Saturday, May 31, 2014

Amanda Boston ~ Panhematin Story

Amanda Boston ~ Panhematin Story

Type of Porphyria: 
Variegate Porphyria (VP)
I had the most amazing privilege participating in the “7203: A double-blind, randomized, placebo-controlled, parallel group trial on the efficacy and safety of Panhematin® in the treatment of acute attacks of porphyria” research study. I met two amazing Doctors that I had only spoken with through email and telephone: Dr. Karl Anderson and Dr. Akshata Moghe. 

The research was performed in Galveston, TX at the UTMB. I was flown into Houston and transported to Galveston. I stayed at the Harbor Hotel until I developed symptoms of an attack, which occurred two days after I arrived, as my attacks are very frequent. For the research, I was blindfolded, the drapes were drawn and foil wrap was put on the cords, so that I wouldn't know if I were getting a placebo or Panhematin™, but my body knows the difference. I was started on the research, but my headaches and abdominal pain was only getting worse. I was about to start an attack. So the rescue treatment, which is Panhematin™, was brought in and administered to me. I felt better the next day. I stand by Panhematin™ , and I truly believe that it is an effective treatment for Porphyria. 
My whole reason for doing this research was to help others and to show that Panhematin does work. When I first got to the UTMB for the research, I found out that I was the first research patient on this particular study. That is a wonderful privilege. I feel a great sense of accomplishment by participating in the Panhematin research study. I feel that I really accomplished my goal, because I was given the opportunity to help others. I thank the APF for helping me to make my goal a reality. Dr. Anderson is the one who developed and oversaw the research. He is an amazing Doctor and Porphyria expert. He knew exactly what I needed from the moment I walked into the research clinic.   I've never met a Doctor that was so educated on Porphyria and so devoted to the research and helping one’s suffering from Porphyria. Also, he is the nicest person you will ever meet. If anyone with Porphyria has the chance and is thinking about being on a research study, I would suggest that you take that opportunity. It is the greatest privilege you will ever have.

Amanda Boston  All of our thoughts and prayers go out to you and your family during your Loss Amanda...

"Remember....Research is the key to your cure!"

Friday, May 30, 2014

EPP Kids' Program

EPP Kids' Program

Camp Discovery Summer Time Parents and Kids!

Camp Discovery offers a wonderful summer camping experience for young people with skin disorders like porphyria.
Every year, the American Academy of Dermatology sponsors a week of fishing, boating, swimming, water skiing, arts and crafts, and just plain fun.
Under the expert care of dermatologists and nurses, Camp Discovery offers the opportunity of spending a week among other young people who have similar skin conditions. Many of the counselors have serious skin conditions as well, and can provide support and advice to campers.
Fun, friendship, and independence are on the top of everyone's agenda. And, everyone shares in the discovery of what it's like to be included.
There is no fee for camp. Full scholarships, including transportation, are provided by the American Academy of Dermatology through generous donations of their Sponsors and other organizations. Sponsors of the Academy are asked to recommend candidates for Camp Discovery.
You might want to ask your dermatologist about the camp and suggest that he/she recommend your child.
Disneyland and Disney World for EPP Kids
Disneyland and Disney World are responsive to people with sun sensitivity. They will provide a pass to enable you to enter attractions without waiting in line in the sun.
Disneyland
Go to "City Hall" and explain your problem of photosensitivity. You should bring a physician's letter with you as well as an APF brochure explaining the cutaneous disorder.
Disney World
Proceed to the "Guest Relations" office at any of their parks (Magic Kingdom, EPCOT, etc.) and request the Special Assistance Pass.
remember to bring the aforementioned documentation because your disability is not necessarily visible. People on duty may not be familiar with light sensitivity and its consequences.

"Remember....Research is the key to your cure!"

Wednesday, May 28, 2014

Join APF In Touch

Join APF In Touch

Because porphyria is a rare disease (defined as affecting fewer than 200,000 sufferers in the U.S.), many newly diagnosed patients have never even heard of the condition before, let alone met someone else who suffers from it. We created the APF In Touch network to meet this need.
APF membership includes access to the In Touch network, through which members can contact others around the country who are dealing with porphyria. Some members form lasting friendships via email, telephone or old-fashioned letters. Others prefer to reach out to members in their region and organize face-to-face get-togethers.
If you are seeking support and fellowship, or are willing to be there for others who are dealing with porphyria, please fill out and send in the In Touch consent form to our address below. For more information on the APF In Touch network, contact the APF office: 866-APF-3635 or 713-266-9617.
American Porphyria Foundation
4900 Woodway, Suite 780
Houston, TX 77056
What the In Touch network has done for me:
I want to share my experience with the In Touch network provided to us by the Foundation. I was diagnosed with AIP after 18 months of symptoms. You know the severe abdominal and back pains with fatigue and nausea. You all know the drill. The scariest part was the rarity of this disease. Every doctor tells you they're not that familiar with it, and very little was actually known about it. People look blankly at you when you try to explain how you feel. I don't have to elaborate to you all that also have it. So I decided to communicate with someone else that had this illness.
This was back in 2001, the time before the wonderful website that we are so blessed with now. So I opened the newsletter and looked at the names before me. I knew that I wanted someone that also had AIP. So I closed my eyes and asked God to help me chose the right one. I opened my eyes and there she was. Lori Brown from Madison, Alabama. I am from Arkansas so she was geographically close to me. I emailed her and introduced myself to her, telling her all of my experiences so far and asked if she would like to share "war stories." She emailed back and was more than happy to do just that. So over the next 7 years Lori and I battled porphyria together.
After a while Lori and I began calling each other on the telephone. Some of our conversations lasted for two hours! We discussed how the disease affected our marriages, children and our lives in general. I don't know if it was misery loves company but I can tell you she helped me so much. To have someone who understands what you are going through is great. I didn't feel alone.
On October 16, 2008 Lori Brown from Madison, Alabama passed away. The battle with porphyria is over. She is free. I never got the privilege of seeing her face or giving her a hug. But she was one of my best friends. So if you are thinking about getting in touch with someone and just haven't done it yet I encourage you to find yourself a Lori too. Find several. I have others as well: Rose, Mira, Judy, Jennifer and Troy. Or attend a meeting scheduled near you. Or reach out and host one yourself. I can assure you it will be a fulfilling experience.
Karen Eubanks
Conway, AR
  • "Remember....Research is the key to your cure!"

Tuesday, May 27, 2014

Sakura Friends (Japan)

Our friends from Japan would like to be part of our Global Partners Program. Like us, their group feels that international cooperation is extremely valuable. Their group is also very eager to learn through exchanging information and sharing communication.
Patients in Japan have difficulties finding a doctor who knows how to treat the porphyrias, just like we do here in the US. Together, we will be able to enhance awareness of the porphyrias all over the world.
Members of the Japanese Sakura Friends, would like to communicate with other people in the US. Please learn about their group below:
Welcome to "SAKURA Friends"
Japanese porphyria patients group, "SAKURA Friends" (SAKURA means cherry blossoms) was formed in 1997 by porphyria patients, families and support volunteers. Today the group has 66 members (as of July 2007).
The group's activities include issuing newsletters three times a year, organizing gatherings and study meetings, providing information and encouraging communication among members in the website, etc. The group makes efforts to:
  • Enhance knowledge about porphyria
  • Encourage communication among members
  • Support research for early diagnosis and improvement in treatment, which ultimately lead to cure
  • Contribute to improve social system and environments for patients and families
We welcome porphyria patients, families and anybody that supports the group's aim and efforts. Welcome!!!
We are also eager to make friends outside Japan so that we can exchange information and experiences and learn from each other.
Those who read Japanese can find more information about our group at www.sakuratomonokai.com
  • "Remember....Research is the key to your cure!"


