Coenzyme Q10 deficiency in patients with hereditary hemochromatosis.

AIM: Hereditary hemochromatosis (HH) is a group of inherited disorders that causes a slow and progressive iron deposition in diverse organs, particularly in the liver. Iron overload induces oxidative stress and tissue damage. Coenzyme Q10 (CoQ10) is a cofactor in the electron-transport chain of the mitochondria, but it is also a potent endogenous antioxidant. CoQ10 interest has recently grown since various studies show that CoQ10 supplementation may provide protective and safe benefits in mitochondrial diseases and oxidative stress disorders. In the present study we sought to determine CoQ10 plasma level in patients recently diagnosed with HH and to correlate it with biochemical, genetic, and histological features of the disease. METHODS: Plasma levels of CoQ10, iron, ferritin, transferrin and vitamins (A, C and E), liver tests (transaminases, alkaline phosphatase and bilirubin), and histology, as well as three HFE gene mutations (H63D, S654C and C282Y), were assessed in thirty-eight patients (32 males, 6 females) newly diagnosed with HH without treatment and in twenty-five age-matched normolipidemic healthy subjects with no HFE gene mutations (22 males, 3 females) and without clinical or biochemical signs of iron overload or liver diseases. RESULTS: Patients with HH showed a significant decrease in CoQ10 levels respect to control subjects (0.31 ±â€¯0.03 µM vs 0.70 ±â€¯0.06 µM, p < 0.001, respectively) independently of the genetic mutation, cirrhosis, transferrin saturation, ferritin level or markers of hepatic dysfunction. Although a decreasing trend in CoQ10 levels was observed in patients with elevated iron levels, no correlation was found between both parameters in patients with HH. Vitamins C and A levels showed no changes in HH patients. Vitamin E was significantly decreased in HH patients (21.1 ±â€¯1.3 µM vs 29.9 ±â€¯2.5 µM, p < 0.001, respectively), but no correlation was observed with CoQ10 levels. CONCLUSION: The decrease in CoQ10 levels found in HH patients suggests that CoQ10 supplementation could be a safe intervention strategy complementary to the traditional therapy to ameliorate oxidative stress and further tissue damage induced by iron overload.

Was the Last Ice Age dusty climate instrumental in spreading of the three "Celtic" diseases (hemochromatosis, cystic fibrosis and palmar fibromatosis)?

Cystic fibrosis, hereditary hemochromatosis and palmar fibromatosis are often described as "Celtic", based on their contemporary prevalence. The former two are among genetically defined disorders that seem to provide survival advantages to heterozygote individuals, while severe health problems happen in homozygote mutation carriers. Although palmar fibromatosis has no defined mutations, its prevalence has been linked to the prevalence of Y-Chromosome Haplogroup I that expanded after the Last Ice Age, thus making th distribution of all three "Celtic" diseases dependent on the global climate from 40 to 8 Kya. During the Last Ice Age, the global climate was dry and dark due to dust-laden atmosphere (20-25 times more than today). It has been postulated that skin pigmentation was related to insolation, UV protection and skin synthesis of vitamin D, so when our ancestors moved to Eurasia, individuals with pale skin became advantageous. Deficiency of vitamin D has several health consequences and some of them have been proposed by other authors as important for the spreading of cystic fibrosis mutations: rickets/osteomalacia; susceptibility to diarrheal diseases and tuberculosis and salt induced arterial hypertension. The here proposed link is between vitamin D deficiency and the anaemia of chronic disease that might have facilitated spreading of the hemochromatosis mutation. It seems plausible that the risk of health problems in the offspring of close relatives might have resulted in social taboos of consanguinity in Eurasian protosocieties. Ancient steam bath rituals seem linked to lower incidences of cystic fibrosis in several European populations, thus suggesting health protection in an arid, dusty climate of the last glaciation, that made CFTR mutations in heterozygote carriers less advantageous.

Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes.

