Liver
Transplantation
Authored by Cosme
Manzarbeitia, MD, Chairman of Transplant Division,
Fellowship Director, Assistant Professor, Department of Surgery, Albert
Einstein Medical Center, Thomas Jefferson University
Cosme Manzarbeitia, MD, is a member of the
following medical societies: American
Association for the Study of Liver Diseases, American
College of Surgeons, American Medical
Association, American Society of Transplant
Surgeons, Association for Academic Surgery,
and Pan American Medical Association
Edited by Tushar Patel, MD,
Associate Professor, Department of Internal Medicine, Texas A&M College of
Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy
Editor, eMedicine; You Min Wu, MD, Chairman, Associate
Professor of Surgery, Transplant Division of Surgery, UIHC; Michael E
Zevitz, MD, Consulting Faculty, Clinical Assistant Professor,
Department of Medicine, Finch University of Health Science, Chicago Medical
School; and Julian Katz, MD, Professor, Department of Internal
Medicine, Division of Gastroenterology, MCP Hahnemann University
eMedicine Journal, June 12 2002, Volume 3, Number 6
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INTRODUCTION |
Section
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History of the Procedure: Liver transplantation (LT) started before the 1960s
with the pivotal baseline work of Thomas Starzl in Chicago and Boston, where
the initial LT techniques were researched in dogs. Starzl attempted the first
human LT in 1963 in Denver, but a successful LT was not achieved until 1967.
In 1970, with an immunosuppressive regimen
largely based on steroids and azathioprine, survival rates were
dismal—approximately 15% at 1-year follow-up. LT did not become a clinical
reality until the early 1980s, after the discovery of cyclosporine and
improvements in rejection rates.
In 1983, the National Institutes of Health
(NIH) established, by consensus, that LT was to be considered out of the
experimental realm and was to be clinically accepted as definitive therapy for
end-stage liver disease (ESLD). Additional improvements in immunosuppression
that were instrumental in advancing the science included the discovery of
monoclonal antibodies (ie, muromonab-CD3 [OKT3]) in 1986.
The combination of improvements in rejection
rates and in surgical technique led to an enormous expansion of the field
during the 1980s, with expansion from 3 centers in 1982 to more than 120
centers today. In 1999, 4500 procedures were performed, up from approximately
100 in 1982.
Of great importance in this expansion was
the development of the University of Wisconsin (UW) solution in 1988, which
increased preservation time and allowed for a smoother surgical procedure,
avoiding a rushed tour de force in the operating room. Finally, the coming of
age of newer immunosuppressants, such as tacrolimus and interleukin (IL)–2
receptor blockers, has paved the way for further growth in this field. All
these advances have produced excellent results, with current 1-year patient
survival rates of 85-90% and 5-year survival rates of 65%. Future advances may
include the development of xenotransplantation, which was pioneered by Starzl
in 1992, and the development of cloning techniques and their impact on organ
availability.
Problem:
End-stage liver disease magnitude and
organ shortage
The following list shows potential International
Classification of Diseases, Ninth Revision, Clinical Modification diagnoses that could indicate candidacy for LT. The
number of patients hospitalized with these primary and secondary diagnoses is
enormous. However, only a small percentage of these patients ultimately are candidates
for transplant because other criteria are also used to determine candidacy.
Diagnoses indicating potential candidacy for LT include the following:
The
major constraint to meeting the demand for transplants is the availability of
donated (cadaver) organs. Several steps have been taken, nationally and
locally, to alleviate the organ shortage. National required request laws
mandate that families of every medically suitable potential donor be offered
the option to donate organs and tissues. In addition, laws such as Act 102,
enacted in Pennsylvania, require all deaths to be reported to organ procurement
organizations. This is resulting in increased organ donations and soon will be
adopted nationwide. Rising public awareness about organ transplantation should
continue to reduce the organ shortage. Finally, aggressive usage of extended
donors and reduced-size, split, and living-related LT continue to expand the
organ donor pool, although these efforts still fail to meet the need.
In
terms of procurement and distribution, major improvements are being made
nationally to optimize distribution and to ensure good matches. Criteria for
inclusion on the waiting list are being standardized with the recent
development of listing criteria for all degrees of sickness. The United Network for Organ Sharing
(UNOS) maintains a computerized registry of all patients waiting for organ
transplants. All organs procured within a region are shared first within the
region; if an appropriate recipient cannot be found within the region, the
organ is directed by UNOS to the recipient with the greatest need in another
region. Organ recovery coordinators are on call 24 h/d and arrange for
serologic testing, removal, preservation, and distribution; additionally, they
educate the public regarding organ donation.