Saturday, May 24, 2014

Clinuvel Updates` Experts in light and skin

Investors Home Image
Clinuvel's Logo

Clinuvel’s management address patients’, shareholders’ questions

Over an extended period of time Clinuvel Pharmaceuticals Ltd (ASX: CUV; XETRA-DAX: UR9; ADR: CLVLY) has received a number of questions from patients, shareholders and the broader biotechnology community regarding the company’s program and the progress being made towards regulatory approval by the EMA (European Medicines Agency) of the company’s drug SCENESSE® (afamelanotide 16mg).
In this release, Clinuvel’s Chairman Stan McLiesh and CEO Dr Philippe Wolgen address those questions most frequently asked of the company.
How long will it take to complete the EMA review of SCENESSE®?
The EMA review is estimated to be completed between July and October 2014, yet further reviews by the Agency are possible.
Why has the review process taken so long?
The dossier we have filed is complex. Firstly, no other melanocortin has ever been submitted to European regulatory bodies.
Secondly, erythropoietic protoporphyria (EPP) is a complex disorder in that patients experience symptoms following light and sun exposure; their fear for the consequences of exposure causes patients to lead a withdrawn life and to deliberately avoid exposure. Patients’ aversion to light makes the interpretation of their clinical behaviour a challenge. In essence, this is the first time that evaluation of light exposure to skin is needed to be assessed in a pharmaceutical submission.
Third, the overwhelming demand for SCENESSE®, from experts and patients, needs to be assessed by the EMA and weighed in their final outcome. The entire evaluation of SCENESSE® requires careful evaluation of the drug’s profile over the past 20 years in general, and the past nine years in EPP patients in particular. Safety is a key issue, with the expected adverse events (commonly known as ‘side effects’, which every drug has) reviewed and an evaluation made of the pharmacovigilance (safety measures in relation to drug and its distribution) once the drug has entered the market.
Do you expect a positive response to your submission?
The decision is taken by the entire Committee for Human Medicinal Products (CHMP) which represents all members of the European Community. The Clinuvel team is optimistic that it will receive a positive response from the EMA which will enable us to provide access to the drug for European EPP patients.
What happens if there is a further delay in the approval of your application?
Naturally, there is a ‘plan B’. On the basis of the safety data generated over the past 20 years, there should not be any safety concerns. This is the first part of EMA’s equation of a risk-benefit analysis. The efficacy of SCENESSE® is subject to patients’ and physicians’ experiences; in this case the statistics are of supporting evidence. Clinical relevance of treatment can only be expressed and confirmed by patient groups and all global experts knowledgeable in the disease.
Should the drug be approved, what will it cost?
The drug is being priced in Italy and Switzerland and, depending on a number of parameters, the final price will be determined and revealed in due course. An important factor is the manufacturing and scalability of the product. However, in EPP Clinuvel will distribute to a relatively small number of patients.
When will you approach the FDA for approval in the USA?
Clinuvel’s teams have been in regular contact with the FDA during the program, as should be expected from a pharmaceutical company. It is increasingly apparent that EMA and FDA exchange information and thoughts. In this light an EMA approval will trigger Clinuvel’s New Drug Application in the US.
How long will this process take?
If a Fast Track Status is granted by the FDA for SCENESSE® treatment in EPP, the review process can be relatively swift.
Is there any way to access the drug now?
The drug has been available through special access schemes for EPP patients in Italy and Switzerland since 2010. Our clinical experiences are excellent, and the distribution of the drug is very much driven by the academic demand, which in turn is driven by patients’ choice to opt in for the treatment.
You’ve spoken many times about a dose for children in EPP. Has any progress been made here?
The ultimate objective of this management was to develop a treatment for children with EPP. The ordeal that parents and children go through in porphyria is unspeakable and really, at times, unimaginable. Clinuvel’s scientists and management had initially underestimated the burden of EPP on juvenile patients and their families, until we actually met with them and discussed their experiences.
The clinical tragedy lies in the fact that patients suffer in their normal development, since they do not understand why they feel out of place and in agony following light exposure. It is not sun that triggers the symptoms but any visible light. Since we live by light, plants and humans alike need it for a normal biological development. It usually takes 6-7 years before patients and parents link clinical symptoms to a light disorder, and even longer when physicians find a diagnostic pathway. In the meantime many of these children end up in the waiting room of clinical psychologists and psychiatrists to assess whether there is a somatic disorder at all.
Most of these adult patients have gone through a traumatic childhood and are still isolated while fearful of phototoxicity. Often burning ‘pain’ is being described as the main symptom, however the traditional understanding of pain is most likely incorrect: these patients do not respond to any analgesic, peripheral, central, NSAID, cyclooxygenase inhibitor or opioid. In our current medical dictionary we have failed to come up with another description of phototoxicity other than pain, however the terminology probably doesn’t do justice to these patients.
Clinuvel is working on a paediatric dose, but can really only accelerate this when EMA approval for adults is in sight.
When will the drug be available for vitiligo?
Vitiligo is in Phase II trials in Asia. An EPP approval will have a spill-over effect on the ability to progress SCENESSE® for vitiligo patients. A regulatory outcome will influence Clinuvel’s choices in vitiligo.
As stated, we are hopeful of a positive outcome, based on years of use of SCENESSE®, the strong and genuine clinical feedback and safety. This last aspect has always dominated and will dictate Clinuvel’s choices.
- End -
Investor relations contacts:
Australia: Clinuvel Pharmaceuticals Limited, T: +61 3 9660 4900
Europe: Clinuvel AG, T: +41 41 767 45 45
Email
Media contact:
Lachlan Hay
Clinuvel AG
   Lachlan.Hay@clinuvel.com
About SCENESSE® (afamelanotide 16mg)
SCENESSE® is a first-in-class therapeutic being developed by Clinuvel, with the generic name (or INN) afamelanotide. An analogue of α-MSH, afamelanotide is a linear peptide which activates eumelanin of the skin, the dark pigment which is known to provide photoprotective properties (offering skin protection against light and UV radiation). SCENESSE® is administered underneath the skin as a dissolvable implant approximately the size of a grain of rice. For more information on SCENESSE® go to      http://www.clinuvel.com/scenesse.
SCENESSE® is a registered trademark of Clinuvel Pharmaceuticals Ltd.
About Clinuvel Pharmaceuticals Limited
Clinuvel Pharmaceuticals Ltd (ASX: CUV; XETRA-DAX: UR9; ADR: CLVLY) is a global biopharmaceutical company focused on developing drugs for the treatment of a range of severe skin disorders. With its unique expertise in understanding the interaction of light and human skin, the company has identified three groups of patients with a clinical need for photoprotection and another group with a need for repigmentation. These patient groups range in size from 10,000 to 45 million. Clinuvel’s lead compound, SCENESSE® (afamelanotide), a first-in-class drug targeting erythropoietic protoporphyria (EPP), has completed Phase II and III trials in the US and Europe, and has been filed for review by the European Medicines Agency. Based in Melbourne, Australia, Clinuvel has operations in Europe, the US and Singapore.
Clinuvel is an Australian biopharmaceutical company focussed on developing its photoprotective drug, SCENESSE® (afamelanotide) for a range of UV-related skin disorders resulting from exposure of the skin to harmful UV radiation. Pharmaceutical research and development involves long lead times and significant risks. Therefore, while all reasonable efforts have been made by Clinuvel to ensure that there is a reasonable basis for all statements made in this document that relate to prospective events or developments (forward-looking statements), investors should note the following:
  • actual results may and often will differ materially from these forward-looking statements;
  • no assurances can be given by Clinuvel that any stated objectives, outcomes or timeframes in respect of its development programme for SCENESSE® can or will be achieved;
  • no assurances can be given by Clinuvel that, even if its development programme for SCENESSE® is successful, it will obtain regulatory approval for its pharmaceutical products or that such products, if approved for use, will be successful in the market place
  • "Remember....Research is the key to your cure!"

