Abstract:The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European des… Show more
“…5b). Conversely, the transcript for HFE , the function of which is to limit iron uptake through its interaction with TFRC at the surface of cells50 and polymorphisms in which have been linked to PZ-induced serum ALT elevation31, showed an increase only in NHT-HLCs after PZ treatment (Fig. 5b).…”
Idiosyncratic drug-induced hepatotoxicity is a major cause of liver damage and drug pipeline failure, and is difficult to study as patient-specific features are not readily incorporated in traditional hepatotoxicity testing approaches using population pooled cell sources. Here we demonstrate the use of patient-specific hepatocyte-like cells (HLCs) derived from induced pluripotent stem cells for modeling idiosyncratic hepatotoxicity to pazopanib (PZ), a tyrosine kinase inhibitor drug associated with significant hepatotoxicity of unknown mechanistic basis. In vitro cytotoxicity assays confirmed that HLCs from patients with clinically identified hepatotoxicity were more sensitive to PZ-induced toxicity than other individuals, while a prototype hepatotoxin acetaminophen was similarly toxic to all HLCs studied. Transcriptional analyses showed that PZ induces oxidative stress (OS) in HLCs in general, but in HLCs from susceptible individuals, PZ causes relative disruption of iron metabolism and higher burden of OS. Our study establishes the first patient-specific HLC-based platform for idiosyncratic hepatotoxicity testing, incorporating multiple potential causative factors and permitting the correlation of transcriptomic and cellular responses to clinical phenotypes. Establishment of patient-specific HLCs with clinical phenotypes representing population variations will be valuable for pharmaceutical drug testing.
“…5b). Conversely, the transcript for HFE , the function of which is to limit iron uptake through its interaction with TFRC at the surface of cells50 and polymorphisms in which have been linked to PZ-induced serum ALT elevation31, showed an increase only in NHT-HLCs after PZ treatment (Fig. 5b).…”
Idiosyncratic drug-induced hepatotoxicity is a major cause of liver damage and drug pipeline failure, and is difficult to study as patient-specific features are not readily incorporated in traditional hepatotoxicity testing approaches using population pooled cell sources. Here we demonstrate the use of patient-specific hepatocyte-like cells (HLCs) derived from induced pluripotent stem cells for modeling idiosyncratic hepatotoxicity to pazopanib (PZ), a tyrosine kinase inhibitor drug associated with significant hepatotoxicity of unknown mechanistic basis. In vitro cytotoxicity assays confirmed that HLCs from patients with clinically identified hepatotoxicity were more sensitive to PZ-induced toxicity than other individuals, while a prototype hepatotoxin acetaminophen was similarly toxic to all HLCs studied. Transcriptional analyses showed that PZ induces oxidative stress (OS) in HLCs in general, but in HLCs from susceptible individuals, PZ causes relative disruption of iron metabolism and higher burden of OS. Our study establishes the first patient-specific HLC-based platform for idiosyncratic hepatotoxicity testing, incorporating multiple potential causative factors and permitting the correlation of transcriptomic and cellular responses to clinical phenotypes. Establishment of patient-specific HLCs with clinical phenotypes representing population variations will be valuable for pharmaceutical drug testing.
“…Modifier mutations in non- HFE iron-related genes described to date explain iron phenotype variability in a small proportion of p.C282Y homozygotes [3,13]. Accordingly, it is assumed that other acquired or environmental factors and non- HFE polymorphisms of unreported or unconfirmed effect on iron absorption or iron stores account for much of the remaining unexplained iron phenotype variability among p.C282Y homozygotes [14].…”
Background
GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes.
Methods
We defined markedly increased iron stores as serum ferritin >2247 pmol/L (>1000 ”g/L) and either hepatic iron >236 ”mol/g dry weight or iron >10 g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin <674.1 pmol/L (<300 ”g/L) or either age â„40 y with iron â€2.5 g iron by induction phlebotomy or age â„50 y with â€3.0 g iron by induction phlebotomy (men only). We compared participant subgroups using univariate methods. Using multivariable logistic regression, we evaluated associations of markedly increased iron stores with these variables: age; iron supplement use (dichotomous); whole blood units donated; erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (heterozygosity or homozygosity).
Results
The mean age of 56 participants (94.6% men) was 55 ± 10 (SD) y; 41 had markedly increased iron stores. Prevalences of swollen/tender 2nd/3rd metacarpophalangeal joints and elevated aspartate or alanine aminotransferase were significantly greater in participants with markedly increased iron stores. Only participants with markedly increased iron stores had cirrhosis. In multivariable analyses, p.D519G positivity was the only exposure variable significantly associated with markedly increased iron stores (odds ratio 9.9, 95% CI [1.6, 60.3], p = 0.0126).
Conclusions
GNPAT p.D519G is strongly associated with markedly increased iron stores in p.C282Y homozygotes after correction for age, iron-related variables, and alcohol consumption.
“…p.C282Y allele frequencies in non-Hispanic whites who reside in North America are 6-7% [19]. Mean serum iron, TS, and SF levels of adults with p.C282Y homozygosity are higher than those of adults with other common HFE genotypes [20].…”
Section: Hfe Hemochromatosismentioning
confidence: 99%
“…In HFE hemochromatosis, excessive iron absorption and increased iron stores are due to lack of hepcidin upregulation, although mutations in non- HFE genes may act as positive âmodifiersâ of iron absorption in some p.C282Y homozygotes [19, 25, 26]. …”
Diabetes in whites of European descent with hemochromatosis was first attributed to pancreatic siderosis. Later observations revealed that the pathogenesis of diabetes in HFE hemochromatosis is multifactorial and its clinical manifestations are heterogeneous. Increased type 2 diabetes risk in HFE hemochromatosis is associated with one or more factors, including abnormal iron homeostasis and iron overload, decreased insulin secretion, cirrhosis, diabetes in first-degree relatives, increased body mass index, insulin resistance, and metabolic syndrome. In p.C282Y homozygotes, serum ferritin, usually elevated at hemochromatosis diagnosis, largely reflects body iron stores but not diabetes risk. In persons with diabetes type 2 without hemochromatosis diagnoses, serum ferritin levels are higher than those of persons without diabetes, but most values are within the reference range. Phlebotomy therapy to achieve iron depletion does not improve diabetes control in all persons with HFE hemochromatosis. The prevalence of type 2 diabetes diagnosed today in whites of European descent with and without HFE hemochromatosis is similar. Routine iron phenotyping or HFE genotyping of patients with type 2 diabetes is not recommended. Herein, we review diabetes in HFE hemochromatosis and the role of iron in diabetes pathogenesis in whites of European descent with and without HFE hemochromatosis.
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