Frequency: According to
the latest US Centers for Disease Control and Prevention sources, cirrhosis
remains the 12th leading cause of death for adults in the United States, with
26,225 deaths reported in 1999 and a death rate of nearly 10 cases per 100,000
persons. This accounts for 1.1% of total deaths. Unfortunately, this number may
grossly underestimate the real impact of ESLD because it does not include acute
liver failure or other etiologies that may lead to the need for LT (see Problem).
Etiology: See Problem.
Clinical: Patients
present with signs and symptoms of ESLD, which is discussed in more detail in
the next section.
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INDICATIONS |
Section
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Currently,
any patient who has chronic or acute liver disease that leads to inability to
sustain a normal quality of life or that results in life-threatening
complications should be considered a candidate for LT.
The
common etiologies and indications for LT in adults can be seen in the red
portion of the pie chart shown in Image 2. The red part
represents the hepatocellular group of diseases, ie, those that primarily
affect hepatocyte function and thus lead to faster clinical deterioration and
life-threatening complications. The green part represents the group of
cholestatic diseases, in which the excretory function of the liver is primarily
compromised. In these latter cases, synthetic function is preserved for
prolonged periods. Additional indications, such as transplantation for
metabolic or inherited diseases (eg, familial hypercholesterolemia,
amyloidosis), are considered on a case-by-case basis.
Clinical
presentation
As
a general rule, the following complications of ESLD warrant LT:
Ascites
is associated with a poor prognosis in the mid- to short-term, especially when
it becomes unmanageable with diuretic therapy and requires repeated
paracentesis, transjugular intrahepatic portosystemic shunt (TIPS), or
insertion of a peritoneovenous shunt. Encephalopathy may develop rather
insidiously in most patients and may be difficult to elicit properly upon
examination.
Clinically,
encephalopathy is divided into 4 stages. Of these, the most obviously
life-threatening are stages 3 and 4 (somnolence and coma). Synthetic
dysfunction is perhaps the earliest manifestation of ESLD, often manifested by
decreased albumin levels alone or in combination with prolongation of the
prothrombin time and jaundice. In its most severe form, it can lead to severe
malnutrition. Portal hypertension can manifest either silently (ie, decreased
platelets and/or WBC count) or overtly, with variceal bleeding. Other
manifestations include the development of hepatocellular carcinoma (HCC), which
is common in patients with hepatitis B and C, or severe intractable pruritus.
Finally, a controversial indication for transplantation in the face of the
organ shortage is in those patients with severe disabling fatigue.
In
general terms, diseases that cause ESLD do so by affecting either the function
of the hepatocyte (eg, hepatocellular diseases) or the excretory function of
the biliary system (eg, cholestatic diseases). Their prognoses are different,
and their management must be individualized. As a general rule, hepatocellular
diseases cause a more profound derangement of hepatic synthetic function early
in the disease process. Conversely, cholestatic diseases preserve
hepatocellular function until more advanced stages of the disease process.
Indications
for LT can also be broadly categorized into severity of disease indications
(ie, the patient’s life is immediately threatened without transplant) and
quality of life indications (ie, the patient is permanently disabled, but his
or her life is not in immediate danger). While the former obviously mandates
urgent transplantation, great expertise is needed to address the latter.
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RELEVANT ANATOMY AND CONTRAINDICATIONS |
Section
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Contraindications: Currently
accepted absolute contraindications to LT by most programs include HIV
positivity, SBP or other active infection, severely advanced cardiopulmonary
disease, extrahepatic malignancy that does not meet cure criteria, active
alcohol or substance abuse, and inability to comply with immunosuppression
protocols because of psychosocial situations.
SBP,
sometimes protean in its manifestations (eg, malaise, abdominal discomfort),
can be devastating and can cause decompensation in an otherwise stable patient
with cirrhosis. The patient may present with encephalopathy, hypotension,
fever, leukocytosis, and an elevated WBC in the peritoneal fluid. The absolute
criteria for diagnosis of SBP are the presence of more than 200-250
polymorphonuclear leukocytes, the identification of bacteria in the fluid by
light microscopy, and/or subsequent positive bacterial culture results in the
appropriate clinical setting. The development of SBP in a patient with
cirrhosis is an indicator of a very poor prognosis.
If
pneumonia or other active infections are present, mortality rates after
transplantation are greatly increased. This emphasizes the need to have a high
index of suspicion for infection. If any doubt exists about the presence of
infection, abdominal paracentesis, chest radiograph, urine analysis, and/or pan
cultures may be indicated. In patients with a prior history of drug use,
examine arms and legs for evidence of new track marks. Patients with a history
of alcohol abuse should have an alcohol level test performed as part of the
preoperative workup through contract arrangements and upon admission for
transplant.
