Diagnosing aceruloplasminemia: navigating through red herrings.

A 58-year-old female was found to have hyperferritinemia (Serum ferritin:1683 ng/mL) during work-up for mild normocytic anemia. Transferrin saturation(TSAT) was low-normal. Magnetic resonance imaging (MRI) abdomen showed evidence of hepatic iron deposition. Liver biopsy showed 4 + hepatic iron deposition without any evidence of steatosis or fibrosis. Quantitative liver iron was elevated at 348.3 µmol/g dry liver weight [Reference range(RR): 3-33 µmol/g dry liver weight]. She was presumptively diagnosed with tissue iron overload, cause uncertain. A diagnosis of ferroportin disease (FD) was considered, but the pattern of iron distribution in the liver, mainly within the hepatic parenchyma (rather than in the hepatic Kupffer cells seen in FD), and the presence of anemia (uncommon in FD) made this less likely. She was treated with intermittent phlebotomy for over a decade with poor tolerance due to worsening normocytic to microcytic anemia. A trial of deferasirox was done but it was discontinued after a month due to significant side effects. During the course of treatment, her ferritin level decreased. Over the past 1.5 years, she developed progressively worsening neurocognitive decline. MRI brain showed areas of susceptibility involving basal ganglia, midbrain and cerebellum raising suspicion for metabolic deposition disease. Neuroimaging findings led to testing for serum copper and ceruloplasmin levels which were both found to be severely low. Low serum copper, ceruloplasmin levels and neuroimaging findings led us to consider Wilson disease however prior liver biopsy showing elevated hepatic iron rather than hepatic copper excluded the diagnosis of Wilson disease. After shared decision making, ceruloplasmin gene analysis was not pursued due to patient's preference and prohibitive cost of testing. The diagnosis of aceruloplasminemia was ultimately made. The biochemical triad of hyperferritinemia, low-normal TSAT and microcytic anemia should raise the possibility of aceruloplasminemia. Since neurological manifestations are rare in most inherited iron overload syndromes, neurological symptoms in a patient with tissue iron overload should prompt consideration of aceruloplasminemia as a differential diagnosis.

Clinical characteristics of HFE C282Y/H63D compound heterozygotes identified in a specialty practice: key differences from HFE C282Y homozygotes.

BACKGROUND: Patients with p.C282Y homozygous (p.C282Y) HFE mutations are more likely to develop hemochromatosis (HC) than p.C282Y/p.H63D compound heterozygotes (p.C282Y/H63D). RESEARCH DESIGN AND METHODS: We conducted a retrospective chart review of 90 p.C282Y and 31 p.C282Y/H63D patients at a referral practice to illustrate the differences in the natural history of the disease in these two HC cohorts. RESULTS: Over a median follow-up of 17 years, p.C282Y had higher mean serum ferritin (1105 mg/dL vs. 534 mg/dL, p = 0.001) and transferrin saturations (75.3% vs. 49.5%, p = 0.001) at diagnosis. p.C282Y underwent more therapeutic phlebotomies (TP) till de-ironing (mean 24 vs. 10), had higher mean mobilized iron stores (4759 mg vs. 1932 mg), and required more annual maintenance TP (1.9/year vs. 1.1/year, p = 0.039). p.C282Y/H63D were more likely to have obesity (45.2% vs. 20.2%, p = 0.007) at diagnosis, with a non-significant trend toward consuming more alcohol. There was no significant difference in the development of HC-related complications between the two cohorts. CONCLUSIONS: p.C282Y have a higher mobilizable iron and require more TP. p.C282Y/H63D likely require additional insults such as obesity or alcohol use to develop elevated ferritin. De-ironing may mitigate the risk of developing HC-related complications.

Should primary care physicians consult on their admitted patients? A single-center survey study.

Background: With the rise of hospital medicine, care has become fragmented between inpatient and outpatient settings. Having primary care physicians (PCPs) consult on their admitted patients through televisits could improve patient and hospital outcomes, but perspectives on this model are unknown in adult hospital medicine. Methods: A single-center cross-sectional survey was conducted to compare PCP and hospitalist attitudes regarding PCP telemedicine consultation for admitted patients in a large US academic hospital. Results: A total of 120 participants (52 hospitalists and 68 PCPs) responded to the survey. Most hospitalists believed that their patients would benefit from PCP consultation, with 45.8% believing it was slightly important, 18.8% moderately important, and 22.9% quite important. The level of importance did not seem to influence the effort required, as most hospitalists would put in only a little effort (35.4%) to obtain a PCP consultation. PCPs were more inclined to consult on their admitted patients; 18.6% considered it slightly important to obtain their consultation, 35.6% believed it was moderately important, and 23.7% believed it was quite important. PCPs were willing to put more effort into setting up a PCP consultation (some effort, 45.8%) vs hospitalists (little effort, 35.4%). The most common challenge perceived by both groups was time commitment (hospitalists, 78.8%; PCPs, 75.0%). Conclusions: Both hospitalists and PCPs agree that a PCP consultation would benefit the patient's medical care in specific situations. However, views on the importance and frequency of PCP consultations vary between the two groups.