INTRODUCTION AND AIM: We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. MATERIAL AND METHODS: We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. RESULTS: Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metacarpophalangeal joints, mean serum ferritin, elevated alanine aminotransferase, elevated aspartate aminotransferase, and mean iron removed; and significantly fewer mean blood pints/units donated. GNPAT p.D519G positivity was detected in 82 of 188 participants (43.6%). In a multivariable model for cirrhosis, there were four significant positive associations: age (10-y intervals) (odds ratio 2.2 [95% confidence interval 1.5, 3.3]); diabetes (3.3; [1.1, 9.7]); alcohol intake (14 g alcohol drinks/d) (1.5 [1.2, 1.8]); and iron removed, g (1.3 [1.2, 1.4]). There was no statistical evidence of two-way interactions between these variables. CONCLUSION: In conclusion, cirrhosis in HFE p.C282Y homozygotes is significantly associated with age, diabetes, daily alcohol intake, and iron removed by phlebotomy, taking into account the effect of other variables.

Haemochromatosis.

Haemochromatosis is defined as systemic iron overload of genetic origin, caused by a reduction in the concentration of the iron regulatory hormone hepcidin, or a reduction in hepcidin-ferroportin binding. Hepcidin regulates the activity of ferroportin, which is the only identified cellular iron exporter. The most common form of haemochromatosis is due to homozygous mutations (specifically, the C282Y mutation) in HFE, which encodes hereditary haemochromatosis protein. Non-HFE forms of haemochromatosis due to mutations in HAMP, HJV or TFR2 are much rarer. Mutations in SLC40A1 (also known as FPN1; encoding ferroportin) that prevent hepcidin-ferroportin binding also cause haemochromatosis. Cellular iron excess in HFE and non-HFE forms of haemochromatosis is caused by increased concentrations of plasma iron, which can lead to the accumulation of iron in parenchymal cells, particularly hepatocytes, pancreatic cells and cardiomyocytes. Diagnosis is noninvasive and includes clinical examination, assessment of plasma iron parameters, imaging and genetic testing. The mainstay therapy is phlebotomy, although iron chelation can be used in some patients. Hepcidin supplementation might be an innovative future approach.

Calcium Pyrophosphate Deposition Disease and Associated Medical Comorbidities: A National Cross-Sectional Study of US Veterans.

OBJECTIVE: Calcium pyrophosphate deposition disease (CPDD) is a common cause of acute and chronic arthritis, yet there are few large epidemiologic studies of CPDD. We sought to characterize CPDD in the national Veterans Affairs (VA) population. METHODS: Using data from the Department of VA Corporate Data Warehouse, patients with International Classification of Diseases, Ninth Revision, codes for CPDD seen at any VA medical center from 2010 through 2014 were matched by age and sex with control patients without CPDD. We used multivariate analysis to compare the prevalence and odds ratios (ORs) of various comorbidities, substance use, medication exposures, and arthroplasties among patients with and without CPDD. RESULTS: We identified 25,157 patients with CPDD, yielding a point prevalence of 5.2 per 1,000. The mean ± SD age was 68.1 ± 12.3 years, and 95% were male. The strongest positive associations with CPDD were hyperparathyroidism (OR 3.35 [95% confidence interval (95% CI) 2.96-3.79]), gout (OR 2.82 [95% CI 2.69-2.95]), osteoarthritis (OR 2.26 [95% CI 2.15-2.37]), rheumatoid arthritis (OR 1.88 [95% CI 1.74-2.03]), and hemochromatosis (OR 1.87 [95% CI 1.57-2.24]). Positive associations were also seen with higher odds for osteoporosis (OR 1.26 [95% CI 1.16-1.36]), hypomagnesemia (OR 1.23 [95% CI 1.16-1.30]), chronic kidney disease (OR 1.12 [95% CI 1.07-1.18]), and calcium supplementation (OR 1.15 [95% CI 1.06-1.24). Negative associations were seen with proton-pump inhibitors (OR 0.58 [95% CI 0.55-0.60]) and loop diuretics (OR 0.80 [95% CI 0.76-0.84]). CONCLUSION: Using a large national data set, we confirmed known associations with CPDD, provided support for positive associations with rheumatoid arthritis, hypomagnesemia, and osteoporosis, and suggested potential novel negative associations with commonly used medications.

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.

Gestational diabetes mellitus (GDM) in the Republic of Kosovo: a retrospective pilot study.