Secondary
liver malignancies are not indications for hepatic replacement because of
universal recurrence of the tumors under immunosuppression. Exceptions to this
rule include metastatic neuroendocrine malignancies such as carcinoid tumors.
An elicited history of previous malignancy in a transplant candidate should
prompt an extensive workup for metastatic disease, staging before and after
surgery or therapy, and consultation with an oncologist.
Relative
contraindications to LT are multiple, and each should be weighed when
considering the prospective recipient’s severity of illness. While no single
relative contraindication alone may prevent a given patient from receiving an
LT, these are red flags that, if multiple or if presenting in an otherwise
high-risk recipient, may proscribe LT. Most commonly, these red flags include
patients with chronic renal failure (in which combined liver-kidney transplant
may be required), advanced cachexia, large HCCs (>5 cm diameter),
lamivudine-resistant hepatitis B virus (HBV) cirrhosis, portal and mesenteric
vein thrombosis, history of prior cancer, active infections, and multisystem
organ failure states. Note that many of these contraindications are
program-specific and depend greatly on the volume and experience of each
individual program.
Age
is no longer considered an absolute contraindication. Physiological age, rather
than chronological age, dictates the individual’s suitability for candidacy.
However, careful judgment should be used in allocating donors to these
patients, given the organ shortage. With the development of refinements in
surgical techniques, selected patients with portal and/or mesenteric venous
thrombosis have undergone successful transplantation. The availability of
venous jump grafts to restore portal flow permits transplantation in these
generally advanced cases.
If
studied carefully, all patients with cirrhosis are found to have a certain
degree of intrapulmonary shunting. In certain patients, this can be disabling
and can lead to hypoxia at rest (hepatopulmonary syndrome). The successful
reversal of these shunts after LT makes this an indication rather than a
contraindication. However, selection of these candidates must be adequate and
precise, with sophisticated and directed pulmonary function testing.
The
presence of established anatomical portopulmonary hypertension is probably an
absolute contraindication for LT, but the situation varies for nonfixed
pulmonary hypertension. LT is contraindicated in patients with severe degrees
of pulmonary hypertension (mean peak airway pressure of >35),
especially if coupled with increased pulmonary vascular resistance. However,
for those patients with mild-to-moderate pulmonary hypertension and reasonable
right heart function, treatment with vasodilators and/or prostaglandin allows
safe LT.
The
existence of prior abdominal surgery and portosystemic shunts does not preclude
successful transplantation, although these factors make it a technical tour de
force and dramatically increase blood loss because of existing portal
hypertension. Recently, some groups have reported good results with selective
shunting or TIPS.
The
great likelihood of recurrent and aggressive disease precludes transplantation
in patients with actively replicating HBV infection. Recently, some groups have
tried xenotransplantation in this population, but better results must be
obtained prior to using this resource more widely. A subgroup of these patients
with a small viral load and/or no active replication but with ESLD may be
considered for candidacy. In these patients, the institution of lamivudine
therapy may render the viral replicative activity undetectable, hence allowing
safe transplantation. The emergence of lamivudine-resistant strains may limit
the long-term use of these therapies.
Very
weak and malnourished patients are poor candidates for LT because of an
extremely poor reserve. If their nutritional status can be improved by means of
total enteral nutrition or total parenteral nutrition, their odds improve. This
is difficult to accomplish in the face of a failing liver.
Frequently,
cirrhosis is associated with development of HCCs. In these patients,
transplantation must be performed under strict guidelines and protocols to
minimize and/or prevent recurrence. As a rule, HCCs smaller than 5 cm, ie,
incidental hepatomas, are associated with less chance of recurrence and
survival rates equal to those of patients undergoing transplant because of
nonmalignant conditions. Protocols using chemoembolization have shown promising
early results for larger tumors.
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WORKUP |
Section
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Lab Studies:
Table 1.
Child-Turcotte-Pugh Scoring System for Assessment of Severity of Disease (with
respect to listing)
|
Parameter |
1 |
2 |
3 |
|
Encephalopathy |
None |
Grade 1-2 |
Grade 3-4 |
|
Ascites |
None |
Medically controlled |
Uncontrolled |
|
Albumin |
>3.5 |
2.8-3.5 |
<2.8 |
|
Bilirubin |
<2 |
2-3 |
>3 |
|
International Normalized Ratio (INR) |
<1.7 |
1.7-2.3 |
>2.3 |
Imaging Studies:
Other Tests:
Diagnostic Procedures:
Histologic Findings: Discussion of all the histopathological findings of
the various diseases that lead to ESLD is beyond the scope of this article. In
general, they can be classified into 3 broad categories: cirrhosis and
fibroticlike states, acute hepatic necrosis, and malignancies.
