Fever

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Drug_interaction

Fever
Other names	Pyrexia, febrile response
An analog medical thermometer showing a temperature of 38.7 °C or 101.7 °F
Specialty	Infectious disease, pediatrics
Symptoms	Initially: shivering, feeling cold Later: flushed, sweating
Complications	Febrile seizure
Causes	Increase in the body's temperature set point
Diagnostic method	Temperature > between 37.2 and 38.3 °C (99.0 and 100.9 °F)
Differential diagnosis	Hyperthermia
Treatment	Based on underlying cause, not required for fever itself
Medication	Ibuprofen, paracetamol (acetaminophen)
Frequency	Common

Fever, also known as pyrexia and febrile response, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using values between 37.2 and 38.3 °C (99.0 and 100.9 °F) in humans. The increase in set point triggers increased muscle contractions and causes a feeling of cold. This results in greater heat production and efforts to conserve heat. When the set point temperature returns to normal, a person feels hot, becomes flushed, and may begin to sweat. Rarely a fever may trigger a febrile seizure. This is more common in young children. Fevers do not typically go higher than 41 to 42 °C (105.8 to 107.6 °F).

A fever can be caused by many medical conditions ranging from non-serious to life-threatening. This includes viral, bacterial and parasitic infections such as the common cold, urinary tract infections, meningitis, malaria and appendicitis among others. Non-infectious causes include vasculitis, deep vein thrombosis, connective tissue disease, side effects of medication, and cancer among others. It differs from hyperthermia, in that hyperthermia is an increase in body temperature over the temperature set point, due to either too much heat production or not enough heat loss.

Treatment to reduce fever is generally not required. Treatment of associated pain and inflammation, however, may be useful and help a person rest. Medications such as ibuprofen or paracetamol (acetaminophen) may help with this as well as lower temperature. Measures such as putting a cool damp cloth on the forehead and having a slightly warm bath are not useful and may simply make a person more uncomfortable. Children younger than three months require medical attention, as might people with serious medical problems such as a compromised immune system or people with other symptoms. Hyperthermia does require treatment.

Fever is one of the most common medical signs. It is part of about 30% of healthcare visits by children and occurs in up to 75% of adults who are seriously sick. While fever is a useful defense mechanism, treating fever does not appear to worsen outcomes. Fever is viewed with greater concern by parents and healthcare professionals than it usually deserves, a phenomenon known as fever phobia.

Signs and symptoms

Michael Ancher, "The Sick Girl", 1882, Statens Museum for Kunst

A fever is usually accompanied by sickness behavior, which consists of lethargy, depression, loss of appetite, sleepiness, hyperalgesia, and the inability to concentrate.

Diagnosis

Temperature classification

Core (rectal, esophageal, etc.) Hypothermia <35 .0="" font="" nbsp=""> Normal 36.5–37.5 °C (97.7–99.5 °F) Fever >37.5 or 38.3 °C (99.5 or 100.9 °F) Hyperthermia >37.5 or 38.3 °C (99.5 or 100.9 °F) Hyperpyrexia >40.0 or 41.0 °C (104.0 or 105.8 °F)

Note: The difference between fever and hyperthermia is the underlying mechanism. Different sources have different cut-offs for fever, hyperthermia and hyperpyrexia.

A range for normal temperatures has been found. Central temperatures, such as rectal temperatures, are more accurate than peripheral temperatures. Fever is generally agreed to be present if the elevated temperature is caused by a raised set point and:

• Temperature in the anus (rectum/rectal) is at or over 37.5–38.3 °C (99.5–100.9 °F) An ear (tympanic) or forehead (temporal) temperature may also be used.
• Temperature in the mouth (oral) is at or over 37.2 °C (99.0 °F) in the morning or over 37.7 °C (99.9 °F) in the afternoon
• Temperature under the arm (axillary) is at or over 37.2 °C (99.0 °F)

In healthy adults, the range of normal, healthy temperatures for oral temperature is 33.2–38.2 °C (91.8–100.8 °F), for rectal it is 34.4–37.8 °C (93.9–100.0 °F), for tympanic membrane (the ear drum) it is 35.4–37.8 °C (95.7–100.0 °F), and for axillary (the armpit) it is 35.5–37.0 °C (95.9–98.6 °F). Harrison's Principles of Internal Medicine defines a fever as a morning oral temperature of >37.2 °C (>98.9 °F) or an afternoon oral temperature of >37.7 °C (>99.9 °F) while the normal daily temperature variation is typically 0.5 °C (0.9 °F).

Normal body temperatures vary depending on many factors, including age, sex, time of day, ambient temperature, activity level, and more. A raised temperature is not always a fever. For example, the temperature of a healthy person rises when he or she exercises, but this is not considered a fever, as the set point is normal. On the other hand, a "normal" temperature may be a fever, if it is unusually high for that person. For example, medically frail elderly people have a decreased ability to generate body heat, so a "normal" temperature of 37.3 °C (99.1 °F) may represent a clinically significant fever.