BACKGROUND: GDM is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy. Pregnancy causes some insulin resistance in all women, but only a few develop GDM. OBJECTIVE: To test the hypothesis that women with GDM have impaired regulation of blood iron storage and transport, decreased renal function due to decreased glomerular filtration rate and occurrence of urinary tract infection (UTI). STUDY DESIGN AND METHODS: Incidence of blood iron storage was investigated in n=30 pregnant kosovar women with GDM after mild of pregnancy and in n=30 pregnant women without GDM (years 2010-2012). RESULTS AND DISCUSSION: Baby weights, both systolic and diastolic BP, creatinine, albumin, lymphocytes, monocytes, WBC and granulocytes in both groups were within their normal ranges in both groups. Compared to control group, glucose was higher in women with GDM (mean +/- SD: 7.43 +/- 2.23 mg/dL vs. 4.33 +/- 0.63 mg/dL; P < 0.001). Women with GDM had also higher RBC (mean +/- SD: 4.4 +/- 0.8% vs. 3.8 +/- 0.3%; P < 0.005) and HGB (mean +/- SD: 13.0 +/- 3.2 g/dL vs. 11.2 +/- 1.4 mg/dL; P < 0.05), and decreased renal functionality (MDRD-GFR: 92.8 +/- 25.8 g/dL vs. 108.2 +/- 38.2 g/dL; P < .05). CONCLUSION: There is a potential association between iron status and GDM. The role of iron from diet and/or from supplementation in GDM pathogenesis needs still to be examined. In addition we have observed a decrease of glomerular filtration rate in women with GDM. Due to the lack of studies on the relationships between GDM and UTI, and to the retrospective design of the present investigation, it is difficult to establish whether UTI may be a GDM causal factor or a consequence of GDM symptoms, signs and/or of its correlated pathologies.

Iron chelation therapy in hereditary hemochromatosis and thalassemia intermedia: regulatory and non regulatory mechanisms of increased iron absorption.

Millions of people are affected by hereditary hemochromatosis (HH) and thalassemia intermedia (TI), the iron overloading disorders caused by chronic increases in iron absorption. Genetic factors, regulatory pathways involving proteins of iron metabolism, non regulatory molecules, dietary constituents and iron binding drugs could affect iron absorption and could lead to iron overload or iron deficiency. Chelators and chelating drugs can affect both iron absorption and excretion. Deferoxamine (DFO), deferiprone (L1) and the DFO/L1 combination therapies have been used effectively for reversing the toxic side effects of iron overload including cardiac and liver damage in TI and HH patients where venesection is contraindicated. Selected protocols using DFO, L1 and their combination could be designed for optimizing chelation therapy in TI and HH. The use of deferasirox (DFRA) in HH and TI could cause an increase in iron and other toxic metal absorption. Future treatments of HH and TI could involve the use of iron chelating and other drugs not only for increasing iron excretion but also for preventing iron absorption.

[Treatment approach of hepatocellular carcinoma in Spain. Analysis of 705 patients from 62 centers]. / Tratamiento del carcinoma hepatocelular en España. Análisis de 705 casos en 62 centros.

BACKGROUND AND OBJECTIVE: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis and its current situation in Spain is not well known. Therefore, a national registry was created to assess the characteristics of patients with de novo HCC. PATIENTS AND METHOD: Between 1/10/2008 and 31/1/2009, 62 centers reported the baseline demographic, clinical and tumor characteristics, the first choice of treatment and eligibility for transplantation (OLT) of HCC diagnosed during this time. RESULTS: There were 705 new cases of HCC, 78% men, mean age 65 years, 89% cirrhosis (58% Child-Pugh class A, 42% HCV, 30% alcohol). Only 334 cases (47%) were diagnosed by screening. The size of the main nodule and BCLC stage were significantly lower in the screening group than in the rest (p<0.001). The applicability of radical therapies (resection and percutaneous ablation) was significantly higher (47.5% versus 24.6%, p<0.001) as well as the evaluation for OLT (31% versus 12%, p<0.001). The screening did not differ according to gender (p=0.204) or age (<50 years, <65, <75, >75 years) (p=0.171). Chemoembolization was the most common treatment: initial tumors (46.4%), tumors >5 cm (15.7%), multifocal HCC (37.9%) and as a bridge to OLT (33%). CONCLUSION: The majority of HCC patients are diagnosed in Spain out of early detection programs, and this limits the chance for early diagnosis and effective therapy.

[Neonatal hemochromatosis: a neonate alloimmune disease].