Thursday, May 22, 2014

Cover up this summer!

Happy Summer to ALL those With Porphyria ! 
Don't forget to cover up!


"Remember....Research is the key to your cure!"

Wednesday, May 21, 2014

Study Available! Research # 7204 Be apart of research

Online: www.RareDiseasesNetwork.org/porphyrias03/Apr/2014

Study Available!


Clinical Diagnosis of Acute Porphyria (7204)


About This Study

The porphyrias are a group of genetic diseases caused by disturbances in the formation of heme, an essential component of hemoglobin and other proteins, leading to either acute (neurologic) and/or chronic (cutaneous) symptoms.
Acute porphyria is often difficult to diagnose because symptoms may not be specific. Unless the patient is in an active attack, laboratory values typically may not be useful for diagnosing porphyria.
The purpose of this study is to test whether a focused questionnaire and laboratory evaluation tool can better define risk factors associated with possible genetic porphyria.

Can I Join this Study?

To read more about this study, see if you are eligible or find a clinical center near you, please visit our web site:
If you are already participating in this study, please disregard this email.
Do We Have Your Correct Information?
Stay Informed!
We want to keep you informed with the latest news and information. Keeping your contact information up to date can be done quickly and easily on the Web:
Click Here to Update Your Information
About the Porphyrias Consortium
The Porphyrias Consortium is a network of physician scientists, and clinical research resources dedicated to conducting clinical research in the Porphyrias. We Can Help You: Become aware of clinical research and clinical trial opportunities; Connect with expert doctors; Get help in managing your disease. 
Learn More >
The Porphyrias Consortium is a part of the National Institutes of Health's Rare Diseases Clinical Research Network. For more information, visit:www.RareDiseasesNetwork.org
The Rare Diseases Clinical Research Network will make every effort to enroll all the patients we can, but we cannot make any guarantees that we will be able to enroll everyone in a particular study who wants to participate. Participation in research studies is voluntary. Deciding not to participate in a research study does not affect your ability to receive care at any of our Clinical Centers or from other physicians.
Rare Diseases Clinical Research Network
www.RareDiseasesNetwork.org
The Rare Diseases Clinical Research Network (RDCRN) was established by the National Institutes of Health (NIH) to develop research studies for rare diseases, and to encourage cooperative partnerships among researchers at over 150 clinical centers around the world. This increased cooperation may lead to discoveries that will help treat and perhaps prevent these rare diseases, as well as produce medical advances that will benefit the population in general. The Rare Diseases Clinical Research Network is comprised of a Data Management and Coordinating Center and 17 consortia studying over 100 rare diseases.
The Porphyrias Consortium is a part of NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project has been provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the NIH Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS).
The National Institutes of Health does not endorse or recommend any commercial products, processes, or services. The views expressed in written materials or publications do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.

For more information please email me your name and phone to see if you qualify for this study Amy.APF@gmail.com


"Remember....Research is the key to your cure!"





"Remember....Research is the key to your cure!"

Tuesday, May 20, 2014

A little diddy from Victor Mejias about EPP


I push myself to go to work all week....
I push myself to do work around the house....
I push myself to be with family and friends....
I push myself to do the things I love to do....
I'm on Fire, can't sleep and depressed.
EPP problems!

What you guys go through stay cool and stay strong EPPers....

 "Remember....Research is the key to your cure!"

Monday, May 19, 2014

Have you Joined the Registry yet?

Have you Joined the Registry yet?


Join the Porphyria Registry and LET THE GOVERNMENT KNOW THEY MUST PROVIDE FUNDING FOR PORPHYRIA RESEARCH!!!!!
To join the Contact Registry, click here to open a page that lists all of the rare disease consortia. Scroll down the page until you come to the Porphyria Consortium and click on your type of porphyria. You will then be asked to complete a simple form including information about the date of your diagnosis, if you know it. If you have copies of your initial diagnostic lab results, you may want to have them handy when you go to the registry website. 
Porphyria experts have created this National Porphyria Registry—a type of partnership between doctors and patients— as a way for those with porphyria to share information about their health and treatment so physicians can learn from their experience and use that knowledge to enhance diagnosis, treatment and eventually find a cure for porphyria.
It is the best means to prove that there are enough porphyria patients who want improved health care. If we don't speak up, we will be left behind when research funding is given. We DO NOT HAVE ENOUGH PEOPLE ON THE REGISTRY. Please join the registry.
Joining the Porphyria Registry is anonymous and free of charge. All data will be stored in a secure, computerized database. No personal identifying information (such as your name, address, telephone number) will be given to anyone without your expressed approval.
_________________________________________________
The registry is not linked to APF membership, but we hope you will join the American Porphyria Foundation too! So please consider joining the Contact Registry, and thank you for continuing to be a member of the APF.
Doctors who study rare diseases see a relatively small number of sufferers over many years of practice. This Registry will give a big boost to medical and scientific understanding of porphyria by bringing together information from patients all over the country.
If you need help enrolling in the registry contact our office toll free at 1-866-APF-3635.

Phones calls will be going on this week 5/20/2014  from 11-7pm Eastern time zone if you need additional help please email me AMY.APF@gmail.com
 "Remember....Research is the key to your cure!"

Wednesday, May 14, 2014

APF and YOU! Please help!

For 30 years, the APF has been the only US foundation with a board of experts who assist porphyria patients. YOUR support has made possible great advances in research, physician and patient education and patient support. The APF is YOUR foundation and exists to serve YOU and YOUR families. Now the APF needs your help to continue all these valuable programs and services. We need YOUR donations to help us continue the PTF program and expand our physician and patient education programs, as well as our research efforts. Every one of YOUR donations are tax deductible. The APF is non-profit. One dollar is as important as one thousand, because it comes from YOU! Thank You. http://www.porphyriafoundation.com/content/support-american-porphyria-foundation


 "Remember....Research is the key to your cure!"

Tuesday, May 13, 2014

Read about Carol Coons and PCT

Read about:

Carol Coons


Type of Porphyria: 
Porphyria Cutanea Tarda (PCT)
I have PCT but was misdiagnosed many times since I first noted that I was blistering in 2004. Three dermatologists in a row were unable to find out what was wrong with me even after I had a biopsy. My ferritin level was accidentally discovered at an unrelated clinic visit, and it was over 900.
At that time, I was told to go to a hematologist, who said that that my only problem was hemochromatosis, even after I showed him my blisters and sores. I did have a genetic H63D heterozygous defect. I had a port put in place and to date, I have had over 45 phlebotomies. My internist sent me to get a second opinion, where I was told that I had PCT. As the treatment was the same, I had not gotten a port or had the other phlebotomies in vain.
I have no idea how I developed PCT, but now I try to stay out of the sun, but it did show up while I was taking Paxil for my fibromyalgia pain and spending a week at the beach. Now I try to stay out of the sun and am careful not to eat too much iron. My liver is fine now, and fortunately I did not need a liver biopsy.

