IL1RN genotype as a risk factor for joint pain in hereditary haemochromatosis?
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Alleles↗
Biomedical subjects
M L Bassett
Publications and source records attributed to M L Bassett.
The 16189 variant of mitochondrial DNA occurs more frequently in C282Y homozygotes with haemochromatosis than those without iron loading.
BACKGROUND: Patients with hereditary haemochromatosis (HH) are usually homozygous for the C282Y mutation in the HFE gene. They have variable expression of iron overload and present with a variety of complications, including liver disease, diabetes, arthropathy, fatigue, and cardiomyopathy. The mitochondrial 16189 variant is associated with diabetes, dilated cardiomyopathy, and low body fat at birth, and might contribute to genetic predisposition in further multifactorial disorders. The objective of this study was to determine the frequency of the 16189 variant in a range of patients with haemochromatosis, who had mutations in the HFE gene. METHODS: Blood DNA was analysed for the presence of the 16189 variant in British, French, and Australian C282Y homozygotes and controls, with known iron status, and in birth cohorts. RESULTS: The frequency of the mitochondrial 16189 variant was found to be elevated in individuals with haemochromatosis who were homozygous for the C282Y allele, compared with population controls and with C282Y homozygotes who were asymptomatic (42/292 (14.4%); 102/1186 (8.6%) (p = 0.003); and 2/64 (3.1%) (p = 0.023), respectively). CONCLUSIONS: Iron loading in C282Y homozygotes with HH was exacerbated by the presence of the mitochondrial 16189 variant.
Adult↗
Small bowel obstruction caused by colonoscopy.
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Aged↗
Anticoagulant therapy, anti-platelet agents and gastrointestinal endoscopy.
BACKGROUND: The increasing use of anticoagulant therapy and anti-platelet agents in the primary and secondary prevention of cardiovascular, cerebrovascular and venous thromboembolic disease has increased the need for guidelines for managing these agents prior to gastrointestinal endoscopy, particularly if therapeutic manoeuvres are required. The continuation of anticoagulant therapy increases the risk of haemorrhagic complications of gastrointestinal endoscopy. Temporary suspension of anticoagulant therapy exposes the patient to the risk of thromboembolism associated with the underlying condition requiring anticoagulant treatment. CONCLUSIONS: This article reviews the literature and proposes guidelines for the management of patients taking anticoagulant and anti-platelet agents who require gastrointestinal endoscopy.
Anticoagulants↗
Antibiotic-associated haemorrhagic colitis.
Antibiotic-associated haemorrhagic colitis is an uncommon cause of bloody diarrhoea in patients taking penicillin or penicillin-related antibiotics. Symptoms of abdominal pain and bloody diarrhoea occur within 1 week of antibiotic use and resolve without specific therapy within days of discontinuing the offending antibiotic. There is an apparent increased incidence of the disease in patients of Oriental ethnicity. The pathogenesis is unknown. We present two cases of haemorrhagic colitis in patients taking penicillin-related antibiotics who presented within 4 months of each other. One of the patients was being treated for Helicobacter pylori infection. The published literature is reviewed with particular emphasis on the histology and pathogenesis of the condition.
Adult↗
Haemochromatosis: diagnosis and management after the cloning of the HFE gene.
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Cloning, Molecular↗
Analysis of the cost of population screening for haemochromatosis using biochemical and genetic markers.
AIMS: To estimate the cost of population screening for haemochromatosis in Australia and to compare the cost of alternative screening strategies. METHODS: The costs of screening for haemochromatosis were analysed in a hypothetical study using transferrin saturation as the primary screening test, with confirmation of the diagnosis by either liver biopsy or DNA testing for the recently-described haemochromatosis gene. RESULTS: Screening, with confirmation of the diagnosis by liver biopsy, would cost between US$5079 and US$8813 per case detected (excluding administrative costs), depending on the screening strategy (Aust$ = US$0.80). If a DNA test were used instead of liver biopsy, the cost would be reduced to an estimated US$3954-US$4410 per case. This would be further reduced to US$2457 by detection of additional cases by screening family members. The least costly strategy utilised a transferrin saturation threshold of 55% and DNA testing for confirmation of the diagnosis; however, a transferrin saturation threshold of 45% increased the cost only marginally. The initial screening step (transferrin saturation) accounted for 74%-94% of the estimated cost of the screening programme. CONCLUSIONS: Screening for haemochromatosis using transferrin saturation involves relatively modest costs which may be recovered if complications of haemochromatosis can be prevented by early detection and treatment. The most cost-effective strategies utilised transferrin saturation for initial screening, followed by DNA testing. Reduction in the cost of transferrin saturation would lead to a significant reduction in total screening costs. Additional benefits of a screening programme include detection of other iron overload disorders and iron deficiency.
Biopsy↗
Case report: gastrointestinal tuberculosis simulating Crohn's disease.
