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Ebola: High Ferritin & GGT affect Disease Severity

We have added this page to discuss emerging concerns over the Ebola virus and describe the common disease mechanisms shared with other acute and chronic viral pathogens. As in most other other infectious diseases, Ebola can invoke the human iron withholding defense systems, promote oxidative and nitrosative stress, and deplete the body's antioxidant reserves. Ebola (and other severe viral infections) pose the greatest severity and mortality risks to those with impaired or weakened defenses coupled with high levels of potentially toxic iron. Most of the below article titles are linked to abstracts archived at the U.S. National Library of Science. Many articles also have Full free text PDF links. Other Science Library pages include:


Use this LINK for: Latest Ebola news and research from the

US National Library of Medicine - National Institutes of Health

This page reviews the epidemiologic, medical and scientific findings from a rapidly evolving body of literature covering threats from the spread of the Ebola virus. Almost all invasive pathogens require iron for at least one of several capacities. The most dangerous ones use iron both to inflict harm and multiply their species. Acute viral infections like Ebola utilize iron for the purpose of viral particle replication and to spread to nearby cells. According to Dr. Eugene Weinberg of Iron Disorders Institute's Medical & Scientific Advisory Board, "In contrast to fungi, protozoa and bacteria, viruses per se do not require iron. Nevertheless, host cells need the metal to catalyze synthesis of viral particles."  

Before addressing the Ebola virus specifically (full or alternate name: "Ebola Hemorrhage Fever"), we will introduce the topic of how iron is utilized by microbial pathogens to initiate, promote and sustain human diseases.


Iron availability and infection

In this 2009 review by Dr. Eugene Weinberg, the abstract noted, "To successfully sustain an infection, nearly all bacteria, fungi and protozoa require a continuous supply of host iron." "Mechanisms of microbial iron acquisition are determinants for the kinds of cells, tissues and hosts in which pathogens can flourish." "As a corollary, hosts possess an array of iron withholding devices whereby they can suppress or abort microbial invasions." "Awareness of environmental and behavioral methods that can prevent iron loading plus development of pharmaceutical agents that can block microbial access to iron may help to reduce our dependence on antibiotics." With specific reference to the HIV-1 virus, Dr. Weinberg noted from several cited studies that in HIV-1 virus infected cells, excessive iron increased reversed transcription activity significantly, caused a 90% reduction in the expression of HFE protein to result in a doubling of intra-macrophage iron and enhanced HIV synthesis. Dr. Weinberg also noted that in a set of 158 patients, increased ferritin was associated with a 1.67 increase in mortality; and in a study of 1,362 HIV patients, the odds ration of mortality with elevated transferrin iron saturation was 1.77 (P less than 0.001), or with heightened serum ferritin 1.40 (P =0.014) and of combined elevated iron status 2.20 (P =0.016).

 

Iron withholding: a defense against viral infections  Free full text

Health-e-Iron note: this extensive review was published in 1996. We recommend reading the full article as that will provide important background for understanding how damaging elevated iron levels can be, particularly when the body's antioxidant defenses are impaired. High GGT (as discussed further below and throughout this web site) has been consistently proved to be suppress the "Iron withholding defense system" and "enhance viral progression."  "A variety of laboratory and clinical investigations during the past 15 years have observed that one of the dangers of excessive iron is its ability to favor animal viral infections. The metal is essential for host cell synthesis of virions and can also impair defense cell function and increase oxidative stress. In both animal models and humans, viral infections cause upregulation of the iron withholding defense system. Factors that suppress the system enhance viral progression; factors that strengthen the system augment host defense. Procedures designed to reinforce the system are being developed and tested; some of these may become useful adjuncts in prevention and management of viral diseases."

 

The below study was published in August, 2014:

Ebola Hemorrhagic Fever: Novel Biomarker Correlates of Clinical Outcome  Free full text

This study was authored by researchers from the CDC together and Emory University School of Medicine. The investigators reviewed biochemical markers of 425 Ebola Hemorrhagic Fever (EHF) patients whose cases were reviewed following the 2000-2001 outbreak of Sudan virus-associated EHF in Uganda. Serum specimens had been preserved in liquid nitrogen since the dates of that outbreak. The investigators measured the serum concentrations of 55 biomarkers. They found that "Death and hemorrhage were associated with elevated thrombomodulin and ferritin levels. Hemorrhage was also associated with elevated levels of soluble intracellular adhesion molecule. Viremia was independently associated with elevated levels of tissue factor and tissue plasminogen activator." "Ferritin levels were also associated with viremia, independent of the associations with death and hemorrhage." The authors also noted: "Ferritin... is a well-established acute-phase reactant that has been associated with severe disease in both dengue and Crimean Congo hemorrhagic fevers. Ferritin is the intracellular storage form of iron, and its levels increase during times of stress or inflammation. Ferritin levels were higher in samples from patients with EHF who had fatal outcomes, detectable viremia, and hemorrhagic manifestations; thus, ferritin could prove to be a useful clinical maker of EHF severity." [Health-e-Iron note: Figure 1 and panels A and B from Figure 3 appear below] 

Figure 3.  Markers of inflammation associated with fatal outcomes (black bars) or hemorrhagic manifestations (red bars)

Below is a very recent full text scientific advisory from the CDC:

Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg Viruses  Free full text

This paper was published in October, 2014 by researchers at the Infectious Disease Pathology Branch of the CDC. "Ebola viruses and marburgviruses include some of the most virulent and fatal pathogens known to humans. These viruses cause severe haemorrhagic fevers with case fatality rates ranging from 25% to 90%." The researchers noted, "The most characteristic histopathological findings are seen in the liver: however findings overlap with many other viral and non-viral haemorrhagic diseases." "The pathogenesis of filovirus infections is complex and involves activation of the mononuclear phagocytic system with release of proinflammatory cytokines, chemokines and growth factors; endothelial dysfunction; alterations of the innate and adaptive immune systems; direct organ and endothelial damage from unrestricted viral replication late in infection; and coagulopathy." They also note that if death occurs, it is generally the result of "hypotensive shock and multi-organ failure, including hepatic damage and renal failure." And, "The liver has the most characteristic histopathological features in filovirus infections." [Health-e-Iron note: we will note throughout this page based on the scientific literature covering Ebola, other hemorrhagic fevers, other viruses such as HIV, and viral liver diseases such as HCV, specifically how derangement of iron metabolism and antioxidant deficiencies promote virulence and extensive rapid viral replication that can quickly defeat the body's ability to fend it off. We will also show the importance of maintaining healthy, normal iron levels and GGT levels as low as possible ]  


Emergence of Zaire Ebola Virus Disease in Guinea  Free full text

"In March 2014, the World Health Organization was notified of an outbreak of a communicable disease characterized by fever, severe diarrhea, vomiting, and a high fatality rate in Guinea. Virologic investigation identified Zaire ebolavirus (EBOV) as the causative agent. Full-length genome sequencing and phylogenetic analysis showed that EBOV from Guinea forms a separate clade in relationship to the known EBOV strains from the Democratic Republic of Congo and Gabon. Epidemiologic investigation linked the laboratory-confirmed cases with the presumed first fatality of the outbreak in December 2013. This study demonstrates the emergence of a new EBOV strain in Guinea." The investigators noted, "The clinical picture of the initial cases was predominantly fever, vomiting, and severe diarrhea. Hemorrhage was not documented for most of the patients with confirmed disease at the time of sampling but may have developed later in the course of the disease."

 

Elevated ferritin has only recently been significantly associated with severity and outcomes of Ebola (EHF), and since it compares with other acute virus-caused hemorrhagic fevers, we are supplying several comparable studies covering other hemorrhagic fevers directly below:

Increased serum ferritin levels in patients with Crimean-Congo hemorrhagic fever: can it be a new severity criterion?  Free full text

This was a 2010-reported study from Turkey. Similar to the adverse outcomes noted above for EHF in Crimean-Congo hemorrhagic fever "CCHF," fifty-one patients (77.3%) in this study had abnormal serum ferritin, with levels above 500 ng/ml in 62.1%. "There was a significant negative correlation between ferritin levels and concordant platelet counts (p<0.001; r=-0.416)and ferritin was also found to be positively correlated with aspartate aminotransferase (p<0.001; r=0.625), and alanine aminotransferase (p<0.001; r=0.479)..." "Receiver operating characteristic analysis revealed that a ferritin level of > or =1862ng/ml had a sensitivity of 87.5% and a specificity of 83.8% in differentiating severe cases from mild ones. The researchers concluded, "Increased serum ferritin levels may suggest a significant role of hemophagocytosis in the pathogenesis of CCHF and may be a useful marker for diagnosis, disease activity, and prognosis." [Health-e-Iron note: Figure 1. from this study appears below. See further below for a more complete description of hemophagocytosis.]

 

 

Can Serum Ferritin Level Predict Disease Severity in Patients with Crimean-Congo Hemorrhagic Fever?  Free full text

Similar to the study described directly above, this 2013-reported study from Iran describes a CCHF outbreak that occurred there in 2011 and 2012. The investigators reported, "...patients were categorized into two groups of mild and severe disease according to disseminated intravascular coagulation (DIC) [see description of DIC below].... Serum ferritin levels were evaluated and compared between these two groups. Receiver operating characteristic (ROC) curve analysis was performed to assess the optimal cutoff value of serum ferritin for predicting the disease severity." "According to DIC severity score, 54.7% of the patients had severe disease and 45.3% had mild disease." "The area under the ROC curve was 0.896 and 95% CI was 0.801-0.991 (p<0.0001). A cut-off point of 1060 ng/dL, had a sensitivity of 78.9%, a specificity of 87%, a positive predictive value of 6% and a negative predictive value of 100%. Positive and negative likelihood ratios for this serum ferritin level were 6.05 and 0.24, respectively." "the mean of serum concentration of fibrin degradation products was in patients with severe DIC was much higher than the mild DIC group (31.4 mg/L versus 8.4 mg/L) and the difference was statistically significant (p<0.0001)." "The mean of serum ferritin in patients classified as having severe DIC was approximately five times the mean serum ferritin concentration in patients with mild DIC." The researchers also noted that hemophagocytic lymphohistiocytosis [as described in the above study and further below] appeared to be an important contributed the the outcomes they reported. The investigators concluded, "Increased serum ferritin level has a significant positive correlation with disease severity in patients with CCHF and can evaluate the prognosis of these patients with a high sensitivity and specificity." [Health-e-Iron note: Figure 1 from this study appears below]

ROC curve analysis was also used to calculate, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio for different levels of serum ferritin

The investigators in this study suggested: "Given the fact that measurement of serum ferritin level is a fast and cost benefit lab test, it is suggested to be performed for all CCHF patients in endemic areas at their admission, so that the disease severity can be evaluated for early preparation of the required therapeutic and supportive measures." [Health-e-Iron adds this editorial note to the author's suggestion: Serum ferritin should be considered for screening all individuals, especially health care workers, located in areas exposed to high risks of infectious diseases. Appropriate prophylactic steps, including potentially iron reduction therapy, can be undertaken to prevent severe disease outcomes in situations where avoidance of the a pathogen might be unsuccessful] 

Dengue virus is another tropical virus that poses a severe threat to survival. The following papers describes how elevated ferritin indicates disease severity in infected individuals.

