<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Blood transfusion and can you explain it in depth? [/INST] Blood transfusion is the process of transferring blood products into a persons circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but modern medical practice commonly uses only components of the blood, such as red blood cells, white blood cells, plasma, clotting factors and platelets.
Red blood cells (RBC) contain hemoglobin, and supply the cells of the body with oxygen. White blood cells are not commonly used during transfusion, but they are part of the immune system, and also fight infections. Plasma is the "yellowish" liquid part of blood, which acts as a buffer, and contains proteins and important substances needed for the bodys overall health. Platelets are involved in blood clotting, preventing the body from bleeding. Before these components were known, doctors believed that blood was homogeneous. Because of this scientific misunderstanding, many patients died because of incompatible blood transferred to them.

Medical uses
Red cell transfusion
Historically, red blood cell transfusion was considered when the hemoglobin level fell below 100g/L or hematocrit fell below 30%. Because each unit of blood given carries risks, a trigger level lower than that, at 70 to 80g/L, is now usually used, as it has been shown to have better patient outcomes. The administration of a single unit of blood is the standard for hospitalized people who are not bleeding, with this treatment followed with re-assessment and consideration of symptoms and hemoglobin concentration. Patients with poor oxygen saturation may need more blood. The advisory caution to use blood transfusion only with more severe anemia is in part due to evidence that outcomes are worsened if larger amounts are given. One may consider transfusion for people with symptoms of cardiovascular disease such as chest pain or shortness of breath. In cases where patients have low levels of hemoglobin due to iron deficiency, but are cardiovascularly stable, parenteral iron is a preferred option based on both efficacy and safety. Other blood products are given where appropriate, e.g., to treat clotting deficiencies.

Procedure
Before a blood transfusion is given, there are many steps taken to ensure quality of the blood products, compatibility, and safety to the recipient. In 2012, a national blood policy was in place in 70% of countries and 69% of countries had specific legislation that covers the safety and quality of blood transfusion.

Blood donation
Blood transfusions use as sources of blood either ones own (autologous transfusion), or someone elses (allogeneic or homologous transfusion). The latter is much more common than the former. Using anothers blood must first start with donation of blood. Blood is most commonly donated as whole blood obtained intravenously and mixed with an anticoagulant. In developed countries, donations are usually anonymous to the recipient, but products in a blood bank are always individually traceable through the whole cycle of donation, testing, separation into components, storage, and administration to the recipient. This enables management and investigation of any suspected transfusion related disease transmission or transfusion reaction. In developing countries, the donor is sometimes specifically recruited by or for the recipient, typically a family member, and the donation occurs immediately before the transfusion.
It is unclear whether applying alcohol swab alone or alcohol swab followed by antiseptic is able to reduce contamination of donors blood.

Processing and testing
Donated blood is usually subjected to processing after it is collected, to make it suitable for use in specific patient populations. Collected blood is then separated into blood components by centrifugation: red blood cells, plasma, platelets, albumin protein, clotting factor concentrates, cryoprecipitate, fibrinogen concentrate, and immunoglobulins (antibodies). Red cells, plasma and platelets can also be donated individually via a more complex process called apheresis.

The World Health Organization (WHO) recommends that all donated blood be tested for transfusion-transmissible infections. These include HIV, hepatitis B, hepatitis C, Treponema pallidum (syphilis) and, where relevant, other infections that pose a risk to the safety of the blood supply, such as Trypanosoma cruzi (Chagas disease) and Plasmodium species (malaria). According to the WHO, 25 countries are not able to screen all donated blood for one or more of: HIV, hepatitis B, hepatitis C, or syphilis. One of the main reasons for this is because testing kits are not always available. However the prevalence of transfusion-transmitted infections is much higher in low income countries compared to middle and high income countries.
All donated blood should also be tested for the ABO blood group system and Rh blood group system to ensure that the patient is receiving compatible blood.
In addition, in some countries platelet products are also tested for bacterial infections due to its higher inclination for contamination due to storage at room temperature. Presence of cytomegalovirus (CMV) may also be tested because of the risk to certain immunocompromised recipients if given, such as those with organ transplant or HIV. However, not all blood is tested for CMV because only a certain amount of CMV-negative blood needs to be available to supply patient needs. Other than positivity for CMV, any products tested positive for infections are not used.
Leukocyte reduction is the removal of white blood cells by filtration. Leukoreduced blood products are less likely to cause HLA alloimmunization (development of antibodies against specific blood types), febrile non-hemolytic transfusion reaction, cytomegalovirus infection, and platelet-transfusion refractoriness.
Pathogen Reduction treatment that involves, for example, the addition of riboflavin with subsequent exposure to UV light has been shown to be effective in inactivating pathogens (viruses, bacteria, parasites and white blood cells) in blood products. By inactivating white blood cells in donated blood products, riboflavin and UV light treatment can also replace gamma-irradiation as a method to prevent graft-versus-host disease (TA-GvHD).

Compatibility testing
Before a recipient receives a transfusion, compatibility testing between donor and recipient blood must be done. The first step before a transfusion is given is to type and screen the recipients blood. Typing of recipients blood determines the ABO and Rh status. The sample is then screened for any alloantibodies that may react with donor blood. It takes about 45 minutes to complete (depending on the method used). The blood bank scientist also checks for special requirements of the patient (e.g. need for washed, irradiated or CMV negative blood) and the history of the patient to see if they have previously identified antibodies and any other serological anomalies.

A positive screen warrants an antibody panel/investigation to determine if it is clinically significant. An antibody panel consists of commercially prepared group O red cell suspensions from donors that have been phenotyped for antigens that correspond to commonly encountered and clinically significant alloantibodies. Donor cells may have homozygous (e.g. K+k+), heterozygous (K+k-) expression or no expression of various antigens (K−k−). The phenotypes of all the donor cells being tested are shown in a chart. The patients serum is tested against the various donor cells. Based on the reactions of the patients serum against the donor cells, a pattern will emerge to confirm the presence of one or more antibodies. Not all antibodies are clinically significant (i.e. cause transfusion reactions, HDN, etc.). Once the patient has developed a clinically significant antibody it is vital that the patient receive antigen-negative red blood cells to prevent future transfusion reactions. A direct antiglobulin test (Coombs test) is also performed as part of the antibody investigation.If there is no antibody present, an immediate spin crossmatch or computer-assisted crossmatch is performed where the recipient serum and donor rbc are incubated. In the immediate spin method, two drops of patient serum are tested against a drop of 3–5% suspension of donor cells in a test tube and spun in a serofuge. Agglutination or hemolysis (i.e., positive Coombs test) in the test tube is a positive reaction and the unit should not be transfused.
If an antibody is suspected, potential donor units must first be screened for the corresponding antigen by phenotyping them. Antigen negative units are then tested against the patient plasma using an antiglobulin/indirect crossmatch technique at 37 degrees Celsius to enhance reactivity and make the test easier to read.
In urgent cases where crossmatching cannot be completed, and the risk of dropping hemoglobin outweighs the risk of transfusing uncrossmatched blood, O-negative blood is used, followed by crossmatch as soon as possible. O-negative is also used for children and women of childbearing age. It is preferable for the laboratory to obtain a pre-transfusion sample in these cases so a type and screen can be performed to determine the actual blood group of the patient and to check for alloantibodies.

Compatibility of ABO and Rh system for Red Cell (Erythrocyte) Transfusion
This chart shows possible matches in blood transfusion between donor and receiver using ABO and Rh system.

Adverse effects
In the same way that the safety of pharmaceutical products is overseen by pharmacovigilance, the safety of blood and blood products is overseen by haemovigilance. This is defined by the World Health Organization (WHO) as a system "...to identify and prevent occurrence or recurrence of transfusion related unwanted events, to increase the safety, efficacy and efficiency of blood transfusion, covering all activities of the transfusion chain from donor to recipient." The system should include monitoring, identification, reporting, investigation and analysis of adverse events near-misses and reactions related to transfusion and manufacturing. In the UK this data is collected by an independent organisation called SHOT (Serious Hazards Of Transfusion).Transfusions of blood products are associated with several complications, many of which can be grouped as immunological or infectious. There is controversy on potential quality degradation during storage.

