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PubMed2004

Minor salivary gland biopsy in neonatal hemochromatosis.

BACKGROUND: Neonatal hemochromatosis (NH), a rare disorder seen in newborns, is defined as liver failure with extrahepatic iron deposition that spares the reticuloendothelial elements. This disorder is considered the pathologic end point of a variety of diseases that result in prenatal liver failure, and mortality without aggressive treatment is common. However, ready diagnosis remains a problem. A liver biopsy specimen showing siderosis is not specific for hemochromatosis and may be risky in patients with coagulopathy. OBJECTIVE: To describe a safe and effective method for diagnosing NH that uses lower-lip minor salivary gland biopsy and can be readily performed even in the most severe cases of coagulopathy under local anesthesia. METHODS: Eleven neonates with suspected NH were identified. After informed consent, a biopsy specimen of lower-lip tissue was taken under local anesthesia by the otolaryngology team. RESULTS: Ten of the 11 neonates had minor salivary gland tissue present (or detected) by initial frozen-section analysis. One of the 11 patients required a second biopsy owing to a lack of sufficient minor salivary gland tissue on the initial specimen, underscoring the importance of frozen-section analysis. Six of 7 neonates with NH had positive biopsy findings and the seventh had a false negative. There were 4 true negatives. Three of 7 children with NH survived, 1 requiring liver transplantation and 2 with medical treatment only. CONCLUSION: Minor salivary gland biopsy is a safe and effective way to quickly diagnose NH, a rapidly progressive, often fatal condition.

Biopsy↗

PubMed1999

Role of surgical biopsies in the management of bone marrow transplant patients.

BACKGROUND: Bone marrow transplantation (BMT) patients frequently develop life-threatening problems that have similar clinical presentations but differing aetiologies. Despite intensive investigation by haematological, biochemical, and microbiological means, accurate diagnosis is not always possible. Histological and microbiological examination of biopsies from the affected organ may be indicated to enable an accurate diagnosis to be made in these patients. Here we assess the indications, findings, and outcomes in patients who have required surgical biopsy after BMT. PROCEDURE: We retrospectively reviewed all BMT patients who had surgical biopsies between February 1994 and January 1997. Twenty-six patients (1-46 years, median age 10 years) underwent 40 biopsies from the upper and lower GI tract, lung, or liver. Indications for BMT were: relapsed leukaemia = 18; other types of leukaemia = 3; aplastic anaemia=3; other diseases = 2. Type of BMT: matched related donor = 3, unrelated T-cell depleted donor = 23. RESULTS: Eleven (42%) cases had a change in management; 4 (16%) patients avoided further aggressive therapy because of poor prognosis. Unexpected diagnoses were found in 7 biopsies: 1 acute colitis, 1 duodenal ulcer, 1 liver aspergilloma, 2 transfusion siderosis, 1 radiation fibrosis of the lung, and 1 cytomegalovirus infection of the lung. Three patients were noted to have complications after their procedure. CONCLUSIONS: Surgical biopsies for undiagnosed problems can be of benefit in the management of very sick patients who have received bone marrow transplantations. Despite the fact that these patients are so unwell, there is a low rate of complications related to surgery and anaesthesia.

Adolescent↗

PubMedDate not supplied

Lysosomal disruption in the pathogenesis of hepatic damage in primary and secondary haemochromatosis.

The disruption of lysosomes with release of their content of lytic enzymes was an early concept for the possible role of these organelles in the pathogenesis of tissue damage. Many examples are known of primary lysosomal storage diseases due to a congenital deficiency of certain acid hydrolases. It is suggested that iron overload due to either primary haemochromatosis or transfusional siderosis is a form of acquired secondary lysosomal storage disease. Subcellular fractionation experiments and electron microscopic studies have shown that liver tissue from patients with iron overload has iron-laden lysosomes. Similar results have been found in iron-overloaded rats. In patients, but not in experimental animals, enzymic analyses have shown increased activities of acid hydrolases and strikingly enhanced lysosomal fragility in liver homogenates. When it has been possible to deplete the patients of the excessive iron, these parameters have returned to normal. The possible mechanisms by which the iron compounds disrupt lysosomes, including distension with ferritin or haemosiderin or free-radical-mediated membrane damage, will be discussed.