Ferritin levels predict severe dengue

This was a 2014-reported study that identified elevated ferritin as a risk factor for sever disease. The investigators noted, "a steady increase in the level of serum ferritin was recorded throughout the course of illness" ..."the elevated ferritin level could predict the disease severity with highest sensitivity and specificity of 76.9 and 83.3%." respectively" "... on the day of admission and the same was found to be 90 and 91.6% around defervescence." The investigators concluded, "On the basis of this diagnostic efficiency, we propose that ferritin may serve as a potential biomarker for an early prediction of disease severity." [Health-e-Iron note: The below image is published by Wikimedia. this suite of symptoms is very similar to the other acute infections, including Ebola, that can result in hemorrhagic fevers in their severe stages.]

 

 

 

Hyperferritinaemia in dengue virus infected patients is associated with immune activation and coagulation disturbances  Free full text

This was a 2014-reported study. "The aim of this study was to investigate whether hyperferritinaemia (high ferritin levels) in dengue patients was associated with clinical markers of extensive immune activation and coagulation disturbances." "Ferritin is an acute-phase reactant and hyperferritinaemia is a hallmark of diseases caused by extensive immune activation, such as haemophagocytic lymphohistiocytosis." "Levels of ferritin were significantly increased in dengue patients compared to patients with other febrile illnesses. Moreover, levels of ferritin associated significantly with the occurrence of viraemia. Hyperferritinaemia was also significantly associated with thrombocytopenia, elevated liver enzymes and coagulation disturbances. The researchers concluded, "...ferritin can also serve as a marker for highly active disease resulting in extensive immune activation, coagulation disturbances and severe clinical symptoms. Therefore, we suggest that patients with hyperferritinaemia are monitored carefully, as they are at higher odds to develop severe disease." [Health-e-Iron note: This study provides an important distinction. Ferritin is one of several molecules that increase in response to the onset of acute infectious diseases. The presence of any infection can result in a high fever (i.e., febrile illness) that can and often does cause a spike in serum ferritin levels. However, unless those infections cause a loss of cell integrity, such as in cell membrane damage causing leakage of red blood cell, macrophage and lysosome contents into the blood stream, such serum ferritin spike would generally not exceed an increase of 100 to perhaps 300 ng/ml. Increases of that magnitude can occur in chronic inflammatory disease as well. In the latter circumstances, however, affected individual will often have fairly low serum iron and iron transferrin saturation levels and have a much larger component of their total iron stores sequestered in macrophage ferritin spread in tissue through the body. That iron represents a potential threat of increased virulence should one of these life-threatening pathogens get beyond or exhaust the body's defense systems.] 


The below reviews provides more information on what Hemophagocytic Syndromes and Disseminated Intravascular Coagulation (DIC) are, and how these conditions are implicated in infectious disease risks, severity and mortality.

Hemophagocytic Syndromes and Infection  Free full text

Authored by David N. Fisman, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. Some text from the last paragraph of this review: "Hemophagocytic syndromes associated with other infectious illnesses, including sepsis, typhoid fever, tuberculosis, and leishmaniasis, may resolve with treatment of the underlying infection, and their recognition is important as they may mimic malignant disease. Further study of these reactive hemophagocytic syndromes may yield important insights into the biology of macrophage activation." The author cited several references in stating, "Most patients have hypertriglyceridemia and marked elevation of ferritin. Serum fibrinogen is typically low, and there may be disseminated intravascular coagulation. Elevated circulating fibrin degradation products and serum ferritin in patients with HLH appear to be associated with increased risk for death."

 

Disseminated Intravascular Coagulation Free full text from Medscape; or as described on this web page LINK to the National Heart Lung and Blood Institute

The below study describes an interesting link between high levels of nitric oxide (NO) and disease severity and mortality in Ebola (Sudan) Hemorrhagic Fever

Analysis of Human Peripheral Blood Samples from Fatal and Nonfatal Cases of Ebola (Sudan) Hemorrhagic Fever: Cellular Responses, Virus Load, and Nitric Oxide Levels   Free full text

This was a study published in 2004 that was based on a 425 presumptive cases of Ebola (Sudan strain) which occurred in northern Uganda. The investigators noted that the infections were characterized by immunosuppressed states and that Ebola virus replication was prominent in the liver, spleen, lungs and vascular systems; and further that the hepatocytes, mono-nuclear phagocytic cells, and endothelial cells support virus replication. The investigators performed quantitative analysis on the patients that died and on those who survived. The nitric oxide (NO) levels in the patients who died was elevated most prominently near the time of death. The patients that survived showed only a slight increase, mainly during days 4 to 7 following the onset of symptoms. The researchers noted the high NO levels were similar to those observed during high viral load in HIV-infected patients and those produced during systemic inflammatory and sepsis. They further cited research noting that extremely high NO levels could lead to the formation of potent oxidants, cardiac distress, heart failure and fatal shock syndromes[Health-e-Iron note: Figure 6 from this study appears below:] 