Immunologic reaction
Acute hemolytic reactions are defined according to Serious Hazards of Transfusion (SHOT) as "fever and other symptoms/signs of haemolysis within 24 hours of transfusion; confirmed by one or more of the following: a fall of Hb, rise in lactate dehydrogenase (LDH), positive direct antiglobulin test (DAT), positive crossmatch" This is due to destruction of donor red blood cells by preformed recipient antibodies. Most often this occurs because of clerical errors or improper ABO blood typing and crossmatching resulting in a mismatch in ABO blood type between the donor and the recipient. Symptoms include fever, chills, chest pain, back pain, hemorrhage, increased heart rate, shortness of breath, and rapid drop in blood pressure. When suspected, transfusion should be stopped immediately, and blood sent for tests to evaluate for presence of hemolysis. Treatment is supportive. Kidney injury may occur because of the effects of the hemolytic reaction (pigment nephropathy). The severity of the transfusion reaction is depended upon amount of donors antigen transfused, nature of the donors antigens, the nature and the amount of recipient antibodies.
Delayed hemolytic reactions occur more than 24 hours after a transfusion. They usually occur within 28 days of a transfusion. They can be due to either a low level of antibodies present prior to the start of the transfusion, which are not detectable on pre-transfusion testing; or development of a new antibody against an antigen in the transfused blood. Therefore, delayed haemolytic reaction does not manifest until after 24 hours when enough antibodies are available to cause a reaction. The red blood cells are removed by macrophages from the blood circulation into liver and spleen to be destroyed, which leads to extravascular haemolysis. This process usually mediated by anti-Rh and anti-Kidd antibodies. However, this type of transfusion reaction is less severe when compared to acute haemolytic transfusion reaction.
Febrile nonhemolytic reactions are, along with allergic transfusion reactions, the most common type of blood transfusion reaction and occur because of the release of inflammatory chemical signals released by white blood cells in stored donor blood or attack on donors white blood cells by recipients antibodies. This type of reaction occurs in about 7% of transfusions. Fever is generally short lived and is treated with antipyretics, and transfusions may be finished as long as an acute hemolytic reaction is excluded. This is a reason for the now-widespread use of leukoreduction – the filtration of donor white cells from red cell product units.
Allergic transfusion reactions are caused by IgE anti-allergen antibodies. When antibodies are bound to its antigens, histamine is released from mast cells and basophils. Either IgE antibodies from the donors or recipients side can cause the allergic reaction. It is more common in patients who have allergic conditions such as hay fever. Patient may feel itchy or having hives but the symptoms are usually mild and can be controlled by stopping the transfusion and giving antihistamines.
Anaphylactic reactions are rare life-threatening allergic conditions caused by IgA anti-plasma protein antibodies. For patients who have selective immunoglobulin A deficiency, the reaction is presumed to be caused by IgA antibodies in the donors plasma. The patient may present with symptoms of fever, wheezing, coughing, shortness of breath, and circulatory shock. Urgent treatment with epinephrine is needed.
Post-transfusion purpura is an extremely rare complication that occurs after blood product transfusion and is associated with the presence of antibodies in the patients blood directed against both the donors and recipients platelets HPA (human platelet antigen). Recipients who lack this protein develop sensitization to this protein from prior transfusions or previous pregnancies, can develop thrombocytopenia, bleeding into the skin, and can display purplish discolouration of skin which is known as purpura. Intravenous immunoglobulin (IVIG) is treatment of choice.
Transfusion-related acute lung injury (TRALI) is a syndrome that is similar to acute respiratory distress syndrome (ARDS), which develops during or within 6 hours of transfusion of a plasma-containing blood product. Fever, hypotension, shortness of breath, and tachycardia often occurs in this type of reaction. For a definitive diagnosis to be made, symptoms must occur within 6 hours of transfusion, hypoxemia must be present, there must be radiographic evidence of bilateral infiltrates and there must be no evidence of left atrial hypertension (fluid overload). It occurs in 15% of the transfused patient with mortality rate of 5 to 10%. Recipient risk factors includes: end-stage liver disease, sepsis, haematological malignancies, sepsis, and ventilated patients. Antibodies to human neutrophil antigens (HNA)  and human leukocyte antigens (HLA) have been associated with this type of transfusion reaction. Donors antibodies interacting with antigen positive recipient tissue result in release of inflammatory cytokines, resulting in pulmonary capillary leakage. The treatment is supportive.
Transfusion associated circulatory overload (TACO) is a common, yet underdiagnosed, reaction to blood product transfusion consisting of the new onset or exacerbation of three of the following within 6 hours of cessation of transfusion: acute respiratory distress, elevated brain natriuretic peptide (BNP), elevated central venous pressure (CVP), evidence of left heart failure, evidence of positive fluid balance, and/or radiographic evidence of pulmonary edema.
Transfusion-associated graft versus host disease frequently occurs in immunodeficient patients where recipients body failed to eliminate donors T cells. Instead, donors T cells attack the recipients cells. It occurs one week after transfusion. Fever, rash, diarrhoea are often associated with this type of transfusion reaction. Mortality rate is high, with 89.7% of the patients dead after 24 days. Immunosuppressive treatment is the most common way of treatment. Irradiation and leukoreduction of blood products is necessary for high risk patients to prevent T cells from attacking recipient cells.

Infection
The use of greater amount of red blood cells is associated with a high risk of infections. In those who were given red blood only with significant anemia infection rates were 12% while in those who were given red blood at milder levels of anemia infection rates were 17%.On rare occasions, blood products are contaminated with bacteria. This can result in a life-threatening infection known as transfusion-transmitted bacterial infection. The risk of severe bacterial infection is estimated, as of 2002, at about 1 in 50,000 platelet transfusions, and 1 in 500,000 red blood cell transfusions. Blood product contamination, while rare, is still more common than actual infection. The reason platelets are more often contaminated than other blood products is that they are stored at room temperature for short periods of time. Contamination is also more common with longer duration of storage, especially if that means more than 5 days. Sources of contaminants include the donors blood, donors skin, phlebotomists skin, and containers. Contaminating organisms vary greatly, and include skin flora, gut flora, and environmental organisms. There are many strategies in place at blood donation centers and laboratories to reduce the risk of contamination. A definite diagnosis of transfusion-transmitted bacterial infection includes the identification of a positive culture in the recipient (without an alternative diagnosis) as well as the identification of the same organism in the donor blood.
Since the advent of HIV testing of donor blood in the mid/later 1980s, ex. 1985s ELISA, the transmission of HIV during transfusion has dropped dramatically. Prior testing of donor blood only included testing for antibodies to HIV. However, because of latent infection (the "window period" in which an individual is infectious, but has not had time to develop antibodies) many cases of HIV seropositive blood were missed. The development of a nucleic acid test for the HIV-1 RNA has dramatically lowered the rate of donor blood seropositivity to about 1 in 3 million units. As transmittance of HIV does not necessarily mean HIV infection, the latter could still occur at an even lower rate.
The transmission of hepatitis C via transfusion currently stands at a rate of about 1 in 2 million units. As with HIV, this low rate has been attributed to the ability to screen for both antibodies as well as viral RNA nucleic acid testing in donor blood.
Other rare transmissible infections include hepatitis B, syphilis, Chagas disease, cytomegalovirus infections (in immunocompromised recipients), HTLV, and Babesia.

Comparison table
Inefficacy
Transfusion inefficacy or insufficient efficacy of a given unit(s) of blood product, while not itself a "complication" per se, can nonetheless indirectly lead to complications – in addition to causing a transfusion to fully or partly fail to achieve its clinical purpose. This can be especially significant for certain patient groups such as critical-care or neonatals.
For red blood cells (RBC), by far the most commonly transfused product, poor transfusion efficacy can result from units damaged by the so-called storage lesion – a range of biochemical and biomechanical changes that occur during storage. With red cells, this can decrease viability and ability for tissue oxygenation. Although some of the biochemical changes are reversible after the blood is transfused, the biomechanical changes are less so, and rejuvenation products are not yet able to adequately reverse this phenomenon. There has been controversy about whether a given product units age is a factor in transfusion efficacy, specifically about whether "older" blood directly or indirectly increases risks of complications. Studies have not been consistent on answering this question, with some showing that older blood is indeed less effective but with others showing no such difference; these developments are being closely followed by hospital blood bankers – who are the physicians, typically pathologists, who collect and manage inventories of transfusable blood units.
Certain regulatory measures are in place to minimize RBC storage lesion – including a maximum shelf life (currently 42 days), a maximum auto-hemolysis threshold (currently 1% in the US, 0.8% in Europe), and a minimum level of post-transfusion RBC survival in vivo (currently 75% after 24 hours). However, all of these criteria are applied in a universal manner that does not account for differences among units of product. For example, testing for the post-transfusion RBC survival in vivo is done on a sample of healthy volunteers, and then compliance is presumed for all RBC units based on universal (GMP) processing standards (RBC survival by itself does not guarantee efficacy, but it is a necessary prerequisite for cell function, and hence serves as a regulatory proxy). Opinions vary as to the "best" way to determine transfusion efficacy in a patient in vivo. In general, there are not yet any in vitro tests to assess quality or predict efficacy for specific units of RBC blood product prior to their transfusion, though there is exploration of potentially relevant tests based on RBC membrane properties such as erythrocyte deformability and erythrocyte fragility (mechanical).Physicians have adopted a so-called "restrictive protocol" – whereby transfusion is held to a minimum – in part because of the noted uncertainties surrounding storage lesion, in addition to the very high direct and indirect costs of transfusions. However, the restrictive protocol is not an option with some especially vulnerable patients who may require the best possible efforts to rapidly restore tissue oxygenation.
Although transfusions of platelets are far less numerous (relative to RBC), platelet storage lesion and resulting efficacy loss is also a concern.