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TREATMENT |
Section
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Medical therapy: Medical
management before transplantation is aimed at preventing and treating the
complications associated with ESLD. Thus, many patients take various
medications to control the consequences of liver failure and portal
hypertension. These complications include (but are not limited to) ascites,
SBP, HRS, encephalopathy, esophageal varices, and intense pruritus.
Ascites
presents a difficult treatment problem. As a first step, paracentesis should be
performed to confirm portal hypertension as the etiology. Initially, salt
restriction may be tried, although this is effective in fewer than 20% of
patients. Fluid restriction should be avoided unless patients have gross
anasarca and/or their serum sodium level is less than 120 mEq/L. Diuretics
remain the mainstay of medical management. The most commonly used are
spironolactone, furosemide, and hydrochlorothiazide. Diuretic therapy should be
adjusted or discontinued if serum sodium levels fall below 120 mEq/L or if the
creatinine level rises to more than 2 mg/dL. Other diuretics that may be used
include amiloride, triamterene, or ethacrynic acid.
If
the ascites become refractory because of an inability to diurese patients
and/or development of electrolyte abnormalities and renal failure, repeat
paracentesis may be performed every 2-3 weeks. TIPS may result in a significant
decrease in ascites; however, risk of ischemic hepatic failure and intractable
encephalopathy is higher, which limits its use in patients with cirrhosis
classified as Child class C because of an increased morbidity and mortality
rate. Other options include using peritoneovenous (LeVeen and Denver) shunts,
although these are prone to occlusion, disseminated intravascular coagulation,
and increased perioperative mortality.
SBP
presents in patients with cirrhosis who have ascites as an unexplained clinical
deterioration, with or without the classic signs of peritonitis, and is
associated with a high mortality rate. Paracentesis findings that are
diagnostic include an absolute neutrophil count in the ascitic fluid of greater
than 250/mm3 and/or positive results from peritoneal fluid cultures.
Antibiotic therapy, directed mostly toward gram-negative enteric organisms,
should be started early. Secondary peritonitis, such as that due to a
perforated viscus, should always be excluded prior to instituting therapy. Prophylactic
antibiotics are frequently employed in patients with cirrhosis who have severe
ascites, previous SBP episodes, or recent variceal bleeding.
HRS
is present in approximately 10% of hospitalized patients with cirrhosis. HRS is
defined as a deterioration of the renal function in a patient with advanced
cirrhosis, with a creatinine level of more than 1.5 mg/dL, a urine volume of
less than 500 mL/d, and a low urinary sodium level (<10 mEq/L). The
condition is common in patients with ascites.
Before
a diagnosis of HRS can be established, other specific causes of renal
dysfunction must be excluded. The diagnostic workup frequently includes
insertion of a Foley catheter, renal ultrasound, and fluid challenge.
Frequently unsuccessful, the medical treatment of HRS has been disappointing.
Preliminary data suggest that TIPS may be useful, but its precise role remains
to be defined for this indication.
As
many as 70% of decompensated patients with cirrhosis have some degree of
encephalopathy, ranging from subtle neurological dysfunction to frank coma.
Seek and correct potential precipitating causes such as GI bleeding,
constipation, infection, medications with CNS effects, or electrolyte
abnormalities. If ascites is present, exclude SBP via paracentesis. A search
for other reasons, such as PVT or occult HCC, should be made.
TIPS
can also lead to severe encephalopathy. In addition to this correction of
precipitating causes, treatment is by means of lactulose orally, via
nasogastric (NG) tube, or through enemas, with doses titrated to achieve both
2-4 soft bowel movements daily and improvement in mental status. Neomycin may
be added, although its potential for nephrotoxicity and ototoxicity can limit
its usefulness. The usefulness of flumazenil, a benzodiazepine antagonist,
remains to be defined.
Esophageal
variceal bleeding (EVB) is a major cause of morbidity and mortality in patients
with ESLD. The mortality rate during the initial EVB incident is as high as
50%, with an additional risk of recurrent bleeding of 70% within the first
year. Initial treatment includes aggressive fluid resuscitation, administration
of blood products to replace blood loss and/or to correct coagulopathy, and
emergent endoscopic evaluation with both diagnostic and therapeutic aims. Intubation
may become necessary because of encephalopathy and for airway protection.
Patients are usually placed on intravenous octreotide to reduce the portal
hypertension, H2 blockers to prevent stress ulceration, and antibiotics for SBP
prophylaxis.