Neonatal hemochromatosis (NH) is a rare disease which has been characterized as severe neonatal liver disease in association with extrahepatic siderosis in a distribution similar to that seen in HFE-associated hereditary hemochromatosis. The clinical presentation is severe liver dysfunction that could lead to intrauterine fetal death or the neonate death. The treatment is antioxidants, chelation or cocktail liver transplant. The prognosis is very bad with less than 40% survival. The etiology and pathogenesis are yet unknown. It has been considered to be a syndrome in which a number of primary etiologies, such as infection, genetic-metabolic disease and toxic insult, lead to a common phenotype. The common hypothesis now is that NH is a consequence of gestational alloimmune disease. The basis for this theory rests on the pattern of recurrence. Little direct evidence for an immune mechanism exists. The fact that high-dose intravenous immunoglobulin appears to lessen the severity, improve infant survival, but not prevent its recurrences, strengthens this idea. The authors present a twenty nine years old Bedouin woman, married with no children. Her bad obstetrical history included one first trimester spontaneous abortion, five intrauterine fetal death and one post partum death. The present review discusses the clinical and epidemiological characteristics of this disease, and focuses on the etiology and treatment.

[Hereditary hemochromatosis]. / Hemocromatose Hereditária.

Hereditary hemochromatosis is an inherited autosomal recessive disease, associated to a mutation in the recently described HFE gene, which is located on the short arm of chromosome 6. The product of this gene combines with the beta-2-microglobulin and the ferritin receptor, and regulates the iron absorption in the small intestine crypt cells. It is possible that the mutation may cause the increased iron uptake by the intestinal cells. The disease is very much common in men after the forties, and its expression is influenced by concomitant alcoholism, iron rich diet, oral and parenteral iron administration, menstrual blood loss or abnormal hemorrhages, blood donations, pregnancy, lactation, and iron malabsorption clinical conditions, like celiac disease. Many patients are asymptomatic, and the diagnosis may be suspected by hepatomegaly of unknown cause, abnormal iron metabolism tests, increased serum aminotransferase levels, diabetes mellitus, and anonymous arthropathy. Less commonly hereditary hemochromatosis presented by symptoms and signs of chronic liver disease, or by the classic triad described by Trousseau skin pigmentation, hepatomegaly and diabetes mellitus. The diagnosis is confirmed by the increased serum ferritin levels and transferrin saturation, and the stainable iron in hepatocytes, measured by scale devised by Scheuer et al, or the measurement of the hepatic iron. The C282Y mutation was found in 64 to 100% of patients; eventually, subjects with hepatic iron overload identical to hereditary hemochromatosis has no mutation, and homozygous for the C282Y mutation do not express iron overload. Iron is best and quickly removed by weekly or twice-weekly phlebotomy of 500 ml, containing approximately 250 mg iron. One to 3 years of weekly phlebotomy may be required to reduce stores to normal. As a guide to long-term maintenance therapy, is recommended phlebotomy every 3 months and the serum ferritin level should be maintained by less than 50 ng/ml.

A survey of 2,851 patients with hemochromatosis: symptoms and response to treatment.

PURPOSE: Hemochromatosis is a genetic disorder of iron absorption that affects 5 per 1,000 persons and is associated with reduced health and quality of life. We sought to determine the type and frequency of symptoms that patients experienced before the diagnosis and the treatments that they received. METHODS: We mailed a questionnaire to 3,562 patients with hemochromatosis who were located using patient advocacy groups, physicians, blood centers, newsletters, and the Internet. RESULTS: Of the 2,851 respondents, 99% were white and 62% were men. Circumstances that led to diagnosis of hemochromatosis included symptoms (35%), an abnormal laboratory test (45%), and diagnosis of a family member with hemochromatosis (20%). The mean (+/- SD) age of symptom onset was 41 +/- 14 years. Symptoms had been present for an average of 10 +/- 10 years before the diagnosis was made. Among the 58% of patients with symptoms, 65% had physician-diagnosed arthritis and 52% had liver disease. The most common and troublesome symptoms were extreme fatigue (46%), arthralgia (44%), and loss of libido (26%). Physician instructions to patients included treatment with phlebotomy (90%), testing family members (75%), and avoiding iron supplements (65%). CONCLUSIONS: The diagnosis of hemochromatosis in most patients was delayed. Physician education is needed to increase the detection of patients with the disease and to improve its management.