Other
A known relationship between intra-operative blood transfusion and cancer recurrence has been established in colorectal cancer. In lung cancer intra-operative blood transfusion has been associated with earlier recurrence of cancer, worse survival rates and poorer outcomes after lung resection. Also studies shown to us, failure of the immune system caused by blood transfusion can be categorized as one of the main factors leading to more than 10 different cancer types that are fully associated with blood transfusion and the innate and adaptive immune system. Allogeneic blood transfusion, through five major mechanisms including the lymphocyte-T set, myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), natural killer cells (NKCs), and dendritic cells (DCs) can help the recipients defense mechanisms. On the other hand, the role for each of the listed items includes activation of the antitumor CD8+ cytotoxic T lymphocytes (CD8+/CTL), temporal inactivation of Tregs, inactivation of the STAT3 signaling pathway, the use of bacteria to enhance the antitumor immune response and cellular Immunotherapy.
Transfusion-associated volume overload is a common complication simply because blood products have a certain amount of volume. This is especially the case in recipients with underlying cardiac or kidney disease. Red cell transfusions can lead to volume overload when they must be repeated because of insufficient efficacy (see above). Plasma transfusion is especially prone to causing volume overload because large volumes are usually required to give any therapeutic benefit.
It has been proved that blood transfusion produce worse outcomes after cytoreductive surgery and HIPEC.
Hypothermia can occur with transfusions with large quantities of blood products which normally are stored at cold temperatures. Core body temperature can go down as low as 32 °C and can produce physiologic disturbances. Prevention should be done with warming the blood to ambient temperature prior to transfusions.
Transfusions with large amounts of red blood cells, whether due to severe hemorrhaging and/or transfusion inefficacy (see above), can lead to an inclination for bleeding. The mechanism is thought to be due to disseminated intravascular coagulation, along with dilution of recipient platelets and coagulation factors. Close monitoring and transfusions with platelets and plasma is indicated when necessary.
Metabolic alkalosis can occur with massive blood transfusions because of the breakdown of citrate stored in blood into bicarbonate.
Hypocalcemia can also occur with massive blood transfusions because of the complex of citrate with serum calcium. Calcium levels below 0.9 mmol/L should be treated.
Blood doping is often used by athletes, drug addicts or military personnel for reasons such as to increase physical stamina, to fake a drug detection test or simply to remain active and alert during the duty-times respectively. However a lack of knowledge and insufficient experience can turn a blood transfusion into a sudden death. For example, when individuals run the frozen blood sample directly in their veins this cold blood rapidly reaches the heart, where it disturbs the hearts original pace leading to cardiac arrest and sudden death.

Frequency of use
Globally around 85 million units of red blood cells are transfused in a given year.In the United States, blood transfusions were performed nearly 3 million times during hospitalizations in 2011, making it the most common procedure performed. The rate of hospitalizations with a blood transfusion nearly doubled from 1997, from a rate of 40 stays to 95 stays per 10,000 population. It was the most common procedure performed for patients 45 years of age and older in 2011, and among the top five most common for patients between the ages of 1 and 44 years.According to the New York Times: "Changes in medicine have eliminated the need for millions of blood transfusions, which is good news for patients getting procedures like coronary bypasses and other procedures that once required a lot of blood." And, "Blood bank revenue is falling, and the decline may reach $1.5 billion a year this year [2014] from a high of $5 billion in 2008." Job losses will reach as high as 12,000 within the next three to five years, roughly a quarter of the total in the industry, according to the Red Cross.

History
Beginning with William Harveys experiments on the circulation of blood, recorded research into blood transfusion began in the 17th century, with successful experiments in transfusion between animals. However, successive attempts by physicians to transfuse animal blood into humans gave variable, often fatal, results.Pope Innocent VIII is sometimes said to have been given "the worlds first blood transfusion" by his physician Giacomo di San Genesio, who had him drink (by mouth) the blood of three 10-year-old boys. The boys subsequently died. The evidence for this story, however, is unreliable and considered a possible anti-Jewish blood libel.

Early attempts
The Incas
The first reported successful blood transfusions were performed by the Incas as early as the 1500s. Spanish conquistadors witnessed blood transfusions when they arrived in the sixteenth century. The prevalence of type O blood among Indigenous people of the Andean region meant such procedures would have held less risk than blood transfusion attempts among populations with incompatible blood types, which contributed to the failures of early attempts in Europe.

Animal blood
Working at the Royal Society in the 1660s, the physician Richard Lower began examining the effects of changes in blood volume on circulatory function and developed methods for cross-circulatory study in animals, obviating clotting by closed arteriovenous connections. The new instruments he was able to devise enabled him to perform the first reliably documented successful transfusion of blood in front of his distinguished colleagues from the Royal Society.According to Lowers account, "...towards the end of February 1665 [I] selected one dog of medium size, opened its jugular vein, and drew off blood, until its strength was nearly gone. Then, to make up for the great loss of this dog by the blood of a second, I introduced blood from the cervical artery of a fairly large mastiff, which had been fastened alongside the first, until this latter animal showed ... it was overfilled ... by the inflowing blood." After he "sewed up the jugular veins", the animal recovered "with no sign of discomfort or of displeasure".
Lower had performed the first blood transfusion between animals. He was then "requested by the Honorable [Robert] Boyle ... to acquaint the Royal Society with the procedure for the whole experiment", which he did in December 1665 in the Societys Philosophical Transactions.The first blood transfusion from animal to human was administered by Dr. Jean-Baptiste Denys, eminent physician to King Louis XIV of France, on June 15, 1667. He transfused the blood of a sheep into a 15-year-old boy, who survived the transfusion. Denys performed another transfusion into a labourer, who also survived. Both instances were likely due to the small amount of blood that was actually transfused into these people. This allowed them to withstand the allergic reaction.
Denyss third patient to undergo a blood transfusion was Swedish Baron Gustaf Bonde. He received two transfusions. After the second transfusion Bonde died. In the winter of 1667, Denys performed several transfusions on Antoine Mauroy with calfs blood.  On the third account Mauroy died.Six months later in London, Lower performed the first human transfusion of animal blood in Britain, where he "superintended the introduction in [a patients] arm at various times of some ounces of sheeps blood at a meeting of the Royal Society, and without any inconvenience to him." The recipient was Arthur Coga, "the subject of a harmless form of insanity." Sheeps blood was used because of speculation about the value of blood exchange between species; it had been suggested that blood from a gentle lamb might quiet the tempestuous spirit of an agitated person and that the shy might be made outgoing by blood from more sociable creatures. Coga received 20 shillings (equivalent to £183 in 2021) to participate in the experiment.Lower went on to pioneer new devices for the precise control of blood flow and the transfusion of blood; his designs were substantially the same as modern syringes and catheters. Shortly after, Lower moved to London, where his growing practice soon led him to abandon research.These early experiments with animal blood provoked a heated controversy in Britain and France. Finally, in 1668, the Royal Society and the French government both banned the procedure. The Vatican condemned these experiments in 1670. Blood transfusions fell into obscurity for the next 150 years.

Human blood
The science of blood transfusion dates to the first decade of the 20th century, with the discovery of distinct blood types leading to the practice of mixing some blood from the donor and the receiver before the transfusion (an early form of cross-matching).In the early 19th century, British obstetrician Dr. James Blundell made efforts to treat hemorrhage by transfusion of human blood using a syringe. In 1818 following experiments with animals, he performed the first successful transfusion of human blood to treat postpartum hemorrhage. Blundell used the patients husband as a donor, and extracted four ounces of blood from his arm to transfuse into his wife. During the years 1825 and 1830, Blundell performed 10 transfusions, five of which were beneficial, and published his results. He also invented a number of instruments for the transfusion of blood. He made a substantial amount of money from this endeavour, roughly $2 million ($50 million real dollars).In 1840, at St Georges Hospital Medical School in London, Samuel Armstrong Lane, aided by Blundell, performed the first successful whole blood transfusion to treat haemophilia.However, early transfusions were risky and many resulted in the death of the patient. By the late 19th century, blood transfusion was regarded as a risky and dubious procedure, and was largely shunned by the medical establishment.
Work to emulate James Blundell continued in Edinburgh. In 1845 the Edinburgh Journal described the successful transfusion of blood to a woman with severe uterine bleeding. Subsequent transfusions were successful with patients of Professor James Young Simpson after whom the Simpson Memorial Maternity Pavilion in Edinburgh was named.Various isolated reports of successful transfusions emerged towards the end of the 19th century. The largest series of early successful transfusions took place at the Edinburgh Royal Infirmary between 1885 and 1892. Edinburgh later became the home of the first blood donation and blood transfusion services.