Types

Performance of the various types of fever
a) Fever continues
b) Fever continues to abrupt onset and remission
c) Remittent fever
d) Intermittent fever
e) Undulant fever
f) Relapsing fever

Different fever patterns observed in Plasmodium infections.

 

The pattern of temperature changes may occasionally hint at the diagnosis:

• Continuous fever: Temperature remains above normal throughout the day and does not fluctuate more than 1 °C in 24 hours, e.g. lobar pneumonia, typhoid, meningitis, urinary tract infection, or typhus. Typhoid fever may show a specific fever pattern (Wunderlich curve of typhoid fever), with a slow stepwise increase and a high plateau. (Drops due to fever-reducing drugs are excluded.)
• Intermittent fever: The temperature elevation is present only for a certain period, later cycling back to normal, e.g. malaria, kala-azar, pyaemia, or sepsis. Following are its types:
  • Quotidian fever, with a periodicity of 24 hours, typical of Plasmodium knowlesi malaria
  • Tertian fever (48-hour periodicity), typical of later in the course of Plasmodium falciparum, Plasmodium vivax, or Plasmodium ovale malaria
  • Quartan fever (72-hour periodicity), typical of later in the course of Plasmodium malariae malaria.
• Remittent fever: Temperature remains above normal throughout the day and fluctuates more than 1 °C in 24 hours, e.g., infective endocarditis, brucellosis.
• Pel–Ebstein fever: A specific kind of fever associated with Hodgkin's lymphoma, being high for one week and low for the next week and so on. However, there is some debate as to whether this pattern truly exists.

A neutropenic fever, also called febrile neutropenia, is a fever in the absence of normal immune system function. Because of the lack of infection-fighting neutrophils, a bacterial infection can spread rapidly; this fever is, therefore, usually considered to require urgent medical attention. This kind of fever is more commonly seen in people receiving immune-suppressing chemotherapy than in apparently healthy people.

Febricula is an old term for a low-grade fever, especially if the cause is unknown, no other symptoms are present, and the patient recovers fully in less than a week.

Hyperpyrexia

Hyperpyrexia is an extreme elevation of body temperature which, depending upon the source, is classified as a core body temperature greater than or equal to 40.0 or 41.5 °C (104.0 or 106.7 °F). Such a high temperature is considered a medical emergency, as it may indicate a serious underlying condition or lead to problems including permanent brain damage, or death. The most common cause of hyperpyrexia is an intracranial hemorrhage. Other possible causes include sepsis, Kawasaki syndrome, neuroleptic malignant syndrome, drug overdose, serotonin syndrome, and thyroid storm.

Infections are the most common cause of fevers, but as the temperature rises other causes become more common. Infections commonly associated with hyperpyrexia include roseola, measles and enteroviral infections. Immediate aggressive cooling to less than 38.9 °C (102.0 °F) has been found to improve survival. Hyperpyrexia differs from hyperthermia in that in hyperpyrexia the body's temperature regulation mechanism sets the body temperature above the normal temperature, then generates heat to achieve this temperature, while in hyperthermia the body temperature rises above its set point due to an outside source.

Hyperthermia

Hyperthermia is an example of a high temperature that is not a fever. It occurs from a number of causes including heatstroke, neuroleptic malignant syndrome, malignant hyperthermia, stimulants such as substituted amphetamines and cocaine, idiosyncratic drug reactions, and serotonin syndrome.

Differential diagnosis

Fever is a common symptom of many medical conditions:

• Infectious disease, e.g., influenza, primary HIV infection, malaria, Ebola, infectious mononucleosis, gastroenteritis, Lyme disease, Dengue
• Various skin inflammations, e.g., boils, abscess
• Immunological diseases, e.g., lupus erythematosus, sarcoidosis, inflammatory bowel diseases, Kawasaki disease, Still disease, Horton disease, granulomatosis with polyangiitis, autoimmune hepatitis, relapsing polychondritis
• Tissue destruction, which can occur in hemolysis, surgery, infarction, crush syndrome, rhabdomyolysis, cerebral bleeding, etc.
• Reaction to incompatible blood products
• Cancers, most commonly kidney cancer and leukemia and lymphomas
• Metabolic disorders: gout, porphyria
• Inherited metabolic disorder: Fabry disease

Persistent fever that cannot be explained after repeated routine clinical inquiries is called fever of unknown origin. 

Teething is not a cause.

Pathophysiology

Hyperthermia: Characterized on the left. Normal body temperature (thermoregulatory set point) is shown in green, while the hyperthermic temperature is shown in red. As can be seen, hyperthermia can be conceptualized as an increase above the thermoregulatory set point.
 

Hypothermia: Characterized in the center: Normal body temperature is shown in green, while the hypothermic temperature is shown in blue. As can be seen, hypothermia can be conceptualized as a decrease below the thermoregulatory set point.
 

Fever: Characterized on the right: Normal body temperature is shown in green. It reads "New Normal" because the thermoregulatory set point has risen. This has caused what was the normal body temperature (in blue) to be considered hypothermic.

