Liver failure or hepatic insufficiency is the inability of the liver to perform its normal synthetic

and metabolic function as part of normal physiology.

Liver failure is a life-threatening condition that demands

urgent medical care. Most often, liver failure occurs
gradually and over many years. However, a more rare
condition known as acute liver failure occurs rapidly (in as
little as 48 hours) and can be difficult to detect initially.
Acute liver failure is a rare but life-threatening critical illness that occurs most often in patients who do not
have preexisting liver disease. With an incidence of fewer than 10 cases per million persons per year in
the developed world, acute liver failure is seen most commonly in previously healthy adults in their 30s
and presents unique challenges in clinical management. The clinical presentation usually includes hepatic
dysfunction, abnormal liver biochemical values, and coagulopathy; encephalopathy may develop, with
multiorgan failure and death occurring in up to half the cases

Two forms are recognised, acute and chronic.

Acute
Acute liver failure is defined as "the rapid development of hepatocellular dysfunction,
specifically coagulopathy and mental status changes (encephalopathy) in a patient without known
prior liver disease".[3]:1557
The disease process is associated with the development of a coagulopathy of liver aetiology, and
clinically apparent altered level of consciousness due to hepatic encephalopathy.
Several important measures are immediately necessary when the patient presents for medical
attention.[4]
The diagnosis of acute liver failure is based on physical exam, laboratory findings, patient history,
and past medical history to establish mental status changes, coagulopathy, rapidity of onset, and
absence of known prior liver disease respectively.[3]:1557
The exact definition of "rapid" is somewhat questionable, and different sub-divisions exist which are
based on the time from onset of first hepatic symptoms to onset of encephalopathy.
One scheme defines "acute hepatic failure" as the development of encephalopathy within 26 weeks
of the onset of any hepatic symptoms.
This is sub-divided into "fulminant hepatic failure", which requires onset of encephalopathy within 8
weeks, and "subfulminant", which describes onset of encephalopathy after 8 weeks but before 26
weeks.[5]
Another scheme defines "hyperacute" as onset within 7 days, "acute" as onset between 7 and 28
days, and "subacute" as onset between 28 days and 24 weeks.[3]:155
Acute liver failure is a broad term that encompasses both fulminant hepatic
failure and subfulminant hepatic failure (or late-onset hepatic failure).
Fulminant hepatic failure is generally used to describe the development of
encephalopathy within 8 weeks of the onset of symptoms in a patient with a
previously healthy liver. Subfulminant hepatic failure is reserved for patients
with liver disease for up to 26 weeks before the development of hepatic
encephalopathy.

Chronic[edit]
Chronic liver failure usually occurs in the context of cirrhosis, itself potentially the result of many
possible causes, such as excessive alcohol intake, hepatitis B or C, autoimmune, hereditary and
metabolic causes (such as iron or copper overload, steatohepatitis or non-alcoholic fatty liver
disease).

During chronic liver failure, your liver becomes inflamed. This inflammation
causes the formation of scar tissue over time. As your body continuously
replaces healthy tissue with scar tissue, your liver begins to fail.

There are three types of alcohol-related liver failure:

Alcoholic fatty liver disease is the result of fat cells deposited in the liver. It
generally affects those who drink a lot of alcohol and those who are obese.
Alcoholic hepatitis is characterized by fat cells in the liver, inflammation, and
scarring. According to the American Liver Foundation, up to 35 percent of
heavy drinkers will develop this condition.
Alcoholic cirrhosis is considered the most advanced out of the three types.
The American Liver Foundation says cirrhosis affects 10 to 20 percent of
heavy drinkers.

Acute on chronic
"Acute on chronic liver failure" is said to exist when someone with chronic liver disease develops
features of liver failure. A number of underlying causes may precipitate this, such as alcohol misuse
or infection. People with ACLF can be critically ill and require intensive care treatment, and
occasionally a liver transplant. Mortality with treatment is 50%.[6]

Causes of Hepatic Failure

Acute liver failure, also known as fulminant hepatic failure, can occur even if
you do not have a preexisting liver disease. According to the Mayo Clinic,
acetaminophen (Tylenol) overdose is the most common cause of acute liver
failure in the United States. Acetaminophen is an over-the-counter drug, so
you should follow the recommended dosage noted on the label. See your
doctor immediately if you think that you may have overdosed.

Acute liver failure may also be caused by:

certain prescription medicines

some herbal supplements
viral infections, such as hepatitis, including hepatitis A, B, and C
toxins
certain autoimmune diseases

It is possible to develop liver failure without being able to identify the exact
cause.

Acute liver failure can also be genetic. You can get an abnormal gene from
one or both of your parents. If you suffer from a genetic liver disease, you are
more susceptible to liver failure.

Chronic liver failure is usually a result of cirrhosis or alcohol-related liver

disease. Alcoholism is considered the most common cause of cirrhosis in the
United States.

Symptoms of Hepatic Failure

Symptoms of liver failure may include:

nausea
a loss of appetite
fatigue
diarrhea
jaundice
weight loss
 bruising or bleeding easily
itching
edema, or fluid buildup in the legs
ascites, or fluid buildup in the abdomen
Yellowing of your skin and eyeballs (jaundice)
Pain in your upper right abdomen
Vomiting
A general sense of feeling unwell (malaise)
Disorientation or confusion
Sleepiness

These symptoms can also be attributed to other problems or disorders, which

can make liver failure hard to diagnose. Some people dont have any signs
until their liver failure has progressed to a deadly stage. You may be
disoriented, drowsy, or even slip into a coma by the time you reach this stage.

If you suffer from alcohol-related liver disease, you may develop jaundice, or a
yellowish color of the skin and eyes. Toxins can build up in your brain and
cause sleeplessness, lack of concentration, and even decreased mental
function. You may also experience an enlarged spleen, stomach bleeding, and
kidney failure. Liver cancer can also develop.

Signs and symptoms of acute failure may include the following:

Encephalopathy
Cerebral edema: May lead to signs of increased intracranial pressure (ICP) (eg,
papilledema, hypertension, bradycardia)
Jaundice: Often present but not always
Ascites: Potential for hepatic vein thrombosis with rapid development in the
presence of fulminant hepatic failure accompanied by abdominal pain
Right upper quadrant tenderness: Variably present
Change in liver span: May be small due to hepatic necrosis or may be enlarged
due to heart failure, viral hepatitis, or Budd-Chiari syndrome
Hematemesis or melena: Due to upper gastrointestinal (GI) bleeding
Hypotension and tachycardia: Due to reduced systemic vascular resistance

Diagnosis and Treatment

If you are experiencing problems, seek help from your doctor. If you have a
history of alcohol abuse, genetic abnormalities, or other medical conditions be
sure to let, your doctor know. Your doctor will be aware of the tests you need.
There are several different blood screening tests that can be done to detect
any abnormalities in the blood, including abnormalities that may imply liver
failure.

If you are suffering from drug poisoning, such as from acetaminophen, your
doctor may prescribe medication to reverse the effects. Your doctor may also
prescribe medication to stop any internal bleeding.

A biopsy is a common test used to determine liver damage. During a liver

biopsy, a small piece of your liver is extracted and examined in a lab. If it is
caught early, some liver damage can be reversed. The damaged liver may
repair itself or medication can help the repair process.

You are more at risk of fatty liver disease if you are overweight or if you have a
diet that is high in fat. Making a lifestyle change to a healthier diet may help. If
you have liver damage and drink alcohol, removing alcohol from your diet is
also important.

Treatment depends on the stage of the disease. Your doctor may prescribe
medications. If only part of your liver is damaged, surgery may be
recommended to remove the damaged part. A doctor can also take imaging
tests of your liver to look for damage. If the damage is too severe, which can
sometimes be the case with fast-acting acute liver failure, a liver transplant
may be necessary.