 

 

 We will start describing the relationship of high serum ferritin, elevated NO, and severe disease end points with elevated free-toxic iron, and impaired antioxidant defenses:

Nitric Oxide Measurements during Endotoxemia  Free full text

The researchers of this 2001-reported rat study how continuous release of NO over extended time periods under pathological conditions as noted in endotoxemia contributes significantly to circulatory failure, hypotension, and septic shock. They cited referenced to support their statements that, "The increase in NO leads to myocardial depression and vascular dysfunction associated with vasorelaxation and hypotension. Decreased skin perfusion, reduced mental alertness, and increased serum lactate concentrations are also characteristics of endotoxemia. Endotoxemia remains the main cause of death in intensive care units. It has a mortality rate in the US of 50–60%. This investigation informed the researchers to conclude that, "The direct measurement of NO concentrations in the rat pulmonary artery demonstrates dynamic changes throughout endotoxemia, which are related to the production of superoxide and the subsequent increase in peroxynitrite. Monitoring endotoxemia with total nitrate plus nitrite is not sensitive to these fluctuations in NO concentration."

 

Nitric oxide and infectious diseases  Free full text

This is a comprehensive review of the literature covering the relationship between NO and infection diseases.

 

Biosynthesis of nitric oxide activates iron regulatory factor in macrophages Free full text

The reviews and studies directly about note the presence of the central role of macrophages and nitric oxide (NO) in the major features of EHF. This earlier, 1993-reported, study noted the "NO is a free radical with a strong affinity for iron."

 

 Ebola Hemorrhagic Fever and Septic Shock  Free full text

This was a very interesting 2003 editorial review authored by two investigators at the National Institute of Allergy and Infectious Diseases (NIAID). They noted findings that the virus had been showed to infect dendritic sites and impair antiviral activity limiting an adaptive immune response in the host. As described above, they noted early disease factors could trigger disseminated intravascular coagulation (DIC). Their synthesis of relevant literature suggested that a "bi-modal" diseases model existed that was very similar to bacterial sepsis. They noted the "pathogen either is successfully cleared by early host responses without causing disease or else escapes these mechanisms and produces systemic illness." The researchers also noted that the comparison of EHF with septic shock suggested that the most important shared feature is the central role of the macrophage in inducing some of the major features of the disease. [Health-e-Iron note: this review suggests that such variable EHF disease expression could be reduced to a set of simple, easy-to-test, predictive biomarkers. The observation that not everyone who becomes infected dies provides important confirmation that protective features can and do prevent extreme virulence, high viral replication counts and death. The statement from above "cleared by early host responses" is confirmation that just contracting an Ebola virus is insufficient to cause death. We will explain that achieving and maintaining both healthy iron levels and low GGT levels are essential components of achieving what just could be life-saving protection.]

More than two decade ago high serum and red cell ferritin were described as significant risk factors for HIV infections. The following study from 1994 provides a good example of some of these earlier studies that first tied iron and ferritin to HIV-AIDS.

Prevalence of high serum and red cell ferritin levels in HIV-infected patients  Free full text

This was a 1994-reported study of 168 Spanish patients infected with the HIV virus. The researchers reported, "Serum ferritin levels (SF) increase with clinical worsening of infection and with decreasing CD4+ lymphocyte counts (ANOVA, p<0.001)." The researchers noted, "Ferritin and iron overload have been linked to a variety of immunosuppressive effects on cell mediated immunity in vitro. We observed a high prevalence of increased SF levels in our patients and their gradual increase with progression of the disease and decrease of CD4+ lymphocyte counts." "The highest mean SF level was found in group 3 and the lowest in group 1. The highest mean red cell ferritin levels were found in group 2. The serum ferritin of the Group 1, the asymptomatic patients had a mean SF of 112 ng/ml.This is a serum level considered to be within the normal serum ferritin range for most men and women. The investigators suggested, "iron overload may contribute to worsen infectious complications in HIV-infected patients and to immunosuppression through inhibitory effects on cell-mediated immunity by ferritin." The group 3 patients were symptomatic, had the highest serum and red blood cell ferritin and expressed the greatest susceptibility to infection. [Health-e-Iron note: Table 2 from this study appears below]

 The above study, from 20-years ago, demonstrated the toxic role of high iron stores in HIV infection. It is certain that low-normal iron stores will help prevent the spread of HIV infection and viral replication, however, ever after two decades of intensive further investigation of the role of iron in HIV infection, the science as to whether chemical iron chelation of HIV-infected cells would protectively reduce HIV-1 transcription and replication remains unsettled. The below study reviews some of the literature on the association of iron stores with HIV with emphasis on the interplay between cellular iron transport and sequestration.   

 

Hepcidin induces HIV-1 transcription inhibited by ferroportin  Free full text

There are several good papers that review the evolving science covering the iron-regulatory functions of ferroportin and hepcidin on Health-e-Iron's Insulin resistance page. The investigators concluded, "Our results suggest that the interplay between ferroportin-mediated iron export and hepcidin mediated degradation of ferroportin might play a role in the regulation of HIV-1 transcription and may be important for understanding of HIV-1 pathogenesis." In the literature review sections of this study, the authors describe prior studies that noted..."Hepcidin binds to ferroportin, and this leads to ferroportin internalization and degradation by lysosomes. Cellular iron is important for HIV-1 transcription, as its removal by iron chelators is associated with inhibition of HIV-1 transcription in cultured cells." And that human studies "Increased iron stores correlated with faster HIV-1 progression in HIV-1- positive thalassemia major patients, in HIV-positive patients given oral iron and in HIV-positive subjects with the haptoglobin 2-2 polymorphism. Survival of HIV-positive patients correlated inversely with higher iron stores in bone marrow macrophages." "Non-anemic HIV-positive women in Zimbabwe with increased serum ferritin concentration had increased viral load, suggesting that high iron stores may adversely affect HIV infection. Elevated iron predicted higher mortality in Gambian adults infected with HIV-1."