EVB
may present overtly, with hematemesis and hemodynamic instability, or more
insidiously, with melena, hematochezia, or encephalopathy. After achieving
hemodynamic stability, perform an endoscopic evaluation of the upper GI tract
with the goals of diagnosis and endoscopic control via rubber band ligation,
sclerotherapy, or both. In approximately 5-10% of patients, these maneuvers
fail to control bleeding; therefore, consider TIPS, balloon tamponade, or
surgical shunts. Reserve the placement of emergency surgical shunts for
patients in Child class A to minimize morbidity and mortality.
Pruritus
is also common in liver disease, mostly in cholestatic liver diseases such as
primary biliary cirrhosis and sclerosing cholangitis, although it is also
common in hepatitis C virus (HCV) cirrhosis. In approximately 90% of patients,
the condition responds to sequential therapy with use of antihistamines,
ursodeoxycholic acid, and cholestyramine. The remaining 10% can be treated with
rifampicin, with a significant reduction of pruritus. Because of the potential
for bone marrow and hepatic toxicity, regular complete blood cell counts and
liver tests are necessary. Opiate antagonists (eg, naloxone, nalmefene,
naltrexone) have increasingly been used in the treatment of refractory pruritus.
Timing
of liver transplantation
The
1983 NIH consensus that finally put LT in the clinical arena stated that, in
order to be successful, LT had to be offered at an optimal time (see Image 3). Optimal timing of LT
is based on the natural history of the disease and the potential for
progression over time. Additionally, the patient must be in the system to have
the opportunity to undergo transplantation, ie, he or she must be listed with
UNOS. All too commonly, patients are referred to the transplant center late in
the stage of their disease, and only then is there an immediate sense of
urgency.
This
scenario results in accelerated and occasionally incomplete evaluations of very
ill patients. If these patients undergo transplantation, they are at a higher
UNOS status (2A or 1), with a resulting lower survival rate and a much greater
cost and length of stay in the hospital and intensive care unit (ICU). To avoid
this, UNOS revises their organ allocation schemes regularly (see Lab Studies). The issue of
transplantation timing is also full of challenges and controversies, as
outlined in Image 4.
To
whom these organs should go is another consideration in the timing of LT. An
ideal approach maximizes patient benefit and graft survival (see Image 5). This is an ongoing
discussion with many perspectives. The right approach is somewhere in the
middle, balancing patient outcome and utility. A move toward this has been made
with the establishment of minimal listing criteria for entry on to the waiting
list. The MELD system, apparently an even better solution for organ allocation,
still awaits full clinical validation.
Surgical therapy: The
different techniques used for liver replacement are discussed at length in the
following paragraphs.
Preoperative details: During
multiorgan procurements, the goal of management is to maintain physiologic
stability (ie, oxygenation, perfusion) so that the organs are in the best
possible condition at harvest. Donors are brain dead and thus do not require an
anesthetic, although they may still exhibit visceral, somatic, and autonomic
reflexes. Additionally, the anesthesiologist may be asked to administer certain
medications (eg, mannitol, furosemide, heparin) as part of the organ
procurement protocol. In general, the goal is to provide supportive care during
the procurement to avoid any insult to the organ(s) being harvested.
Anesthetic
management during the organ implantation procedure follows the same general
provisions as for other procedures, ie, hypnosis, amnesia, analgesia,
neuromuscular blockade, and hemodynamic stability. A rapid sequence induction
is used. Nasal intubation is avoided because of the potential for severe
epistaxis. Isoflurane in air plus a narcotic is the usual anesthetic technique,
and long-acting drugs, such as pancuronium, lorazepam, and methadone, may be
used. Nitrous oxide is avoided because of its effect on enteric distension.
Regional anesthesia for postoperative analgesia is contraindicated because of
actual or potential coagulopathies.
Besides
the standard intraoperative monitors, arterial and pulmonary artery catheters
are placed. In some centers, transesophageal echocardiography is added if
questions arise concerning cardiac function or to help detect significant
pulmonary emboli after reperfusion. An oral gastric tube is inserted, which
later may be changed to an NG tube.
Intraoperatively,
the Rapid Infusor System (RIS, Haemonetics Corporation, Braintree, Mass) is
routinely used. This device can warm and pump the contents of a reservoir at
rates up to 1.5 L/min through large-bore venous access. Blood products and
crystalloid solution are administered via the RIS.
Venovenous
bypass is used to divert inferior vena cava and portal blood flow around the
retrohepatic portion of the inferior vena cava when it is clamped. Cannulas are
usually placed in the femoral vein and the right internal jugular (IJ) or
axillary vein. A third cannula is inserted intraoperatively into the
recipient’s native portal vein. Blood from the femoral and portal cannulas is
then pumped via a centrifugal bypass pump toward the IJ or axillary vein
cannula. Placement of these cannulas can be accomplished percutaneously or via
direct cut down. The right IJ cannula also serves as the infusion site for the
RIS. These cannulae are not needed if bypass is not a requirement of the
surgical procedure.