Diagnosis

The most important step in the assessment of patients with acute liver failure is to
identify the cause, because certain conditions necessitate immediate and specific
treatment and affect prognosis. All patients with clinical or laboratory evidence of
moderate or severe acute hepatitis should have immediate measurement of
prothrombin time (PT) and careful evaluation of mental status. The presence of PT
prolongation or mental status changes is grounds for hospital admission.
Laboratory testing
Complete blood count: May reveal thrombocytopenia
 Coagulation studies: PT and/or international normalized ratio (INR)
Liver function tests: Often elevated levels of aspartate aminotransferase
(AST)/serum glutamic-oxaloacetic transaminase (SGOT), alanine
aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT), alkaline
phosphatase (ALP)
Serum bilirubin level: Elevated
Serum ammonia level: May be dramatically elevated (accuracy: arterial > venous
level)
Serum glucose level: May be dangerously low
Serum (arterial) lactate level: Often elevated
Arterial blood gas: May reveal hypoxemia
Serum creatinine level: May be elevated
Serum free copper and ceruloplasmin levels: Low levels with Wilson disease
Serum phosphate level: May be low
Acetaminophen and acetaminophen-protein adducts levels
Drug screening: Consider in patients who are intravenous drug abusers
Blood cultures: For patients with suspected infection
Viral serologies: Consider for hepatitis A virus immunoglobulin M (IgM), hepatitis B
surface antigen (HBsAg), hepatitis B virus anticore IgM; hepatitis C viral load
testing; hepatitis D virus IgM if HBsAg is positive; in posttransplantation or
immunosuppressed setting, consider studies for cytomegalovirus viremia,
cytomegalovirus antigenemia, and herpes simplex virus
Autoimmune markers (for autoimmune hepatitis diagnosis): Antinuclear antibody
(ANA), anti-smooth muscle antibody (ASMA), and immunoglobulin levels
Other studies may include the following:
Electroencephalography
Intracranial pressure monitoring
Percutaneous (contraindicated in the presence of coagulopathy) or transjugular
liver biopsy
Imaging studies
Hepatic Doppler ultrasonography
Abdominal computed tomography (CT) scanning or magnetic resonance imaging
without contrast
Cranial CT scanning

Management

The most important aspect of treatment for acute liver failure is to provide good
intensive care support, including protection of the airways. [1, 2, 3, 4, 5] Specific therapy is
also dependent on the cause of the patients liver failure and the presence of any
complications.
Pay careful attention to the patients fluid management and hemodynamics. It is crucial
to monitor their metabolic parameters, assess for infection, maintain nutrition, and
promptly recognize GI bleeding.
Pharmacotherapy
Various medications may be necessary because of the variety of complications that
may occur from fulminant hepatic failure. In specific cases, antidotes that effectively
bind or eliminate toxins are essential.
The following medications may be used in the management of acute liver failure:
Antidotes (eg, penicillin G, silibinin, activated charcoal, N-acetylcysteine)
Osmotic diuretics (eg, mannitol)
Barbiturate agents (eg, pentobarbital, thiopental)
Benzodiazepines (eg, midazolam)
Anesthetic agents (eg, propofol)
Surgery
Liver transplantation is the definitive treatment for acute liver failure. In selected patients
for whom no allograft is immediately available, consider support with a bioartificial liver.
This is a short-term measure that only leads to survival if the liver spontaneously
recovers or is replaced. [6, 7, 8, 9]
Nonbiologic extracorporeal liver support systems, such as hemodialysis, hemofiltration,
charcoal hemoperfusion, plasmapheresis, and exchange transfusions permit temporary
liver support until a suitable donor liver is found. However, no controlled study has
shown long-term benefit.
The most important aspect of treatment in patients with acute liver failure is to provide
good intensive care support. [1, 2, 3, 4, 5, 36, 37] Patients with grade II encephalopathy
should be transferred to the intensive care unit (ICU) for monitoring. As encephalopathy
progresses, protection of the airway becomes increasingly important.
Most patients with acute liver failure tend to develop some degree of circulatory
dysfunction. Careful attention should be paid to fluid management and
hemodynamics. [36, 37] Monitoring of metabolic parameters, surveillance for infection,
maintenance of nutrition, and prompt recognition of gastrointestinal bleeding are crucial.
Coagulation parameters, complete blood cell count, and metabolic panel should be
checked frequently. Serum aminotransferases and bilirubin are generally measured
daily to follow the course of the disease.
Bed rest is recommended.
Airway Protection
As patients with fulminant hepatic failure drift deeper into coma, the ability to
protect their airway from aspiration decreases. Patients who are in stage III
coma should have a nasogastric tube (NGT) inserted for stomach
decompression. When patients progress to stage III coma, intubation should
be performed.
Short-acting benzodiazepines in low doses (eg, midazolam, 2-3 mg) may be
used before intubation, or propofol (50 mcg/kg/min) may be initiated before
intubation and continued as an infusion. Propofol is also known to decrease
the cerebral blood flow and intracranial hypertension (ICH). It may be
advisable to use endotracheal lidocaine before endotracheal suctioning.
Management of Encephalopathy and Cerebral Edema
Patients with grade I encephalopathy may sometimes be safely managed in a
medicine ward. Frequent mental status checks should be performed, and
transfer to an intensive care unit (ICU) is warranted with progression to grade
II encephalopathy.
Sedation should be avoided if possible. Unmanageable agitation may be
treated with short-acting benzodiazepines in low doses.
Patients should be positioned with the head elevated at 30. Efforts should be
made to avoid patient stimulation. Maneuvers that cause straining or, in
particular, Valsalva-like movements may increase intracranial pressure (ICP).
There is increasing evidence that ammonia may play a pathogenic role in the
development of cerebral edema. Reducing elevated ammonia levels with
enteral administration of lactulose might help prevent or treat cerebral edema.
In the late stages of encephalopathy, to reduce the risk of aspiration, avoid
providing lactulose by mouth or nasogastric tube in the absence of
endotracheal intubation.
The occurrence of cerebral edema and intracranial hypertension (ICH) in
patients with acute liver failure is related to the severity of encephalopathy.
Cerebral edema is seldom observed in patients with grades I-II
encephalopathy. The risk of edema increases to 25-35% with progression to
grade III and increases to 65-75% (or more) in patients reaching grade IV
coma.
Patients in the advanced stages of encephalopathy require close follow-up
care. Monitoring and management of the hemodynamic and renal parameters,
as well as glucose, electrolytes, and acid/base status, become
critical. [36, 37] Frequent neurologic evaluation for signs of elevated ICP should
be conducted.
Intracranial pressure monitoring

In patients with grade III or IV encephalopathy, consider placement of an ICP

monitor. ICP monitoring helps in the early recognition of cerebral edema.
The clinical signs of elevated ICP, including hypertension, bradycardia, and
irregular respirations (Cushing triad), are not uniformly present; these and
other neurologic changes, such as papillary dilatation or signs of
decerebration, are typically evident only late in the course. Computed
tomography (CT) scanning of the brain does not reliably detect edema,
especially in the early stages.
The primary purpose of ICP monitoring is to detect elevations in ICP and reductions in
cerebral perfusion pressure (CPP; calculated as mean arterial pressure [MAP] minus
ICP) so that interventions can be made to prevent herniation while preserving brain
perfusion. The ultimate goal of such measures is to maintain neurologic integrity and to
prolong survival while awaiting the receipt of a donor organ or recovery of sufficient
functioning hepatocyte mass. Additionally, refractory ICH and/or decreased CPP are
considered contraindications to liver transplantation in many centers.
If an ICP monitor is placed, ICP should be maintained below 20-25 mm Hg, if possible,
with CPP maintained above 50-60 mm Hg. Support of systemic blood pressure may be
required to maintain adequate CPP.
Management of intracranial hypertension