Acetylglucosaminidase↗

PubMed1980

Occupational Health and Safety in the smelting and foundry industries in Mexico.

This paper reviews the epidemiological features of the accidents and illnesses in smelters and foundries affiliated with Instituto Mexicano del Seguro Social for the year 1977. The accident rate per 100 workers was 26, which was second to mining among all industries listed; this rate is almost double that for all factories as a whole, and the accidents tended to be more severe. In contrast, there was little reporting of occupational illnesses in smelters and foundries. There were only 29 illnesses with 20 resulting in permanent disability and one in death. The most common occupational illnesses were: acoustic trauma (50%), industrial bronchitis (20%), siderosis (10%), chemical and physical conjunctivitis (5%), and miscellaneous including poisonings (15%).

Accidents, Occupational↗

PubMed1980

Distribution of iron in the gastrointestinal tract of the common vampire bat: evidence for macrophage-linked iron clearance.

Iron in the tissues of the digestive tract of the common vampire bat (Desmodus rotundus) has been studied using histochemical, electron microscopic, and autoradiographic methods. This animal is an obligate sanguivore and has a daily intake of dietary iron 800 times that of man. The amount and distribution of tissue iron is not affected by either a single blood meal or starvation but does reflect the degree of siderosis of each animal's liver and spleen. By 7 days after the injection of a trace amount of 55Fe into the peritoneal cavity, labelled siderotic macrophages are present both on the serosa and within the walls of the stomach and intestine. In the lower intestine, such cells can be derived from the germinal centers of Peyer's patches. Siderotic macrophages are often situated in the lamina propria under areas of siderotic epithelium. Label is also present in the apical cytoplasm of mucosal epithelial cells, a region of abundant siderosomes. The ultrastructure of these organelles is extremely variable. Accumulations of membranous whorls and stacks, "stippled bodies," ferritin molecules, and larger "ferruginous" complexes are bounded by one or a number of membranes. Iron is excreted when these epithelial cells are desquamated into the gut lumen. Similar Prussian blue-positive granules are present in the feces. Unlike other glandular cells, the parietal cells of the fundic caecum are siderotic. Their cytoplasm contains abundant siderosomes and ferritin with accumulations of amembranous ferritin bodies in the intracellular canalicular spaces. Prussian blue-positive granules are present in the lumens of fundic glands.

Animals↗

PubMed1992

Saturability of hepatic iron deposits in genetic hemochromatosis.

The relationship of pretreatment serum ferritin and hepatic iron concentration to body iron removed by venesections was evaluated in 33 patients with genetic hemochromatosis. The median values of the three variables considered were 1,950 micrograms/L (range = 255 to 10,000), 1,175 micrograms/100 mg dry weight (range = 270 to 4,310) and 10 gm (range = 2 to 41), respectively. At basal liver biopsy 18 patients had cirrhosis, 6 patients had fibrosis and 9 patients had a normal pattern; siderosis was degree 3 in 6 patients and degree 4 in 27 patients. The results of fitting a polynomial regression of second degree showed that the curve of serum ferritin on iron removed was a straight line (R2 = 0.79, with a significant coefficient of linearity, p less than 0.01, and a nonsignificant coefficient of curvature), whereas that of hepatic iron concentration on iron removed showed a curvature (R2 = 0.62, with significant coefficient of linearity and curvature, p less than 0.01) and reached a plateau. The sigmoid model fit the curve of hepatic iron concentration on iron removed (R2 = 0.61), which suggested a saturation of hepatic iron storage capability; the asymptote corresponded to a hepatic iron concentration of about 2,000 micrograms/100 mg. In alcoholic patients (17 cases) the location of the sigmoid was greater than in nonalcoholic patients. Our results suggest that iron deposition occurs in the liver before other organs are involved and that with massive iron overload hepatic deposits reach saturation, after which hepatic iron concentration does not always reflect the amount of total stores. Alcohol consumption could slow the saturation of hepatic iron deposits.