After
reperfusion, inotropics, vasoconstrictors, calcium chloride, and nitroglycerin
should be immediately available. Epinephrine, norepinephrine, and phenylephrine
are the agents most commonly used at the author’s institution. Nitroglycerin
occasionally is needed after reperfusion if pulmonary artery pressures are
elevated. Transfusion of blood products is often required in LT. Packed red
blood cells and fresh frozen plasma (FFP) are administered via the RIS. Platelets
and cryoprecipitate generally are administered via a peripheral or central vein
after proper filtration.
Other
important intraoperative considerations include the use of antibiotics,
immunosuppression, cytoprotection, and adequate temperature homeostasis.
Prophylactic antibiotics are used frequently and dosed around the operative
procedure, which can be quite lengthy. After complete revascularization of the
allograft, methylprednisolone (1 g) is administered as immunoinduction.
In
addition, prostaglandin E1 is administered at a rate of 0.3-0.6
mg/kg/h in the postanhepatic portion of the surgery as a hepatic and renal
cytoprotective agent, adjusted to blood pressure levels. Finally, maintenance
of temperature is important because it plays a vital role in optimizing the
function of the coagulation system. Methods to achieve this include maintenance
of room temperature, warm air blankets, fluid warming via the RIS, low fresh
gas flow rates, and heat-moisture exchangers. If the venovenous bypass circuit
is used, a heating element may be placed in-line.
Intraoperative details: The
3 elements involved in a successful LT are donor procurement, recipient
implantation, and surgical coordination of these 2 procedures.
Donor
availability is made known to the transplant center with a suitable recipient,
usually with a certain margin of time. The allocation follows the rules of
UNOS. Surgical coordination of both the donor and the recipient operations is
made when declaration of death, proper consent, and adequacy of the donor liver
are evaluated and found to be adequate for the prospective recipient. The donor
team is then transported to the donor's hospital.
The
donor operation proceeds in cooperation with any other procurement teams present.
A long midline incision from suprasternal notch to the pubis is performed to
gain full exposure to the abdomen. The chest is opened via a median sternotomy.
This maneuver properly exposes the intrathoracic structures, allowing both
cardiac and pulmonary organ harvest; it also allows easier hepatic dissection
and extraction for the abdominal surgeon.
The
dissection starts with the mobilization of the liver by dividing its
ligamentous attachments. Sequentially, the left triangular and falciform
ligaments are divided with the aid of electrocautery and are joined in the
midline. Next, the gallbladder is emptied of its bile content by incising it at
the fundus and irrigating it with warm saline until the returns are clear.
Attention is then directed towards the hepatic hilum, which is carefully
examined and palpated by placing a finger in the Winslow foramen to assess for
the presence or absence of anatomic variations. The following are the most
frequently encountered variations:
The
importance of identifying these abnormalities is that any of these replaced or
substituted trunks may contribute a significant amount, if not all, of the
arterial blood supply to the respective lobe; therefore, preserve them whenever
possible. Also, the presence of an aberrant left branch means that the
dissection will be more tedious and delicate in order to preserve the left
gastric artery, the main origin of this aberrant branch, alongside the lesser
gastric curvature. Similarly, a right substituted or replaced branch requires
the delicate dissection of the SMA up to the point of its origin in the aorta.
At
this point in the operative procedure, a decision is made to either proceed in
the usual fashion or resort to the rapid flush technique. This depends on the
stability of the donor. For stable donors, the hepatic hilum is dissected
systematically, dividing and ligating successively the right gastric artery and
the gastroduodenal artery. The other branches of the celiac trunk are isolated
and tied, ie, the splenic artery on the superior edge of the pancreas and the
left gastric artery along the upper lesser curvature of the stomach; the ties are
cut long for posterior identification.
The
free edge of the common bile duct is exposed laterally and isolated, ligating
the distal portion and transecting it. This normally allows dissection of the
common hepatic artery upward and the pancreatic edge downward, thus bringing
into view the anterior surface of the portal vein. Mild blunt dissection is
used to separate the anterior portal surface from the pancreas, with care to
not injure minor tributaries. This allows visualization of the splenic, superior,
and inferior mesenteric veins and cannulation of the splenic vein with the
portal cannula for the portal flush afterward. To do this, the size of the
cannula is adjusted to the size of the vein (introduced after appropriate
venotomy) and is secured with ties.
After
the portal cannula is in place, attention is directed to the infrarenal aorta,
which is dissected free near its bifurcation; during this step, the inferior
mesenteric artery is divided near its origin to obtain a proper segment of
aorta for cannulation. Isolation of the supraceliac aorta follows by retracting
the esophagus to the left and the previously mobilized left hepatic lobe to the
right, thus exposing and dividing the diaphragmatic crura. This is used later
as the site for cross clamping.