ICH is managed initially with the use of mannitol. Osmotic diuresis with intravenous (IV)
mannitol is effective in the short term in decreasing cerebral edema. Administration of IV
mannitol (in a bolus dose of 0.5-1 g/kg or 50-100 g) is recommended to treat ICH in
acute liver failure. The dose may be repeated once or twice, as needed, provided that
serum osmolality has not exceeded 320 mOsm/L. Volume overload is a risk with
mannitol use in patients with renal impairment and may necessitate the use of dialysis
to remove excess fluid.
If life-threatening ICH is not controlled with mannitol infusion and other general
management as outlined above, hyperventilation may be instituted temporarily in an
attempt to acutely lower the ICP and to prevent impending herniation. Hyperventilation
to reduce the partial pressure of carbon dioxide in the blood (PaCO2) to 25-30 mm Hg
can quickly lower ICP via vasoconstriction, causing decreased cerebral blood flow, but
this effect is short lived.
Other therapies used to decrease ICH but not routinely recommended may be
considered in refractory ICH. These include hypertonic saline, barbiturates, and
hypothermia.
A controlled trial of administration of 30% hypertonic saline, 5-20 mL/hour, to maintain
serum sodium levels of 145-155 mmol/L in patients with acute liver failure and severe
encephalopathy suggested that induction and maintenance of hypernatremia may be
used to prevent the rise in ICP values. [40]
Barbiturate agents (thiopental or pentobarbital) may also be considered when severe
ICH does not respond to other measures; administration of these drugs has been
shown to effectively decrease ICP. Significant systemic hypotension frequently limits
their use and may necessitate additional measures to maintain adequate mean arterial
pressure. Doses of barbiturates for ICH are as follows:
Thiopental: 5-10 mg/kg IV loading dose, followed by 3-5 mg/kg IV infusion
Pentobarbital: 3-5 mg/kg IV loading dose, followed by 1-3 mg/kg/h infusion
Moderate hypothermia (32-34C) may prevent or control ICH in patients with acute liver
failure. An external cooling blanket may be used to achieve this goal. Potential
deleterious effects of hypothermia include increased risk of infection, coagulation
disturbance, and cardiac arrhythmias.

Hemodynamic Monitoring
Hemodynamic derangements consistent with multiple organ failure occur in
acute liver failure. Hypotension (ie, systolic blood pressure <80 mm Hg) may
be present in 15% of patients. Most patients will require fluid resuscitation on
admission. Intravascular volume deficits may be present on admission due to
decreased oral intake or gastrointestinal blood loss.
Hemodynamic derangement resembles that of sepsis or cirrhosis with
hepatorenal syndrome (low systemic vascular resistance [SVR] with normal or
increased cardiac output). An arterial line should be placed for continuous
blood pressure monitoring.
A Swan-Ganz catheter should be placed, and fluid replacement with colloid
albumin should be guided by the filling pressure. If needed, dopamine or
norepinephrine can be used to correct hypotension.
Management of Coagulopathy
In the absence of bleeding, it is usually not necessary to correct clotting
abnormalities with fresh frozen plasma (FFP). The exception is when an
invasive procedure is planned or in the presence of profound coagulopathy
(international normalized ratio [INR] >7). [41]
Prothrombin time (PT) and partial thromboplastin time (PTT) become
prolonged when plasma coagulation components are diluted to less than 30%,
and abnormal bleeding occurs when they are less than 17%. One unit of FFP
increases the coagulation factor by 5%; 2 units increase it by 10%. An FFP
infusion of 15 mL/kg of body weight or 4 units will correct the deficiency. If the
fibrinogen level is very low (<80 mg/dL), consider administering
cryoprecipitate.
Recombinant factor VIIa may be used in patients whose condition is
nonresponsive to FFP. It is used in a dose of 4 g/kg intravenous (IV) push
over 2-5 minutes. PT is normalized in 20 minutes and remains normalized for
3-4 hours.
Platelet transfusions are not used until the platelet count is below 10,000/L or
if an invasive procedure is being done and the platelet count is less than
50,000/L. Six to 8 units of random donor platelets (1 random donor unit
platelet/10 kg) will increase the platelet count to greater than 50,000/L. The
platelet count should be checked after 1 hour and 24 hours. Transfused
platelets survive 3-5 days.
Management of Acetaminophen Toxicity
Treat acetaminophen (paracetamol, APAP) overdose with N-acetylcysteine
(NAC).[42] Researchers theorize that this antidote works by a number of
protective mechanisms. Early after an overdose, NAC prevents the formation
and accumulation of N-acetyl-p-benzoquinone imine (NAPQI), a free radical
that binds to intracellular proteins, nonspecifically resulting in toxicity.
NAC increases glutathione stores, combines directly with NAPQI as a
glutathione substitute, and enhances sulfate conjugation. NAC also functions
as an anti-inflammatory and antioxidant and has positive inotropic and
vasodilating effects, which improve the microcirculatory blood flow and oxygen
delivery to tissues. These latter effects decrease morbidity and mortality once
hepatotoxicity is well established.
The protective effect of NAC is greatest when administered within 8 hours of
ingestion; however, when indicated, administer NAC regardless of the time
since the overdose. Therapy with NAC has been shown to decrease mortality
in late-presenting patients with fulminant hepatic failure (in the absence of
acetaminophen in the serum).
If patients present within 4 hours of overdosing on acetaminophen, administer
activated charcoal just prior to starting NAC. [1, 2]
Never administer aminoglycosides or nonsteroidal anti-inflammatory drugs
(NSAIDs) to patients with acetaminophen hepatotoxicity, because the
potential for nephrotoxicity is greatly exaggerated in this setting.
Liver Transplantation
Liver transplantation is the definitive treatment in liver failure, but a detailed discussion
is beyond the scope of this article. For more information on liver transplantation, see the
Medscape articles Liver Transplants and Pediatric Liver Transplantation. The American
Association for the Study of Liver Diseases (AASLD) has produced guidelines on the
evaluation of adult and pediatric patients for liver transplantation, [43, 44, 45] as well as the
long-term management of these patients.[46, 47] Preoperative management is
emphasized in this section.
In selected patients for whom no allograft is immediately available, consider support
with a bioartificial liver. This is a short-term measure that only leads to survival if the
liver spontaneously recovers or is replaced. [6, 7, 8, 9]
Artificial liver support systems can be divided into two major categories: biologic
(bioartificial) and nonbiologic.
The bioartificial liver is composed of a dialysis cartridge with mammalian or porcine
hepatocytes filling the extracapillary spaces. These devices have undergone controlled
trials. One multicenter trial reported improved short-term survival for a subgroup of
patients with acute liver failure who were treated with a porcine hepatocyte-based
artificial liver. [9]
Nonbiologic extracorporeal liver support systems, such as hemodialysis, hemofiltration,
charcoal hemoperfusion, plasmapheresis, and exchange transfusions, have been used;
however, no controlled study has shown long-term benefit.
These modalities permit temporary liver support until a suitable donor liver is found.
Although extracorporeal hemoperfusion of charcoal and other inert substances provide
some measure of excretory function, this technique provides no synthetic capacity.
Among the liver support systems currently available, albumin dialysis using the
molecular adsorbent recirculating system (MARS) is the one that has been most
extensively investigated. In this device, blood is dialyzed across an albumin-
impregnated membrane against 20% albumin. Charcoal and anion exchange resin
columns in the circuit cleanse and regenerate the albumin dialysate. Clinical studies
have shown that this system improves hyperbilirubinemia and encephalopathy.
Two other systems based on the removal of albumin bound toxins are the Prometheus,
using the principle of fractionated plasma separation and adsorption (FPSA), and the
single pass albumin dialysis (SPAD). A clinical trial is in the process of recruiting
patients to to compare the MARS and SPAD systems with regard to their biologic and
clinical efficacy, pulsatility index of middle cerebral artery modification, and tolerance. [48]
Currently available liver support systems are not routinely recommended
outside of clinical trials. In the future, hepatocyte transplantation, which has
shown dramatic results in animal models of acute liver failure, may provide
long-term support, but this approach remains investigational.