Below is the most recent study (August, 2014) of hepciden, the iron regulatory hormone, in connection with three different viruses, HIV-1, HBV, and HCV.

Distinct patterns of hepcidin and iron regulation during HIV-1, HBV, and HCV infections  Free full text

Data from this most recent paper on iron regulation in three different viruses indicates that the Ebola virus strains might be most similar to HIV-1 in terms of iron regulation; however, that statement cannot be made without further proof. The common ground shared by all three of these viruses, and perhaps by Ebola as well, could be summarized by this "Significance" statement that highlights the points established by this study:

"Altered iron levels correlate with disease progression in HIV type-1 (HIV-1) infection, and cellular iron promotes HIV-1 replication. In chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, increased liver iron levels contribute to disease. The peptide hormone hepcidin controls iron distribution. We find that hepcidin increases during the acute phase of HIV-1 infection, early hepcidin predicts later plasma viral set-point, and hepcidin remains high even in chronically infected individuals receiving antiretroviral therapy. Conversely hepcidin is not induced, and blood iron is not decreased, during the acute response to HBV and HCV. Therefore, the nature of iron redistribution during the response to infections is a pathogen-specific phenomenon; furthermore, the deleterious effects of chronic infection on hepcidin and iron appear to be established early in infection." [Health-e-Iron note: differentiation of virus types and strains will be integral to disease management once an infection strikes. However, since iron overload in any form poses a pathologic threat, and it might be many years before the science of treating deranged iron homeostasis during active Ebola infection is established, the safe preventive measure would be to take steps to ensure existing iron levels are within the bounds of normal levels. Many American populations have elevated iron stores, a condition that is certainly more common that iron deficiency, which can also be troublesome in controlling infections diseases.]

Iron status in HIV-1 infection: implications in disease pathology Free full text

In this 2012-reported study from Nigeria, investigators studied the iron status and clinical measures of 80 anti-retroviral naive HIV-1 positive and 50 sero-negative controls. "Concentrations of serum total iron, transferrin, total iron binding capacity (TIBC), CD4+ T -lymphocytes, vitamin C, zinc, selenium and transferrin saturation were estimated." The investigators found significant iron derangement among the HIV-1 positive subject, but not among the controls. Based on their analysis, the concluded, "It could be inferred that derangement in iron metabolism, in addition to oxidative stress, might have contributed to the depletion of CD4+ T cell population in our subjects and this may result in poor prognosis of the disease." [Health-e-Iron note: Tables 1 & 2 from this study are below]



 

Viral pathogens utilize iron to damage cells, tissue and DNA by catalyzing oxidative and nitrosative stress. The body's most effective defenses are its cellular reserves of glutathione (GSH). As described on other pages and in GGT sections on this web site, GGT levels measured in the serum correlate inversely and strongly with cellular GSH. Also, high GGT levels can cause the leakage of iron from otherwise protective iron storage and transit proteins, which exacerbates the destruction processes. In the context of life-threatening viral infections, GGT is most studied as a predictor of adverse clinical outcomes and mortality, and impairment of the body's ability to launch effective virological responses and to respond favorably to pharmaceutical drugs with proven efficacy in patients with lower iron stores and GGT levels.   

Revisiting predictors of virologic response to PEGIFN + RBV therapy in HIV-/HCV-coinfected patients: the role of metabolic factors and elevated GGT levels  Free full text

This was a 2014-reported study of 64 Austrian patients who were coinfected with both HIV and HCV. The investigators also included a validation cohort of 124 patients who were also infected with both viruses. The researchers reported, "In HCV-monoinfected patients, the association between elevated gamma-glutamyltransferase (GGT) levels and virologic response has been intensively studied. In contrast, in HIV/HCV, no association between GGT levels and virologic response has yet been reported." "The aim of this study was to evaluate metabolic factors and elevated GGT levels as independent predictors of treatment failure in a thoroughly documented cohort of HIV/HCV." Interestingly, "advanced liver fibrosis (OR 1.64; 95%CI 0.7–3.84; P = 0.259) was not an independent predictors of treatment failure." In both study cohorts, elevated GGT emerged as an independent predictor of treatment failure. The researcher concluded, "Our findings suggest that GGT elevation is an independent predictor of treatment failure in HIV/HCV that can easily be incorporated into predictive algorithms." [Health-e-Iron note: Figures 1 and 2 from this study appear below]

We below-provide several links to other U.S. National Library of Medicine journal articles in which additional proof of is provided describing how elevated GGT impairs the body's ability to derive benefit from standard pharmaceutical treatment for hepatitis-C virus (HCV):

Insulin resistance predicts rapid virological response in non-diabetic, non-cirrhotic genotype 1 HCV patients treated with peginterferon alpha-2b plus ribavirin

Estimating the likelihood of sustained virological response in chronic hepatitis C therapy

Peginterferon plus ribavirin and sustained virological response in HCV-related cirrhosis: outcomes and factors predicting response

