hemoglobin

1/8/2007

A.) What is hemoglobin?

Hemoglobin is a protein that is carried by red cells. It picks up oxygen in the lungs and delivers it to the peripheral tissues to maintain the viability of cells. Hemoglobin is made from two similar proteins that "stick together". Both proteins must be present for the hemoglobin to pick up and release oxygen normally. One of the component proteins is called alpha, the other is beta. Before birth, the beta protein is not expressed. A hemoglobin protein found only during fetal development, called gamma, substitutes up until birth.

B.) How is hemoglobin made?

Like all proteins, the "blueprint" for hemoglobin exists in DNA (the material that makes up genes). Normally, an individual has four genes that code for the alpha protein, or alpha chain. Two other genes code for the beta chain. (Two additional genes code for the gamma chain in the fetus). The alpha chain and the beta chain are made in precisely equal amounts, despite the differing number of genes. The protein chains join in developing red blood cells, and remain together for the life of the red cell.

C.) How do abnormal hemoglobins arise?

The composition of hemoglobin is the same in all people. The genes that code for hemoglobin are identical throughout the world. Occasionally, however, one of the genes is altered by any of a variety of "accidents" that can occur in nature. These alterations in the genes (called "mutations") are very rare. Since genes are inherited, and they contain the information needed to make a protein, if a mutation produces an abnormal hemoglobin gene in a person, the gene will be passed on to his or her children. The children will produce a modified hemoglobin identical to that of the parent. Most mutations in hemoglobin produce no problem. Occasionally, however, the alteration in the protein changes aspects of its behavior. The types of disorders that can result include sickle cell disease and thalassemia.

D.) What about all the different blood types?

Blood cells are made up of two components. The hemoglobin is in solution inside the cell. The cell is surrounded by a membrane that holds in the hemoglobin. A rough analogy would be a rubber water balloon. The rubber would be the membrane, and the water would be the hemoglobin. The blood types that most of us know, A, B, O, and Rh, are properties of the membrane. The hemoglobin inside the red cells of a person with type O blood and that inside the red cells of a person with type A blood are identical. The analogy would be of water balloons made from blue and red balloons. The color of the ballon would differ, but the material inside (water) would be the same.

E.) How many types of abnormal hemoglobins are there?

Although the changes that produce abnormal hemoglobins are rare, several hundred abnormal (or more precisely, "variant") hemoglobins exist. These have accumulated over the millions of years of human existence. Most variant hemoglobins ******** normally, and are only found through specialized research techniques. Some hemoglobins, however, do not ******** normally and can produce clinical disorders, such as sickle cell disease.

F.) What happens if a hemoglobin gene "burns out"?

Genes can suffer damage to an extent that they no longer produce normal amounts of hemoglobin. Usually, only one of the sets of hemoglobin genes is affected, that is the alpha gene set or the beta gene set. For example, one of the two beta globin genes may fail to produce a normal quantity of beta chain protein. The alpha globin gene set will continue to produce a normal quantity of alpha chain protein. An imbalance develops in the amount of alpha chain and beta chain protein in the cell. There is too much alpha chain for the amount of beta chain that is present. This imbalance is called "thalassemia ". In this example, it would be beta thalassemia, because it is the beta chain gene that has failed. An analogy would be cars coming out of the factory. Engines and bodies must be made in equal numbers to have ********al automobiles. If the engine plant goes on strike (thalassemia), the bodies produced by the body plant are useless

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hemophilia

1/8/2007

What Is Hemophilia?

Hemophilia (heem-o-FILL-ee-ah) is a rare, inherited bleeding disorder in which your blood doesn’t clot normally. If you have hemophilia, you may bleed for a longer time than others after an injury. You also may bleed internally, especially in your knees, ankles, and elbows. This bleeding can damage your organs or tissues and, sometimes, be fatal.

People born with hemophilia have little to none of a protein needed for normal blood clotting. The protein is called a clotting factor. There are several types of clotting factors, and they work together with platelets to help the blood clot. Platelets are small pieces of blood cells that are formed in the bone marrow. They play a major role in blood clotting.

When blood vessels are injured, clotting factors help the platelets stick together to plug cuts and breaks at the site of the injury to stop the bleeding. Without clotting factors, normal blood clotting can’t take place. Sometimes people with hemophilia need injections of a clotting factor or factors to stop bleeding.

There are two main types of hemophilia. If you have hemophilia A, you have little to no clotting factor VIII (8). About 9 out of 10 people with hemophilia have type A. If you have hemophilia B, you’re missing or have low levels of clotting factor IX (9).