Diet
Patients with acute liver failure are, by necessity, on nothing by mouth (NPO)
status. They may require large amounts of intravenous (IV) glucose to avoid
hypoglycemia.
When enteral feeding via a feeding tube is not feasible (eg, as in a patient with
paralytic ileus), institute total parenteral nutrition (TPN). (See also Nutritional
Requirements of Adults Before Transplantation and Nutritional Requirements
of Children Prior to Transplantation.) Restricting protein (amino acids) to 0.6
g/kg body weight per day was previously routine in the setting of hepatic
encephalopathy. However, this may not be necessary.
Complications
Potential complications of acute liver failure include seizures, hemorrhage,
infection, renal failure, and metabolic imbalances.
Seizures

Seizures, which may be seen as a manifestation of the process that leads to

hepatic coma and intracranial hypertension (ICH), should be controlled with
phenytoin. The use of any sedative is discouraged in light of its effects on the
evaluation of mental status. Only minimal doses of benzodiazepines should
be used, given their delayed clearance by the failing liver. Seizure activity may
acutely elevate and may also cause cerebral hypoxia and, thus, contribute to
cerebral edema.
Hemorrhage

Hemorrhage develops as a result of the profoundly impaired coagulation that

manifests in patients with acute liver failure. Gastrointestinal bleeding may
develop from esophageal, gastric, or ectopic varices as a result of portal
hypertension. Portal hypertensive gastropathy and stress gastritis may also
develop. Any minor trauma may result in extensive percutaneous bleeding or
internal hemorrhage.
The first step in management is to correct coagulopathy. The transfusion
requirements for coagulation products (fresh frozen plasma [FFP], platelets)
may be enormous. Multiple transfusions with packed red blood cells may be
needed. Consider retroperitoneal hemorrhage if large transfusion
requirements are not matched by an obvious blood loss.
Infection

Periodic surveillance cultures should be performed to detect bacterial and

fungal infections. Empiric broad-spectrum antibiotics and antifungals should
be given in the following circumstances:
Progressive encephalopathy (start antibiotics in all patients listed for
transplantation)
Signs of systemic inflammatory response syndrome
(SIRS) (temperature, >38C or <36C; white blood cell [WBC] count,
>12,000/L or <4,000/L; pulse rate, >90 bpm)
Persistent hypotension
Piperacillin/tazobactam (Zosyn) and fluconazole should be the initial
antimicrobial choice. In hospital-acquired intravenous (IV) catheter infections,
consider vancomycin.
Renal failure

Acute renal failure is a frequent complication in patients with acute liver failure
and may be due to dehydration, hepatorenal syndrome, or acute tubular
necrosis. [37] To preserve renal function, maintain adequate blood pressure,
avoid nephrotoxic medications and nonsteroidal anti-inflammatory agents
(NSAIDs), and promptly treat infections.
When dialysis is needed, continuous (ie, continuous venovenous
hemodialysis [CVVHD]) rather than intermittent renal replacement therapy is
preferred. Hemodialysis may significantly lower the mean arterial pressure
such that cerebral perfusion pressure is compromised.
Metabolic imbalances

Alkalosis and acidosis occur in acute liver failure. Identify and treat the underlying
cause. Base deficits can be corrected by THAM solution (tromethamine injection), which
prevents a rise in carbon dioxide, osmolality, and serum sodium.
Severe hypoglycemia occurs in approximately 40% of patients with fulminant hepatic
failure. Although hypoglycemia occurs more frequently in children, blood sugar needs to
be monitored in adult patients as well. Blood sugars should be maintained in the range
of 60-200 mg/dL, using 10% dextrose solution.
Phosphate, magnesium, and potassium levels tend to be low in acute liver failure.
Frequent supplementation is required.

Prevention of Hepatic Failure

One of the easiest ways to prevent liver failure is to moderate your drinking
level. The Mayo Clinicrecommends that healthy women limit their alcohol
consumption to one drink per day. Healthy men over the age of 65 should
also limit their alcohol consumption to one drink a day. Men under 65 should
consume no more than two drinks per day.

Other preventive measures include:

practicing safe sex

not engaging in drug use or needle sharing
getting vaccinated for hepatitis
protecting your skin from toxic chemicals
using aerosol spray cans in ventilated areas

You should see your doctor if you have any of the symptoms mentioned. You
may not have liver failure, but if you do, early detection is important. Liver
failure can be a silent killer because you may not experience symptoms until it
is too late. With the proper treatment, you can control liver disease and lead a
normal life.

Specific therapies

Where appropriate, a specific antidote should be administered as soon as possible. In

cases of paracetamol overdose, N-acetyl cysteine (NAC) should be commenced at the
earliest opportunity, regardless of blood results and paracetamol concentrations, as
early treatment has great impact on the subsequent outcome. Improved outcome has
been shown when NAC is administered even more than 24 h after paracetamol
overdose. After the loading dose of NAC 150 mg kg1, the infusion is continued at the
recommended maintenance dose of 100 mg kg1 until the INR (international
normalized ratio) improves to less than 2.0. There is growing evidence that NAC
administration may be clinically beneficial in non-paracetamol-induced ALF, though
the mechanism of action of NAC in this situation is unclear. In these cases, the usual
loading and maintenance dose recommended for paracetamol overdose applies.

Prophylactic antimicrobials with broad-spectrum coverage of gram-positive and gram-

negative activity including an anti-fungal (e.g. piperacillin with tazobactam and
fluconazole) should be administered on admission, as this halves the incidence of
infective episodes when compared with commencement at the time of suspected
infection. However, this benefit must be balanced against the risk of developing multi-
resistant pathogens.

Liver transplantation

Orthotopic liver transplantation (OLT) is the definitive treatment in ALF patients who
meet the criteria for transplantation. Patient selection is based on the KCH prognostic
criteria (Table 2), which have a positive predictive value for ICU death without
transplantation of 0.98 and a negative predictive value of 0.82. Other criteria using
factor V concentrations have also been validated. The 1-yr and 5-yr survival of
patients undergoing OLT for ALF is about 20% lower than elective cases for cirrhotic
patients. These differences reflect the severity of illness and the lack of choice in
donor graft selection. Auxiliary liver transplantation is an alternative option in which
a partial liver graft is placed while awaiting the native liver to regenerate. The main
advantage of this procedure is the potential to withdraw immunosuppression at a later
date. Despite initial enthusiasm, the procedure has not been used extensively because
of poor initial function with the partial graft and the failure of long-term regeneration
and withdrawal of immunosuppression in the majority of patients. Recently, living
related donation for ALF has been used in some countries with some success,
especially in children.

Absolute contraindications to OLT include overwhelming sepsis, refractory

hypotension, acquired immunodeficiency syndrome and uncontrolled intracranial
hypertension with suspected permanent neurological damage. Once a patient has been
selected to undergo OLT, their suitability for transplantation must be reviewed
regularly because of the progressive nature of the disease.

Hepatic assist devices

The development of an effective hepatic assist device has been ongoing for over 40
yrs. The methods can be either biological or non-biological. The ultimate aim is to
provide full hepatic support on an extra-corporeal circuit. To date, these approaches
have met with limited success. Non-biological methods that have been successfully
used for renal failure (haemofiltration, haemodialysis and plasmapheresis) have been
adapted for ALF. The molecular adsorption and recirculation system (MARS) is an
adaptation of haemodialysis in which blood is dialysed against 20% albumin solution.
It supports the excretory function of the failing liver by removing albumin-bound
toxins. MARS has been shown to improve encephalopathy, renal function and
haemodynamic parameters in patients with acute-on-chronic liver failure. However,
its efficacy in the management of ALF has yet to be studied in a randomized control
trial, and these approaches are limited by the absence of provision of metabolic and
synthetic function. Several bio-artificial devices are currently undergoing phase II
assessment, with some improvement in biochemical and clinical parameters, although
further evaluation and randomized trials are needed. The key issues to be considered
are safety and choice of cellular component (human hepatocytes, tumour cell lines or
xenogenic).