20th century
Only in 1901, when the Austrian Karl Landsteiner discovered three human blood groups (O, A, and B), did blood transfusion achieve a scientific basis and become safer.Landsteiner discovered that adverse effects arise from mixing blood from two incompatible individuals. He found that mixing incompatible types triggers an immune response and the red blood-cells clump. The immunological reaction occurs when the receiver of a blood transfusion has antibodies against the donor blood-cells. The destruction of red blood cells releases free hemoglobin into the bloodstream, which can have fatal consequences. Landsteiners work made it possible to determine blood group and allowed blood transfusions to take place much more safely. For his discovery he won the Nobel Prize in Physiology and Medicine in 1930; many other blood groups have been discovered since.George Washington Crile is credited with performing the first surgery using a direct blood transfusion in 1906 at St. Alexis Hospital in Cleveland while a professor of surgery at Case Western Reserve University.Jan Janský also discovered the human blood groups; in 1907 he classified blood into four groups: I, II, III, IV. His nomenclature is still used in Russia and in states of the former USSR, in which blood types O, A, B, and AB are respectively designated I, II, III, and IV.
Dr. William Lorenzo Mosss (1876–1957) Moss-blood typing technique of 1910 was widely used until World War II.William Stewart Halsted, M.D. (1852–1922), an American surgeon,  performed one of the first blood transfusions in the United States. He had been called to see his sister after she had given birth. He found her moribund from blood loss, and in a bold move withdrew his own blood, transfused his blood into his sister, and then operated on her to save her life.

Blood banks in WWI
While the first transfusions had to be made directly from donor to receiver before coagulation, it was discovered that by adding anticoagulant and refrigerating the blood it was possible to store it for some days, thus opening the way for the development of blood banks. John Braxton Hicks was the first to experiment with chemical methods to prevent the coagulation of blood at St Marys Hospital, London in the late-19th century. His attempts, using phosphate of soda, however, proved unsuccessful.
The Belgian doctor Albert Hustin performed the first non-direct transfusion on March 27, 1914, though this involved a diluted solution of blood. The Argentine doctor Luis Agote used a much less diluted solution in November of the same year. Both used sodium citrate as an anticoagulant.The First World War (1914-1918) acted as a catalyst for the rapid development of blood banks and transfusion techniques. Canadian doctor and Lieutenant Lawrence Bruce Robertson became instrumental in persuading the Royal Army Medical Corps to adopt the use of blood transfusion at the Casualty Clearing Stations for the wounded. In October 1915, Robertson performed his first wartime transfusion with a syringe to a patient who had multiple shrapnel wounds. He followed this up with four subsequent transfusions in the following months, and his success was reported to Sir Walter Morley Fletcher, director of the Medical Research Committee.

Robertson published his findings in the British Medical Journal in 1916 and, with the help of a few like-minded individuals (including the eminent physician Edward William Archibald (1872–1945), who introduced the citrate anticoagulant method), was able to persuade the British authorities of the merits of blood transfusion. Robertson went on to establish the first blood-transfusion apparatus at a Casualty Clearing Station on the Western Front in the spring of 1917.Oswald Hope Robertson, a medical researcher and U.S. Army officer, was attached to the RAMC in 1917, where he became instrumental in establishing the first blood banks in preparation for the anticipated Third Battle of Ypres. He used sodium citrate as the anticoagulant; blood was extracted from punctures in the vein and was stored in bottles at British and American Casualty Clearing Stations along the Front. Robertson also experimented with preserving separated red blood cells in iced bottles. Geoffrey Keynes, a British surgeon, developed a portable machine that could store blood to enable transfusions to be carried out more easily.

Expansion
The secretary of the British Red Cross, Percy Oliver, established the worlds first blood-donor service in 1921. In that year, Oliver was contacted by Kings College Hospital, where they were in urgent need of a blood donor.
 After providing a donor, Oliver set about organizing a system for the voluntary registration of blood donors at clinics around London, with Sir Geoffrey Keynes appointed as a medical adviser. Volunteers were subjected to a series of physical tests to establish their blood group. The London Blood Transfusion Service was free of charge and expanded rapidly in its first few years of operation. By 1925 it was providing services for almost 500 patients; it was incorporated into the structure of the British Red Cross in 1926. Similar systems developed in other cities, including Sheffield, Manchester and Norwich, and the services work began to attract international attention. France, Germany, Austria, Belgium, Australia and Japan established similar services.Alexander Bogdanov founded an academic institution devoted to the science of blood transfusion in Moscow in 1925. Bogdanov was motivated, at least in part, by a search for eternal youth, and remarked with satisfaction on the improvement of his eyesight, suspension of balding, and other positive symptoms after receiving 11 transfusions of whole blood. Bogdanov died in 1928 as a result of one of his experiments, when the blood of a student with malaria and tuberculosis was given to him in a transfusion. Following Bogdanovs lead, Vladimir Shamov and Sergei Yudin in the USSR pioneered the transfusion of cadaveric blood from recently deceased donors. Yudin performed such a transfusion successfully for the first time on March 23, 1930, and reported his first seven clinical transfusions with cadaveric blood at the Fourth Congress of Ukrainian Surgeons at Kharkiv in September. However, this method was never used widely, even in the Soviet Union. Nevertheless, the Soviet Union was the first to establish a network of facilities to collect and store blood for use in transfusions at hospitals.

Frederic Durán-Jordà established one of the earliest blood banks during the Spanish Civil War in 1936. Duran joined the Transfusion Service at the Barcelona Hospital at the start of the conflict, but the hospital was soon overwhelmed by the demand for blood and the paucity of available donors. With support from the Department of Health of the Spanish Republican Army, Duran established a blood bank for the use of wounded soldiers and civilians. The 300–400 mL of extracted blood was mixed with 10% citrate solution in a modified Duran Erlenmeyer flask. The blood was stored in a sterile glass enclosed under pressure at 2 °C. During 30 months of work, the Transfusion Service of Barcelona registered almost 30,000 donors, and processed 9,000 liters of blood.In 1937 Bernard Fantus, director of therapeutics at the Cook County Hospital in Chicago, established the first hospital blood-bank in the United States. In setting up a hospital laboratory that preserved, refrigerated and stored donor blood, Fantus originated the term "blood bank". Within a few years, hospital and community blood-banks were established across the United States.Frederic Durán-Jordà fled to Britain in 1938 and worked with Dr Janet Vaughan at the Royal Postgraduate Medical School at Hammersmith Hospital to establish a system of national blood banks in London. With the outbreak of war appearing imminent in 1938, the War Office created the Army Blood Supply Depot (ABSD) in Bristol, headed by Lionel Whitby and in control of four large blood-depots around the country. British policy through the war was to supply military personnel with blood from centralized depots, in contrast to the approach taken by the Americans and Germans where troops at the front were bled to provide required blood. The British method proved more successful in adequately meeting all requirements, and over 700,000 donors were bled over the course of the war. This system evolved into the National Blood Transfusion Service established in 1946, the first national service to be implemented.
Stories tell of Nazis in Eastern Europe during World War II using captive children as repeated involuntary blood-donors.

Medical advances
A blood-collection program was initiated in the US in 1940 and Edwin Cohn pioneered the process of blood fractionation. He worked out the techniques for isolating the serum albumin fraction of blood plasma, which is essential for maintaining the osmotic pressure in the blood vessels, preventing their collapse.
Gordon R. Ward, writing in the correspondence columns of the British Medical Journal, proposed the use of blood plasma as a substitute for whole blood and for transfusion purposes as early as 1918. At the onset of World War II, liquid plasma was used in Britain. A large project, known as "Blood for Britain", began in August 1940 to collect blood in New York City hospitals for the export of plasma to Britain. A dried plasma package was developed, which reduced breakage and made transportation, packaging, and storage much simpler.

The resulting dried plasma package came in two tin cans containing 400 mL bottles. One bottle contained enough distilled water to reconstitute the dried plasma contained within the other bottle. In about three minutes, the plasma would be ready to use and could stay fresh for around four hours. Dr. Charles R. Drew was appointed medical supervisor, and he was able to transform the test-tube methods into the first successful technique for mass production.
Another important breakthrough came in 1937–40 when Karl Landsteiner (1868–1943), Alex Wiener, Philip Levine, and R.E. Stetson discovered the Rhesus blood group system, which was found to be the cause of the majority of transfusion reactions up to that time. Three years later, the introduction by J.F. Loutit and Patrick L. Mollison of acid–citrate–dextrose (ACD) solution, which reduced the volume of anticoagulant, permitted transfusions of greater volumes of blood and allowed longer-term storage.
Carl Walter and W.P. Murphy Jr. introduced the plastic bag for blood collection in 1950. Replacing breakable glass bottles with durable plastic bags made from PVC allowed for the evolution of a collection system capable of safe and easy preparation of multiple blood components from a single unit of whole blood.
In the field of cancer surgery, the replacement of massive blood-loss became a major problem. The cardiac-arrest rate was high. In 1963 C. Paul Boyan and William S. Howland discovered that the temperature of the blood and the rate of infusion greatly affected survival rates, and introduced blood warming to surgery.Further extending the shelf-life of stored blood up to 42 days was an anticoagulant preservative, CPDA-1, introduced in 1979, which increased the blood supply and facilitated resource-sharing among blood banks.As of 2006 about 15 million units of blood products were transfused per year in the United States. By 2013 the number had declined to about 11 million units, because of the shift towards laparoscopic surgery and other surgical advances and studies that have shown that many transfusions were unnecessary. For example, the standard of care reduced the amount of blood transfused in one case from 750 to 200 mL.