 

Temperature is ultimately regulated in the hypothalamus. A trigger of the fever, called a pyrogen, causes release of prostaglandin E2 (PGE2). PGE2 in turn acts on the hypothalamus, which creates a systemic response in the body, causing heat-generating effects to match a new higher temperature set point.

In many respects, the hypothalamus works like a thermostat. When the set point is raised, the body increases its temperature through both active generation of heat and retention of heat. Peripheral vasoconstriction both reduces heat loss through the skin and causes the person to feel cold. Norepinephrine increases thermogenesis in brown adipose tissue, and muscle contraction through shivering raises the metabolic rate. If these measures are insufficient to make the blood temperature in the brain match the new set point in the hypothalamus, then shivering begins in order to use muscle movements to produce more heat. When the hypothalamic set point moves back to baseline either spontaneously or with medication, the reverse of these processes (vasodilation, end of shivering and nonshivering heat production) and sweating are used to cool the body to the new, lower setting.

This contrasts with hyperthermia, in which the normal setting remains, and the body overheats through undesirable retention of excess heat or over-production of heat. Hyperthermia is usually the result of an excessively hot environment (heat stroke) or an adverse reaction to drugs. Fever can be differentiated from hyperthermia by the circumstances surrounding it and its response to anti-pyretic medications.

Pyrogens

A pyrogen is a substance that induces fever. These can be either internal (endogenous) or external (exogenous) to the body. The bacterial substance lipopolysaccharide (LPS), present in the cell wall of gram-negative bacteria, is an example of an exogenous pyrogen. Pyrogenicity can vary: In extreme examples, some bacterial pyrogens known as superantigens can cause rapid and dangerous fevers. Depyrogenation may be achieved through filtration, distillation, chromatography, or inactivation.

Endogenous

In essence, all endogenous pyrogens are cytokines, molecules that are a part of the immune system. They are produced by activated immune cells and cause the increase in the thermoregulatory set point in the hypothalamus. Major endogenous pyrogens are interleukin 1 (α and β) and interleukin 6 (IL-6). Minor endogenous pyrogens include interleukin-8, tumor necrosis factor-β, macrophage inflammatory protein-α and macrophage inflammatory protein-β as well as interferon-α, interferon-β, and interferon-γ. Tumor necrosis factor-α also acts as a pyrogen. It is mediated by interleukin 1 (IL-1) release.

These cytokine factors are released into general circulation, where they migrate to the circumventricular organs of the brain due to easier absorption caused by the blood–brain barrier's reduced filtration action there. The cytokine factors then bind with endothelial receptors on vessel walls, or interact with local microglial cells. When these cytokine factors bind, the arachidonic acid pathway is then activated.

Exogenous

One model for the mechanism of fever caused by exogenous pyrogens includes LPS, which is a cell wall component of gram-negative bacteria. An immunological protein called lipopolysaccharide-binding protein (LBP) binds to LPS. The LBP–LPS complex then binds to the CD14 receptor of a nearby macrophage. This binding results in the synthesis and release of various endogenous cytokine factors, such as interleukin 1 (IL-1), interleukin 6 (IL-6), and the tumor necrosis factor-alpha. In other words, exogenous factors cause release of endogenous factors, which, in turn, activate the arachidonic acid pathway. The highly toxic metabolism-boosting supplement 2,4-dinitrophenol induces high body temperature via the inhibition of ATP production by mitochondria, resulting in impairment of cellular respiration. Instead of producing ATP, the energy of the proton gradient is lost as heat.

PGE2 release

PGE2 release comes from the arachidonic acid pathway. This pathway (as it relates to fever), is mediated by the enzymes phospholipase A2 (PLA2), cyclooxygenase-2 (COX-2), and prostaglandin E2 synthase. These enzymes ultimately mediate the synthesis and release of PGE2.

PGE2 is the ultimate mediator of the febrile response. The set point temperature of the body will remain elevated until PGE2 is no longer present. PGE2 acts on neurons in the preoptic area (POA) through the prostaglandin E receptor 3 (EP3). EP3-expressing neurons in the POA innervate the dorsomedial hypothalamus (DMH), the rostral raphe pallidus nucleus in the medulla oblongata (rRPa), and the paraventricular nucleus (PVN) of the hypothalamus . Fever signals sent to the DMH and rRPa lead to stimulation of the sympathetic output system, which evokes non-shivering thermogenesis to produce body heat and skin vasoconstriction to decrease heat loss from the body surface. It is presumed that the innervation from the POA to the PVN mediates the neuroendocrine effects of fever through the pathway involving pituitary gland and various endocrine organs.

Hypothalamus

The brain ultimately orchestrates heat effector mechanisms via the autonomic nervous system or primary motor center for shivering. These may be:

• Increased heat production by increased muscle tone, shivering and hormones like epinephrine (adrenaline)
• Prevention of heat loss, such as vasoconstriction.