Antidotes
Antidotes neutralize toxic agents and neutralize or counteract any form of
poisoning.
Penicillin G (Pfizerpen)

Intravenous penicillin G is the drug of choice for the treatment of mushroom

poisoning from Amanita phalloides. Its mode of action is unclear in this
setting.
Silibinin (Silibinin Plus)

Silibinin is a water-soluble derivative of silymarin, which is the active

ingredient in the herbal preparation milk thistle. This agent possesses
antioxidant properties that may benefit liver disease management.
Activated charcoal (Actidose-Aqua, Liqui-Char, CharcoAid)

In patients who have recently ingested Amanita phalloides, activated charcoal

may bind the toxin and prevent absorption.
N-acetylcysteine (Mucomyst, Mucosil)

N-acetylcysteine is the drug of choice in acetaminophen overdose. N-

acetylcysteine provides reducing equivalents to help restore depleted
intrahepatic glutathione levels.
Mannitol (Osmitrol)

Osmotic diuresis with intravenous mannitol is effective in the short term for decreasing
cerebral edema. Administration of intravenous mannitol (in a bolus dose of 0.5-1 g/kg or
50-100 g) is recommended to treat intracranial hypertension in acute liver failure. The
dose may be repeated once or twice, as needed, provided that serum osmolality has
not exceeded 320 mOsm/L. Volume overload is a risk with mannitol use in patients with
renal impairment and may necessitate the use of dialysis to remove the excess fluid

Barbiturate Agents
Class Summary

Barbiturate agents such as thiopental and pentobarbital may be considered

when severe intracranial hypertension does not respond to other measures.
Administration has been shown to effectively decrease intracranial pressure
(ICP). Significant systemic hypotension frequently limits their use and may
necessitate additional measures to maintain adequate mean arterial pressure.
Pentobarbital (Nembutal)

View full drug information

Pentobarbital is a short-acting barbiturate with sedative, hypnotic, and
anticonvulsant properties. It may be used at high dosages to induce
barbiturate coma for the treatment of refractory increased ICP. The
recommended dose is 3-5 mg/kg intravenously as a loading dose, followed by
infusion at 1-3 mg/kg/h intravenously.
Thiopental (Pentothal)

Thiopental is an ultrashort-acting central nervous system depressant that

decreases intracranial pressure. The recommended dose of thiopental for
intracranial hypertension is 5-10 mg/kg as a loading dose, followed by an
infusion of 3-5 mg/kg intravenously.
Benzodiazepine
Class Summary

As patients with fulminant hepatic failure drift deeper into coma, the ability to
protect their airway from aspiration decreases. Short-acting benzodiazepines
in low doses may be used before intubation.
Midazolam

View full drug information

Midazolam is a shorter-acting benzodiazepine sedative-hypnotic useful in
patients requiring acute and/or short-term sedation. Midazolam is used for
sedation for mechanically ventilated patients. It is given through continuous
intravenous infusion for sedation of intubated and mechanically ventilated
patients.
Anesthetic Agents
Class Summary

Anesthetic agents such as propofol have sedative and hypnotic effects that
are used for induction.
Propofol (Diprivan)

View full drug information

Propofol is a sedative-hypnotic that decreases the cerebral blood flow and
intracranial hypertension. Propofol (50 mcg/kg/min) may be initiated before
intubation and continued as an infusion.

A liver transplant is an operation that replaces a patient's diseased liver with a whole or partial
healthyliver from another person. This article explains the current indications for liver
transplantation, types of donor livers, the operation itself, and the immunosuppression that is
required aftertransplantation.

Who Needs a Liver transplant?

Liver transplantation surgically replaces a failing or diseased liver with one that is normal
and healthy. At this time, transplantation is the only cure for liver insufficiency or liver failure
because no device or machine reliably performs all of the functions of the liver. People who
require liver transplants typically have one of the following conditions.
Acute Liver Failure
Acute liver failure, also known as fulminant hepatic failure, occurs when a previously healthy
liver suffers massive injury resulting in clinical signs and symptoms of liver insufficiency.
Any number of things can lead to acute liver failure but the most common causes are
acetaminophen (Tylenol) overdose, viral infections (known or yet unknown virus),
ingestion of a toxin such as poisonous mushrooms, or an idiosyncratic drug reaction.
 The hallmark of this condition is the development of confusion (encephalopathy) within eight
weeks after the onset of yellowing of the skin (jaundice). Confusion occurs because toxins
typically metabolized by the liver accumulate. Unlike patients with chronic liver disease, who
can survive weeks to months to years while awaiting liver transplantation, patients with
acute liver failure may die within days if not transplanted. These patients are listed at
highest priority (Status I), placing them at the top of local, regional and national waiting lists
for a donor liver.
Chronic liver failure
The liver has a remarkable ability to repair itself in response to injury. Nevertheless,
repeated injury and repair, typically over many years and even decades, scars the liver
permanently. The end stage of scarring is termed cirrhosis and corresponds to the point
where the liver can no longer repair itself. Once a person has cirrhosis, he or she may begin
to show signs of inadequate liver function. This is termed "decompensated liver disease."
Although medications can decrease the symptoms caused by the liver failure, liver
transplantation represents the only permanent cure.
Back to top
Signs and Symptoms of Decompensated Liver Disease

Gastrointestinal bleeding: As the liver becomes increasingly scarred, the resistance to

portal blood flow increases leading to increased pressure in the portal venous system. This
portal hypertension necessitates alternative routes for blood to return to the heart. Small
veins throughout the abdomen, but outside of the liver, then become enlarged and thin-
walled due to the abnormally high amount of blood flowing through them under increased
pressure. These fragile veins, called varices, often line portions of the gastrointestinal tract,
especially the esophagus and the stomach, and are prone to rupture and bleeding. When
bleeding occurs into the intestinal tract, it can be life-threatening.
Fluid retention: One function of the liver is to synthesize many of the proteins circulating in
the bloodstream, including albumin. Albumin and other proteins in the blood stream retain
fluid in the vascular space by exerting what is known as an oncotic (or osmotic) pressure. In
liver failure, low albumin levels force fluid out of the bloodstream, which cannot be re-
absorbed. Fluid therefore accumulates in tissues and body cavities, most commonly, in the
abdominal cavity, which is termed "ascites." Fluid can also accumulate in the legs
(peripheral or pedal edema), or in the chest cavity (hydrothorax). Fluid retention is treated
first by strict limitation of dietary salt intake, second with medications (diuretics) that force
increased salt and water loss through the kidneys and, lastly, by intermittent drainage
through insertion of a needle into the abdominal or chest cavity.
Encephalopathy: Failure of the liver to clear ammonia and other toxins from the blood
allows these substances to accumulate. These toxins result in cognitive dysfunction that
ranges from disturbed sleep-wake cycle patterns to mild confusion to coma.
Jaundice: One of the main functions of the liver is to eliminate the degradation products of
hemoglobin, the molecule that carries oxygen in our blood. Bilirubin is one of those
degradation products processed and excreted by the liver. In liver failure, bilirubin is not
cleared from the body and bilirubin levels increase in the blood. The skin and all tissues of
the body will then assume a yellow color.
Back to top
 Causes of Chronic Liver Injury