Special populations
Neonate
To ensure the safety of blood transfusion to pediatric patients, hospitals are taking additional precautions to avoid infection and prefer to use specially tested pediatric blood units that are guaranteed negative for Cytomegalovirus. Most guidelines recommend the provision of CMV-negative blood components and not simply leukoreduced components for newborns or low birthweight infants in whom the immune system is not fully developed. These specific requirements place additional restrictions on blood donors who can donate for neonatal use.
Neonatal transfusions typically fall into one of two categories:

"Top-up" transfusions, to replace losses due to investigational losses and correction of anemia.
Exchange (or partial exchange) transfusions are done for removal of bilirubin, removal of antibodies and replacement of red cells (e.g., for anemia secondary to thalassemias and other hemoglobinopathies).

Significant blood loss
A massive transfusion protocol is used when significant blood loss is present such as in major trauma, when more than ten units of blood are needed. Packed red blood cells, fresh frozen plasma, and platelets are generally administered. Typically higher ratios of fresh frozen plasma and platelets are given relative to packed red blood cells.

Unknown blood type
Because blood type O negative is compatible with anyone, it is often overused and in short supply. According to the American Association of Blood Banks, the use of this blood should be restricted to persons with O negative blood, as nothing else is compatible with them, and women who might be pregnant and for whom it would be impossible to do blood group testing before giving them emergency treatment. Whenever possible, the AABB recommends that O negative blood be conserved by using blood type testing to identify a less scarce alternative.

Religious objections
Jehovahs Witnesses may object to blood transfusions because of their belief that blood is sacred.

Research into alternatives
Although there are clinical situations where transfusion with red blood cells is the only clinically appropriate option, clinicians look at whether alternatives are feasible. This can be due to several reasons, such as patient safety, economic burden or scarcity of blood. Guidelines recommend blood transfusions should be reserved for patients with or at risk of cardiovascular instability due to the degree of their anaemia. In these cases parenteral iron is recommended.
Thus far, there are no available oxygen-carrying blood substitutes, which is the typical objective of a blood (RBC) transfusion; however, there are widely available non-blood volume expanders for cases where only volume restoration is required. These are helping doctors and surgeons avoid the risks of disease transmission and immune suppression, address the chronic blood donor shortage, and address the concerns of Jehovahs Witnesses and others who have religious objections to receiving transfused blood.
The research in this area is ongoing. A number of blood substitutes have been explored, but thus far they all have serious limitations. Most attempts to find a suitable alternative to blood thus far have concentrated on cell-free hemoglobin solutions. Blood substitutes could make transfusions more readily available in emergency medicine and in pre-hospital EMS care. If successful, such a blood substitute could save many lives, particularly in trauma where massive blood loss results. Hemopure, a hemoglobin-based therapy, is approved for use in South Africa.

Other uses
Minor blood transfusions are used by a minority of nyaope drug addicts in South Africa to economically share the high the drug induces in a practice colloquially known as Bluetoothing, named after the wireless technology of the same name.

Veterinary use
Veterinarians also administer transfusions to other animals </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Invasive candidiasis and can you explain it in depth? [/INST] Invasive candidiasis is an infection (candidiasis) that can be caused by various species of Candida yeast.  Unlike Candida infections of the mouth and throat (oral candidiasis) or vagina (Candidal vulvovaginitis), invasive candidiasis is a serious, progressive, and potentially fatal infection that can affect the blood (fungemia), heart, brain, eyes, bones, and other parts of the body.

Signs and symptoms
Symptoms of invasive candidiasis can be confused with other medical conditions, however, the most common symptoms are fever and chills that do not improve with antibiotic treatment. Other symptoms develop as the infection spreads, depending on which parts of the body are involved.

Presentation
Invasive candidiasis can manifest as serious diseases including as fungemia, endocarditis, endophthalmitis, osteomyelitis, and central nervous system infections.

Cause
Invasive candidiasis is caused by 15 of the more than 150 known species of Candida. These species, all confirmed by isolation from patients, are: C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, C. krusei, C. guilliermondii, C. lusitaniae, C. dubliniensis, C. pelliculosa, C. kefyr, C. lipolytica, C. famata, C. inconspicua, C. rugosa, and C. norvegensis. Over the last 20–30 years, C. albicans has been responsible for 95% of infections, with, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei causing the majority of the remaining cases. Recently, C. auris, a species first reported in 2009, has been found to cause invasive candidiasis. C. auris has attracted attention because it can be resistant to the antifungal medications used to treat candidiasis.

Resistance
Resistance to antifungal treatment can arise from species with intrinsic resistance that experience selection pressure or spontaneous induction of resistance in isolates from normally susceptible species. For Candida, the most common is the former, as seen by the emergence of resistant C. glabrata  following the introduction of fluconazole and of C. parapsilosis where there was increased use of echinocandins. Insufficient dosing of azoles has also led to the emergence of resistance. Observed rates of echinocandin resistance for C. glabrata are between 2 and 12%. Acquired echinocandin resistance has also been reported for C. albicans, C. tropicalis, C. krusei, C. kefyr, C. lusitaniae, and C. dubliniensis.

Emergent species
Candida auris is an emerging multidrug-resistant yeast that can cause invasive candidiasis and is associated with high mortality. It was first described in 2009. Since then, C. auris infections, specifically fungemia, have been reported from South Korea, India, South Africa, Kuwait, Colombia, Venezuela, Pakistan, the United Kingdom and the United States. The strains isolated in each region are genetically distinct, indicating that this species is emerging  in different locations. The reason for this pattern is unknown.

Risk factors
Patients with the following conditions, treatments or situations are at increased risk for invasive candidiasis.
Critical illness
Long-term intensive care unit stay
Abdominal surgery (aggravated by anastomotic leakage or repeat laparotomies)
Immunosuppressive diseases
Acute necrotizing pancreatitis
Malignant hematologic disease
Solid-organ transplantation
Hematopoietic stem cell transplantation
Solid-organ tumors
Neonates (especially low birth weight and preterm infants)
Broad-spectrum antibiotic treatment
Central venous catheter
Internal prosthetic device
Total parenteral nutrition
Hemodialysis
Glucocorticoid use
Chemotherapy
Noninvasive Candida colonization (particularly if multifocal)

Transmission
Invasive candidiasis is a nosocomial infection with the majority of cases associated with hospital stays.

Diagnosis
Because many Candida species are part of the human microbiota, their presence in the mouth, the vagina, sputum, urine, stool, or skin is not definitive evidence for invasive candidiasis.Positive culture of Candida species from normally sterile sites, such as blood, cerebrospinal fluid, pericardium, pericardial fluid, or biopsied tissue, is definitive evidence of invasive candidiasis. Diagnosis by culturing allows subsequent susceptibility testing of causative species.  Sensitivity of blood culture is far from ideal, with a sensitivity reported to be between 21 and 71%. Additionally, whereas blood culture can establish a diagnosis during fungemia, the blood may test negative for deep-seated infections because candida may have been successfully cleared from the blood.Diagnosis of invasive candidiasis is supported by histopathologic evidence  (for example, yeast cells or hyphae) observed in specimens of affected tissues.Additionally, elevated serum β-glucan can demonstrate invasive candidiasis while a negative test suggests a low likelihood of systemic infection.The emergence of multidrug-resistant C. auris as a cause of invasive candidiasis has necessitated additional testing in some settings. C. auris-caused invasive candidiasis is associated with high mortality. Many C. auris isolates have been found to be resistant to one or more of the three major antifungal classes (azoles, echinocandins, and polyenes) with some resistant to all three classes – severely limiting treatment options. Biochemical-based tests currently used in many laboratories to identify fungi, including API 20C AUX and VITEK-2, cannot differentiate C. auris from related species (for example, C. auris can be identified as C. haemulonii). Therefore, the Centers for Disease Control and Prevention recommends using a diagnostic method based on matrix-assisted laser desorption/ionization-time of flight mass spectrometry or a molecular method based on sequencing the D1-D2 region of the 28s rDNA to identify C. auris in settings where it may be present.

Prevention
Preventive antifungal treatment is supported by studies, but only for specific high-risk groups in intensive care units with conditions that put them at high risk for the disease. For example, one group would be patients recovering from abdominal surgery that may have gastrointestinal perforations or anastomotic leakage. Antifungal prophylaxis can reduce the incidence of fungemia by approximately 50%, but has not been shown to improve survival. A major challenge limiting the number of patients receiving prophylaxis to only those that can potentially benefit, thereby avoiding the creation of selective pressure that can lead to the emergence of resistance.

Treatment
Antifungals are used for treatment with the specific type and dose depending on the patients age, immune status, and specifics of the infection. For most adults, the initial treatment is an echinocandin class antifungal (caspofungin, micafungin, or anidulafungin) given intravenously. Fluconazole, amphotericin B, and other antifungals may also be used. Treatment normally continues for two weeks after resolution of signs and symptoms and Candida yeasts can no longer can be cultured from blood samples. Some forms of invasive candidiasis, such as infections in the bones, joints, heart, or central nervous system, usually need to be treated for a longer period. Retrospective observational studies suggest that prompt presumptive antifungal therapy (based on symptoms or biomarkers) is effective and can reduce mortality.