In infants, the autonomic nervous system may also activate brown adipose tissue to produce heat (non-exercise-associated thermogenesis, also known as non-shivering thermogenesis). Increased heart rate and vasoconstriction contribute to increased blood pressure in fever.

Usefulness

There are arguments for and against the usefulness of fever, and the issue is controversial. There are studies using warm-blooded vertebrates with some suggesting that they recover more rapidly from infections or critical illness due to fever. Studies suggest reduced mortality in bacterial infections when fever was present.

In theory, fever can aid in host defense. There are certainly some important immunological reactions that are sped up by temperature, and some pathogens with strict temperature preferences could be hindered.

Research has demonstrated that fever assists the healing process in several important ways:

• Increased mobility of leukocytes
• Enhanced leukocyte phagocytosis
• Endotoxin effects decreased
• Increased proliferation of T cells

Management

Fever should not necessarily be treated. Most people recover without specific medical attention. Although it is unpleasant, fever rarely rises to a dangerous level even if untreated. Damage to the brain generally does not occur until temperatures reach 42 °C (107.6 °F), and it is rare for an untreated fever to exceed 40.6 °C (105 °F). Treating fever in people with sepsis does not affect outcomes.

Conservative measures

Some limited evidence supports sponging or bathing feverish children with tepid water. The use of a fan or air conditioning may somewhat reduce the temperature and increase comfort. If the temperature reaches the extremely high level of hyperpyrexia, aggressive cooling is required (generally produced mechanically via conduction by applying numerous ice packs across most of the body or direct submersion in ice water). In general, people are advised to keep adequately hydrated. Whether increased fluid intake improves symptoms or shortens respiratory illnesses such as the common cold is not known.

Medications

Medications that lower fevers are called antipyretics. The antipyretic ibuprofen is effective in reducing fevers in children. It is more effective than acetaminophen (paracetamol) in children. Ibuprofen and acetaminophen may be safely used together in children with fevers. The efficacy of acetaminophen by itself in children with fevers has been questioned. Ibuprofen is also superior to aspirin in children with fevers. Additionally, aspirin is not recommended in children and young adults (those under the age of 16 or 19 depending on the country) due to the risk of Reye's syndrome.

Using both paracetamol and ibuprofen at the same time or alternating between the two is more effective at decreasing fever than using only paracetamol or ibuprofen. It is not clear if it increases child comfort. Response or nonresponse to medications does not predict whether or not a child has a serious illness.

With respect to the effect of antipyretics on the risk of death in those with infection, studies have found mixed results as of 2019. Animals models have found worsened outcomes with the use of antipyretics in influenza as of 2010 but they have not been studied for this use in humans.

Epidemiology

About 5% of people who go to an emergency room have a fever.

History

A number of types of fever were known as early as 460 BC to 370 BC when Hippocrates was practicing medicine including that due to malaria (tertian or every 2 days and quartan or every 3 days). It also became clear around this time that fever was a symptom of disease rather than a disease in and of itself.

Society and culture

Etymology

Pyrexia is from the Greek pyr meaning fire. Febrile is from the Latin word febris, meaning fever, and archaically known as ague.

Fever phobia

Fever phobia is the name given by medical experts to parents' misconceptions about fever in their children. Among them, many parents incorrectly believe that fever is a disease rather than a medical sign, that even low fevers are harmful, and that any temperature even briefly or slightly above the oversimplified "normal" number marked on a thermometer is a clinically significant fever. They are also afraid of harmless side effects like febrile seizures and dramatically overestimate the likelihood of permanent damage from typical fevers. The underlying problem, according to professor of pediatrics Barton D. Schmitt, is "as parents we tend to suspect that our children’s brains may melt."

As a result of these misconceptions parents are anxious, give the child fever-reducing medicine when the temperature is technically normal or only slightly elevated, and interfere with the child's sleep to give the child more medicine.

Other animals

Fever is an important feature for the diagnosis of disease in domestic animals. The body temperature of animals, which is taken rectally, is different from one species to another. For example, a horse is said to have a fever above 101 °F (38.3 °C). In species that allow the body to have a wide range of "normal" temperatures, such as camels, it is sometimes difficult to determine a febrile stage.

Fever can also be behaviorally induced by invertebrates that do not have immune-system based fever. For instance, some species of grasshopper will thermoregulate to achieve body temperatures that are 2–5 °C higher than normal in order to inhibit the growth of fungal pathogens such as Beauveria bassiana and Metarhizium acridum. Honeybee colonies are also able to induce a fever in response to a fungal parasite Ascosphaera apis. 

Liver transplantation

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Liver_transplantation 

 

Liver transplantation
Human liver
Specialty	hepatology
ICD-9-CM	50.5
MeSH	D016031
MedlinePlus	003006

Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, although availability of donor organs is a major limitation. The most common technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic position as the original liver. The surgical procedure is complex, requiring careful harvest of the donor organ and meticulous implantation into the recipient. Liver transplantation is highly regulated, and only performed at designated transplant medical centers by highly trained transplant physicians and supporting medical team. The duration of the surgery ranges from 4 to 18 hours depending on outcome. Favorable outcomes require careful screening for eligible recipient, as well as a well-calibrated live or cadaveric donor match.