Adult↗

PubMed1993

Hepatitis C virus antibodies and liver disease in patients with porphyria cutanea tarda.

The recent identification of the hepatitis C virus and development of assays to detect antibodies to hepatitis C virus has allowed assessment of the prevalence of hepatitis C virus infection in patients with a variety of liver and other diseases. The aim of this study was to investigate the prevalence of hepatitis C virus antibodies and severity of liver injury in patients with porphyria cutanea tarda. Sixty-two patients were studied. Serum samples were analyzed for liver function parameters and markers of hepatitis B virus infection. Frozen serum samples from 34 patients with porphyria cutanea tarda, obtained when patients were seen at the hospital for the first time, were analyzed for hepatitis C virus antibodies with enzyme-linked immunosorbent assays (first- and second-generation) and a recombinant immunoblot assay. As controls, serum samples from 19,788 blood donors, 40 patients with alcoholic liver disease and 138 hospitalized patients without liver disease were also tested for hepatitis C virus antibodies. Liver biopsy was performed in 42 porphyria cutanea tarda patients. Specimens were evaluated for steatosis, siderosis, fibrosis, severity of inflammation and the presence of cirrhosis. In addition, the degree of necroinflammatory change and fibrosis were quantitated with the histologic activity index described by Knodell et al. The prevalence of hepatitis C virus antibodies in patients with porphyria cutanea tarda (62%) was higher than that in blood donors (0.79%), patients with alcoholic liver disease (17.5%) or hospitalized patients without liver disease (5.8%).(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗

PubMed2004

Increased duodenal expression of divalent metal transporter 1 and iron-regulated gene 1 in cirrhosis.

Hepatic hemosiderosis and increased iron absorption are common findings in cirrhosis. It has been proposed that a positive relation exists between intestinal iron absorption and the development of hepatic hemosiderosis. The current study investigated the duodenal expression of the iron transport molecules divalent metal transporter 1 (DMT1 [IRE]), iron-regulated gene 1 (Ireg1 [ferroportin]), hephaestin, and duodenal cytochrome b (Dyctb) in 46 patients with cirrhosis and 20 control subjects. Total RNA samples were extracted from duodenal biopsy samples and the expression of the iron transport genes was assessed by ribonuclease protection assays. Expression of DMT1 and Ireg1 was increased 1.5 to 3-fold in subjects with cirrhosis compared with iron-replete control subjects. The presence of cirrhosis per se and serum ferritin (SF) concentration were independent factors that influenced the expression of DMT1. However, only SF concentration was independently associated with Ireg1 expression. In cirrhosis, the expression of DMT1 and Ireg1 was not related to the severity of liver disease or cirrhosis type. There was no correlation between the duodenal expression of DMT1 and Ireg1 and the degree of hepatic siderosis. In conclusion, the presence of cirrhosis is an independent factor associated with increased expression of DMT1 but not Ireg1. The mechanism by which cirrhosis mediates this change in DMT1 expression has yet to be determined. Increased expression of DMT1 may play an important role in the pathogenesis of cirrhosis-associated hepatic iron overload.

Adult↗

PubMed2004

Patient and graft survival after liver transplantation for hereditary hemochromatosis: Implications for pathogenesis.