Epidemiology
Invasive candidiasis is estimated to affect more than 250,000 people and cause more than 50,000 deaths worldwide every year. The CDC estimates that approximately 46,000 cases of healthcare-associated invasive candidiasis occur each year in the US. The estimated mortality attributable to fungemia is 19-40%. However, because the majority of people who develop invasive candidiasis are already sick, it can be difficult to determine if the cause of death is directly attributable to the fungal infection. Fungemia is one of the most common bloodstream infections in the United States. In general, observed incidence rates have been stable or trending higher but declining rates have been achieved with improvements in hygiene and disease management.Deep-seated infections in bones, muscles, joints, eyes, or central nervous system can arise from a bloodstream infection or direct inoculation of Candida may occur, for example, during intestinal surgery.The distribution of Candida species causing invasive candidiasis has changed over the past decades. C. albicans had been the dominant pathogen but now accounts for just half of the isolates. Increasing dominance of C. glabrata in northern Europe, the United States, and Canada has been observed while C. parapsilosis has become more prominent in southern Europe, Asia, and South America. Regional species distribution guides treatment recommendations since the species exhibit different susceptibilities to azole and echinocandin classes of antifungals.The virulence of Candida species differs considerably, with C. parapsilosis and C. krusei being less virulent than C. albicans, C. tropicalis, and C. glabrata. This variation is reflected in mortality rates.

References
Further reading
Pfaller MA, Diekema DJ (2007). "Epidemiology of invasive candidiasis: a persistent public health problem". Clinical Microbiology Reviews. 20 (1): 133–163. doi:10.1128/CMR.00029-06 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Glycogen storage disease type I and can you explain it in depth? [/INST] Glycogen storage disease type I (GSD I) is an inherited disease that results in the liver being unable to properly break down stored glycogen. This impairment disrupts the livers ability to break down stored glycogen that is necessary to maintain adequate blood sugar levels. GSD I is divided into two main types, GSD Ia and GSD Ib, which differ in cause, presentation, and treatment. GSD Ia is caused by a deficiency in the enzyme glucose-6-phosphatase, while GSD Ib is caused a deficiency in the enzyme glucose-6-phosphate translocase. Since glycogenolysis is the principal metabolic mechanism by which the liver supplies glucose to the body during periods of fasting, both deficiencies cause severe low blood sugar and, over time, excess glycogen storage in the liver and (in some cases) the kidneys.
GSD I patients typically present with an enlarged liver from non-alcoholic fatty liver disease as the result of this glycogen buildup. Other functions of the liver and kidneys are initially intact in GSD I, but are susceptible to a variety of other problems. Without proper treatment, GSD I gives rise to chronic low blood sugar, which can result in derangements including excessive levels of lactic acid and abnormally high levels of lipids in the bloodstream. Frequent feedings of cornstarch or other carbohydrates are the principal treatment for all forms of GSD I.
GSD Ib also features chronic neutropenia due to a dysfunction in the production of neutrophils in the bone marrow. This immunodeficiency, if untreated, makes GSD Ib patients susceptible to infection. The principal treatment for this feature of GSD Ib is filgrastim; however, patients often still require treatment for frequent infections, and a chronically enlarged spleen is a common side effect. GSD Ib patients often present with inflammatory bowel disease.It is the most common of the glycogen storage diseases. GSD I has an incidence of approximately 1 in 100,000 births in the American population, and approximately 1 in 20,000 births among Ashkenazi Jews. The disease was named after German doctor Edgar von Gierke, who first described it in 1929.

Signs and symptoms
Early research into GSD I identified numerous clinical manifestations falsely thought to be primary features of the genetic disorder. However, continuing research has revealed that these clinical features are the consequences of only one (in GSD Ia) or two (in GSD Ib) fundamental abnormalities:

impairment in the livers ability to convert stored glycogen into glucose through glycogenolysis
in GSD Ib, impairment of the neutrophils ability to take up glucose, resulting in neutrophil dysfunction and neutropeniaThese fundamental abnormalities give rise to a small number of primary clinical manifestations, which are the features considered in diagnosis of GSD I:

Low blood sugar (hypoglycemia), due to impairment of glycogen breakdown (glycogenolysis) causing insufficient fasting blood glucose
hepatomegaly of non-alcoholic fatty liver disease, due to impairment of glycogenolysis causing glycogen accumulation in the liver
in GSD Ib, increased infection risk, due to neutropenia and neutrophil dysfunctionAffected people commonly present with secondary clinical manifestations, linked to one or more of the primary clinical manifestations:

High levels of uric acid in the blood and attendant risk of gout or kidney damage, caused by low serum insulin levels in prolonged hypoglycemia
High levels of lactic acid in the blood, in extreme cases leading to lactic acidosis, caused by prolonged hypoglycemia
hepatic adenomas developing in adulthood and attendant risk of anemia, suspected to be caused by blood glucose dysregulation in the presence of non-alcoholic fatty liver disease
in GSD Ib, inflammatory bowel disease and attendant risk of anemia, caused by neutrophil dysfunction and exacerbated by the increased carbohydrate intake required to prevent hypoglycemiaIn addition, there are several clinical manifestations that often result from the treatment of the primary clinical manifestations:

pancreatic hypertrophy, due to increased carbohydrate intake causing frequent engagement of the insulin response
in GSD Ib, splenomegaly, due to the long-term use of filgrastim to treat neutropenia causing sequestration of blood factors in the spleen
in GSD Ib, an abnormally low number of platelets in the blood may occur, due to long-term use of filgrastim causing sequestration of platelets in the spleen
in GSD Ib, anemia, due to long-term use of filgrastim causing sequestration of hemoglobin in the spleen, potentially exacerbated by uncontrolled inflammatory bowel disease

Hypoglycemia
Low blood sugar (hypoglycemia) is the primary clinical symptom common to both GSD Ia and GSD Ib and most often prompts initial diagnosis of the disease. During fetal development in utero, maternal glucose transferred across the placenta prevents hypoglycemia. However, after birth, the inability to maintain blood glucose from stored glycogen in the liver causes measurable hypoglycemia in no more than 1–2 hours after feedings. Without proper dietary treatment after birth, prolonged hypoglycemia often leads to sudden lactic acidosis that can induce primary respiratory distress in the newborn period, as well as ketoacidosis.Neurological manifestations of hypoglycemia are less severe in GSD I than in other instances. Rather than acute hypoglycemia, GSD I patients experience persistent mild hypoglycemia. The diminished likelihood of neurological manifestations is due to the habituation of the brain to mild hypoglycemia. Given the reduced blood glucose level, the brain adapts to using alternative fuels like lactate. These gradual metabolic adaptations during infancy make severe symptoms like unconsciousness or seizure uncommon before diagnosis.In the early weeks of life, undiagnosed infants with GSD I tolerate persistent hypoglycemia and compensated lactic acidosis between feedings without symptoms. Without consistent carbohydrate feeding, infant blood glucose levels typically measure between 25 and 50 mg/dL (1.4 to 2.8 mmol/L). After weeks to months without treatment with consistent oral carbohydrates, infants will progress to show clear symptoms of hypoglycemia and lactic acidosis. Infants may present with paleness, clamminess, irritability, respiratory distress, and an inability to sleep through the night even in the second year of life. Developmental delay is not an intrinsic effect of GSD I, but is common if the diagnosis is not made in early infancy.

Genetics
GSD I is inherited in an autosomal recessive manner. People with one copy of the faulty gene are carriers of the disease and have no symptoms. As with other autosomal recessive diseases, each child born to two carriers of the disease has a 25% chance of inheriting both copies of the faulty gene and manifesting the disease. Unaffected parents of a child with GSD I can be assumed to be carriers. Prenatal diagnosis has been made by fetal liver biopsy at 18–22 weeks of gestation, but no fetal treatment has been proposed. Prenatal diagnosis is possible with fetal DNA obtained by chorionic villus sampling when a fetus is known to be at risk.The most common forms of GSD I are designated GSD Ia and GSD Ib, the former accounting for over 80% of diagnosed cases and the latter for less than 20%. A few rarer forms have been described.

GSD Ia results from mutations of G6PC, the gene for glucose-6-phosphatase, located on chromosome 17q21.
GSD Ib results from mutations of the gene for SLC37A4 or "G6PT1", the glucose-6-phosphate transporter.
GSD Ic results from mutations of SLC17A3 or SLC37A4.Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. The catalytic unit is associated with a calcium binding protein, and three transport proteins (T1, T2, T3) that facilitate movement of glucose-6-phosphate (G6P), phosphate, and glucose (respectively) into and out of the enzyme.