Medical uses

Liver transplantation is a potential treatment for acute or chronic conditions which cause irreversible and severe ("end-stage") liver dysfunction. Since the procedure carries relatively high risks, is resource-intensive, and requires major life-modifications after surgery, it is reserved for dire circumstances. 

Judging the appropriateness/effectiveness of liver transplant on case-by-case basis is critically important, as outcomes are highly variable.

Contraindications

Although liver transplantation is the most effective treatment for many forms of end-stage liver disease, the tremendous limitation in allograft availability and widely variable post-surgical outcomes make case selection critically important. Assessment of a person's transplant eligibility is made by a multi-disciplinary team that includes surgeons, medical doctors, and other providers.

The first step in evaluation is to determine whether the patient has irreversible liver-based disease which will be cured by getting a new liver. Thus, those with diseases which are primarily based outside the liver or have spread beyond the liver are generally considered poor candidates. Some examples include:

• someone with advanced liver cancer, with known/likely spread beyond the liver
• active alcohol/substance abuse
• severe heart/lung disease
• existing high cholesterol levels in the patient
• dyslipidemia 

Importantly, many contraindications to liver transplantation are considered reversible; a person initially deemed "transplant-ineligible" may later become a favorable candidate if their situation changes. Some examples include:

• partial treatment of liver cancer, such that risk of spread beyond liver is decreased (for those with primary liver cancer or secondary spread to the liver, the medical team will likely rely heavily on the opinion of the patient's primary provider, the oncologist, and the radiologist)
• cessation of substance abuse (time period of abstinence is variable)
• improvement in heart function, e.g. by percutaneous coronary intervention or bypass surgery
• treated HIV infection (see Special populations)
• for those with high cholesterol or triglyceride levels or other dyslipidemias, using lifestyle changes (diet, portions, exercise) and drugs and counseling to lower one's levels, and to control any hyperglycemia or (pre-)diabetes or obesity

Risks/complications

Graft rejection

After a liver transplantation, immune-mediated rejection (also known as rejection) of the allograft may happen at any time. Rejection may present with lab findings: elevated AST, ALT, GGT; abnormal liver function values such as prothrombin time, ammonia level, bilirubin level, albumin concentration; and abnormal blood glucose. Physical findings may include encephalopathy, jaundice, bruising and bleeding tendency. Other nonspecific presentation may include malaise, anorexia, muscle ache, low fever, slight increase in white blood count and graft-site tenderness. 

Three types of graft rejection may occur: hyperacute rejection, acute rejection, and chronic rejection.

• Hyperacute rejection is caused by preformed anti-donor antibodies. It is characterized by the binding of these antibodies to antigens on vascular endothelial cells. Complement activation is involved and the effect is usually profound. Hyperacute rejection happens within minutes to hours after the transplant procedure.
• Acute rejection is mediated by T cells (versus B-cell-mediated hyperacute rejection). It involves direct cytotoxicity and cytokine mediated pathways. Acute rejection is the most common and the primary target of immunosuppressive agents. Acute rejection is usually seen within days or weeks of the transplant.
• Chronic rejection is the presence of any sign and symptom of rejection after one year. The cause of chronic rejection is still unknown, but an acute rejection is a strong predictor of chronic rejections.

Technique

Before transplantation, liver-support therapy might be indicated (bridging-to-transplantation). Artificial liver support like liver dialysis or bioartificial liver support concepts are currently under preclinical and clinical evaluation. Virtually all liver transplants are done in an orthotopic fashion; that is, the native liver is removed and the new liver is placed in the same anatomic location. The transplant operation can be conceptualized as consisting of the hepatectomy (liver removal) phase, the anhepatic (no liver) phase, and the postimplantation phase. The operation is done through a large incision in the upper abdomen. The hepatectomy involves division of all ligamentous attachments to the liver, as well as the common bile duct, hepatic artery, hepatic vein and portal vein. Usually, the retrohepatic portion of the inferior vena cava is removed along with the liver, although an alternative technique preserves the recipient's vena cava ("piggyback" technique).

The donor's blood in the liver will be replaced by an ice-cold organ storage solution, such as UW (Viaspan) or HTK until the allograft liver is implanted. Implantation involves anastomoses (connections) of the inferior vena cava, portal vein, and hepatic artery. After blood flow is restored to the new liver, the biliary (bile duct) anastomosis is constructed, either to the recipient's own bile duct or to the small intestine. The surgery usually takes between five and six hours, but may be longer or shorter due to the difficulty of the operation and the experience of the surgeon.

The large majority of liver transplants use the entire liver from a non-living donor for the transplant, particularly for adult recipients. A major advance in pediatric liver transplantation was the development of reduced size liver transplantation, in which a portion of an adult liver is used for an infant or small child. Further developments in this area included split liver transplantation, in which one liver is used for transplants for two recipients, and living donor liver transplantation, in which a portion of a healthy person's liver is removed and used as the allograft. Living donor liver transplantation for pediatric recipients involves removal of approximately 20% of the liver (Couinaud segments 2 and 3).