The clinical outcome of patients who have undergone liver transplantation for hereditary hemochromatosis (HH) or who have received iron-loaded donor grafts is unclear. We reviewed 3,600 adult primary orthotopic liver transplants and assessed the outcomes in 22 patients with HH. We also evaluated graft function and iron mobilization in 12 recipients of iron-loaded donor grafts. All 22 subjects who received liver transplants for HH were male; 13 had other risk factors for liver disease. HH patients had comparatively poor outcomes following transplantation: survival at 1, 3, and 5 years posttransplantation were 72%, 62%, and 55%, respectively. Recurrent hepatocellular cancer was the most common cause of death. There was no convincing evidence of reaccumulation of iron in the grafted liver in HH; however, 1 subject demonstrated increased serum ferritin concentration and grade 2 hepatic siderosis. Liver iron stores were slow to mobilize in 7 of the 12 recipients of iron-loaded grafts. These recipients had appropriate early graft function, but 2 patients with heavy iron loading and increased hepatic iron developed hepatic fibrosis. In conclusion, (1) HH is an uncommon indication for liver transplantation, and the majority of patients requiring transplantation had other risk factors for chronic liver disease; (2) reaccumulation of liver iron in HH patients is very unusual, but increased iron stores may be slow to mobilize in normal recipients of iron-loaded grafts, potentially compromising late graft function; (3) post-liver transplant survival is reduced in HH, and affected patients require careful clinical evaluation of perioperative and postoperative risk factors. Our data suggest that iron excess in HH does not wholly depend on intestinal iron absorption but is also influenced by liver factors that moderate iron metabolism.

Adult↗

PubMed1996

Alcoholism in hereditary hemochromatosis revisited: prevalence and clinical consequences among homozygous siblings.

The relationship between alcoholism and hereditary hemochromatosis remains controversial. Previous studies have included patients with alcoholic siderosis rather than hereditary hemochromatosis. In this retrospective study, the clinical features, iron status, alcohol history, liver histology, and long-term survival were reviewed in 105 homozygotes for hemochromatosis using rigid diagnostic criteria including an HLA identical sibling with iron overload. Heavy alcohol consumption (>80 g ethanol/day) was found in 15 percent of hemochromatosis patients. Histological features of alcoholic liver disease (Mallory's hyaline bodies, pericentral fibrosis, polymorphonuclear infiltrate, and fatty infiltration) were uncommon in hemochromatosis. Hemochromatosis patients with heavy alcohol consumption had a higher prevalence of cirrhosis than hemochromatosis patients without heavy alcohol consumption. Hepatic iron concentration and hepatic iron index did not significantly differ between these two hemochromatosis groups. Long-term survival was significantly reduced in patients with heavy alcohol consumption (mean follow-up, 9.22 years). This suggests that chronic alcohol consumption has an additive hepatotoxic effect despite the paucity of histological features of alcoholic liver disease.

Alcoholism↗

PubMed1997

The frequency of hemochromatosis-associated alleles is increased in British patients with sporadic porphyria cutanea tarda.

The cause of the hepatic siderosis and iron overload that is common in porphyria cutanea tarda (PCT) is uncertain. Heterozygosity for genetic hemochromatosis has been supported by some studies of the association between the HLA-A3 antigen and porphyria cutanea tarda but not by others. The hemochromatosis gene is now believed to be located telomeric to HLA-A3 and close to the DNA microsatellite marker D6S1260. We have used this and other microsatellite markers, which together define an ancestral haplotype that is strongly linked to hemochromatosis, to reinvestigate the relationship between these disorders in 41 British patients with sporadic PCT. Fifteen patients carried the hemochromatosis-associated alleles D6S265-1 and D6S105-8. Four of these were homozygous for the ancestral haplotype D6S265-1 : D6S105-8: D6S1260-4. We estimate that approximately 37% of British patients with sporadic PCT carry at least one hemochromatosis gene compared with 10% of the general population.

Adult↗

PubMed2001

Circumscripted pigmentations after iron injections-treatment with Q-switched laser systems.

BACKGROUND AND OBJECTIVE: Cutaneous brown discolorations in the area of injection can be a cosmetically bothersome side effect from a parenteral iron treatment, and have not responded to an effective therapy until now. STUDY DESIGN/PATIENTS AND METHODS: We report retrospectively on five patients who were treated with the Q-switched ruby and/or Nd:YAG laser for circumscripted siderosis after intramuscular or intravenous iron injection. RESULTS: The number of required laser treatments was between 3 and 16. The clinical improvement after the first 2-4 sessions was the most impressive, especially after the application of the Nd:YAG laser. Hypopigmentation and scars did not develop. In one case hyperpigmentation appeared. CONCLUSIONS: This study shows that there is an effective method of clearing persistent brown discolorations with few side effects after parenteral iron therapy, using Q-switched laser technology.