Everyone should be tested for iron disorders.

Routinely measuring iron status is necessary because about 6% of Americans have negative iron balance, about 10% have a gene for positive balance, and about 1% have iron overload. Deviations from normal iron status are as follows. (a) Stage I and II negative iron balance, ie, iron depletion: In these stages iron stores are low and there is no dysfunction. In stage I negative iron balance, reduced iron absorption produces moderately depleted iron stores. Stage II negative iron balance is characterized by severely depleted iron stores. More than half of all cases of negative iron balance fall into these two stages. When persons in these stages are treated with iron, they never develop dysfunction or disease. (b) Stage III and IV negative iron balance, ie, iron deficiency: Iron deficiency is characterized by inadequate body iron for normal function, producing dysfunction and disease. In stage III negative iron balance, dysfunction is not accompanied by anemia; anemia develops in stage IV negative iron balance. (c) Stage I and II positive iron balance: Stage I positive balance usually lasts for several years with no dysfunction. Supplements of iron and/or vitamin C promote progression to dysfunction or disease. Iron removal prevents progression to disease. Iron overload disease develops in stage II positive iron balance after years of iron overload has caused progressive damage to tissues and organs. Again, iron removal stops disease progression. There are a variety of indicators of iron status. Serum ferritin is in equilibrium with body iron stores.(ABSTRACT TRUNCATED AT 250 WORDS)

Iron disorders can mimic anything, so always test for them.

Routinely measuring iron status is necessary because not only are about 6% of Americans in significant negative iron balance, but about 1% have iron overload. Serum ferritin is in equilibrium with body iron stores, and is the only blood test that measures them. Barring inflammation, each one ng (0.0179 pmol) ferritin/ml of serum indicates approximately 10 mg (0.179 mmol) of body iron stores. Very early Stage I positive balance is best recognized by measuring saturation of iron binding capacity. Conversely, serum ferritin best recognizes early (Stage I and II) negative balance. Deviations from normal are: 1. Both stages of iron depletion (i.e. low stores, no dysfunction). Negative iron balance Stage I is reduced iron absorption producing moderately depleted iron stores. Stage II is severely depleted stores, without dysfunction. These stages include over half of all cases of negative iron balance. Treated with iron, they never progress to dysfunction, i.e. to disease. 2. Both stages of iron deficiency. Deficiency is inadequate iron for normal function, i.e. dysfunction, disease. Negative balance Stage III is dysfunction without anemia; Stage IV is with anemia. 3. Positive iron balance: Stage I is a multi-year period without dysfunction. Supplements of iron and/or vitamin C promote progression to dysfunction (disease). Iron removal prevents progression. Stage II is iron overload disease, encompassing years of insidiously progressive damage to tissues and organs from iron overload. Iron removal arrests progression.

Hemochromatosis and dietary iron supplementation: implications from US mortality, morbidity, and health survey data.

Trends in the mortality rates, morbidity rates, and hematologic screening parameters for hemochromatosis in the United States over the past 20 years were examined to assess whether dietary iron supplementation is a precipitating factor for hemochromatosis. From 1968 through 1987, there was an increase in the overall hemochromatosis mortality rates attributable to white women. From 1979 through 1987, the hospitalization rates for hemochromatosis ranged from 4 to 13 per 100,000 persons in Medicaid data (1984) and the National Hospital Discharge Survey (1979-1987) and are similar to estimates in the literature from 1955. Although the iron nutritional status of persons under 55 years of age increased from the first to the second National Health and Nutrition Examination Survey, there was no corresponding increase at the 95th percentile in the hemochromatosis screening parameters--serum iron concentration and transferrin saturation. A hypothetical scenario was used to examine the progression from homozygous gene frequency to phenotypic expression. It is concluded that clinical hemochromatosis is rarer than prevalence estimates of 100 to 500 per 100,000 persons predicted by gene frequency. In addition, there is no strong evidence of an increase in hemochromatosis from mortality, morbidity, or health survey data, which implies that dietary iron supplementation begun in 1940 has not accelerated manifestations of hemochromatosis. Any increase in hemochromatosis since iron fortification can probably be attributed to accuracy in diagnosis and enhanced awareness of the disease by physicians rather than to environmental factors.