Further advance in liver transplant involves only resection of the lobe of the liver involved in tumors and the tumor-free lobe remains within the recipient. This speeds up the recovery and the patient stay in the hospital quickly shortens to within 5–7 days.

Many major medical centers are now using radiofrequency ablation of the liver tumor as a bridge while awaiting for liver transplantation. This technique has not been used universally and further investigation is warranted.

Cooling

Between removal from donor and transplantation into the recipient, the allograft liver is stored in a temperature-cooled preservation solution. The reduced temperature slows down the process of deterioration from normal metabolic processes, and the storage solution itself is designed to counteract the unwanted effects of cold ischemia. Although this "static" cold storage method has long been standard technique, various dynamic preservation methods are under investigation. For example, systems which use a machine to pump blood through the explanted liver (after it is harvested from the body) during a transfer have met some success.

Living donor transplantation

Volume rendering image created with computed tomography, which can be used to evaluate the volume of the liver of a potential donor.

Living donor liver transplantation (LDLT) has emerged in recent decades as a critical surgical option for patients with end stage liver disease, such as cirrhosis and/or hepatocellular carcinoma often attributable to one or more of the following: long-term alcohol abuse, long-term untreated hepatitis C infection, long-term untreated hepatitis B infection. The concept of LDLT is based on (1) the remarkable regenerative capacities of the human liver and (2) the widespread shortage of cadaveric livers for patients awaiting transplant. In LDLT, a piece of healthy liver is surgically removed from a living person and transplanted into a recipient, immediately after the recipient’s diseased liver has been entirely removed.

Historically, LDLT began with terminal pediatric patients, whose parents were motivated to risk donating a portion of their compatible healthy livers to replace their children's failing ones. The first report of successful LDLT was by Christoph Broelsch at the University of Chicago Medical Center in November 1989, when two-year-old Alyssa Smith received a portion of her mother's liver. Surgeons eventually realized that adult-to-adult LDLT was also possible, and now the practice is common in a few reputable medical institutes. It is considered more technically demanding than even standard, cadaveric donor liver transplantation, and also poses the ethical problems underlying the indication of a major surgical operation (hemihepatectomy or related procedure) on a healthy human being. In various case series, the risk of complications in the donor is around 10%, and very occasionally a second operation is needed. Common problems are biliary fistula, gastric stasis and infections; they are more common after removal of the right lobe of the liver. Death after LDLT has been reported at 0% (Japan), 0.3% (USA) and <1 2006="" 2012.="" altruistic="" as="" britain="" changed="" december="" decrease="" donation="" donations="" experience="" first="" further="" gain="" in="" law="" likely="" liver="" living="" more="" non-directed="" organ="" p="" permit="" place="" procedure.="" risks="" since="" surgeons="" the="" this="" to="" took="" uk="" urope="" was="" with="">

In a typical adult recipient LDLT, 55 to 70% of the liver (the right lobe) is removed from a healthy living donor. The donor's liver will regenerate approaching 100% function within 4–6 weeks, and will almost reach full volumetric size with recapitulation of the normal structure soon thereafter. It may be possible to remove up to 70% of the liver from a healthy living donor without harm in most cases. The transplanted portion will reach full function and the appropriate size in the recipient as well, although it will take longer than for the donor.

Living donors are faced with risks and/or complications after the surgery. Blood clots and biliary problems have the possibility of arising in the donor post-op, but these issues are remedied fairly easily. Although death is a risk that a living donor must be willing to accept prior to the surgery, the mortality rate of living donors in the United States is low. The LDLT donor's immune system does diminish as a result of the liver regenerating, so certain foods which would normally cause an upset stomach could cause serious illness.

Donor requirements

CT scan performed for evaluation of a potential donor. The image shows an unusual variation of hepatic artery. The left hepatic artery supplies not only left lobe but also segment 8. The anatomy makes right lobe donation impossible. Even used as left lobe or lateral segment donation, it would be very technically challenging in anastomosing the small arteries.

Any member of the family, parent, sibling, child, spouse or a volunteer can donate their liver. The criteria for a liver donation include:

• Being in good health
• Having a blood type that matches or is compatible with the recipient's, although some centres now perform blood group incompatible transplants with special immunosuppression protocols
• Having a charitable desire of donation without financial motivation
• Being between 20 and 60 years old
• Have an important personal relationship with the recipient
• Being of similar or larger size than the recipient
• Before one becomes a living donor, the donor must undergo testing to ensure that the individual is physically fit, in excellent health, and not having uncontrolled high blood pressure, liver disease, diabetes or heart disease. Sometimes CT scans or MRIs are done to image the liver. In most cases, the work up is done in 2–3 weeks.