Thank you Carol for sharing your story with us!

 "Remember....Research is the key to your cure!"

Thursday, May 8, 2014

Healthwell Foundation

Dear members, the HealthWell Foundation provides financial assistance to eligible individuals to cover coinsurance, copayments, health care premiums and deductibles for certain medications and therapies for acute porphyria treatment (like Panhematin®). To determine eligibility and apply online, visit: http://www.healthwellfoundation.org/eligibility
The HealthWell Foundation stands ready to serve you! If you are a person with a diagnosis and are seeking assistance, please continue on this page. If you are applying on another person's behalf, please see Apply for Patient.





"Remember....Research is the key to your cure!"
HEALTHWELLFOUNDATION.ORG

Wednesday, May 7, 2014

A wonderful overall text book medical journal READ SAVE AND PRINT!

I would like to say that this article is a really nice overall document to print save, and share with your Doctors.  Its reliable and it is a medical journal you will see below many familiar names of Experts Doctors and/or Protect the Future Doctors.  That is why it is critical to be informed for your health.  Enjoy!

Published online Mar 13, 2014. doi:  10.3390/nu6031080
PMCID: PMC3967179

Heme, an Essential Nutrient from Dietary Proteins, Critically Impacts Diverse Physiological and Pathological Processes

1. Introduction

Proteins are the building blocks of life. They are also the major source of dietary nutrients. When proteins are digested, amino acids are released to the body for biosynthetic purposes or for generating cellular energy. Besides amino acids, proteins also provide other nutrients, particularly metals. Iron is the most abundant metal in the human body; one adult human body needs 3–4 g of iron. Dietary iron is found in two forms, heme and non-heme iron. Heme iron, which is present mainly in meat, poultry and fish, is well absorbed. Non-heme iron, which accounts for the majority of the iron in plants [], is less well absorbed. More than 95% of functional iron in the human body is in the form of heme []. Hence, heme should be considered an essential nutrient for humans, although historically iron is the primary concern in nutrition studies. Particularly, recent studies have shown that heme is efficiently absorbed by the small intestinal enterocytes [,]. In Western countries, heme iron derived from myoglobin and hemoglobin makes up two-thirds of the average person’s total iron stores, although it constitutes only one-third of the ingested iron []. Evidently, heme is a bona fide essential dietary nutrient. Further, heme directly impacts many physiological and disease processes in humans. In this review, we present the current knowledge of how heme is absorbed in humans and the diseases associated with disturbed heme homeostasis.

2. Dietary Heme Is Efficiently Absorbed in the Small Intestine

Heme is found in highest abundance in meat in the form of hemoglobin and myoglobin. Heme is released from these proteins because of the low pH in the stomach and the action of proteolytic enzymes in the stomach and small intestine [,] (Figure 1). Concentrated heme produced from hemoglobin hydrolysis in the stomach is poorly absorbed, because pure heme is poorly soluble at the low gastric pH, but the availability of heme is unaffected by gastric secretion [,]. There is some evidence that neutralization of gastric contents by pancreatic juice also leads to polymerization of heme, which reduces its availability unless other protein degradation products are present to inhibit polymer formation. The interaction of heme with peptides produced from proteolytic digestion of globin prevents the formation of insoluble heme polymers. Heme solubility is increased significantly by the presence of protein, which is important, given the fact that heme-rich diet have high protein content [,,,,,]. Hence, the peptides and amino acids produced from meat hydrolysis can enhance the absorption of heme and non-heme iron [,].
Figure 1
Heme absorption in gut from dietary proteins. Low pH of stomach releases heme-containing proteins hemoglobin and myoglobin from dietary meat. Heme is released by the action of proteases in stomach and intestine. Intake of heme into enterocytes can be ...
Heme is absorbed by the mucosa as an intact metalloporphyrin [Fe(II)-protoporphyrin-IX] in the lumen by the enterocytes [,,,] (Figure 1). This may be facilitated by a vesicular transport system, presumably binding first to the brush-border membrane of enterocytes, and then undergoing internalization into the cytoplasm, finally appearing within enclosed vesicles []. Internalized heme may be released to the blood via the action of the heme exporter FLVCR1 (Figure 1). FLVCR2 is another putative heme transporter, which might be involved in intracellular heme import []. Heme in the blood might be taken up directly by various cells, including liver and erythroid cells, for making hemoproteins. Although heme from dietary hemoglobin has not been demonstrated to be reused directly in animals or humans, heme has been shown to be taken up directly by both intestinal and non-intestinal cells and promote direct cellular responses [,,,]. Alternatively, heme can be degraded, releasing the iron via the action of heme oxygenase (HO) (Figure 1). Iron then enters the low molecular weight pool of iron in the enterocyte, along with iron absorbed as inorganic non heme-iron (inorganic) iron [,,,]. In a study tracking the absorption of 59Fe-hemoglobin in closed duodenal loops, it is reported that heme degradation is the rate limiting step in heme absorption, as opposed to hemoglobin degradation, heme uptake, or iron transfer to the circulation [,]. Subsequently, the elemental iron is released to the bloodstream by the enterocytes via the basolateral transporter ferroportin [,,,,]. Absorbed iron in the blood is delivered to the marrow for hemoglobin synthesis, and a small amount is stored mainly in the liver. All of this iron is carried by a single plasma protein known as transferrin. Transferrin, also known as siderophilin, has a molecular weight of about 80 kDa, with two ferric iron binding sites [].