Gamma-glutamyltransferase and rapid virological response as predictors of successful treatment with experimental or standard peginterferon-alpha-2b in chronic hepatitis C non-responders

Revisiting predictors of virologic response to PEGIFN+RBV therapy in HIV-/HCV-coinfected patients: the role of metabolic factors and elevated GGT levels

The determination of GGT is the most reliable predictor of nonresponsiveness to interferon-alpha based therapy in HCV type-1 infection

Low Rates of Sustained Virologic Response with Peginterferon Plus Ribavirin for Chronic Hepatitis C Virus Infection in HIV Infected Patients in Rio de Janeiro, Brazil


 

Association of γ-glutamyl transferase (GGT) activity with treatment and clinical outcomes in chronic hepatitis C (HCV)  Free full text


This was a 2013-reported study from the
HALT-C Study in the US. The investigators noted, "We examined GGT as a predictor of both virological response to treatment and long-term clinical outcomes in the Hepatitis C Anti-viral Treatment Against Cirrhosis Trial (HALT-C). Analyses were performed for 1,319 patients who had GGT measured prior to initiation of treatment. Increases in risk with each increase in quintile of GGT (10-57, 58-89, 90-139, 140-230, 231-2,000 IU/L) were determined. Baseline GGT was associated with male sex, nonwhite ethnicity, diabetes and insulin resistance, interleukin (IL)... and numerous markers of liver disease injury and severity. In the lead-in phase, increasing GGT was strongly associated with diminished week 20 response, end of treatment response, and sustained virological response in both univariate and multivariate analyses controlling for factors known to be associated with treatment response (P < 0.0001). GGT was also associated with all clinical outcomes in univariate and multivariate analysis (P < 0.05) except for hepatocellular carcinoma (P = 0.46 in multivariate analysis). The researchers concluded, "GGT is an independent predictor of both virological response and clinical outcomes among patients with advanced liver disease due to HCV." [Health-e-Iron note: Figure 1 from this study is below]

Fig. 1. Association of quintile of GGT activity (IU/L) with probability of virological response during the lead-in phase of HALT-C. EVR, early virological response; SVR, sustained virological response.


 

Circulating Biomarkers of Iron Storage and Clearance of Incident Human Papillomavirus Infection  Free full text

The researchers in this 2012 study provided this background and hypothesis: "Iron is an essential mineral for both cellular and pathogen survival and is essential for viral replication. In turn, iron metabolism has been shown to be altered by several viral infections. However, little is known regarding the association between iron status and HPV natural history. We hypothesize iron to be an HPV-cofactor that is associated with longer duration of infection."  "Ferritin and soluble transferrin receptor (sTfR) were measured in baseline serum samples from 327 women." "Women with ferritin levels above the median were less likely to clear an incident oncogenic HPV... and HPV-16 infections ... Using physiological cut-points, women with enriched iron stores (>120dg/mL) were less likely to clear incident oncogenic HPV infections compared to those with low-levels of iron (<20dgm/L)( AHR=0.34; 95%CI 0.15-0.81). the researchers concluded, "This study observed that women with the highest ferritin levels were less likely to clear incident oncogenic and HPV-16 infections compared to women with low ferritin. Rising iron stores may decrease probability of clearing new HPV infection, possibly by promoting viral activity and contributing to oxidative DNA damage. Impact: This novel study suggests that elevated iron stores may put women at risk for persistent HPV infection, an early event in cervical carcinogenesis. Further examination of the association between iron status and HPV natural history is warranted." [Health-e-Iron note: for those unfamiliar with the context of the word "reduces" in relation to iron, it does not mean a reduction in the quantity of iron, but rather it refers to to a change of iron molecules from a relatively benign state to a potentially highly toxic one that can promote dangerous biochemical reactions within the body including oxidative damage, the production of free radicals and the growth of many pathogens]

 

Iron loading and disease surveillance  Free full text

This 1999 review and the accompanying full paper describe, "Iron is an oxidant as well as a nutrient for invading microbial and neoplastic cells. Excessive iron in specific tissues and cells (iron loading) promotes development of infection, neoplasia, cardiomyopathy, arthropathy, and various endocrine and possibly neurodegenerative disorders. To contain and detoxify the metal, hosts have evolved an iron withholding defense system, but the system can be compromised by numerous factors. An array of behavioral, medical, and immunologic methods are in place or in development to strengthen iron withholding. Routine screening for iron loading could provide valuable information in epidemiologic, diagnostic, prophylactic, and therapeutic studies of emerging infectious diseases." [Health-e-Iron note: Tables 1 and 2 from this paper appear below]

 

 

Histoplasma capsulatum secreted gamma-glutamyltransferase reduces iron by generating an efficient ferric reductant  Free full text

In this 2008 study the University of Wisconsin note, "The intracellular fungal pathogen Histoplasma capsulatum (Hc) resides in mammalian macrophages and causes respiratory and systemic disease. Iron limitation is an important host antimicrobial defense, and iron acquisition is critical for microbial pathogenesis. Hc displays several iron acquisition mechanisms, including secreted glutathione-dependent ferric reductase activity (GSH-FeR). Observations from this laboratory study provide insight into the biological process that this pathogen employes through GGT expression and the consequent reduction of ferric iron to highly catalytic ferrous iron, a process that promotes the survival and growth of this fungal pathogen."


