Among patients with hepatic iron overload, the distinction between hereditary hemochromatosis (HH), a common yet treatable genetic disease, and other causes of siderosis remains problematic. The recent discovery of a specific homozygous mutation (C282Y) in a novel major histocompatibility complex class I-like gene (named HLA-H or HFE) in 80% to 100% of well-characterized cases of HH suggests that direct DNA-based mutation analysis may help resolve this dilemma. To assess the clinical utility of direct HLA-H mutation analysis in a typical diagnostic setting, we measured genotypic and phenotypic parameters of iron overload in 37 subjects with biopsy-proven hepatic siderosis (2+ or greater) and in 127 healthy control subjects. The prevalence of C282Y homozygotes was significantly greater in the hepatic siderosis group (32%) than in the control group (0%), confirming the association between this homozygous mutation and hepatic iron overload. In the hepatic siderosis group, C282Y homozygotes had significantly higher hepatic iron and ferritin levels, a significantly lower prevalence of hepatitis C virus or alcoholic liver disease, but no significant difference in the saturation of serum transferrin. Of the 20 subjects with a hepatic iron index (HII) in the previously defined "hemochromatosis range" (>1.9), 9 (45%) were C282Y homozygotes. Of the 11 nonhomozygous subjects with an HII greater than 1.9 (presumed false-positive HIIs), 10 (91%) had hepatic cirrhosis compared with 3 of 9 (33%) homozygotes with an HII greater than 1.9 who had cirrhosis (P<.02). The HII thus has poor diagnostic specificity for predicting genotypic HH in patients with cirrhosis. We conclude that direct determination of the HLA-H C282Y genotype may be the single best diagnostic test for HH, particularly in patients with cirrhosis, for whom the HII is quite nonspecific.
Hepatology
Volume 25, Issue 2, February 1997, Pages 495-496
Hemochromatosis and "HLA-H": Definite!
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Abstract
Background/Aims: Hereditary hemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi-organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage-disequilibrium and full haplotype analysis, we have identified a 250kb region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by-descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in hemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class I-like proteins in iron metabolism
MHC associations with IDDM in the Korean population were studied to investigate genetic susceptibility to this disorder. The frequencies of HLA-DR3, -DR4 and -DR9 were significantly higher in diabetic patients. However, the frequency of DR2 was significantly decreased in diabetic patients. DQA1 ∗0301 and DQA1 ∗0501 were positively and DQA1 ∗0102 and DQA1 ∗0201 negatively associated with IDDM. DQB1 ∗0301 and DQB1 ∗0601 were negatively associated with IDDM. Heterodimers DQA1 ∗0301-DQB1 ∗0201, DQA1 ∗0501-DQB1 ∗0201 and DQA1 ∗0501-DQB1 ∗0302 were positively associated and DQA1 ∗0102-DQB1 ∗0601 negatively associated with IDDM. The frequencies of DR3-DQA1 ∗0301-DQB1 ∗0201 and -DQA1 ∗0501-DQB1 ∗0201 were significantly higher in diabetic patients. The frequencies of DR4-DQA1 ∗0301-DQB1 ∗0201 and DR9-DQA1 ∗0301-DQB1 ∗0303 were significantly higher in diabetic patients. The presence of non-aspartic acid at position 57 of the DQβ-chain was not associated with susceptibility to IDDM. However, the frequency of Arg 52 homozygotes was significantly higher in diabetic patients. These results suggest a role of the MHC molecule and also suggest racial differences in susceptibility to IDDM even within the Asian populations.
D serious Carbon ,Faramarz Naeim, ... Wayne W. Grody, in Hematopathology, 2008
Enteropathy-Type T-Cell Lymphoma
Enteropathy-type T-cell lymphoma is a rare intraepithelial T-cell intestinal lymphoma consisting of a polymorphic lymphoid infiltrate of medium to large atypical lymphocytes [1, 142–144].
Etiology and Pathogenesis
The etiology and pathogenesis of this disorder are not known. There is a strong association with celiac disease with the evidence of serologic markers such as positive antigliadin antibodies and HLA-DQA1, B1, and HLA–DRB1 types [145, 146]. Some cases in South and Central America have been associated with EBV [147].
Pathology
Morphology
The neoplasm often appears as multifocal ulcerating intestinal lesions consisting of a pleomorphic lymphoid infiltrate [1]. Jejunum and ileum are the most frequently affected sites. There is a predominance of atypical medium to large lymphoid cells with variable amount of pale cytoplasm, round or irregular vesicular nuclei, and prominent nucleoli. Anaplastic large cells or multinucleated giant cells may be present, mimicking ALCL. The infiltrate is commonly mixed with inflammatory cells such as histiocytes and eosinophils.
Immunophenotype
The neoplastic cells express CD3, CD7, TIA-1, granzyme B, and CD103. They are negative for CD4 and CD5. Tumors consisting of small- to medium-sized lymphoid cells may express CD8 and/or CD56 [1, 148]. In most cases, a various proportion of tumor cells are also CD30+ [148].
Molecular and Cytogenetic Studies
The TCR genes, most commonly γ and δ, are rearranged [149]. Loss of heterozygosity (LOH) at chromosome 9p21 and gains at chromosome 9q, 7q, 5q, and 1q have been reported in some cases [150–152].
Clinical Aspects
Most patients have a history of celiac disease and present with abdominal pain and sometimes evidence of intestinal perforation [1]. The clinical outcome is usually poor. Differential diagnosis includes inflammatory bowel disorders and other types of lymphomas.
Genetics
A genetic predisposition to autoimmune gastritis (AIG) is supported by an association with HLA DRB1∗04 and DQB1∗03 alleles. A weak association between the presence of PCA and HLA-DQA1∗0501- DQB1∗0301 has been shown in patients with type 1 diabetes mellitus (T1DM) and AIG, also with a genotype DR3/DR4 [1].
Experimental studies performed in mouse models have identified four distinct gene regions that confer susceptibility to AIG, and in particular two loci located on chromosome 4, called Gasa1 and Gasa2, and two located on chromosome 6, called Gasa3 and Gasa4.
The positions of Gasa1 and Gasa2 correspond closely to two autoimmune diabetes susceptibility loci, Idd11 and Idd9. This genetic concordance is the strongest association identified between two autoimmune diseases [1].
Genetic Factors
Genetic factors appear important in MN. There is a strong link to the major histocompatibility antigens in humans. Many studies have shown association of HLA-DR3 with MN in Caucasians.5 A strong association with HLA-DQA1 allelle has also been reported in two HLA-identical brothers.6 In patients with MN, there is an extra Bss HII restriction enzyme cutting site in the vicinity of the HLA-DP genes.7 This structural heterogeneity in the area containing genes for antigen peptide processing and transport could have implications for genetic susceptibility for developing MN. A significant increase in HLA-DR2 antigens and relatively low frequency of HLA-DR3 antigens have been found in the Japanese population.