3. The Heme Transporters HCP1, HRG-1 and FLVCR1 Are Important for Maintaining Heme Homeostasis

Research in the past decade has identified several transporters involved in maintaining heme homeostasis []. Particularly, the function of three heme transporters have been characterized: proton-coupled folate transporter/heme carrier protein 1 (PCFT/HCP1), heme responsive gene 1 (HRG-1), and cell surface receptor for feline leukemia virus, subgroup C, cellular receptor 1 (FLVCR1) [,] (Figure 1). HCP1 has been characterized as a folate/proton symporter and appears to play a key role in intestinal heme and folate absorption. HCP1 is a low affinity heme transporter [,,,]. It has a higher affinity for folate (Km = 1.67 μM) as compared to heme (Km = 125 μM) []. HCP1 mRNA was found to be highly expressed in the duodenal mucosa, which is the main site of intestinal heme absorption. However, virtually no expression is found in the ileum []. The highly conserved murine HCP1 is a 50 kDa protein, with 9 predicted transmembrane domains (TM). Xenopus oocytes and HeLa cells expressing HCP1 exhibit 2- to 3-fold increase in heme uptake that is both saturable and temperature dependent []. HCP1 is post-translationally regulated in iron deficient mice and transcriptionally under hypoxia. In normal mice, HCP1 resides in the cytoplasm; however, in iron-deficient mice, HCP1 relocalizes from cytoplasm to plasma membrane. Conversely, feeding a high dose of iron to iron-deficient mice redistributed HCP1 from the brush border membrane of the duodenum to the cytoplasm. Levels of HCP1 mRNA are less responsive to iron deficiency but are induced under hypoxia [,,,]. HCP1 is localized in plasma membrane in non-polarized cells for heme uptake from body fluids, whereas in polarized cells, it is localized in the apical membrane for heme uptake from diet []. The post-translational regulation of HCP1 is interesting, because it provides an efficient and fast way to uptake dietary heme before it is lost to gut peristalsis. It also prevents the unnecessary uptake of heme intracellularly when cellular iron content is normal. This mechanism might prevent the accumulation of excess heme and iron, both of which are toxic to cells in excess []. It is observed that mRNA expression of HCP1, and by reasoning heme uptake, is regulated by heme []. Further investigation is needed to understand the precise mechanism of heme transport via HCP1 [,]. Nonetheless, existing studies strongly suggest that HCP1 plays a crucial role in the uptake of heme iron in the intestine, with its expression controlled by the levels of iron and heme in the organism. Recent evidence suggests that HRG-1 is responsible for transporting heme from the endosome to the cytosol []. HRG-1 has been reported to be primarily localized on endosome and lysosome related organelles and partially (~10%) on the plasma membrane [,,,]. It is reported to be expressed on the basolateral, and not apical surface, of polarized Madin-Darby canine kidney cells []. HRG-1 is found to be highly expressed in kidney, brain, heart and small intestine [,]. The expression of HRG-1 mRNA is tissue dependent, with some studies reporting direct relation between HRG-1 expression and heme concentrations. Transcription factor Bach1 represses anti-oxidant response genes, including HRG-1 and heme oxygenase genes. When intracellular heme concentrations increase, heme binds to Bach1 via HRMs (heme regulatory or responsive motifs) and Bach1 mediated repression is released, Bach1 then dimerizes with the activator protein Maf to stimulate the expression of HRG-1, heme oxygenase and other Bach1 repressed genes [,,,]. A recent study showed that HRG-1 is the phagolysosomal heme transporter for microphage heme-iron recycling []. It mediates heme transport from the phagolysosome during erythrophagocytosis and may play a similar role in the intestine.
FLVCR1, a member of the major facilitator superfamily of transporter proteins, was identified as the cell surface receptor for feline leukemia virus, subgroup C. FLVCR1 is highly expressed in tissues that either transport heme (i.e., intestinal or hepatic cells) or synthesize high levels of heme (erythroid cells). FLVCR1 exports cytoplasmic heme. Heme export by FLVCR1 is time and temperature-dependent; interference with FLVCR1 function blocks heme export and increases cellular heme content [,]. FLVCR1 expression is induced during early erythroid differentiation. It functions as a heme exporter to protect the cells from excess heme build up during the CFU-E stage of erythropoiesis. Even under heme deficient conditions, FLVCR1 does not reverse function to increase heme uptake.

4. Heme Is Degraded, and Iron Is Recycled by the Action of Heme Oxygenase (HO) in Mammals

HO is localized to the endoplasmic reticulum (ER) and requires NADPH-cytochrome P-450 reductase for its catalytic turnover [,,,]. It is a rate-limiting enzyme in the catabolism of heme and plays a key role in regulating the intracellular heme levels [,]. Three isoforms of HO have been identified so far: HO-1, HO-2 and HO-3. HO-1 is a 32 kDa protein, which can be induced by heme and heavy metals, hyperoxia, hypoxia, UV light, hydrogen peroxide, lipopolysaccharide, hyperthermia or endotoxin [,]. HO-1 is transcriptionally regulated, while the 36 kDa protein HO-2 is constitutively synthesized []. HO-3 is reported to be derived from a processed pseudogene [,,,]. HO-1 is expressed in relatively low amounts in all tissues, while HO-2 is constitutive and mainly expressed in brain and testis. HO-1 is constitutively expressed in colonic, gastric and intestinal mucosa []. Yanatori et al. reported that changes in heme concentrations do not affect the localization of HO-1 in HEp-2 cells []. HO expression is highest in duodenum, in which heme absorption is highest, as well as the site for highest expression of HCP1. HO activity increases during iron deficiency []. Thus, HO plays important roles in maintaining heme and iron homeostasis.
Besides iron, degradation of heme by HO results in the production of carbon monoxide (CO) and biliverdin IX-α (BV) [,]. CO acts as a physiological regulator of cGMP and may function as a neuromodulator []. Water soluble biliverdin is released as a result of heme degradation and is further reduced to the orange bile pigment, bilirubin IX-α (BR), by biliverdin reductase (BVR). Bilirubin is then released into the gastrointestinal tract (GI) [,,]. Bilirubin is a lipophilic and water insoluble compound, which is responsible for the yellow color associated with bruises, urine, brown color of feces and yellow discoloration in jaundiced patients []. Bilirubin scavenges ROS and is considered to be a potent antioxidant and antinitrosative [,]. High baseline serum levels of bilirubin are found to be associated with lower incidences of retinal damage in newborns, reduced risk of ischemia heart disease and reduced rates of cancer-related mortality [,]. Bilirubin has antioxidant properties, but unconjugated bilirubin becomes neurotoxic if produced in excess, such as in hemolytic anemia or sepsis. Unconjugated billirubin can result in disruption of cell membrane, a reduction of mitochondrial potential and activation of the apoptotic cascade []. Thus, HO activity is responsive to many stimuli, in addition to those related to iron and heme.

5. High Heme Intake Is Associated with Increased Risk of Cancer

Dietary differences in the world likely contribute to global variations in cancer cases []. Meat is an important source of proteins and provides essential amino acids. It is one of the largest dietary sources of heme [,]. Epidemiological and experimental studies have suggested that the high heme content in red meat is associated with several diseases, including heart diseases, diabetes and cancer []. Red meat (beef, lamb and pork) has 10-fold high heme content as compared to white meat (chicken) []. Studies have shown that an increased risk of several types of cancer is associated with diets high in red meat. On the contrary, consumption of substantial amounts of green vegetables is associated with decreased risk of colon cancer, likely because vegetables contain low levels of heme iron [,,]. Below we provide an overview of recent epidemiological data showing the association of increased risk of cancer with high heme iron intake.