Adult↗

PubMed2005

Neonatal hemochromatosis--medical treatment vs. transplantation: the king's experience.

The aim of our study was to compare the outcome of medical treatment vs. liver transplantation in infants with neonatal hemochromatosis (NH) referred to King's College Hospital from 1990-2002. We conducted a retrospective review of 19 children from 14 families. Fifteen children presented at birth and 4 during the first week of life. One child was diagnosed by cordocentesis at 30 weeks of gestation. NH recurred in 7 of 9 families with further children. In one family, 2 children from different fathers were affected. All patients had elevated ferritin levels, hypoalbuminemia, and coagulopathy. Liver histology showed parenchymal collapse, diffuse fibrosis, and moderate to severe hepatocyte hemosiderin deposition. Extrahepatic siderosis was demonstrated by magnetic resonance in 2 patients, lip biopsy in 3, and autopsy in 10. Ten patients received a chelation-antioxidant cocktail: 1 survived, 4 died, and 5 required liver transplantation, of whom 2 died. One of the 9 infants who did not receive the cocktail survived with medical support, 3 died, and 5 required transplantation, of whom 3 died. Seven children are alive, 5 after transplantation, at a median follow-up of 5.6 years, with excellent quality of life and no recurrence of the disease. In conclusion, chelation-antioxidant treatment does not appear to modify the prognosis of NH, at least in severe cases. Liver transplantation, with 50% long-term survival, remains the treatment of choice and should be promptly offered to those infants who do not improve with supportive medical treatment.

Antioxidants↗

PubMed1993

The possible role of iron in the etiopathology of Parkinson's disease.

The identification of 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as dopaminergic neurotoxins that can induce parkinsonism in humans and animals has contributed to a better understanding of Parkinson's disease (PD). Although the involvement of similar neurotoxins has been implicated in PD, the etiology of the disease remains obscure. However, the recently described pathology of PD supports the view for a state of oxidative stress in the substantia nigra (SN), resulting as a consequence of the selective accumulation of iron in SN zona compacta and within the melanized dopamine neurons. Whether iron is directly involved cannot be ascertained. Nevertheless, the biochemical changes due to oxidative stress resulting from tissue iron overload (siderosis) are similar to those now being identified in parkinsonian SN. These include the reduction of mitochondrial electron transport, complex I and III activities, glutathione peroxidase activity, glutathione (GSH) ascorbate, calcium-binding protein, and superoxide dismutase and increase of basal lipid peroxidation and deposition of iron. The participation of iron-induced oxygen free radicals in the process of nigrostriatal dopamine neuron degeneration is strengthened by recent studies in which the neurotoxicity of 6-OHDA has been linked to the release of iron from its binding sites in ferritin. This is further supported by experiments with the prototype iron chelator, desferrioxamine (Desferal), a free-radical inhibitor, which protects against 6-OHDA-induced lesions in the rat. Indeed, intranigral iron injection in rats produces a selective lesioning of dopamine neurons, resulting in a behavioral and biochemical parkinsonism.

Animals↗

PubMed1994

Superficial hemosiderosis of the central nervous system.

Superficial hemosiderosis (SH) of the CNS is a rare disease caused by repeated subarachnoid hemorrhage, with progressive superficial siderosis of the CNS. We report a patient with SH whose clinical picture was marked by progressive gait ataxia, hearing loss, dysarthria, and recurrent episodes of hemifacial spasm. Iron and ferritin levels in the CSF were significantly higher than in a control group of patients. Six month's treatment with the iron-chelating agent trientine dihydrochloride led to clinical improvement, with a concomitant reduction of CSF iron level. We suggest that, in addition to magnetic resonance imaging findings, CSF levels of iron and ferritin should be used as diagnostic criteria for SH, as well as to estimate the efficacy of iron chelation treatment.