Ferritin as an Iron Source for Pathogens Free full text* (see below)

[Health-e-Iron note*: the publishers of this 2012 book have make this chapter available as a "Free Access" document. If you link to the abstract you can access the full text in a PDF format. However there are restrictions covering duplication of the material contained therein, and we may not store the document on our web site, nor replicate some of the tables contained in the chapter] The authors describe how some pathogens are able to destroy cells and tissue and gain "easy access to ferritin and make use of its iron." "Due to the high amount of iron atoms that ferritin is able to capture, this protein is really a remarkable iron source for every intracellular pathogen." "In the literature, there are only a few reports about pathogens using ferritin as an iron source, but this is an exciting growing field of research. Each pathogen has developed its own manner to obtain iron from ferritin:.." The authors describes the various mechanisms by which many different pathogenic invaders can free iron from ferritin. Table 1 starting on page 5 of this chapter cites the scientific names of  10 such microorganism (8 bacteria, 2 parasite and 1 fungi), the known iron acquisition systems from ferritin and the tissue or organ sites where the microorganisms obtain ferritin. We have reproduced parts of this table below the scientific names of the microorganisms, their common names and the tissue or organ sites where ferritin is obtained:

 

Microorganism
Common Name or related illness

Tissue of Organ Site where microorganism obtains ferritin

 Bacteria    
Bacillus cereus
 food sickness
 intestinal cells, oral epithelium, retinal tissue, CNS, blood, liver, striated muscle, skin, heart tricuspid-valve
Burkholderia cenocepacia
common in cystic fibrosis and granulomatous diseases
 Lungs, macrophages, epithelial cells
Escherichia coli, and Yersinia pestis

1. E. coli    2. the plagues

 E. coli: intestinal cells, urinary tract, kidneys, CNS, blood

Yerisinia pestis: blood, lungs, lymph nodes, macrophages

Listeria monocytogenes
Listeria  Intestinal cells, macrophages, hepatocytes, epithelial cells, fibroblasts, endothelial cells, neurons
Mycrobacterium spp
non- tuberculosis mycrobacterium
 Lungs, macrophages
 Neisseria meningitidis
 meningococcal diseases  Respiratory tract, blood, CNS
Streptococcus pyogenes
Group A Strep infections
 Lungs, throat, epithelium, skin
 Parasite    
Entamoeba histolytica
Protozoan infection
 Blood, brain, instestinal cell, hepatocyte, lungs
Trichomonas vaginalis
Sexually transmitted infection
 Vaginal muscosa
 Fungi    
Candida albicans
Yeast infection
 Vaginal, oral-pharyngeal, and gastrointestinal mucosae; blood, CNS, internal organs like lungs and heart

 

Iron availability increases the pathogenic potential of Salmonella typhimurium and other enteric pathogens at the intestinal epithelial interface  Free full text

Reported in 2012, this research team noted, "Recent trials have questioned the safety of untargeted oral iron supplementation in developing regions. Excess of luminal iron could select for enteric pathogens at the expense of beneficial commensals in the human gut microflora, thereby increasing the incidence of infectious diseases." The researchers observed in this laboratory study that, "Growth of Salmonella typhimurium and other enteric pathogens was increased in response to iron." The researchers concluded, "our data fit with the consensus that oral iron supplementation is not without risk as iron could, in addition to inducing pathogenic overgrowth, also increase the virulence of prevalent enteric pathogens." [Health-e-Iron note: Figure 1 and Table 2 from this research appear below]

Figure 1. Effect of iron on growth of enteric bacteria. Effect of various concentrations of ferric citrate on in vitro growth of (A) S. typhimurium, (B) C. freundii, (C) E. coli, (D) E. faecalis and (E) L. plantarum. 

 

Figure 2. Effect of iron on bacterial adhesion to an epithelial monolayer. Adhesion (mean+SD) of enteric bacteria to a monolayer of Caco-2 cells is given as percentage of the inoculum. A: S. typhimurium, n=8. B: C. freundii, n=4. C: E. coli, n=6. D: E. faecalis, n=6. E: L. plantarum, n=5. Means without a common letter differ, P,0.05. Notably, adhesion data of S. typhimurium were derived from 4 separate experiments performed at 13, 15, 18 and 21 days post-seeding of Caco-2 cells. The fact that each experiment revealed the same trend is indicative for similar physiochemical properties of the monolayer at these time points. 

 

Regulatory interactions for iron homeostasis in Aspergillus fumigatus inferred by a Systems Biology approach  Free full text

The researchers in this 2012 study noted, "Aspergillus fumigatus is a major human fungal pathogen. One important virulence trait is its ability to gain sufficient amounts of iron during infection process. Even though some regulatory interactions are known, we are still far from a complete understanding of the way iron homeostasis is regulated." In this paper the researcher employ a Systems Biology approach (an interlocking circle between experimental and theoretical work) to deduce the role of iron metabolism in several pathogens.