5.1. High Heme Intake in Diet Increases the Risk of Colon Cancer

A number of studies have demonstrated a positive association between high intake of red meat and colorectal cancer (CRC). However, the association between red meat intake and other cancer types such as gastrointestinal, lung cancer, pancreatic, breast and esophageal are understudied and less consistent [,,]. Table 1 provides a summary of recent epidemiological studies investigating the association of heme iron intake with an array of diseases, including cancer. Colorectal cancer is the third leading cause of death around the world and accounts for more than 1 million cases and 600,000 deaths each year [,]. CRC is most commonly associated with dietary preferences high in red meat, suggesting that the risk of CRC can be reduced by controlling dietary intake [,].
Table 1
Summary of epidemiological studies investigating the association between dietary intake of heme iron and/or red meat with various diseases.
A meta-analysis performed in 2006 by Larsson and coworkers showed an elevated overall relative risk (RR) of 1.28 of colorectal cancer (95% confidence interval (CI) = 1.15–1.42) for red meat in the highest versus lowest category of intake. They estimated the RR of 1.28 (95% CI = 1.18–1.39) for an increase of 120 g/day of red meat []. Another study suggested an increased risk of colon cancer in men with a diet high in heme and decreased intake of chlorophyll []. In 2011 a meta-analysis of prospective cohort studies of colon cancer reported heme intake of 566,607 individuals and 4734 cases of colon cancer []. The study compared the RR of subjects with highest category of heme intake with those in lowest category and determined an RR of colon cancer to be 1.18 (95% CI = 1.06–1.32). In their analysis of experimental studies in rats with chemically induced colon cancer, they showed that dietary hemoglobin and red meat promote a putative cancer lesion, an aberrant cryptic foci []. Another meta-analysis study showed a significant association between high intake of red and processed meat with increased risk of colorectal, colon and rectal cancers []. In this study, the overall RR for colorectal cancer for highest versus lowest intake of fresh red meat for every 100 g/day increase is 1.17 (95% CI = 1.05–1.31). The study showed similar results for colon cancer, but no significant association is found for rectal cancer [].
In 2013, a meta-analysis further suggested a positive-dose response association of heme intake and the risk for colorectal cancer []. In the analysis of eight studies, the authors found a 14% higher risk for CRC in subjects with high intake of heme, compared to the subjects with lowest intake of heme []. The observed overall RR for CRC in their study was 1.14 (95% CI = 1.04–1.24) for heme intake []. Gene expression profiling of the colon mucosa in mice showed that heme is involved in the downregulation of the inhibitors of proliferation, Wnt inhibitory factor 1, Indian Hedgehog, bone morphogenetic protein 2 and Interleukin-15. The expression of amphiregulin, epiregulin and cyclo-oxygenase-2 mRNA is upregulated by heme in surface cells vs. crypt cells. These results suggest that heme inhibits the surface to crypt signaling of feedback inhibitors of proliferation and induces colonic hyperproliferation and hyperplasia, which increases the risk of colon cancer [].
Several potential mechanisms have been suggested to explain the association between high intake of red meat and the risk of colorectal cancer. Heme is more bioavailable and readily absorbed as compared to non-heme. However, detrimental effects are associated with heme specifically, which includes cytotoxicity and the increased formation of endogenous N-nitroso compounds (NOCs), which may increase the overall mutation rate in the DNA of colonic tissue [,,]. Heme in red meat may catalyze the production of endogenous NOCs within the colon and thereby catalyze the formation of cytotoxic and genotoxic aldehydes by lipoperoxidation [,,,]. It has been shown that under anaerobic conditions, hemoproteins, hemoglobin and myoglobin in meat can react with nitric oxide to form nitrosating agents. In addition, hemes are known to be nitrosating agents and can be easily nitrosated under certain conditions, which is facilitated by the anaerobic and reductive environment of the small intestine by maintaining heme in its ferrous state []. Nitrosyl heme and nitroso thiols contribute significantly in the endogenous production of NOCs. Amines and amides produced by bacterial decarboxylation can be N-nitrosated in the presence of these nitrosating agents to produce NOCs. A majority of the NOCs investigated are shown to be carcinogens [,,].

5.2. Risk of Gastrointestinal and Pancreatic Cancer Is Associated with High Heme Intake

With the availability of large amounts of epidemiological data for colorectal cancer, the positive relation between colorectal cancer and high intake of red meat (high heme content) is convincing; however, limited data is available for other gastrointestinal malignancies. A 2011 study showed a positive association between red meat intake and squamous cell carcinoma of the esophagus []. They observed a hazard ratios (HR) of 1.47 (95% CI = 0.99–2.20, P for trend = 0.063) for highest versus lowest quintile of heme intake, suggesting a positive association between esophagus adenocarcinoma and heme intake []. Jakszyn and coworkers observed a statistical significant association between heme intake and gastric cancer (GC) with HR of 1.13 (95% CI = 1.01–1.26 for a doubling of intake), which was adjusted by age, BMI, sex, tobacco smoking, education level, and energy intake []. Their study included 481,419 individuals and 444 cases of GC []. Ward and coworkers has also suggested a positive association between the consumption of heme from red meat and increased risk for esophageal and stomach cancer [].
Pancreatic cancer is one of the most deadly cancers. Hence, previous studies have focused on the association between risk of pancreatic cancer and diet. A meta-analysis performed in 2012 found that there is an increased risk of pancreatic cancer in men, positively associated with consumption of red meat []. In that study, RR for risk of pancreatic cancer in men is 1.29 (95% CI = 1.08–1.53), suggesting a significant association of red meat intake and risk of pancreatic cancer. However, the authors did not observe a significant association in women (RR = 0.93, 95% CI = 0.74–1.16) [].

5.3. High Heme Intake Increases the Risk of Endometrial Cancer in Women

Endometrial cancer accounts for 10–20 per 105 people a year in western countries []. An association between heme intake from red meat and the risk of endometrial cancer in women was suggested, but the studies were very limited. Kabat and coworkers [] (2008) used data from a large cohort study of Canadian women and assessed the risk of endometrial cancer associated with dietary intake of heme. The authors found no association between heme intake and the risk of endometrial cancer []. However, a case control study by Kallianpur and coworkers (2010) observed an increased risk of endometrial cancer of ~2-fold with higher heme intake, predominantly after menopause and in women with BMI ≥ 25 kg/m2 []. Another recent study by Genkinger and coworkers [] (2012) also suggested a moderately positive association between risk of endometrial cancer and heme intake. The comparison between highest vs. lowest quartile in their study showed a 20%–30% of higher risk associated with higher intakes of heme, with a RR of 1.24 (95% CI = 1.01, 1.53 for ≥1.63 compared with <0.69 mg/day) []. A few mechanisms have been proposed to explain how heme intake may lead to onset of endometrial cancer: (1) Heme can lead to a higher per-oxidant load and lead to higher oxidative stress and DNA damage; (2) Heme intake is also reported to be associated with increased risk of obesity, diabetes and the markers of obesity and diabetes, which are suspected associated factors for the risk of endometrial cancer [,,,].

5.4. Epidemiological and Molecular Studies Reveal the Link between High Heme Intake and Lung Cancer

Several case control and cohort studies have been reported for an association between high meat (or heme intake) and risk for lung cancer, but these limited studies show inconsistent findings []. A study in 2009 reported a strong positive association between intake of heme from meat and lung cancer in men as compared to women []. It was found that for association between heme intake and risk for lung carcinoma, hazard ratios (HRs) in comparison with quintiles 5 with 1 (Q5 vs Q1) is 1.25 (95% CI = 1.07, 1.45) in men and 1.18 (95% CI = 0.99, 1.42) in women. The study showed an even higher risk of lung cancer in men with high intake of bioavailable heme and lower intakes of antioxidants []. On the contrary, Tasevska and coworkers in 2011 reported no significant association between consumption of diet high in red meat and lung cancer []. In their study population, they did not observe any association between intake of heme and risk for lung cancer.
To associate a link between intake of fresh red meat and heme, Lam and coworkers performed a mechanistic study in meat-related lung carcinogenesis by using whole genome expression []. They measured the genome-wide expression in tumors and non-involved fresh frozen lung tissues of 64 adenocarcinoma patients. Out of 232 annotated genes in tumor tissue, they found that ~28% (63 genes) were involved in heme transport, absorption (e.g., HFE), binding (e.g., CYP4A11, HPX and NENF), biosynthesis (e.g., ALAS2) and heme/iron mediated wnt signaling pathway (e.g., WNTs, LEF1, PTPRT, TNF) []. These results are entirely consistent with recent data gained from molecular studies of lung cancer cells []. Notably, a recent molecular study comparing non-small cell lung cancer (NSCLC) cells with nontumorigenic lung epithelial cells suggested a novel, key mechanism underlying heme function in cancer progression []. This mechanism can explain the result from epidemiological studies indicating a positive role of heme in promoting cancer. In that study, using a matched pair of cell lines representing normal nonmalignant HBEC30KT and non-small-cell lung cancer (NSCLC) HCC4017 cells developed from the same patient, Hooda and colleagues identified metabolic changes linked with the transformation of normal to cancer cells []. They found that oxygen consumption and heme synthesis are intensified significantly in lung cancer cells, compared to the normal cells. Furthermore, the levels of heme uptake proteins and oxygen-utilizing hemoproteins are dramatically increased in cancer cells and xenograft tumors. Inhibition of heme synthesis or mitochondrial function preferentially suppresses cancer cell proliferation, colony formation and cell migration (Figure 2). These results demonstrated that heme availability is significantly increased in cancer cells and tumors, which leads to elevated production of hemoproteins, resulting in intensified oxygen consumption and cellular energy production for fueling cancer cell progression. This provides a unifying mechanism for heme function in promoting cancer progression [].
Figure 2
A cartoon illustrating a putative mechanism by which heme fuels cancer cell progression. Heme from blood can be taken up by cells via heme transporters HCP1 and HRG-1. Cancer cells have intensified internal heme synthesis as well as increased heme uptake...
In Figure 2, we suggest that dietary heme may be directly reused by cells. This deviates from the traditionally accepted view that dietary heme is degraded in the liver, and iron is released. However, existing data do not counter and are consistent with the idea that heme in the blood can be taken up directly and used by cells. For example, diverse cells, including K562, Caco-2, HepG2 and neuronal cells, are known to directly uptake heme [,,,]. Thus, under conditions under which heme is needed, as is the case when cancer cells try to proliferate and invade, dietary heme may be released into the blood and taken up by cancer cells to make hemoproteins directly. The highly elevated expression of heme transporters in the cancer cells would drive heme uptake by cancer cells.