The
scenario now is set for perfusion of the organs. The donor is heparinized with
20,000-30,000 IU of heparin, the aortic cannula is introduced in the infrarenal
aorta, the distal aorta is tied, and the suprarenal aorta is clamped. The
organs are then perfused with ice-cold UW solution, and the suprahepatic vena
cava is vented in the pericardial space. At this point, the cold, topical, iced
solution is poured in the abdomen for surface cooling. Some surgeons also vent
the vena cava via the infrarenal portion.
Removal
of the liver then proceeds. The suprahepatic vena cava is taken along with a
generous patch of diaphragm. The left gastric artery is dissected back, as is
the splenic artery. The duodenum is kocherized, and fingers are placed behind
the pancreas; the portal vein is dissected back, and its tributaries are
divided. The SMA is felt through the pancreatic parenchyma, is dissected free,
and is placed on traction with aid of a clamp. Sharp dissection proceeds to the
left of the SMA and is carried down to the aorta; then, dissection from left to
right is performed to identify potential right branches. The celiac trunk is
then removed along with a generous Carrel patch of aorta.
After
the hepatic hilar dissection is completed, the inferior vena cava is divided
above the renal veins and is taken along with the bisected right adrenal vein.
The remaining attachments of the liver and its hilar structures are carefully
divided, and the organ is removed and taken to the back table for an immediate
flush.
This
general procedure is modified in cases of aberrant vessels to include
dissection of the left gastric artery along the lesser curvature of the stomach
(for left branches), or the SMA is included in the Carrel patch and is
dissected very carefully from left to right to avoid injury to accessory right
branches. In unstable donors, the portal system is cannulated first, prior to
the hilar dissection, via the superior mesenteric vein in the inframesocolic
space; the aortic control and cannulation quickly follow, and, after
cross-clamping the supraceliac aorta, the cold flushing is performed.
Thereafter, hilar dissection and removal of the liver is performed in an
asanguinous field. Exquisite care must be exercised to avoid injury to the
vessels or biliary structures.
Once
removed from the body, the liver is again flushed with 1 L of UW on the back
table. After the organ has been properly flushed and packed, the internal iliac
arteries and veins of the donor are procured for potential use as grafts.
Transportation to the recipient's hospital immediately follows, in close
coordination with the recipient's preparation.
Back
table allograft preparation
Prior
to engraftment, the donor liver is removed from ice and prepared for implantation
in a back table procedure. In this procedure, the superfluous tissues that
accompany organs removed en bloc are trimmed, and, if any vascular
reconstruction is necessary, it is performed. The aim of the vascular
reconstruction procedures, usually arterial, is to provide a single common
inflow vessel of sufficient length so that only 1 anastomosis needs to be
performed in the recipient. All vessels are then tested for patency and
integrity by flushing with sterile preservation solution. The donor iliac
arteries and veins routinely procured at the termination of the donor operation
are also prepared for use, if necessary, as venous or arterial grafts in the
recipient.
Full
liver recipient procedure
The
goals of an orthotopic LT operation are to remove the diseased liver (total
hepatectomy) and then to replace it in exactly the same location with a healthy
liver. The recipient hepatectomy could result in massive bleeding; therefore,
paying careful attention to the meticulous gentle handling of tissues and
having a strict systematic approach to hemostasis at all times are crucial.
Proper usage of venovenous bypass and blood products can optimize this part of
the operation, thus decreasing morbidity rates.
A
bilateral subcostal incision with a midline extension to the xiphoid process is
routinely used (ie, "Mercedes-Benz" incision). After mobilizing and
dividing the round and falciform ligaments, a large self-retaining upper
abdominal retractor is placed (see Image 6). The ligamentous
attachments of the liver (ie, left triangular, right triangular, and
gastrohepatic ligaments) are then dissected to mobilize the liver in its
entirety.
Dissection
of the hilar structures then proceeds (see Image 7), with systematic
ligation of the hepatic artery, cystic duct, and common hepatic duct. The
portal vein is then cleaned of surrounding tissue from the level of the head of
the pancreas up to its bifurcation into right and left branches. The hepatic
artery is now formally dissected proximal to the gastroduodenal artery,
exposing the common hepatic artery to allow for subsequent anastomosis. The
gastroduodenal artery is left untied to avoid distal thrombosis or dissection,
which may happen if this is ligated.
Venovenous
bypass may now be initiated (see Image
8). Whether and when to start bypass depends on the degree of portal
hypertension, the extent of previous surgery with vascularized adhesions, and
the degree of bleeding within the operative field, notoriously from the
retroperitoneum. Thus, initiation of bypass may occur early or late during the
hepatectomy phase, as judged by the operating surgeon.