Viral Hepatitis
Hepatitis B: Hepatitis B infection accounts for 5% of all liver transplants performed in the
United States but accounts for a larger proportion of liver transplants in other parts of the
world, especially Asia and Australia / New Zealand.
Hepatitis C: This is the most common indication for liver transplantation in the United
States, affecting nearly 50% of all liver transplant recipients.
Alcoholic Liver Disease
Liver failure due to alcohol abuse is the second most common indication for liver
transplantation in the United States. Most centers require at least a six-month period of
abstinence, often within a recognized substance abuse program such as Alcoholics
Anonymous, as a condition of listing for transplantation.
Metabolic Liver Disease
Non-alcoholic steatohepatitis (NASH): Deposition of fat within liver cells may result in
inflammation that injures and scars the liver. Risk factors for the development of fatty liver
and NASH include obesity and metabolic conditions such as diabetes and hyperlipidemia
(increased cholesterol). The percentage of patients being transplanted for this condition has
increased 35 fold from 2000 to 2005.
Autoimmune Liver Disease
Autoimmune hepatitis (destruction of the liver by the patient's own immune system)
Cholestatic Liver Diseases
Primary Biliary Cirrhosis (PBC) (destruction of small bile ducts within the liver)
Primary Sclerosing Cholangitis (PSC) (destruction of bile ducts inside and outside the liver).
Seventy percent of patients with PSC also suffer from ulcerative colitis, an autoimmune
disorder of the colon.
Neonatal sclerosing cholangitis (infection and scarring of the bile ducts in the liver of an
infant)
Biliary atresia (absence of bile ducts outside the liver)
Caroli's disease (abnormality of the bile ducts within the liver)
TPN-induced cholestasis. Patients who receive intravenous nutrition, termed total
parenteral nutrition (TPN) sometimes develop bile stasis (slowing or stopping of normal bile
flow) that can, over time, lead to liver injury and failure.
Genetic Liver Disease
Hemachromatosis: excess iron deposition in the liver
Wilson's disease: abnormal copper metabolism
Alpha-1 anti-trypsin deficiency: lack of a gene product that limits the activity of trypsin, an
enzyme that digests protein. Over time this leads to progressive destruction of the liver and
lung.
Glycogen storage disease (type I, III, IV): an inherited metabolic disorder
Tyrosinemia: a disorder of tyrosine metabolism
 Vascular Liver Disease
Budd-Chiari syndrome is thrombosis (clotting) of the hepatic veins which leads to poor
blood flow though the liver.
Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is a primary cancer of the liver, meaning that it originates
from abnormal liver cells. HCC occurs only rarely in a normal, non-cirrhotic liver. Its
incidence is, however, strikingly increased in the background of cirrhosis and, in particular,
by certain types of liver disease that lead to cirrhosis (hepatitis B and C, hemachromatosis,
and tyrosinemia). Although the cancer first starts within the liver, as it grows it can spread to
other organs, a process called metastasis. HCC most frequently spreads to the lungs or to
bones. The risk of spread outside of the liver increases with the size of the cancer.
Liver transplantation definitively cures a patient of HCC, provided that the tumor has not
spread beyond the liver. Because there are far more people in need of liver transplants than
there are available organs, specific guidelines, called the Milan Criteria, have been
established to define which patients with HCC are eligible for transplantation. These criteria
define limits of tumor number and size that ensure a very low likelihood of cancer spread
outside of the liver.
Who Are Not Candidates for a Liver Transplant

There are many people with cirrhosis and decompensated liver disease but not all are
appropriate candidates for liver transplantation. A patient must be able to survive the
operation and the potential post-operative complications, reliably take the medications that
prevent rejection and opportunistic infections, comply with frequent clinic visits and
laboratory tests, and not engage in activity that would injure the liver, such as drinking
alcohol. The conditions listed below are generally considered to be absolute contra-
indications to liver transplantation.
Severe, irreversible medical illness that limits short-term life expectancy
Severe pulmonary hypertension (mean pulmonary artery pressure greater than 50mmHg)
Cancer that has spread outside of the liver
Systemic or uncontrollable infection
Active substance abuse (drugs and/or alcohol)
Unacceptable risk for substance abuse (drugs and/or alcohol)
History of non-compliance, or inability to adhere to a strict medical regimen
Severe, uncontrolled psychiatric disease
Types of Organ Donors