 

Hepatic iron overload is common in chronic hepatitis B and is more severe in patients coinfected with hepatitis D virus 

In this 2012 study from Italy the researchers noted, "Hepatic iron overload has been described in chronic hepatitis C as a cofactor affecting fibrosis progression. Data in patients with chronic hepatitis B infection are scarce. We investigated hepatic iron deposits and serum iron indices in 205 consecutive patients with hepatitis B and compensated liver disease. Mean age of the patients was 42.4 ± 12.4 years and 72.5% were males." "Hepatic iron deposits were detected in 35.1% of patients, most of them being minimal (grade I) (59.7%) or mild (grade II) (27.8%). Variables significantly associated with hepatic iron deposits were male gender (P = 0.001), serum ferritin (P = 0.008), GGT (P = 0.05) and alkaline phosphatase (P = 0.05) levels." "A significant correlation between coinfection with HDV and hepatic iron deposits was also found (OR 4.23, 95% CI 1.52-11.82, P = 0.003). When compared to monoinfected cases, HDV positive patients had more elevated GGT (P = 0.03), more advanced fibrosis and more severe iron deposits (P < 0.0001)." "In conclusion, in well-compensated chronic hepatitis B infection, hepatic iron deposits and elevation of serum iron indices are common, especially in male gender and in patients coinfected with HDV. As HBV/HDV liver disease is generally more rapidly progressive than that caused by HBV monoinfection, we speculate that iron overload may be one of the factors contributing to the severity of liver disease." 


Siderophore-mediated iron acquisition in the staphylococci 

This is a 2010 review of the uptake mechanisms utilized by staphylococci to obtain iron molecules from animal hosts.

 

Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy 

In this large 2012 European study the researchers reported, "...serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N = 970), fibrosis (N = 980), steatosis (N = 886), and response to treatment (N = 876)." "We found that serum ferritin ≥ the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.34-0.60). This association remained highly significant in a multivariate analysis (P = 0.0002, OR = 0.35, 95% CI = 0.20-0.61)..." "Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR = 2.67, 95% CI = 1.68-4.25) and steatosis (P = 0.002, OR = 2.29, 95% CI = 1.35-3.91), but not with necroinflammatory activity (P = 0.3).  The researchers concluded, "In patients with CHC (chronic hepatitis C), elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy."

 

Iron homeostasis--Achilles' heel of Aspergillus fumigatus? Free full text

In this 2011 research from Austrian investigators, an interesting hypothesis is explored, "The opportunistic fungal pathogen Aspergillus fumigatus adapts to iron limitation by upregulation of iron uptake mechanisms including siderophore biosynthesis and downregulation of iron-consuming pathways to spare iron. These metabolic changes depend mainly on the transcription factor HapX. Consistent with the crucial role of iron in pathophysiology, genetic inactivation of either HapX or the siderophore system attenuates virulence of A. fumigatus in a murine model of aspergillosis. The differences in iron handling between mammals and fungi might serve to improve therapy and diagnosis of fungal infections." [Health-e-Iron note: Figures 1 and 2 from this research appear below]

A. fumigatus mechanisms for iron uptake and storage. (a) Schematic summary of iron uptake and storage mechanisms. (b) Siderophore structures. R = H in FsC and R = acetyl in TAFC; the hydroxylation site in FC is unknown. (c) Siderophore biosynthetic pathway. See text for details.

 

Fatal laboratory-acquired infection with an attenuated Yersinia pestis Strain--Chicago, Illinois, 2009  Free full text

The CDC published this report in 2011 on a widely publicize event that occurred in 2009 when a laboratory worker died after contact with an attenuated strain of Yersinia pestis (the "plague"). The patient was later found out to have undiagnosed hereditary hemochromatosis (HHC). The CDC hypothesized, "One possible explanation for the unexpected fatal outcome in this patient is that hemochromatosis-induced iron overload might have provided the infecting KIM D27 strain, which is attenuated as a result of defects in its ability to acquire iron, with sufficient iron to overcome its iron-acquisition defects and become virulent."

 

A new article from Scientific America:

How Ebola Blindsides the Body's Defenses

“Although it contains only seven genes, Ebola is an exquisitely effective killer of humans and other primates once it enters a body. Unlike the spiky sea urchin that is influenza, or the golf-ball shaped poliovirus, Ebola resembles noosed ropes under the electron microscopes used to capture viral images." Credit: NIAID via Wikimedia Commons


Can People Receiving Live Virus Vaccines Transmit Vaccine Strain Virus to Others?

Dr. Mercola Interviews Barbara Loe Fisher

“Barbara Loe-Fisher is the co-founder and president of the National Vaccine Information Center (NVIC), a non-profit charity dedicated to preventing vaccine injuries and deaths through public education and defending the legal right for everyone to make vaccine choices.” LINK to article and video interview


Several studies summarized to the left emphasize that elevated serum ferritin is significantly related to poor outcomes including mortality in infected patients. Link on the study entitled directly below which provides mortality findings in the general population of Denmark for a population of 8,988 of which 6,364 died over a median follow-up of 23 years.

Total and Cause-Specific Mortality by Moderately and Markedly Increased Ferritin Concentrations:
General Population Study and Metaanal
ysis

Current life expectancy in Denmark is 80 years. Key findings of this study were: 

  • When baseline SF was ≥600 µg/L, mean survival was 55 years
  • When baseline SF was between 400-599 µg/L, mean survival was 72 years
  • When baseline SF was between 200-399 µg/L, mean survival was 76 years
  • When baseline SF was between <200, mean survival was 79 years

Corresponding adjusted HRs for ferritin ≥600 vs <200 g/L were 1.6 (1.1–2.3;P = 0.01) for cancer mortality, 2.9 (1.7–5.0; P = 0.0001) for endocrinological mortality, and 1.5 (1.1–2.0; P = 0.01) for cardiovascular mortality. [Health-e-Iron note: Figure 3 from this study is replicated below]:

Fig. 3. HRs by increasing ferritin concentration (g/L) for total mortality (A), cancer mortality (B), endocrinological mortality (C), and cardiovascular mortality (D).