Astrocytoma↗

PubMed1995

The hypotransferrinaemic mouse: ultrastructural and laser microprobe analysis observations.

Homozygote hypotransferrinaemic mice (hpx/hpx) have cytopathological features similar to those of human congenital atransferrinaemia, genetic haemochromatosis, and neonatal haemochromatosis. These conditions all have in common high levels of cytotoxic non-transferrin-bound serum iron. This study describes the ultrastructural features of iron overload in liver, pancreas, heart, and small intestine of 2- and 12-month-old hypotransferrinaemic mice. Electron microscopic studies of unstained sections showed early parenchymal cell siderosis, with accumulation of numerous ferritin particles and clusters in the cytosol, as well as ferritin and haemosiderin in lysosomes (siderosomes). In the 12-month-old animals, iron was also found in Kupffer cells and macrophages in other tissues. In addition, there were conspicuous iron-containing compounds in the bile canaliculi, and marked iron deposition in the pancreas and heart. Laser microprobe mass analysis (LAMMA) enabled localization and relative quantitation of iron deposition in subcellular compartments providing in situ documentation of iron accumulation in siderosomes and contributed in assessing total cytosolic iron in various cell types. Moreover, it demonstrated the importance and magnitude of the biliary route for iron excretion in these animals.

Animals↗

PubMed2006

Successful pregnancy outcome following maternal intravenous immunoglobulin treatment in a woman with recurrent perinatal haemochromatosis.

OBJECTIVE: We report a case of successful pregnancy outcome following maternal intravenous immunoglobulin treatment in a woman with previous history of recurrent fetal hydrops secondary to perinatal haemochromatosis. METHODS: A 32-year old woman had two successive pregnancies complicated by fetal hydrops and perinatal deaths. Pathological examination of the fetus showed severe liver destruction with siderosis of hepatocytes at extrahepatic sites, but sparing of the reticulo-endothelial elements, consistent with the diagnosis of perinatal haemochromatosis. In the subsequent pregnancy, maternal intravenous immunoglobulin was administered weekly from the 18th week of gestation until delivery by elective caesarean section at 38 weeks. The infant was treated with desferrioxamine, N-acetylcysteine, vitamins K and E. RESULTS: The infant was born in good health, but had high serum ferritin levels, markedly elevated percent transferrin saturation, and mild transient derangement of liver and coagulation function. The infant made an excellent recovery and the treatment was stopped at 7 weeks of age. The liver and coagulation parameters and the serum ferritin levels returned to normal values. CONCLUSIONS: Haemochromatosis should be considered in the differential diagnosis of hydrops fetalis. The recurrence risk is high, and immunomodulation with intravenous immunoglobulin treatment appears to alter the course of the disease with better infant survival.

Acetylcysteine↗

PubMed1996

'Free' iron, as detected by electron paramagnetic resonance spectroscopy, increases unequally in different tissues during dietary iron overload in the rat.

'Free' iron concentration, as determined by electron paramagnetic resonance (EPR) spectroscopy, and lipid peroxidation (LPO), as determined by thiobarbituric acid test, were assessed in the lung, heart, liver, spleen, brain and kidney of rats subjected to experimental iron overload. Two tests, Desferal- and NO-available iron, were used to measure 'free' iron and gave comparable results. The most pronounced accumulation of 'free' iron was observed in liver, kidney and spleen. Differences between control and iron loaded animals increased during the initial 90 days of treatment. Between 90 and 180 days 'free' iron concentration reached a steady state level, or even decreased, as in the case of liver. Lipid peroxidation level, measured in the organs of both treated and matched controls, did not give any significant difference during the initial 90 days of treatment. A significant augmentation was observed in liver, kidney, spleen and heart at 180 days. The results of the present research show that, under conditions of moderate siderosis, the occurrence of LPO is partially related to the level of 'free' iron.

Animals↗