Brain dead organ donors

Most livers used for transplantation are obtained from patients that are brain dead. Brain
death is usually due to a large stroke or massive trauma to the head from blunt injury (for
example, impact to the head from a motor vehicle or a motorcycle accident) or penetrating
injury (for example, a gun shot wound). The trauma has stopped all brain function although
other organs including the liver may continue to function normally.
There are strict definitions as to what constitutes brain death based on the complete
absence of any type of brain function. Because patients that meet criteria for brain death
are legally dead, they are appropriate organ and tissue donors. In the United States, the
family of someone who is brain dead must provide consent for organ and/or tissue donation.
In other countries, such as France, consent for organ donation is presumed and allowed,
unless the family objects.
Typically, transplant centers whose patients will be receiving organs from a particular donor
will dispatch a team of surgeons to procure the relevant organ. The organ procurement
procedure takes place in an operating room in the donor's hospital. Organs are removed
and preserved in a fashion to optimize their condition during the storage and transportation
time period. Each procured organ is then transported to the hospitals where the designated
recipient awaits.
Cardiac death organ donors
Sometimes a patient suffers a devastating brain injury and carries a dismal neurological
prognosis but fails to meet the strict criteria defining brain death in that there is still
detectible brain function. In these circumstances, the patient's family may decide to
withdraw life-sustaining medical support with the intention of allowing the patient to die. In
this scenario, death is not defined by brain death but rather cardiac death. Organ donation
can occur after cardiac death but, again, only if the family gives consent.
Only AFTER the family's decision to withdraw support may the patient be considered for
organ donation after death. Under these circumstances, support is withdrawn, as desired by
the family and managed by the patient's physician, and the patient is allowed to expire. The
patient's physician, someone who is not involved in any aspect of organ transplantation, is
present to determine when the heart stops beating and circulation has stopped such that
the patient no longer has any signs of life. He or she then declares the patient's death.
An urgent operation is then performed to preserve and remove organs for transplantation.
This mode of cardiac death, in contrast to brain death, results in increased injury to the
organs during two time periods. The first period is that between withdrawal of life support
and death. As the donor's breathing and circulation deteriorates, the organs may no longer
be receiving sufficient oxygen. The second time period constitutes the minutes immediately
after death and until the organs are flushed with preservation solution and cooled. As a
result, livers procured from cardiac death donors are associated with an increased risk of
primary non function or poor early organ function, hepatic artery thrombosis, and biliary
complications (see Complications section).
Living Donors
Although each person has only one liver and would die without it, it is possible to donate a
portion of the liver for transplantation into another individual. The segmental anatomy (see
figure below) allows surgeons to create grafts of varying size, depending upon the
recipient's requirement for liver tissue. The partial livers in both the donor and the recipient
will grow to provide normal liver function for both individuals.
Historically, this procedure was developed to enable transplantation of children as it was
difficult to find suitable livers from deceased donors for this group. To transplant a child,
typically a graft comprised of segments 2 and 3, together known as the left lateral segment
representing 20-25% of the whole liver volume, is used.
 Transplantation of an older child or perhaps a petite adult, however, may require segments
2, 3, and 4, together known as the left lobe and representing approximately 40% of the
whole liver volume. During the past decade, however, this technique has been further
extended to enable transplantation of adults using the right lobe, segments 5, 6, 7, and 8,
which account for approximately 60% of the total liver volume. An adult-to-adult living donor
liver transplant is highly complex and technically challenging procedure that carries a
significant risk for both the donor and the recipient.
The Liver Transplant Operation
A liver transplant involves the removal of and preparation of the donor liver, removal of the
diseased liver, and implantation of the new organ. The liver has several key connections
that must be re-established for the new organ to receive blood flow and to drain bile from
the liver. The structures that must be reconnected are the inferior vena cava, the portal vein,
the hepatic artery, and the bile duct. The exact method of connecting these structures
varies depending on specific donor and anatomy or recipient anatomic issues and, in some
cases, the recipient disease.
For someone undergoing liver transplantation, the sequence of events in the operating
room is as follows:
1. Incision
2. Evaluation of the abdomen for abnormalities that would preclude liver transplantation (for
example: undiagnosed infection or malignancy)
3. Mobilization of the native liver (dissection of the liver attachments to the abdominal cavity)
4. Isolation of important structures (the inferior vena cava above, behind, and below the liver;
the portal vein; the common bile duct; the hepatic artery)
5. Transection of the above mentioned structures and removal of the native, diseased liver.
(Figure 7)
6. Sewing in the new liver: First, venous blood flow is re-established by connecting the donor's
and the recipient's inferior vena cava and portal veins. Next, arterial flow is re-established
by sewing the donor's and recipient's hepatic arteries. Finally, biliary drainage is achieved
by sewing the donor's and recipient's common bile ducts.
7. Ensuring adequate control of bleeding
8. Closure of the incision
Surgical Complications
As with any surgical procedure, complications related to the operation may occur, in
addition to the many possible complications that may happen to any patient who is
hospitalized. Some of the problems specific to liver transplantation that may be encountered
include:
Primary non-function or poor function of the newly transplanted liver occurs in
approximately 1-5% of new transplants. If the function of the liver does not improve
sufficiently or quickly enough, the patient may urgently require a second transplant to
survive.
Hepatic artery thrombosis, or clotting of the hepatic artery (the blood vessel that brings
oxygenated blood from the heart to the liver) occurs in 2-5% of all deceased donor
transplants. The risk is doubled in patients who receive a living donor transplant. The liver
cells themselves typically do not suffer from losing blood flow from the hepatic artery
because they are primarily nourished by blood by the portal blood flow. In contrast, the bile
 ducts depend strongly on the hepatic artery for nutrition and loss of that blood flow may lead
to bile duct scarring and infection. If this occurs, then another transplant may be necessary.
Portal vein thrombosis or clotting of the large vein that brings blood from the abdominal
organs (the intestines, the pancreas, and the spleen - the organs that belong to the portal
circulation) to the liver occurs infrequently. This complication may or may not require a
second liver transplant.
Biliary complications: In general, there are two types of biliary problems: leak or stricture.
Biliary complications affect approximately 15% of all deceased donor transplants and up to
40% of all living donor transplants.
o Biliary leak means that bile is leaking out of the bile duct and into the abdominal cavity.
Most frequently, this occurs where the donor and recipient bile ducts were sewn together.
This is often treated by placing a stent, or plastic tube, across the connection through the
stomach and small intestine and then allowing the connection to heal. In the case of living
donor or split liver transplants, bile can also leak from the cut edge of the liver. Typically, a
drain is placed and left during the transplant operation along the cut edge to remove any
bile that may leak. As long as the bile does not collect in the abdomen, the patient does not
become ill. Leaks will often heal with time, but may require additional treatment procedures.
o Biliary stricture means narrowing of the bile duct, resulting in relative or complete blockage
of the bile flow and possible infection. Most frequently, the narrowing occurs at a single site,
again where the donor and recipient ducts are sewn together. This narrowing can often be
treated by dilating the narrowed area with a balloon and/or inserting a stent across the
stricture. If these methods are unsuccessful, surgery is often done to create a new
connection between the liver's bile duct and a segment of intestine. Rarely, biliary strictures
occur at multiple or innumerable sites throughout the biliary tree. This occurs most
frequently because the biliary tree was poorly preserved during the period when the liver
was not in either the donor or recipient circulation. Livers procured from cardiac death
donors are at higher risk than those from brain dead donors. Alternatively, diffuse biliary
strictures may occur if the biliary tree has inadequate blood supply because of an
abnormality with the hepatic artery.
Bleeding is a risk of any surgical procedure but a particular risk after liver transplantation
because of the extensive nature of the surgery and because clotting requires factors made
by the liver. Most transplant patients bleed a minor amount and may get additional
transfusions after the operation. If bleeding is substantial or brisk, return to the operating
room for control of bleeding is often necessary. In general, approximately 10% of transplant
recipients will require a second operation for bleeding.
Infection - Infections can occur during the healing of the wound created by any operation.
Liver transplant recipients are also at risk for infections deep within the abdomen,
particularly if there is a collection of blood or bile (from a bile leak). The immunosuppressive
medications along with the history of liver failure increase the liver transplant recipient's risk
for developing an infection after transplantation.
Immunosuppression
The human body has developed a very sophisticated series of defenses against bacteria,
viruses, and tumors. The machinery of the immune system has evolved over millions of
years to identify and attack anything that is foreign or not "self." Unfortunately, transplanted
organs fall into the category of foreign, not self. A number of drugs are given to transplant
recipients to dampen the responses of their immune system in an attempt to keep the organ
safe and free of immunologic attack. If the immune system is not sufficiently weakened,
 then rejection - the process by which the immune system identifies, attacks, and injures the
transplanted organ - ensues.
Commonly used drugs to prevent rejection by suppressing the immune system are listed
below. They work through different mechanisms to weaken the immune system's responses
to stimuli and are associated with different side effects. As a result, these medications are
frequently used in various combinations which increase the overall immunosuppressive
effect while minimizing side effects.
Corticosteroids (methylprednisolone is given intravenously; prednisone is given orally):
Corticosteroids are a class of anti-inflammatory agents that inhibit production of cytokines,
the signaling molecules produced by cells of the immune system to orchestrate and
intensify the immune response. Corticosteroids therefore prevent activation of lymphocytes,
the main soldiers of the immune response against transplanted organs. This is thought to
prevent T-cell (a subset of lymphocytes) activation in a non-specific manner. Side effects of
corticosteroids are broad and include hyperglycemia, hypertension, decreased bone
density, and impaired wound healing,
Calcineurin inhibitors (cyclosporine, tacrolimus): This class of drugs blocks the function of
calcineurin, a molecule critical to a very important lymphocyte signaling pathway that
triggers the production of multiple cytokines. These drugs, first developed approximately 20
years ago, revolutionized organ transplantation. They substantially reduced the incidence of
rejection, improved the longevity of transplanted organs and thereby ushered in the
contemporary era of transplantation and immunosuppression. Unfortunately, these drugs
come with a significant side effect profile. The most serious toxicity, particularly with long-
term use, is kidney injury. Calcineurin inhibitors also raise blood pressure, glucose levels,
and cholesterol - and cause tremors and headaches.
Mycophenolate mofetil (Cellcept, Myfortic): This drug is converted in the body to
mycophenolic acid, which inhibits the ability of lymphocytes to replicate DNA, the genetic
material essential to every cell. If lymphocytes cannot synthesize DNA, then they are unable
to divide to generate additional cells. Mycophenolate mofetil, therefore, dampens the
immune response by preventing proliferation of lymphocytes. The primary side effects of
mycophenolate mofetil affect the intestinal system resulting in stomach upset and/or
diarrhea. It can also depress bone marrow function and thereby, reduce blood levels of
white cells (infection fighting cells), red cells (oxygen carrying cells), and platelets (clotting
agents).
mTOR inhibitors (sirolimus; everolimus): mTOR stands for mammalian Target Of
Rapamycin. mTOR belongs to a family of enzymes known as kinases and is involved in
checkpoint regulation of the cell cycle, DNA repair, and cell death. Inhibition of mTOR stops
T cells from progressing through the various phases of the cell cycle, leading to cell cycle
arrest. Thus, lymphocytes are not able to divide to amplify the immune response. Side
effects of mTOR inhibitors include bone marrow depression, poor wound healing, and
increased cholesterol levels.
Antibodies that target the IL-2 receptor, a signaling molecule that amplifies the immune
response (basiliximab, daclizumab): T cells, the agents of acute rejection, express
increasing amounts of IL2-receptors when they are stimulated. The IL-2 receptor allows
ongoing amplification of an immune response. Blockage of this receptor therefore dampens
the immune response. These antibodies are most frequently used for a short time period
beginning at the time of transplant to provide additional immunosuppression during this
period of highest rejection risk. Immediate side effects include fever, rash, cytokine release
 syndrome, and anaphylaxis. They do appear to increase the risk of infections hen combined
with other immunosuppressive medications.
Antibodies that remove T cells from the circulation (Thymoglobulin, OKT-3): These
agents are molecules that target different cells of the immune system, bind them, inactivate,
and remove them. They can be used at the time of liver transplantation. but more often are
used to treat severe rejection or rejection that does not respond to lesser treatment
strategies. Immediate side effects of these medications range from fever and rash to
cytokine release syndrome resulting in flash pulmonary edema and hypotension. These
drugs may also result in increased incidence of PTLD and skin cancers (see below)
investigational drugs - As our understanding of the immune system improves, researchers
have identified new cells, molecules, and pathways that play a role in the body's response
to transplanted organs. Each discovery presents new opportunities in the form of new
targets for drug development. Some of these medicines are currently being tested in clinical
trials to determine if they are safe and effective for use in transplantation. Future
generations of drugs will hopefully be more specific in preventing rejection without
interfering significantly with the other functions of the immune system or causing non-
immunologic side effects.
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Rejection