Complications

Living donor surgery is done at a major center. Very few individuals require any blood transfusions during or after surgery. All potential donors should know there is a 0.5 to 1.0 percent chance of death. Other risks of donating a liver include bleeding, infection, painful incision, possibility of blood clots and a prolonged recovery. The vast majority of donors enjoy complete and full recovery within 2–3 months.

Pediatric transplantation

In children, due to their smaller abdominal cavity, there is only space for a partial segment of liver, usually the left lobe of the donor's liver. This is also known as a "split" liver transplant. There are four anastomoses required for a "split" liver transplant: hepaticojejunostomy (biliary drainage connecting to a roux limb of jejunum), portal venous anatomosis, hepatic arterial anastomosis, and inferior vena cava anastomosis.

 

In children, living liver donor transplantations have become very accepted. The accessibility of adult parents who want to donate a piece of the liver for their children/infants has reduced the number of children who would have otherwise died waiting for a transplant. Having a parent as a donor also has made it a lot easier for children - because both patients are in the same hospital and can help boost each other's morale.

Benefits

There are several advantages of living liver donor transplantation over cadaveric donor transplantation, including:

• Transplant can be done on an elective basis because the donor is readily available
• There are fewer possibilities for complications and death than there would be while waiting for a cadaveric organ donor
• Because of donor shortages, UNOS has placed limits on cadaveric organ allocation to foreigners who seek medical help in the USA. With the availability of living donor transplantation, this will now allow foreigners a new opportunity to seek medical care in the USA.

Screening for donors

Living donor transplantation is a multidisciplinary approach. All living liver donors undergo medical evaluation. Every hospital which performs transplants has dedicated nurses that provide specific information about the procedure and answer questions that families may have. During the evaluation process, confidentiality is assured on the potential donor. Every effort is made to ensure that organ donation is not made by coercion from other family members. The transplant team provides both the donor and family thorough counseling and support which continues until full recovery is made.

All donors are assessed medically to ensure that they can undergo the surgery. Blood type of the donor and recipient must be compatible but not always identical. Other things assessed prior to surgery include the anatomy of the donor liver. However, even with mild variations in blood vessels and bile duct, surgeons today are able to perform transplantation without problems. The most important criterion for a living liver donor is to be in excellent health.

Post-transplant immunosuppression

Like most other allografts, a liver transplant will be rejected by the recipient unless immunosuppressive drugs are used. The immunosuppressive regimens for all solid organ transplants are fairly similar, and a variety of agents are now available. Most liver transplant recipients receive corticosteroids plus a calcineurin inhibitor such as tacrolimus or ciclosporin, (also spelled cyclosporine and cyclosporin) plus a purine antagonist such as mycophenolate mofetil. Clinical outcome is better with tacrolimus than with ciclosporin during the first year of liver transplantation. If the patient has a co-morbidity such as active hepatitis B, high doses of hepatitis B immunoglubins are administrated in liver transplant patients.

Liver transplantation is unique in that the risk of chronic rejection also decreases over time, although the great majority of recipients need to take immunosuppressive medication for the rest of their lives. It is possible to be slowly taken off anti rejection medication but only in certain cases. It is theorized that the liver may play a yet-unknown role in the maturation of certain cells pertaining to the immune system. There is at least one study by Thomas E. Starzl's team at the University of Pittsburgh which consisted of bone marrow biopsies taken from such patients which demonstrate genotypic chimerism in the bone marrow of liver transplant recipients.

Recovery and outcomes

The prognosis following liver transplant is variable, depending on overall health, technical success of the surgery, and the underlying disease process affecting the liver. There is no exact model to predict survival rates; those with transplant have a 58% chance of surviving 15 years. Failure of the new liver occurs in 10% to 15% of all cases. These percentages are contributed to by many complications. Early graft failure is probably due to preexisting disease of the donated organ. Others include technical flaws during surgery such as revascularization that may lead to a nonfunctioning graft.

History

As with many experimental models used in early surgical research, the first attempts at liver transplantation were performed on dogs. The earliest published reports of canine liver transplantations were performed in 1955 by Vittorio Staudacher at Opedale Maggiore Policlinico in Milan, Italy. This initial attempt varied significantly from contemporary techniques; for example, Staudacher reported "arterialization" of the donor portal vein via the recipient hepatic artery, and use of cholecystostomy for biliary drainage.

The first attempted human liver transplant was performed in 1963 by Thomas Starzl, although the pediatric patient died intraoperatively due to uncontrolled bleeding. Multiple subsequent attempts by various surgeons remained unsuccessful until 1967, when Starzl transplanted a 19 month old girl with hepatoblastoma who was able to survive for over 1 year before dying of metastatic disease. Despite the development of viable surgical techniques, liver transplantation remained experimental through the 1970s, with one year patient survival in the vicinity of 25%. The introduction of ciclosporin by Sir Roy Calne, Professor of Surgery Cambridge, markedly improved patient outcomes, and the 1980s saw recognition of liver transplantation as a standard clinical treatment for both adult and pediatric patients with appropriate indications. Liver transplantation is now performed at over one hundred centers in the US, as well as numerous centres in Europe and elsewhere.