Pathophysiology
Normal carbohydrate balance and maintenance of blood glucose levels
Glycogen in liver and (to a lesser degree) kidneys serves as a form of stored, rapidly accessible glucose, so that the blood glucose level can be maintained between meals. For about 3 hours after a carbohydrate-containing meal, high insulin levels direct liver cells to take glucose from the blood, to convert it to glucose-6-phosphate (G6P) with the enzyme glucokinase, and to add the G6P molecules to the ends of chains of glycogen (glycogen synthesis). Excess G6P is also shunted into production of triglycerides and exported for storage in adipose tissue as fat.
When digestion of a meal is complete, insulin levels fall, and enzyme systems in the liver cells begin to remove glucose molecules from strands of glycogen in the form of G6P. This process is termed glycogenolysis. The G6P remains within the liver cell unless the phosphate is cleaved by glucose-6-phosphatase. This dephosphorylation reaction produces free glucose and free PO4 anions. The free glucose molecules can be transported out of the liver cells into the blood to maintain an adequate supply of glucose to the brain and other organs of the body. Glycogenolysis can supply the glucose needs of an adult body for 12–18 hours.
When fasting continues for more than a few hours, falling insulin levels permit catabolism of muscle protein and triglycerides from adipose tissue. The products of these processes are amino acids (mainly alanine), free fatty acids, and lactic acid. Free fatty acids from triglycerides are converted to ketones, and to acetyl-CoA. Amino acids and lactic acid are used to synthesize new G6P in liver cells by the process of gluconeogenesis. The last step of normal gluconeogenesis, like the last step of glycogenolysis, is the dephosphorylation of G6P by glucose-6-phosphatase to free glucose and PO4.
Thus glucose-6-phosphatase mediates the final, key, step in both of the two main processes of glucose production during fasting. The effect is amplified because the resulting high levels of glucose-6-phosphate inhibit earlier key steps in both glycogenolysis and gluconeogenesis.

Pathophysiology
The principal metabolic effects of deficiency of glucose-6-phosphatase are hypoglycemia, lactic acidosis, hypertriglyceridemia, and hyperuricemia.

The hypoglycemia of GSD I is termed "fasting", or "post-absorptive", usually about 4 hours after the complete digestion of a meal. This inability to maintain adequate blood glucose levels during fasting results from the combined impairment of both glycogenolysis and gluconeogenesis. Fasting hypoglycemia is often the most significant problem in GSD I, and typically the problem that leads to the diagnosis. Chronic hypoglycemia produces secondary metabolic adaptations, including chronically low insulin levels and high levels of glucagon and cortisol.
Lactic acidosis arises from impairment of gluconeogenesis. Lactic acid is generated both in the liver and muscle and is oxidized by NAD+ to pyruvic acid and then converted via the gluconeogenic pathway to G6P. Accumulation of G6P inhibits conversion of lactate to pyruvate. The lactic acid level rises during fasting as glucose falls. In people with GSD I, it may not fall entirely to normal even when normal glucose levels are restored.
Hypertriglyceridemia resulting from amplified triglyceride production is another indirect effect of impaired gluconeogenesis, amplified by chronically low insulin levels. During fasting, the normal conversion of triglycerides to free fatty acids, ketones, and ultimately acetyl-CoA is impaired. Triglyceride levels in GSD I can reach several times normal and serve as a clinical index of "metabolic control".
Hyperuricemia results from a combination of increased generation and decreased excretion of uric acid, which is generated when increased amounts of G6P are metabolized via the pentose phosphate pathway. It is also a byproduct of purine degradation. Uric acid competes with lactic acid and other organic acids for renal excretion in the urine. In GSD I increased availability of G6P for the pentose phosphate pathway, increased rates of catabolism, and diminished urinary excretion due to high levels of lactic acid all combine to produce uric acid levels several times normal. Although hyperuricemia is asymptomatic for years, kidney and joint damage gradually accrue.

Elevated lactate and lactic acidosis
High levels of lactic acid in the blood are observed in all people with GSD I, due to impaired gluconeogenesis. Baseline elevations generally range from 4 to 10 mol/mL, which will not cause any clinical impact. However, during and after an episode of low blood sugar, lactate levels will abruptly rise to exceed 15 mol/mL, the threshold for lactic acidosis. Symptoms of lactic acidosis include vomiting and hyperpnea, both of which can exacerbate hypoglycemia in the setting of GSD I. In cases of acute lactic acidosis, patients need emergency care to stabilize blood oxygen, and restore blood glucose. Proper identification of lactic acidosis in undiagnosed children presents a challenge, since the first symptoms are typically vomiting and dehydration, both of which mimic childhood infections like gastroenteritis or pneumonia. Moreover, both of these common infections can precipitate more severe hypoglycemia in undiagnosed children, making diagnosis of the underlying cause difficult.
As elevated lactate persists, uric acid, ketoacids, and free fatty acids further increase the anion gap. In adults and children, the high concentrations of lactate cause significant discomfort in the muscles. This discomfort is an amplified form of the burning sensation a runner may feel in the quadriceps after sprinting, which is caused by a brief buildup of lactic acid. Proper control of hypoglycemia in GSD I eliminates the possibility for lactic acidosis.

Elevated urate and complications
High levels of uric acid often present as a consequence of elevated lactic acid in GSD I patients. When lactate levels are elevated, blood-borne lactic acid competes for the same kidney tubular transport mechanism as urate, limiting the rate that urate can be cleared by the kidneys into the urine. If present, increased purine catabolism is an additional contributing factor. Uric acid levels of 6 to 12 mg/dl (530 to 1060 umol/L) are common among GSD I patients, if the disease is not properly treated. In some affected people, the use of the medication allopurinol is necessary to lower blood urate levels. Consequences of hyperuricemia among GSD I patients include the development of kidney stones and the accumulation of uric acid crystals in joints, leading to kidney disease and gout, respectively.

Hyperlipidemia and plasma effects
Elevated triglycerides in GSD I result from low serum insulin in patients with frequent prolonged hypoglycemia. It may also be caused by intracellular accumulation of glucose-6-phosphate with secondary shunting to pyruvate, which is converted into Acetyl-CoA, which is transported to the cytosol where the synthesis of fatty acids and cholesterol occurs. Triglycerides above the 3.4 mmol/L (300 mg/dL) range may produce visible lipemia, and even a mild pseudohyponatremia due to a reduced aqueous fraction of the blood plasma. In GSD I, cholesterol is typically only mildly elevated compared to other lipids.

Hepatomegaly
Impairment in the livers ability to perform gluconeogenesis leads to clinically apparent hepatomegaly. Without this process, the body is unable to liberate glycogen from the liver and convert it into blood glucose, leading to an accumulation of stored glycogen in the liver. Hepatomegaly from the accumulation of stored glycogen in the liver is considered a form of non-alcoholic fatty liver disease. GSD I patients present with a degree of hepatomegaly throughout life, but severity often relates to the consumption of excess dietary carbohydrate. Reductions in the mass of the liver are possible, since most patients retain residual hepatic function that allows for the liberation of stored glycogen at a limited rate.
GSD I patients often present with hepatomegaly from the time of birth. In fetal development, maternal glucose transferred to the fetus prevents hypoglycemia, but the storage of glucose as glycogen in the liver leads to hepatomegaly. There is no evidence that this hepatomegaly presents any risk to proper fetal development.
Hepatomegaly in GSD type I generally occurs without sympathetic enlargement of the spleen. GSD Ib patients may present with splenomegaly, but this is connected to the use of filgrastim to treat neutropenia in this subtype, not comorbid hepatomegaly. Hepatomegaly will persist to some degree throughout life, often causing the abdomen to protrude, and in severe cases may be palpable at or below the navel. In GSD-related non-alcoholic fatty liver disease, hepatic function is usually spared, with liver enzymes and bilirubin remaining within the normal range. However, liver function may be affected by other hepatic complications in adulthood, including the development of hepatic adenomas.

Hepatic adenomas
The specific etiology of hepatic adenomas in GSD I remains unknown, despite ongoing research. The typical GSD I patient presenting with at least one adenoma is an adult, though lesions have been observed in patients as young as fourteen. Adenomas, composed of heterogeneous neoplasms, may occur individually or in multiples. Estimates on the rate of conversion of a hepatocellular adenoma into hepatocellular carcinoma in GSD I range from 0% to 11%, with the latter figure representing more recent research. One reason for the increasing estimate is the growing population of GSD I patients surviving into adulthood, when most adenomas develop.
Treatment standards dictate regular observation of the liver by MRI or CT scan to monitor for structural abnormalities. Hepatic adenomas may be misidentified as focal nodular hyperplasia in diagnostic imaging, though this condition is rare. However, hepatic adenomas in GSD I uniquely involve diffuse Mallory hyaline deposition, which is otherwise commonly observed in focal nodular hyperplasia. Unlike common hepatic adenomas related to oral contraception, hemorrhaging in GSD I patients is rare.
While the reason for the high prevalence of adenomas in GSD I is unclear, research since the 1970s has implicated serum glucagon as a potential driver. In studies, patients that have been put on a dietary regimen to keep blood sugar in a normal range spanning 72 to 108 mg/dL (4.0 to 6.0 mmol/L) have shown a decreased likelihood of developing adenomas. Moreover, patients with well controlled blood glucose have consistently seen a reduction in the size and number of hepatic adenomas, suggesting that adenomas may be caused by imbalances of hepatotropic agents like serum insulin and especially serum glucagon in the liver.