Hemophilia can be mild, moderate, or severe, depending on how much clotting factor is in the blood. About 7 out of 10 people who have hemophilia A have the severe form of the disorder. People who don’t have hemophilia have a factor VIII activity of 100 percent; people who have severe hemophilia A have a factor VIII activity of less than 1 percent.

In addition to being inherited, hemophilia also can be acquired, which means that you can develop it during your lifetime. It can develop if your body forms antibodies to the clotting factors in your bloodstream. The antibodies can block the clotting factors from working. Only inherited hemophilia is discussed in this article.

About 18,000 people in the United States have hemophilia. Each year, about
400 babies are born with the disorder. Hemophilia usually occurs only in males (with very rare exceptions).

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hepatite

1/8/2007

Where does it come from ?

Until the advent of efficient screening tests for hepatitis C virus (HCV), contamination was through transfusion of blood or derivated products (anti-hemophilia factors). In the last years, the number of children of HCV-infected mothers, is increasing (1) : the risk of transmission is overall low (about 5% in HIV-negative viremic mothers, 3 times higher when HIV-positive), but the number of potential mothers is high. The risk increases with the viral load (2). The risk factor of vaginal delivery is controversial : in a recent study the risk of contamination was nil when elective caesarean section was performed, before membrane rupture (3) ; however the number of cases was small (31), and this has to date not be confirmed in other series (2, 4). In utero contamination is postulated when HCV-RNA is found in the baby from birth (2). Many retrospective studies demonstrate that, although the virus can be found in colostrum and breast milk, breast-feeding does not transmit it (5). The general recommendations are thus not to contra-indicate breast-feeding. However some are more prudent and advocate a " tailored " approach, weighing the socioeconomic status and the advantages of breast-feeding against a theoretical slight increase in the risk of late transmission (6).

What is the short term risk ?

Clinical liver disease due to HCV is extremely rare in childhood. The exceptions are mainly children with other risk factors (other viruses, chemotherapy, immunosuppression). The daily clinical experience is of healthy children or teenagers with normal clinical examination (7, 8). However, histology may be more severe than the clinical picture : histological cirrhosis in described in some series : 3 among 40 children (9), one among 39 (10). In contrast, the histology is always or most often mild in other series (11,12).

Is spontaneous cure possible ?

The rate of spontaneous clearance of HCV in children infected at birth is about 20% (13, 14). In our experience this can happen during the first three years of life. Whether it can happen later is probable but undemonstrated. Long-term studies of patients contaminated with transfusion demonstrate a 25 to 50% rate of spontaneously negative viremia (see below). Further studies are needed on this issue.

What is the long term risk ?

The first adult reports were comforting, with little additional mortality due to HCV (15). It was confirmed with 8 more years of follow-up, 23 % of patients having cleared spontaneously the virus. Nevertheless 14 % had clinical signs of cirrhosis (17). Then arrived large (and probably highly biased) series from big hepatology units mentioning about 20 % of cirrhosis after 20 years of infection (17, 18, 19). More relevant to the pediatric situation is probably the long-term (17 to 20 years) follow-up of women infected with anti-D immune globulins (20, 21), and children infected during neonatal cardiac surgery (22). In these large (376, 917 and 67 patients, respectively) series, the rate of apparent spontaneous cure is high (only half have a positive HCV-PCR), the rate of clinical liver disease is very low, and possibly related to additional factors (alcohol, heart failure, hepatitis B). Histological cirrhosis is also very rare. We can probably reasonably tell the families that, avoiding alcohol (even a "normal" regular intake), vaccinated against hepatitis B, their children have a very low risk to develop significant liver disease in the future. A recent publication demonstrates also an increased risk of liver lesions with cigarette smoking (23) : we should educate our patients to lead a very healthy life...