The limited supply of liver allografts from non-living donors relative to the number of potential recipients spurred the development of living donor liver transplantation. The first altruistic living liver donation in Britain was performed in December 2012 in St James University Hospital Leeds.

Society and culture

Famous liver transplant recipients

• Eric Abidal (born 1979), French footballer (Olympique Lyonnais, FC Barcelona), transplant in 2012
• Gregg Allman (1947-2017), American musician (The Allman Brothers Band), transplant in 2010 (survival: 7 years)
• George Best (1946-2005), Northern-Irish footballer (Manchester United), transplant in 2002 (survival: 3 years)
• David Bird (1959–2014), American journalist (The Wall Street Journal), transplant in 2004 (survival: 10 years)
• Jack Bruce (1943-2014), English musician (Cream), transplant in 2003 (survival: 11 years)
• Robert P. Casey (1932-2000), American politician (42nd Governor of Pennsylvania), transplant in 1993 (survival: 7 years)
• David Crosby (born 1941), American musician (The Byrds, Crosby Stills, Nash (& Young)), transplant in 1994
• Gerald Durrell (1925-1995), British zookeeper (Durrell Wildlife Park), transplant in 1994 (survival <1 small="" year="">
• Shelley Fabares (born 1944), American actress (The Donna Reed Show, Coach) and singer ("Johnny Angel"), transplant in 2000
• Freddy Fender (1937-2006), American musician ("Before the Next Teardrop Falls," "Wasted Days and Wasted Nights"), transplant in 2004 (survival: 2 years)
• "Superstar" Billy Graham (born 1943), American wrestler (WWF), transplant in 2002
• Larry Hagman (1931-2012), American actor (Dallas, Harry and Tonto, Nixon, Primary Colors), transplant in 1995 (survival: 17 years)
• Steve Jobs (1955-2011), American businessman (Apple Inc.), transplant in 2009 (survival: 2 years)
• Chris Klug (born 1972), American snowboarder, transplant in 2000
• Evel Knievel (1938-2007), American stunt performer, transplant in 1999 (survival: 8 years)
• Chris LeDoux (1948-2005), American musician and rodeo champion, transplant in 2000 (survival: 5 years)
• Phil Lesh (born 1940), American musician (Grateful Dead), transplant in 1998
• Linda Lovelace (1949-2002), American pornographic actress (Deep Throat), transplant in 1987 (survival: 15 years)
• Mickey Mantle (1931-1995), American baseball player (New York Yankees), transplant in 1995 (survival: <1 small="" year="">
• Mike MacDonald (1954-2018), Canadian comedian and actor (Mr. Nice Guy), transplant in 2013 (survival: 5 years)
• Jim Nabors (1930-2017), American actor (The Andy Griffith Show), transplant in 1994 (survival: 23 years)
• John Phillips (1935-2001), American musician (The Mamas & the Papas), transplant in 1992 (survival: 9 years)
• Lou Reed (1942-2013), American musician (The Velvet Underground), transplant in 2013 (survival: <1 small="" year="">
• U. Srinivas (1969-2014), Indian musician, transplant in 2014 (survival: <1 small="" year="">

Research directions

Cooling

There is increasing interest in improving methods for allograft preservation following organ harvesting. The standard "static cold storage" technique relies on decreased temperature to slow of anaerobic metabolic breakdown. This is currently being investigated at cold (hypothermic), body temperature (normothermic), and under body temperature (subnormothermic). Hypothermic machine perfusion has been used successfully at Columbia University and at the University of Zurich. A 2014 study showed that the liver preservation time could be significantly extended using a supercooling technique, which preserves the liver at subzero temperatures (-6 °C)  More recently, the first randomised controlled clinical trial comparing machine preservation with conventional cold storage showed comparable outcomes, with better early function, fewer discarded organs, and longer preservation times compared with cold stored livers.

Special populations

Alcohol dependence

The high incidence of liver transplants given to those with alcoholic cirrhosis has led to a recurring controversy regarding the eligibility of such patients for liver transplant. The controversy stems from the view of alcoholism as a self-inflicted disease and the perception that those with alcohol-induced damage are depriving other patients who could be considered more deserving. It is an important part of the selection process to differentiate transplant candidates who suffer from alcoholism as opposed to those who were susceptible to non-dependent alcohol use. The latter who gain control of alcohol use have a good prognosis following transplantation. Once a diagnosis of alcoholism has been established, however, it is necessary to assess the likelihood of future sobriety.

HIV

Historically, HIV was considered an "absolute" contraindication to liver transplantation. This was in part due to concern that the infection would be worsened by the immunosuppressive medication which is required after transplantation.

However, with the advent of highly active antiretroviral therapy (HAART), people with HIV have much improved prognosis. Transplantation may be offered selectively, although consideration of overall health and life circumstances may still be limiting. Uncontrolled HIV disease (AIDS) remains an absolute contraindication.