A male Caucasian presented with abdominal pain and a right iliac fossa mass. There were no risk factors for Mycobacterium tuberculosis infection. He was investigated by upper and lower gastrointestinal endoscopy, chest and small bowel radiology. The latter showed stricturing of the third and fourth parts of the duodenum, mid-jejunum and terminal ileum. Biopsies were non-specific and he was thought to have Crohn's disease. Subsequent treatment with corticosteroids resulted in improved well being and weight gain; however, the patient demonstrated disease progression with the development of complex fistulae and Escherichia coli septicaemia. At surgery the patient was found to have an ileal inflammatory mass with fistulae to the sigmoid colon. The terminal ileum, fistulae and a segment of colon were resected. Treatment with anti-tuberculous drugs ensued and the patient is now asymptomatic after 15 months of follow-up. This case serves to highlight the difficulty in making the diagnosis of gastrointestinal tuberculosis, a disease that may mimic Crohn's disease, and the need for caution in the use of corticosteroids in any disease in which tuberculosis enters into the differential diagnosis. The role of surgery in making the diagnosis and managing the complications, in conjunction with anti-tuberculous drugs, and the prospect of cure are exemplified by this case.
Adult↗
Case report: gastrointestinal haemorrhage from jejunal diverticulosis, probably induced by low dose aspirin.
A 66-year-old female, who had been taking low dose aspirin for approximately 6 months, was admitted to hospital with severe gastrointestinal bleeding. The source of bleeding could not be demonstrated despite gastroscopy, mesenteric angiography and 99mTc-labelled red blood cell scanning. Mesenteric angiography was repeated, demonstrating a site of bleeding in the proximal small intestine. Laparotomy revealed blood-filled jejunal diverticulosis. Resection of the affected segment resulted in cessation of haemorrhage and the patient remains well in follow up. The present report illustrates a rare cause of gastrointestinal haemorrhage, the possible role of aspirin in causation and the difficulty in diagnosis of bleeding from jejunal diverticulosis.
Aged↗
Liver failure while taking coumarin.
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Aged↗
Increased brain uptake of gamma-aminobutyric acid in a rabbit model of hepatic encephalopathy.
Transfer of the inhibitory neurotransmitter gamma-aminobutyric acid across the normal blood-brain barrier is minimal. One prerequisite for gamma-aminobutyric acid in plasma contributing to the neural inhibition of hepatic encephalopathy would be that increased transfer of gamma-aminobutyric acid across the blood-brain barrier occurs in liver failure. The aim of the present study was to determine if brain gamma-aminobutyric acid uptake is increased in rabbits with stage II-III (precoma) hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. A modification of the Oldendorf intracarotid artery-injection technique was applied. [3H] gamma-aminobutyric acid, [14C] butanol, and 113mIn-labeled serum protein (transferrin) were injected simultaneously 4 s before decapitation. The ipsilateral brain uptake index of gamma-aminobutyric acid was determined from measurements of the 3 isotopes in 5 brain regions. Uncorrected or simple brain uptake indices of [3H] gamma-aminobutyric acid and [113mIn] transferrin were calculated using [14C] butanol as the highly extracted reference compound. The [113mIn] transferrin data were also used to "correct" the brain uptake index of [3H] gamma-aminobutyric acid for intravascular retention of [3H] gamma-aminobutyric acid. The methodology adopted minimized problems attributable to rapid [3H] gamma-aminobutyric acid metabolism, and slow brain washout and recirculation of the radiolabeled tracers. Both the uncorrected and corrected brain uptake indices of gamma-aminobutyric acid as well as the simple brain uptake index of transferrin were significantly increased in both stage II and III hepatic encephalopathy in all brain regions studied. Moreover, these brain uptake indices were significantly greater in stage III hepatic encephalopathy than in stage II hepatic encephalopathy. These findings indicate that transfer of gamma-aminobutyric acid from plasma to brain extracellular fluid is increased in the model of hepatic encephalopathy studied; hence, they provide support for the hypothesis that plasma-derived gamma-aminobutyric acid may contribute to the neural inhibition of hepatic encephalopathy due to fulminant hepatic failure.
Animals↗
Could an endogenous benzodiazepine ligand contribute to hepatic encephalopathy?
High affinity recognition sites for benzodiazepines are part of the gamma-aminobutyric acid (GABA) supramolecular complex on the plasma membrane of neurons in the mammalian brain. Synthetic agonist benzodiazepines promote GABA-ergic neurotransmission, and hence the hypnotic and anxiolytic effects of this class of drugs, by binding to these sites. A normal physiological role for these binding sites is unknown, and an endogenous ligand for benzodiazepine receptors has not been definitely identified in normal animals. In animals and human beings with hepatic encephalopathy, however, benzodiazepine receptor antagonists have induced amelioration of the encephalopathy, and an endogenous substance that competitively binds to benzodiazepine receptors has been found in cerebrospinal fluid. These findings suggest that an endogenous ligand for the benzodiazepine receptor with agonist properties contributes to hepatic encephalopathy by promoting GABA-ergic neurotransmission.