Osteopenia
Patients with GSD I will often develop osteopenia. The specific etiology of low bone mineral density in GSD is not known, though it is strongly associated with poor metabolic control. Osteopenia may be directly caused by hypoglycemia, or the resulting endocrine and metabolic sequelae. Improvements in metabolic control have consistently been shown to prevent or reverse clinically relevant osteopenia in GSD I patients. In cases where osteopenia progresses with age, bone mineral density in the ribs is typically more severe than in the vertebrae. In some cases bone mineral density T-score will drop below -2.5, indicating osteoporosis. There is some evidence that osteopenia may be connected with associated kidney abnormalities in GSD I, particularly glomular hyperfiltration. The condition also seems responsive to calcium supplementation. In many cases bone mineral density can increase and return to the normal range given proper metabolic control and calcium supplementation alone, reversing osteopenia.

Kidney effects
The kidneys are usually 10 to 20% enlarged with stored glycogen. In adults with GSD I, chronic glomerular damage similar to diabetic nephropathy may lead to kidney failure. GSD I may present with various kidney complications. Renal tubular abnormalities related to hyperlactatemia are seen early in life, likely because prolonged lactic acidosis is more likely to occur in childhood. This will often present as Fanconi syndrome with multiple derangements of renal tubular reabsorption, including tubular acidosis with bicarbonate and phosphate wasting. These tubular abnormalities in GSD I are typically detected and monitored by urinary calcium. Long term these derangements can exacerbate uric acid nephropathy, otherwise driven by hyperlactatemia. In adolescence and beyond, glomerular disease may independently develop, initially presenting as glomerular hyperfiltration indicated by elevated urinary eGFR.

Splenomegaly
Enlargement of the spleen (splenomegaly) is common in GSD I and has two primary causes. In GSD Ia, splenomegaly may be caused by a relation between the liver and the spleen which causes either to grow or shrink to match the relative size of the other, to a lessened degree. In GSD Ib, it is a side effect of the use of filgrastim to treat neutropenia.

Bowel effects
Intestinal involvement can cause mild malabsorption with greasy stools (steatorrhea), but usually requires no treatment.

Infection risk
Neutropenia is a distinguishing feature of GSD Ib, absent in GSD Ia. The microbiological cause of neutropenia in GSD Ib is not well understood. Broadly, the problem arises from compromised cellular metabolism in the neutrophil, resulting in accelerated neutrophil apoptosis. The neutropenia in GSD is characterized by both a decrease in absolute neutrophil count and  diminished neutrophil function. Neutrophils use a specific G6P metabolic pathway which relies on the presence of G6Pase-β or G6PT to maintain energy homeostasis within the cell. The absence of G6PT in GSD Ib limits this pathway, leading to endoplasmic reticulum stress, oxidative stress within the neutrophil, triggering premature apoptosis. Granulocyte colony-stimulating factor (G-CSF), available as filgrastim, can reduce the risk of infection. In some cases, G-CSF formulated as pegfilgrastim, sold under the trade name Neulasta, may be used as a slow-acting alternative, requiring less frequent dosing.

Thrombocytopenia and blood clotting problems
Impaired platelet aggregation is an uncommon consequence of chronic hypoglycemia, seen in GSD I patients. Research has demonstrated decreased platelet function, characterized by decreased prothrombin consumption, abnormal aggregation reactions, prolonged bleeding time, and low platelet adhesiveness. Severity of platelet dysfunction typically correlates with clinical condition, with the most severe cases correlating with lactic acidosis and severely lipidemia. It may cause clinically significant bleeding, especially epistaxis. Additionally, GSD I patients may present with thrombocytopenia as a consequence of splenomegaly. In the setting of splenomegaly various hematologic factors may be sequestered in the tissues of the spleen as blood is filtered through the organ. This can diminish levels of platelets available in the bloodstream, leading to thrombocytopenia.

Developmental effects
Developmental delay is a potential secondary effect of chronic or recurrent hypoglycemia, but is at least theoretically preventable. Normal neuronal and muscle cells do not express glucose-6-phosphatase, and are thus not impacted by GSD I directly. However, without proper treatment of hypoglycemia, growth failure commonly results from chronically low insulin levels, persistent acidosis, chronic elevation of catabolic hormones, and calorie insufficiency (or malabsorption). The most dramatic developmental delays are often the cause of severe (not just persistent) episodes of hypoglycemia.

Diagnosis
Several different problems may lead to the diagnosis, usually by two years of age:

seizures or other manifestations of severe fasting hypoglycemia
hepatomegaly with abdominal protuberance
hyperventilation and apparent respiratory distress due to metabolic acidosis
episodes of vomiting due to metabolic acidosis, often precipitated by minor illness and accompanied by hypoglycemiaOnce the diagnosis is suspected, the multiplicity of clinical and laboratory features usually makes a strong circumstantial case. If hepatomegaly, fasting hypoglycemia, and poor growth are accompanied by lactic acidosis, hyperuricemia, hypertriglyceridemia, and enlarged kidneys by ultrasound, GSD I is the most likely diagnosis. The differential diagnosis list includes glycogenoses types III and VI, fructose 1,6-bisphosphatase deficiency, and a few other conditions (page 5), but none are likely to produce all of the features of GSD I.
The next step is usually a carefully monitored fast. Hypoglycemia often occurs within six hours. A critical blood specimen obtained at the time of hypoglycemia typically reveals a mild metabolic acidosis, high free fatty acids and  beta-hydroxybutyrate, very low insulin levels, and high levels of glucagon, cortisol, and growth hormone. Administration of intramuscular or intravenous glucagon (0.25 to 1 mg, depending on age) or epinephrine produces little rise of blood sugar.
The diagnosis is definitively confirmed by liver biopsy with electron microscopy and assay of glucose-6-phosphatase activity in the tissue and/or specific gene testing, available in recent years.

Treatment
The primary treatment goal is prevention of hypoglycemia and the secondary metabolic derangements by frequent feedings of foods high in glucose or starch (which is readily digested to glucose). To compensate for the inability of the liver to provide sugar, the total amount of dietary carbohydrate should approximate the 24-hour glucose production rate. The diet should contain approximately 65–70% carbohydrate, 10–15% protein, and 20–25% fat. At least a third of the carbohydrates should be supplied through the night, so that a young child goes no more than 3–4 hours without carbohydrate intake.
Once a diagnosis is made, the priority in GSD I treatment is to maintain an adequate blood glucose. Patients aim to maintain a blood glucose above the 72 mg/dL (4.0 mmol/L) cutoff for hypoglycemia. GSD Ib patients have an additional treatment priority relating to neutropenia. Proper management of blood glucose in GSD I is critical in avoiding the more severe effects of high leves of lactic acid and uric acid in the blood, and the development of hepatic adenomas.
In the last 30 years, two methods have been used to achieve this goal in young children: (1) continuous nocturnal gastric infusion of glucose or starch; and (2) night-time feedings of uncooked cornstarch. An elemental formula, glucose polymer, and/or cornstarch can be infused continuously through the night at a rate supplying 0.5–0.6 g/kg/h of glucose for an infant, or 0.3–0.4 for an older child. This method requires a nasogastric or gastrostomy tube and pump. Sudden death from hypoglycemia has occurred due to malfunction or disconnection, and periodic cornstarch feedings are now preferred to continuous infusion.
Cornstarch is an inexpensive way to provide gradually digested glucose. One tablespoon contains nearly 9 g carbohydrate (36 calories). Although it is safer, less expensive, and requires no equipment, this method does require that parents arise every 3–4 hours to administer the cornstarch. A typical requirement for a young child is 1.6 g/kg every 4 hours.
Long-term management should eliminate hypoglycemic symptoms and maintain normal growth. Treatment should achieve normal glucose, lactic acid, and electrolyte levels, and only mild elevations of uric acid and triglycerides.

Avoidance of other sugars
Intake of carbohydrates which must be converted to G6P to be utilized (e.g., galactose and fructose) should be minimized. Although elemental formulas are available for infants, many foods contain fructose or galactose in the forms of sucrose or lactose. Adherence becomes a contentious treatment issue after infancy.

Other therapeutic measures
Persistent elevation of uric acid above 6.5 mg/dl warrants treatment with allopurinol to prevent uric acid deposition in kidneys and joints.
Because of the potential for impaired platelet function, coagulation ability should be checked and the metabolic state normalized before surgery. Bleeding time may be normalized with 1–2 days of glucose loading, and improved with ddavp. During surgery, IV fluids should contain 10% dextrose and no lactate.
A patient with GSD, type 1b was treated with a liver transplant at UCSF Medical Center in 1993 that resulted in the resolution of hypoglycemic episodes and the need for the patient to stay away from natural sources of sugar. Other patients have undergone this procedure as well with positive results. Although a liver transplant resulted in the resolution of hypoglycemia it did not however resolve the chronic neutropenia and the risk of infection among patients.

Treatment of acute metabolic acidosis episodes
The most significant acute problem in childhood is a vulnerability to episodes of metabolic acidosis precipitated by minor illnesses </s>