Breast cancer detection using enhanced IRI-numerical engine and inverse heat transfer modeling: model description and clinical validation.

Effective treatment of breast cancer relies heavily on early detection. Routine annual mammography is a widely accepted screening technique that has resulted in significantly improving the survival rate. However, it suffers from low sensitivity resulting in high false positives from screening. To overcome this problem, adjunctive technologies such as ultrasound are employed on about 10% of women recalled for additional screening following mammography. These adjunctive techniques still result in a significant number of women, about 1.6%, who undergo biopsy while only 0.4% of women screened have cancers. The main reason for missing cancers during mammography screening arises from the masking effect of dense breast tissue. The presence of a tumor results in the alteration of temperature field in the breast, which is not influenced by the tissue density. In the present paper, the IRI-Numerical Engine is presented as an adjunct for detecting cancer from the surface temperature data. It uses a computerized inverse heat transfer approach based on Pennes's bioheat transfer equations. Validation of this enhanced algorithm is conducted on twenty-three biopsy-proven breast cancer patients after obtaining informed consent under IRB protocol. The algorithm correctly predicted the size and location of cancerous tumors in twenty-four breasts, while twenty-two contralateral breasts were also correctly predicted to have no cancer (one woman had bilateral breast cancer). The tumors are seen as highly perfused and metabolically active heat sources that alter the surface temperatures that are used in heat transfer modeling. Furthermore, the results from this study with twenty-four biopsy-proven cancer cases indicate that the detection of breast cancer is not affected by breast density. This study indicates the potential of the IRI-Numerical Engine as an effective adjunct to mammography. A large scale clinical study in a statistically significant sample size is needed before integrating this approach in the current protocol.

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.

A Rare Case of Three Distinct Epstein-Barr Virus Associated Lymphoproliferative Disorders Over Sixteen Years of Human Immunodeficiency Virus Infection.

Epstein Barr virus (EBV) is well known to cause different types of malignancies. In immunocompromised patients, such as those infected with human immunodeficiency virus (HIV), there is a higher likelihood of EBV related malignant transformation. Diagnosis of EBV related malignancies may be difficult and sometimes requires clinical and pathological correlation. It is very rare to have more than one type of EBV related malignancy in a single patient. Until now, there are no specific guidelines for treatment of EBV related malignancies and lymphoproliferative disorders (LPD). We present a patient who developed three different types of EBV related LPD during a sixteen-year course of HIV infection.

Decision points in the treatment of transfusional iron overload in patients with myelodysplastic syndromes: why, when, and how to chelate.

INTRODUCTION: Patients with myelodysplastic syndromes (MDS) differ from those with other transfusion-dependent conditions (eg, thalassemia) as they are typically older, have comorbid conditions, and a generally shorter life expectancy. The underlying disease process in MDS and frequent use of red blood cell transfusions lead to iron accumulation and ultimately organ damage. Whether iron-reducing interventions such as chelation therapy can improve outcomes in this population is currently under investigation. Areas covered: We reviewed published English-language articles from PubMed on the topic of iron overload (IO) in MDS, and the use of iron chelation therapies (ICTs) to alleviate iron burden. Expert commentary: Data on IO-associated complications in MDS are derived largely from retrospective studies and there are limited data to guide clinicians on major treatment decisions. Although effective and well-tolerated oral ICTs are available, and general recommendations may be made regarding usage in MDS, guidance is not yet based on prospective data. The clinical endpoints and assessments for MDS may differ substantively from those used in patients with thalassemia, as an older population may have competing causes for morbidity. We expect that emergent data from clinical trials currently underway will define more appropriate endpoints/assessments for the MDS population in clinical trials.

GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes.

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 >2247pmol/L (>1000µg/L) and either hepatic iron >236µmol/g dry weight or iron >10g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin <674.1pmol/L (<300µg/L) or either age≥40y with iron ≤2.5g iron by induction phlebotomy or age≥50y with ≤3.0g 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.

Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload.

UNLABELLED: To identify polymorphisms associated with variability of iron overload severity in HFE-associated hemochromatosis, we performed exome sequencing of DNA from 35 male HFE C282Y homozygotes with either markedly increased iron stores (n = 22; cases) or with normal or mildly increased iron stores (n = 13; controls). The 35 participants, residents of the United States, Canada, and Australia, reported no or light alcohol consumption. Sequencing data included 82,068 single-nucleotide variants, and 10,337 genes were tested for a difference between cases and controls. A variant in the GNPAT gene showed the most significant association with severe iron overload (P = 3 × 10(-6) ; P = 0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of twenty-two participants with severe iron overload had glyceronephosphate O-acyltransferase (GNPAT) polymorphism p.D519G (rs11558492; 15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of GNPAT deficiency, we performed small interfering RNA-based knockdown of GNPAT in the human liver-derived cell line, HepG2/C3A. This knockdown resulted in a >17-fold decrease in expression of the messenger RNA encoding the iron-regulatory hormone, hepcidin. CONCLUSION: GNPAT p.D519G is associated with a high-iron phenotype in HFE C282Y homozygotes and may participate in hepcidin regulation.