Treatment

Should we treat ? The best results in adults are currently obtained with a combination of a-interferon plus ribavirin, for 6 or 12 months (24). Sustained response (negativation of viremia and no relapse in the year following the end of treatment), can be achieved after 6 months of combined therapy in 65-70% of patients with genotype 2 or 3. In patients with genotype 1 (and 4 ?) and a high viral load (more than 2 million copies/ml), sustained response is only 30-40% after 12 months of treatment, slightly better if the viral load is low. The predictive factors for good response are age (< 40 years), sex (female), genotype (non 1), viral load, absence of cirrhosis (25). The side effects of interferon are well-known : fever, fatigue, depression, weight loss, thrombopenia, neutropenia, hypothyroidism. Ribavirin may cause anemia. Recently, encouraging results in adults have been published with pegylated interferon (interferon covalently bound to a polyethylene glycol moiety, that confers a longer half-life), that allows once weekly injections, with improvement of the response rate as compared with interferon, and better tolerance (26). Studies are now being designed using a combination of Peginterferon and ribavirin. In children, studies are limited, include small numbers of patients, and use a monotherapy with interferon (Table I) : the success rate ranges from 8 to 56%, with a mean at 40%, that is better than the overall response rate to monotherapy in adults (15-30%). The series are too small to evaluate the role of genotype or mode of contamination. No series has been published using a combination with ribavirin. We thus don't know if we should treat, given the good medium-term prognosis in most cases. We don't know either what is the optimal treatment in children. Further studies are needed... When to test the neonate of an HCV-positive mother ? Only children of viremic mothers have a risk of infection. The diagnosis is not an emergency given the good prognosis and the uncertainties about treatment. A "non-agressive " attitude is to control HCV serology in the child after the age of 12-15 months, when he should have lost the maternal antibodies. If negative no other control is performed. If positive, viremia and transaminases are controlled on a regular basis (every 6-12 months). A more agressive approach is to perform HCV-RNA by PCR at 3 months of age (too many false results before this age) : the specificity and sensitivity are close to 97%. If positive the follow-up will be as above. If negative, the risk of infection is very low... and will be controlled by a serology performed after 12-15 months. What is the follow-up ? Should a liver biopsy be performed ? It depends on the decision for treatment, that depends itself on the result of biopsy. In children with normal transaminases, no treatment will be offered anyway, as its efficiency is very low in adults in this situation. The risk to find severe lesions is also very low. In children with elevated transaminases, liver biopsy is discussed after 10-15 years of contamination, or in the presence of additional risk factors (hepatitis B, HIV, chemotherapy), when a treatment has reasonably to be discussed. The biological follow-up depends on the individual habits of the center, but should not be more frequent than 2-3 times a year. Viremia should be controlled qualitatively, except for treatment (quantitative viremia is one of the pronostic factors). The level of viremia is not related to the importance of liver lesions. Vaccine We are not yet there, despite major efforts (27). The major problems are the high rate of mutation (quasi-species), the hypervariable region being the site of a principal neutralization epitope, the late emergence of neutralizing antibodies, the difficulties of establishing a convenient tissue culture (28), and the use of the only animal model, that is the chimpanzee. However a strong cellular immune response exists and is implicated in viral clearance. The current approches are with DNA-based vaccination (29), or more probably chimeric viruses expressing HCV genes (30), or viruslike particles (31).

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gilbert

1/8/2007

You’re yellow, you feel sick, can’t think straight and are exhausted, what is happening?

GS is named after a French Gastroenterologist, and it’s sometimes called ‘Unconjugated hyperbilirubinaemia’.
GS is thought by some scientisists to be inherited and it is caused by a mutated gene UDP - glucuronosyltransferase), which leaves those affected with less of the related enzyme (called UGT for short).  An enzyme is a chemical substance in your body that causes a chemical reaction to happen. Lack of this particular enzyme, UGT, is the key to what happens in our body and results in the symptoms we can experience:

Jaundice –
Red blood cells release ‘bilirubin’ into the bloodstream, which the liver should pick up and convert to bile, and then flush from the body. In GS, without the enzyme needed to do this properly, the bilirubin builds up and and can make you look yellow.  It’s also key in diagnosing GS, through blood tests which identify fluctuating levels of bilirubin in the blood. GS is also known by this symptom as Unconjugated hyperbilirubinaemia.

Toxic reactions –
Parts of the liver, called the ‘Phase II’ pathways, process certain toxins, for example: pollution; chemical fumes; and chemicals in some drugs.  This process, called glucuronidation, has been reported to be 31% slower in the typical person with GS.  Numerous studies have shown various drugs are processed less well by people with GS.

Many of the resulting symptoms of our liver’s reduced ability to do the cleaning it’s designed to – jaundice, nausea, fatigue, shakiness, bowel complaints, vomiting, ‘brain-fog’ or difficulty concentrating, are experienced in varying degrees by those with GS.

It seems that certain activities may make these symptoms worse, by placing further stress upon the liver.  Missing meals, lack of sleep, vigorous exercise, illness and stress can all bring on the symptoms.

Most important in keeping your liver ********ing as well as possible is maintaining stable blood sugar levels.  This is because the enzyme we don’t have much of uses sugar to help get rid of the toxins it is supposed to deal with.  We can also fool the liver into making more of the enzyme by eating certain foods and diet plays an important part in managing GS.

At present there isn’t a clear link between all the processes involved, or even that GS is actually hereditary.  AGS hopes that, through funding research and creating a higher profile for GS, we can better understand and treat the symptoms of Gilbert’s Syndrome.

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