Benzodiazepines↗
Is all genetic (hereditary) hemochromatosis HLA-associated.
1. GH in Australia is significantly associated with the HLA-A3 antigen, which is the only independent marker for the disease (B7 in linkage disequilibrium with A3). 2. The haplotype A3, B7, DR2 is the only one with increased prevalence in this disease, presumably due to its being the predominant haplotype among early immigrants. 3. Exceptions to HLA association in GH are rare and can be explained by: (1) incorrect HLA serotyping, (2) chromosomal recombination, or (3) rare homozygous-homozygous mating. 4. These data are consistent with GH being due to a mutant gene or genes in close proximity to HLA-A. 5. Heavy alcohol ingestion does not lead to expression of hemochromatosis in heterozygous subjects.
Alcohol Drinking↗
Genetic hemochromatosis and HLA linkage.
We previously reported five families with primary, genetic (idiopathic) hemochromatosis in whom HLA typing of subjects indicated that a homozygous-heterozygous mating had almost certainly occurred and in whom inheritance of the disease trait was best explained by an autosomal recessive mode of inheritance. However, in one family, two children apparently homozygous for hemochromatosis did not manifest overt evidence of the disease, and alternative explanations were postulated, including autosomal dominant inheritance in this family. Subsequent study of the family members, including repeat HLA-DR serology with more recently defined antisera and DNA genotyping at the HLA-DR locus has, we believe, provided the true explanation for the previous apparent anomaly and adds further evidence for the tight linkage of the disease to the HLA-A locus.
Female↗
Amelioration of hepatic encephalopathy by pharmacologic antagonism of the GABAA-benzodiazepine receptor complex in a rabbit model of fulminant hepatic failure.
Three separate, but allosterically interacting, sites on the gamma-aminobutyric acid (GABA) supramolecular complex in the brain were pharmacologically blocked in rabbits with hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure to determine whether decreased GABAergic neurotransmission can ameliorate the syndrome of hepatic encephalopathy. Bicuculline (a GABAA receptor blocker), Ro 15-1788 (a benzodiazepine receptor antagonist), or isopropylbicyclophosphate (a chloride channel blocker) consistently induced a transient but unequivocal decrease in the clinical severity of the encephalopathy and also corrected the abnormal pattern of the visual evoked response associated with hepatic encephalopathy. Rabbits with hepatic encephalopathy exhibited increased resistance to the convulsive effects of bicuculline. In encephalopathies induced in rabbits by gamma-vinyl-GABA (an inhibitor of GABA catabolism) or diazepam (a benzodiazepine receptor agonist), abnormalities of the visual evoked response similar to those found in hepatic encephalopathy occurred and were corrected by bicuculline and Ro 15-1788, respectively. These findings suggest that in hepatic encephalopathy due to fulminant hepatic failure (a) there is increased GABAergic tone, (b) an amelioration of encephalopathy can be induced by blockade of GABA or benzodiazepine receptors, (c) benzodiazepine receptor antagonists may be of clinical value in the management of hepatic encephalopathy, and (d) an endogenous substance with GABA potentiating properties may be present in hepatic encephalopathy.
Animals↗
Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases.
The risk of hepatocellular carcinoma (HCC) and other internal malignancies was examined in patients with genetic hemochromatosis (GH) by following 208 patients from the time of diagnosis to June 1983 and by comparing the numbers of cancers they developed with expected values constructed from cancer registry incidence data by means of actuarial methods. In addition, cancers occurring in a comparison group of 148 subjects with other chronic nonalcoholic liver diseases (CLD) were determined. Among the GH group, 16 new cases of HCC occurred subsequent to the diagnosis of GH, together with 8 other malignancies. The 16 cases of HCC reflect a 200-fold excess risk, which from all indications represents the first quantitation of the risk of this tumor in GH. There appears to be no increased risk of other malignancies in this disease. Among the CLD group only 1 HCC and 1 other malignancy occurred.
Adolescent↗
Valproate hepatotoxicity: a review and report of two instances in adults.
Two patients with severe liver damage induced by sodium valproate are described. Both were adults. One had taken valproate for longer than one year before complications developed. The other, in whom the disorder was fatal, had a predominantly 'hepatic' pattern of liver damage with centrilobular necrosis and he also developed pancreatitis. The first patient, who recovered following cessation of valproate intake, manifested a predominantly cholestatic illness with portal tract inflammation. In addition he had a degree of reversible renal failure. Neither subject had microvesicular steatosis on liver biopsy. This report indicates that valproate hepatotoxicity is not always confined to children, that it may develop much later in the course of valproate therapy than has been previously recognized, that it is not necessarily fatal if valproate intake is ceased early enough, and that it may be associated with reversible renal insufficiency.
Adolescent↗