A phase 1/2, dose-escalation trial of deferasirox for the treatment of iron overload in HFE-related hereditary hemochromatosis.

UNLABELLED: Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption that may result in iron overload. Although phlebotomy is widely practiced, it is poorly tolerated or contraindicated in patients with anemias, severe heart disease, or poor venous access, and compliance can vary. The once-daily, oral iron chelator, deferasirox (Exjade) may provide an alternative treatment option. Patients with HH carrying the HFE gene who were homozygous for the Cys282Tyr mutation, serum ferritin levels of 300-2000 ng/mL, transferrin saturation ≥ 45%, and no known history of cirrhosis were enrolled in this dose-escalation study to characterize the safety and efficacy of deferasirox, comprising a core and an extension phase (each 24 weeks). Forty-nine patients were enrolled and received starting deferasirox doses of 5 (n = 11), 10 (n = 15), or 15 (n = 23) mg/kg/day. Adverse events were generally dose-dependent, the most common being diarrhea, headache, and nausea (n = 18, n = 10, and n = 8 in the core and n = 1, n = 1, and n = 0 in the extension, respectively). More patients in the 15 mg/kg/day than in the 5 or 10 mg/kg/day cohorts experienced increases in alanine aminotransferase and serum creatinine levels during the 48-week treatment period; six patients had alanine aminotransferase > 3 × baseline and greater than the upper limit of normal range, and eight patients had serum creatinine > 33% above baseline and greater than upper limit of normal on two consecutive occasions. After receiving deferasirox for 48 weeks, median serum ferritin levels decreased by 63.5%, 74.8%, and 74.1% in the 5, 10, and 15 mg/kg/day cohorts, respectively. In all cohorts, median serum ferritin decreased to < 250 ng/mL. CONCLUSION: Deferasirox doses of 5, 10, and 15 mg/kg/day can reduce iron burden in patients with HH. Based on the safety and efficacy results, starting deferasirox at 10 mg/kg/day appears to be most appropriate for further study in this patient population.

Pharmacoeconomic benefits of deferasirox in the management of iron overload syndromes.

Deferasirox is a once-daily, orally administered, tridentate iron chelator that is indicated in the treatment of iron overload resulting from regular packed red blood cell transfusions in patients with transfusion-dependent anemias, such as beta-thalassemia, sickle cell disease, myelodysplastic syndrome and other rare anemias. Randomized, controlled trials have established its efficacy to reduce liver iron concentration and serum ferritin levels to be comparable to the historic standard iron chelator, deferoxamine, which is administered as a parenteral infusion. However, deferasirox may be more effective than deferoxamine in actual clinical practice owing to the improvement in quality of life and, hence, increased compliance associated with the oral route of administration. The higher acquisition cost of deferasirox may be counterbalanced by savings in the administration cost, as well as the treatment of complications of iron overload that result from noncompliance with therapy attributable to the parenteral mode of administration. Deferasirox may also have potential as an important supplement and even an alternative to phlebotomies in nontransfusional, genetic iron overload disorders, such as hereditary hemochromatosis.

Differences in hepatic phenotype between hemochromatosis patients with HFE C282Y homozygosity and other HFE genotypes.

OBJECTIVE: There are limited data comparing hepatic phenotype among hemochromatosis patients with different HFE genotypes. The goal of this study was to compare hepatic histopathologic features and hepatic iron concentration (HIC) among patients with phenotypic hemochromatosis and different HFE genotypes. METHODS: We studied 182 US patients with phenotypic hemochromatosis. Degree of hepatic fibrosis, pattern of iron deposition, presence of steatosis or necroinflammation, and HIC were compared among different HFE genotypes. RESULTS: C282Y/H63D compound heterozygotes and patients with HFE genotypes other than C282Y/C282Y were more likely to have stainable Kupffer cell iron (31.1% vs. 9.5%; P=0.02), portal or lobular inflammation (28.9% vs. 15.6%; P=0.03), and steatosis (33.3% vs. 10.2%; P<0.01) on liver biopsy than C282Y homozygotes. Mean log10 HIC (P<0.05) and log10 ferritin (P<0.05) were higher among C282Y homozygotes than in patients with other HFE genotypes. In a logistic regression analysis using age, sex, HFE genotype, log10 ferritin, and log10 HIC as independent variables, log10 serum ferritin (P=0.0008), male sex (P=0.0086), and log10 HIC (P=0.047), but not HFE genotype (P=0.0554) were independently associated with presence or absence of advanced hepatic fibrosis. CONCLUSIONS: C282Y/H63D compound heterozygotes and other non-C282Y homozygotes which express the hepatic hemochromatosis phenotype frequently have evidence of steatosis or chronic hepatitis and lower body iron stores than C282Y homozygotes. These data suggest that presence of concomitant liver disease may explain expression of the hemochromatosis phenotype among non-C282Y homozygotes. Increased age, HIC, and ferritin are associated with advanced hepatic fibrosis, regardless of HFE genotype.