determined with a polymerase chain reaction-based analysis. RESULTS: Two of the 505 subjects (0.4%) were homozygous and 75 (14.9%) were heterozygous for the C282Y mutation. Median serum ferritin among the heterozygotes was 59 microg/l, compared with 47 microg/l among individuals without the C282Y mutation (P = 0.12). Median transferrin saturation among the heterozygotes was 31%, compared with 24% among individuals without C282Y mutation (P < 0.001). Twenty-three individuals (4.6%) had a serum ferritin level > 200 microg/l. Eight of these (35%) had the C282Y mutation: two homozygotes and six heterozygotes. Transferrin saturation > 50% was observed in 25 individuals (5.0%). Twelve of these (48%) had the C282Y mutation; two were homozygotes and 10 heterozygotes. Only eight individuals (1.6%) had a transferrin saturation > 60%: one homozygote, five heterozygotes, and two individuals without mutation. CONCLUSIONS: Fifteen per cent of a healthy Norwegian population is heterozygous for the HFE gene mutation C282Y. This is among the highest reported prevalence values among healthy individuals. Half of the subjects with transferrin saturation greater than 50% were carriers of the C282Y mutation.

Skin injuries afflicting three oil workers following contact with calcium bromide and/or calcium chloride.

Calcium bromide brine is a highly concentrated aqueous solution of calcium bromide and calcium chloride. It is used extensively in the oil industry. This solution and its components are recognized as causes of skin injury and information is available from the manufacturers on their safe use and handling. Two patients who were injured following unprotected skin exposure to this solution and one patient who was injured following exposure to calcium chloride powder are reported. All sustained skin injuries characterised by an absence of pain and a delayed clinical appearance of the full extent of the injury. Furthermore healing was complicated by graft loss or was slow. Although organic bromine compounds are recognized as a cause of skin injuries, no previous reports of such injuries to humans secondary to calcium chloride or bromide exposure were found in the medical literature. Our experience with these patients is described.

Cranial fasciitis of childhood: an incidental finding of a lytic skull lesion.

We describe a case of cranial fascitis presenting as an incidental finding. A 2 1/2-year-old girl had skull radiographs performed after sustaining a minor head injury, which revealed a lytic skull lesion. We describe the salient features of the case and review the current literature of this rare benign inflammatory condition.

Familial adenomatous polyposis in a 5 year old child: a clinical, pathological, and molecular genetic study.

A girl aged 5 years 8 months presented with rectal bleeding; her father had had familial adenomatous polyposis (FAP) and a colectomy at the age of 23. Endoscopy showed extensive polyposis and she had a colectomy. The proband and her father had the common codon 1309 5 bp deletion APC mutation. This mutation predisposes to early onset of FAP, and consideration needs to be given to having molecular testing of at risk members of these families done in childhood.

[Circadian variations in the incidence of transient ischemic myocardial episodes during hospitalization for acute myocardial infarct]. / Variazioni circadiane nell'incidenza di episodi di ischemia miocardica transitoria nel periodo pre-dimissione dopo infarto miocardico acuto.

The aim of this research was to evaluate the incidence and circadian variation of episodes of transient myocardial ischemia in the predischarge period after acute myocardial infarction (AMI). One hundred and ninety patients were selected in stable clinical condition, 83 with inferoposterior AMI, 61 with anterior AMI, 12 with lateral AMI (34 patients with non Q AMI). The patients with unstable clinical course during the first 48 hours after admission were excluded. All patients underwent dynamic electrocardiography (Pathfinder 3 Reynolds Medicals) between the tenth and the fifteenth day of the in-hospital phase. Sixteen/190 patients showed ECG changes due to transient myocardial ischemia, with a length higher than 60 sec and with an interval between episodes higher than 60 sec. Ten patients had ST depression, 6 patients had ST elevation. In total, the ischemic episodes were 25, silent 21 and symptomatic 4, with incidence from 1 to 4 during 24 hours, with a length from 1 to 17 min (mean 8 min); mean heart rate increased during ischemic episodes. Seventeen/25 ischemic episodes occurred between the twelfth and the twenty-fourth hours. A follow-up of 15 +/- 3 months was carried-out: 1 patient died after reinfarction, 1 patient died of non cardiac cause, 6 patients showed unstable angina (in 4 of them myocardial revascularization procedure was performed), 8 patients were asymptomatic; on the contrary, 32/174 patients without episodes of myocardial ischemia presented cardiac events, with lesser incidence than ischemic patients (p < 0.01). This retrospective analysis showed higher evidence of episodes due to transient myocardial ischemia during the afternoon and evening hours in the in-hospital phase after AMI.(ABSTRACT TRUNCATED AT 250 WORDS)

[Experience with intravenous amiodarone in hyperkinetic supraventricular arrhythmias]. / Esperienze con amiodarone endovena in alcune aritmie ipercinetiche sopraventricolari.

The Authors tested the effectiveness of amiodarone hydrochloride i.v. in 50 cases of supraventricular hyperkinetic arrhythmias recently aroused. 50 patients, aged 41 to 85 years, with paroxysmal supraventricular tachycardia (PSVT, 21 cases), atrial flutter (7 cases) or fibrillation (22 cases) were treated with 4 mg/Kg of body weight of amiodarone i.v. over 2 min., followed by other 1500 mg/24 hours over 48 hours while amiodarone per os was started for antiarrhythmic prophylaxis; a 12 leads surface ECG and blood pressure were periodically recorded. The sinus rhythm was restored within 3 hours in every case of PSVT (100% of success), within 30 hours in 19 cases of atrial fibrillation (86% of success) and in 5 cases of atrial flutter (71% of success). A slowing down of ventricular frequency ranging from 15 to 40% occurred within 10 min. in case of failure of restoration of sinus rhythm; a slight and transient lengthening of P-R occurred in 1 case; no particular side effects nor noteworthy changes of blood pressure were observed. Amiodarone i.v. proved to be a very effective remedy, handy and well tolerated for the arrhythmias considered above.

[Idiopathic aneurysm of the left ventricle. Report of two cases and review of literature (author's transl)]. / Aneurisma idiopatico del ventricolo sinistro. Descrizione di due casi e rassegna della letteratura

Two cases of left ventricular aneurysm occurring in young patients (23 and 29 years respectively) are reported. Coronary arteriograms were normal. Pertinent literature was reviewed. About 70 cases of left ventricular aneurysm in patients under 35 years of age have been reported: approximately half of them are congenital. They include both diverticuli of the apex, as a part of a syndrome of congenital defects, and those, much rarer, following myocardial infarction in children with anomalous origin of coronary arteries. A few cases may be attributed to trauma or myocarditis. In 26 patients, including the two reported here, etiology was uncertain (idiopathic aneurysm of the left ventricle) in as much as malformation or an infectious disease might have been the underlying cause.