6. High Heme Intake Is also Associated with an Increased Risk of Type-2 Diabetes and Coronary Heart Disease

6.1. High Heme Intake Correlates with Increased Risk of Type-2 Diabetes

Previous epidemiological studies have suggested an association between high heme iron intake and diabetes, as well as coronary heart disease. Diabetes mellitus, also referred to as diabetes, is a growing problem in the modern society characterized by impaired carbohydrate, protein and lipid metabolism caused by insulin resistance and an insufficient amount of insulin secreted. In 2000, the WHO reported that around 47 million people were suffering from diabetes. In 2004, an estimated 3.4 million people had died because of high blood sugar level, with a similar number of deaths reported in 2010. WHO projects that diabetes will be the 7th leading cause of death by 2030 with type-2 diabetes (T2D), accounting for almost 90% of the diagnosed cases [].
Several cross-sectional and cohort studies have demonstrated positive association between heme intake and T2D [,,,] (see also Table 1). These studies have been performed in males and females of different ages, and pregnant women. In 1983, Loma Linda University’s Adventist Health Study showed evidence of a positive association between heme from meat and T2D []. Since then, several studies have been carried out in different countries to establish this association with different subjects groups [,,,]. In a large cohort study conducted by Jiang et al., authors followed 422,846 persons/year for a period of 12 years from 1986 to 1998 with 1168 reported cases of T2D, to determine possible elevated risk of T2D in men consuming red meat as source of heme intake []. They found that men on red meat diet show an increased risk of T2D. However, when chicken, fish, or eggs are the primary source of heme, the association between heme and T2D disappears []. In 2004, Lee et al. examined the relationship between heme intake and T2D in women []. This study was carried out over an 11-year follow-up period []. The authors also reported a positive association between heme intake and T2D in women with RR 1.0, 1.07, 1.12, 1.14 and 1.28 across quintiles of heme intake. Interestingly, the association appeared to be stronger among women consuming alcohol, with the risk of T2D increasing with higher alcohol consumption. Particularly, subjects consuming 15 g/day of alcohol have RR across quintiles of heme ranging from 1.0, 2.26, 3.22, 1.92, to 4.42 [], non-heme iron was inversely associated with incidence of T2D. In 2011, Qui et al. showed increased heme intake to be associated with gestational diabetes mellitus (GDM) in pregnant women []. Along with dietary heme intake, the association was confounded among women who smoked during pregnancy with a significant RR of 2.09 (95% CI 0.42–10.41), while the corresponding RR for non-smokers is 1.48 (95% CI 0.89–2.46) [].
The positive association found between heme and T2D is consistent with other studies evaluating the relationship between red meat (heme iron intake) and T2D. The positive association between processed red meat and T2D was confirmed by various studies, suggesting that the risk of T2D increases with higher consumption of processed red meat, regardless of gender, age, ethnicity and BMI [,,,,]. Frank Hu and coworkers carried out three cohort studies to evaluate association between unprocessed red meat and T2D []. Their result for association of unprocessed red meat with T2D is consistent with that of processed meat. The meta-analyses of the data suggested that a 100 g/day increase in intake of unprocessed meat increases the risk of T2D by 19% (95% CI: 4%–37%) [] (Table 1).

6.2. High Dietary Heme Intake Can Increase the Risk of Coronary Heart Disease Significantly

It is worth noting that previous studies have also demonstrated a positive association between heme and CHD. Ascherio et al. reported the earliest evidence of this association in 1994 []. They found an increased risk of myocardial infarction among men consuming red meat as the main source of heme and iron []. A study of 329 Greek men and women also positively associated the increased risk of CHD among men and women, especially those older than 60 year with an increased dietary heme intake []. In another study Snowdon et al. used meat intake as a measure of dietary heme and found a 60% increased risk of CHD among men who consume meat six times a week compared with men who consume meat less than once a week []. Similar studies have been performed in Netherlands, Italy, USA and Japan [,,,]. These studies, except the one in Japan, show a statistical correlation between heme intake and increased risk of CHD. Higher heme intake significantly associated with elevated risk of developing CHD with an RR of 31% (95% CI 4%–67%). Meta-analysis of these studies show an 27% increased risk of CHD with a 1 mg/day increase in heme intake. The study in Japan performed by Zhang et al. did not show the positive association between heme and CHD []. The source of heme in Japanese diet is mainly from fish. It is likely that levels of heme in fish are not high enough to cause CHD. Also, fish and shellfish are excellent source of vitamin D and n-3 fatty acids, which protect against CHD [,]. Therefore, the dietary profile may have obscured the association between heme and CHD in this study.

6.3. Multiple Mechanisms May Underlie the Association of Heme Intake with T2D and CHD

Although the exact mechanism for association of increased dietary heme with T2D and CHD is uncertain, several mechanisms have been proposed. In western countries, heme in the diet is mainly derived from red meat. The feedback mechanism for iron absorption functions better for non-heme iron as compared to that for heme. At any serum ferritin level, the percentage of heme absorbed is higher compared to non-heme iron. As a result, heme continues to be absorbed by the body even in events of excess serum ferritin []. Excess of heme intake also leads to iron overload in the body. Iron is a strong pro-oxidant and catalyzes production of reactive oxygen species in various cellular reactions []. Excess of iron causes damage to various tissues, especially pancreatic beta cells through increasing oxidative stress by the reactive oxygen species generated, resulting in the damage of insulin production and excretion [].
Additionally, excessive heme intake leads to deposition of iron deposition in pancreatic beta cells and other tissues, which induces insulin resistance [,]. The highly active iron damages the DNA and cell integrity and interferes with glucose uptake by various tissues. An excess of iron was shown to diminish utilization of glucose by muscle tissues [,]. This results in shift from glucose utilization to fatty acid production [,]. The highly reactive hydroxyl free radicals generated by iron promote oxidation of low-density lipoprotein cholesterol [,]. Two studies have indicated that macronutrients like sodium and nitrites present in the meat along with heme increase the risk of type-2 diabetes [,]. A recent study in Finland suggested that sodium in the processed red meat contributes to T2D []. In addition, the nitrites used in the preservation of red meat enter the body as nitrosamines []. These nitrosamines have been shown to be toxic to pancreatic beta cells and increase the risk of type 2-diabetes. Therefore, from a health point of view, a decrease in the red meat consumption, particularly processed red meat, and substitute with other source of heme, such as chicken, eggs, fish, nuts, dairy products and whole grains, should be considered to decrease potential T2D and CHD risk.