Rejection is a term that is applied to organ dysfunction caused by the recipient's immune
system reaction to the transplanted organ. Injury to the liver is typically mediated by immune
cells, T cells or T lymphocytes. Rejection typically causes no symptoms; patients do not feel
any differently or notice anything. The first sign is usually abnormally elevated liver
laboratory test results. When rejection is suspected, a liver biopsy is performed. Liver
biopsies are easily done as a bedside procedure using a special needle that is introduced
through the skin. The tissue is then analyzed and inspected under the microscope to
determine the pattern of liver injury and also to look for the presence of immune cells.
Acute cellular rejection occurs in 25-50% of all liver transplant recipients within the first year
after transplantation with the highest risk period within the first four to six weeks of
transplantation. Once the diagnosis is made, treatment is fairly straightforward and
generally very effective. The first line of treatment is high dose corticosteroids (see
Immunosuppression section). The patient's maintenance immunosuppression regimen is
also escalated to prevent subsequent rejection. A small proportion of acute rejection
episodes, approximately 10-20%, does not respond to corticosteroid treatment and are
termed "steroid refractory," requiring additional treatment.
The second line of rejection treatment is strong antibody preparations (see
Immunosuppression Section). In liver transplantation, unlike other organs, acute cellular
rejection does not generally affect overall chances for graft survival. This is believed to be
because the liver has the unique ability to regenerate when injured thereby restoring full
liver function.
Chronic rejection occurs in 5% or less of all transplant recipients. The strongest risk factor
for the development of chronic rejection is repeated episodes of acute rejection and/or
refractory acute rejection. Liver biopsy shows loss of bile ducts and obliteration of small
arteries. Chronic rejection, historically, has been difficult to reverse, often necessitating
repeat liver transplantation. Today, with our large selection of immunosuppressive drugs,
chronic rejection is more often reversible.
Recurrent Disease
Some of the processes that led to the failure of the patient's own liver can damage the new
liver and eventually destroy it. Perhaps the best example is hepatitis B infection. In the early
1990's, patients who received liver transplants for hepatitis B infection had less than 50%
five year survival. The vast majority of these patients suffered from very aggressive
reinfection of the new liver by hepatitis B virus. During the 1990's, however, several drugs
and strategies to prevent re-infection and damage of the new liver were developed and
instituted widely by transplant centers. These approaches have been highly successful such
that recurrent disease is no longer a problem. Hepatitis B, once considered a contra-
indication to transplantation, is now associated with excellent outcomes, superior to many of
the other indications for liver transplantation.
Currently, our primary problem with recurrent disease is focused on hepatitis C. Any patient
that enters transplantation with hepatitis C virus circulating in their blood will have ongoing
hepatitis C after transplantation. However, those who have completely cleared their virus
and do not have measurable hepatitis C in the blood will not have hepatitis C after
transplantation.
Unlike hepatitis B where recurrent disease leading to liver failure occurs very rapidly,
recurrent hepatitis C typically causes a more gradual attrition of liver function. Only a small
percentage of hepatitis C recipients, approximately 5%, return to cirrhosis and end stage
liver disease within two years of transplantation.
Most have more gradually progressive disease such that as many as half will have cirrhosis
at approximately 10 years after transplant. Interferon preparations in combination with
ribavirin, widely used in pre-transplant hepatitis C patients, can also be prescribed after
transplantation. Chances for permanent cure are somewhat lower than treatment before
transplantation. Moreover, the treatment is associated with a significant complement of side
effects. Recurrent disease is responsible for the fact that hepatitis C liver transplant
recipients have worse medium and long-term post-transplant outcomes compared to liver
transplant recipients without hepatitis C (Figure 8).
Several other diseases may also recur after transplantation, but typically the disease is mild
and only slowly progressive. Primary sclerosing cholangitis (PSC) and primary biliary
cirrhosis (PBC) both recur approximately 10-20% of the time and, only very rarely, result in
recurrent cirrhosis and end stage liver disease. Perhaps the biggest unknown in today's age
is fatty liver disease after transplantation as it is clearly a problem of increasing frequency.
Fatty liver disease can occur in those transplanted for NASH but also in patients who were
transplanted for other indications and develop risk factors for fatty liver disease. The
frequency, trajectory, and prognosis of recurrence of fatty liver disease after transplant and
its course are active areas of research.
Opportunistic Infections and Cancer
As previously stated, the immune system's primary role is to identify and attack anything
that is foreign or non-self. The main targets were not intended to be transplanted organs,
but rather bacteria, viruses, fungi, and other microorganisms that cause infection. Taking
immunosuppression weakens a transplant recipient's defenses against infection
As a result, transplant recipients are at increased risk to develop not only standard
infections that may affect all people but also "opportunistic" infections, infections that only
occur in people with compromised immune systems. The changes in the immune system
predispose transplant recipients to different infections based on the time relative to their
transplant operation.
They can be divided into three periods: month one, months one to six, and beyond six
months. During the first month, infections with bacteria and fungi are most common. Viral
infections such as cytomegalovirus and other unusual infections such as tuberculosis and
pneumocystis carinii are seen within the first six months.
In addition to fighting infection, the immune system also fights cancer. It is believed that a
healthy immune system detects and eliminates abnormal, cancerous cells before they
multiply and grow into a tumor. It is well-recognized that transplant recipients are at
increased risk for developing several specific types of cancers.
Post-Transplant Lymphoprolipherative Disorder (PTLD)
Post-Transplant Lymphoprolipherative Disorder (PTLD) is an unusual type of cancer that
arises exclusively in transplant recipients, as suggested by its name. It is almost always
associated with Epstein-Barr virus (EBV), the same virus that causes infectious
mononucleosis or "the kissing disease."
The majority of adults have been exposed to EBV, most commonly in their childhood or
teenage years. For these patients, EBV-associated PTLD can develop after transplantation
because immunosuppression allows the virus to reactivate. In contrast, many children come
to liver transplantation without ever having been exposed to EBV. If patients are exposed to
EBV after transplantation and therefore under the influence of immunosuppression, they
may be unable to control the infection.
PTLD arises in either scenario when EBV-infected B cells (a subset of lymphocytes) grow
and divide in an uncontrolled fashion. As it is fundamentally a result of a compromised
immune system, the first line of treatment is simply stopping or substantially reducing
immunosuppression. While this approach frequently works, it also risks graft rejection which
would then necessitate increased immunosuppression. Recently, a drug that specifically
eliminates B cells, the cells infected by EBV, has become available.
Today, a common approach is therefore to give this drug, rituximab, in conjunction with less
drastic cuts of the immunosuppression drugs. If this approach does not control PTLD, then
more conventional chemotherapy drug regimens typically given to treat lymphomas that
develop in non-immunosuppressed patients, are used. The majority of PTLD cases can be
successfully treated with preservation of the transplanted organ.
Non-Melanoma Skin Cancer (NMSC)
Skin cancers are the most common malignancy in the post-transplant population. The rate
of skin cancer in patients who have undergone organ transplantation is 27% at 10 years,
reflecting a 25-fold increase in risk relative to the normal population. In light of this
substantial risk, it is strongly recommended that all transplant recipients minimize sun
exposure.
Moreover, all transplant recipients should be regularly examined to ensure early diagnosis
and expeditious treatment of any skin cancer. There is some evidence to suggest that
sirolimus, an immunosuppressant in the class of mTOR inhibitors (see Immunosuppression
section) does not increase risk of skin cancers.
Therefore, transplant recipients who develop multiple skin cancers can be considered for a
switch to a sirolimus-based, calcineurin-inhibitor free immunosuppression regimen.
Currently, there is no data to indicate that liver transplant recipients are at increased risk to
develop other common cancers such as breast, colon, prostate, or other cancers.
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Outcomes
Overall, outcomes for liver transplantation are very good, but vary significantly depending
on the indication for liver transplant as well as factors associated with the donor. Currently,
the overall patient survival one year after liver transplant is 88%. Patient survival five years
after liver transplant is 73%.