7. Heme Deficiency Can Cause Serious Health Problems in Humans

While high dietary intake of heme may have adverse effects on health, heme deficiency can also cause serious health problems. In the human body, roughly 80% of heme is present in red blood cells, 15% is synthesized and present in liver, and the rest is distributed in other tissues [,,]. Previously, Tatyana and coworkers have summarized the following newly identified roles of heme: (1) Role in gene expression regulation in yeast Hap1, mammalian Bach1 and bacterial Irr transcription factor proteins; (2) Role in controlling the ion channels (such as, high conductance voltage and Ca2+ activated potassium channels); (3) Role in binding to different nuclear receptor proteins; (4) Role in the regulation of circadian clock (day-night cycle); (5) Role in erythrocytes [].

7.1. Defects in Heme Biosynthesis Can Cause Anemia and Porphyrias in Humans

Heme biosynthesis involves eight enzymes, and a defect in any one of them is associated with diseases. Such a defect can be caused by genetic mutations or environmental factors that suppress heme synthesis, such as the presence of lead or lack of iron. Defective heme synthesis can cause acute porphyrias, which are associated with neurological problems in peripheral nervous system (e.g., motor weakness and sensory changes, such as abdominal pain, paresthesia and loss of sensation) and CNS (e.g., insomnia, depression, anxiety, hallucination, seizures and paranoia) []. Sideroblastic anemia is a rare X-linked disease, which is caused by the defect in the erythroid-specific enzyme 5-aminolevulinic acid synthase-2 (ALAS2). Defects in any of the other seven enzymes are associated with porphyria []. Porphyrias are divided into erythropoietic porphyrias and acute hepatic porphyrias []. Neuronal problems are associated with the following four known types of hepatic porphyrias: 5-aminolevulinate dehydratase deficient porphyria (ADP), acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP) []. Three out of four hepatic porphyrias are dominantly inherited, except ADP, which is rare and a dominant recessive disease []. Overproduction and accumulation of porphyrins and porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) represents the clinical manifestations of the porphyrias. Besides genetic defects, lack of iron can also cause heme deficiency, as is the case in iron deficiency anemia. Lack of iron can be caused by low dietary iron intake, as in the case of vegetarians, or by blood loss, for example, heavy menstrual bleeding.

7.2. Heme Regulates Diverse Neuronal Genes

Heme is involved in the regulation of neuronal specific genes, particularly through the NGF signaling pathway [,]. It has been reported that heme deficiency induces apoptosis in NGF-induced neuronal cell lines. Heme deficiency induced pro-apoptotic JNK signaling pathway and inactivated the pro-survival Ras-ERK1/2 signaling pathway []. One possible mechanism of heme regulatory action may be through modulation of kinase activity. Work in the Zhang lab showed that heme actively interacts with Jak2 and Src and affects the phosphorylation of key tyrosine residues in Jak2 and Src []. In addition, our microarray data showed that heme deficiency in NGF-induced rat neuronal cells altered the activity of several important neuronal specific genes. They include the structural genes encoding neurofilament proteins and synaptic vesicle proteins, regulatory genes encoding signaling components β-arrestin and p38 MAPK, and stress-response genes encoding hsp70 [].

7.3. Altered Heme Metabolism Is Associated with Alzheimer’s Disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder, a common cause of age-related dementia. It is characterized by memory loss caused by a decline in synaptic function, the formation of neurofibrillary tangles, and neuronal cell death, which is followed by a further decline in cognitive and physical functions. Amyloid-β (Aβ) peptide aggregation is associated with the pathophysiology of AD and is associated with the loss of iron homeostasis and mitochondrial complex IV [,]. Altered heme metabolism is found in the brains of AD patients []. Defective heme metabolism is associated with aberrations in the electron transport chain (loss of complex IV), dimerization of APP, free-radical production, markers of oxidative damage and ultimately cell death, which represents key cytopathologies of AD []. The expression levels of heme synthetic enzymes ALAS1 and porphobilinogen deaminase are substantially decreased, which may be associated with the heme deficiency seen in AD, suggesting that the heme biosynthesis is altered in AD patients. The expression levels of heme oxygenase (HO) have been reported to be increased in the cerebral cortex and hippocampus in AD patients []. There are conflicting views about the effects of HO; it is not clear whether HO is associated with heme deficiency or an increased heme synthesis []. Due to increased heme degradation in AD patients, the levels of bilirubin, a product of heme degradation, are increased in the CSF of AD patients []. Aβ binds two molecules of heme with a binding constant of Ka1 = 7.27 × 10−6 M−1 (n1 = 1.5) and Ka2 = 2.89 × 10–6 M−1 (n2 = 1.8), forming Aβ-heme complex, which may lead to the functional heme-deficiency in the brains of AD patients []. Heme binding with Aβ prevents the formation of Aβ aggregates, although the Aβ-heme complex is a peroxidase and can oxidize several biomolecules. Sequestration of heme by Aβ creates a heme-deficient environment leading to dysfunctional mitochondria and altered metabolic activity in AD brain [].

7.4. Heme Is Important in the Regulation of Circadian Rhythm in Humans

Circadian rhythm is the clock governing many important behaviors and physiological processes in humans, such as sleep/wake cycle, feeding, body temperature, hormone secretion, and metabolism []. Molecular and biochemical studies suggested an involvement of heme in the regulation of circadian rhythms. Neuronal PAS domain protein 2 (NPAS2) is a heme-binding protein and plays a role in the regulation of circadian rhythms [,]. DNA binding activity of heme-bound NPAS2 can be inhibited by low micromolar concentrations of carbon monoxide, suggesting that the expression of its target genes are regulated by the gas through a heme-based sensor [,]. Heme acts as a ligand for the nuclear hormone receptors REV-ERBα and REV-ERBβ. REV-ERBα regulates a number of physiological functions, including circadian rhythms and metabolic gene pathways. It acts as a heme sensor for the coordination of circadian and metabolic pathway [,,]. A study in mice suggests that a defect in heme biosynthesis, especially heme deficiency, can affect the phase and period of circadian clock []. Thus, heme acts as a factor modulating the function of mammalian circadian clock genes [].

8. Conclusions

This review offers a comprehensive analysis of the current literature on the health benefits and risks of heme as an essential nutrient. Heme constitutes 95% of the functional iron in the human body and accounts for two-thirds of iron intake for people in Western countries. Therefore, heme ought to be a crucial factor when considering human nutrition and health. This review summarizes both epidemiological and molecular studies regarding heme function in health and diseases. It can serve as a starting point for further discussion of heme function as an essential nutrient and investigation of heme function in the pathogenesis of diverse diseases.

Conflicts of Interest

There are no conflicts of interest.

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Important EPP Survey URGENT ASAP!!!

Important EPP Survey Dear EPP Community, As you know, the diagnosis of EPP is often delayed for many years. Researchers at the Icah...