Once
bypass is initiated, the remaining attachments to the liver can be divided
rapidly and the liver can be removed, leaving both upper and lower caval cuffs
for later anastomosis. Depending on the degree of bleeding and the size of the
donor liver to be implanted, the bare area of the liver may be oversewn.
Following this, the vena caval cuffs are shaped for anastomosis.
Implantation
and caval techniques
To confirm adequacy
of the vascular reconstructions, flow is then measured with an ultrasonic or
electromagnetic flow meter. If flow is inadequate, the inflow, outflow, and
anastomoses are examined to determine the reason and to correct the problem(s).
After
achievement of adequate hemostasis, biliary reconstruction can begin. If the
recipient bile duct is of normal caliber and is free of intrinsic disease, a
donor-to-recipient duct-to-duct reconstruction can be performed over an
indwelling T-tube stent that is exteriorized through a separate stab wound
incision. If the 2 ends of the bile duct can be tailored to meet perfectly
without redundancy and are of similar caliber, this end-to-end reconstruction
can be performed without a T-tube. If the patient's native bile duct is
diseased or if the duct is too small, the bile duct of the donor is anastomosed
to a defunctionalized Roux-en-Y loop of jejunum over an internal stent (see Image 12).
Cholangiography
is performed to confirm a technically sound biliary reconstruction and may be
performed through the T-tube or via the cystic duct. With this completed,
closing the abdomen after leaving 3 closed suction drains above and below the
liver concludes the operation.
Recipient
procedure (special cases)
Partial
liver recipient procedures
While
the number of LTs has grown exponentially, the number of organ donors has not
kept pace with the growing number of candidates. This widening gap between
supply and demand has led to higher mortality rates among candidates on the
waiting list. In attempts to narrow this gap, transplant centers have broadened
their donor selection criteria and have begun to employ innovative surgical
techniques such as reduced-size LT, split LT, and living-donor LT.
Reduced-size
LT was introduced in the mid 1980s to provide size-matched grafts for pediatric
patients. In reduced-size LT, a cadaveric liver procured using standard
techniques is resected on the back table to create a smaller graft. The liver
allograft can be tailored based on the recipient’s body size. It is possible to
create a right lobe graft, left lobe graft, or left lateral segment graft. The
rest of the liver is discarded.
In
living-donor LT (see Image 13),
part of the liver from a living donor is resected and transplanted into a
recipient. The technique was first used for pediatric recipients and now has
been extended to the adult recipient population because of excellent results
and established donor safety. In pediatric recipients, either left lateral
segments or full left lobes usually suffice. For adults, right lobe grafts are
necessary to ensure enough liver volume.
This
new procedure provides many advantages to the recipient because of the elective
nature of the procedure (usually before severe hepatic decompensation) and the
assurance of a healthy donor organ with a short ischemia time, resulting in
better graft quality than with cadaveric liver allografts. Technical problems
in the recipient, such as hepatic artery thrombosis and biliary leaks, were
observed initially but have decreased dramatically with increasing experience
in technique and recipient selection. For the donors, the advantage is mainly
psychological.
Because
living-donor LT subjects a healthy individual to major surgery, donor safety is
essential and informed consent is crucial. The American Society of Transplant
Surgeons published guidelines for living-donor transplantation. The risks and
benefits of the living-donor operation must be explained to the donor, the
recipient, and their immediate families. In addition, donors should be thoroughly
evaluated by an unbiased physician. The workup should include a full medical,
psychosocial, and anatomical evaluation of prospective donors. Finally,
although the donor operation has been associated with low morbidity and
mortality rates, long-term follow-up is necessary to confirm the safety of this
procedure for donors, especially for donors of right lobe grafts.
In this case,
removal of the native liver by a piggyback technique is mandatory. The portal
vein anastomosis is performed between the allograft portal vein and the
recipient portal vein using 6-0 Prolene continuous suture. The hepatic artery
anastomosis is performed between the allograft hepatic artery (either right or
left) and the recipient right or left hepatic artery using 8-0 Prolene
interrupted sutures. Sometimes, an operating microscope may be needed,
especially for small arterial anastomoses. Extension grafts are rarely needed.
In most cases, the bile duct anastomosis is accomplished by Roux-Y
hepaticojejunostomy (although sometimes performing duct-to-duct anastomosis is
possible) using interrupted 6-0 polydioxanone sutures.
Not
all donors are suitable for split procedures. Donors should be older than 50
years and should be hospitalized for less than 3 days with perfect liver
function, minimal pressor support, and no steatosis. The final decision of
whether a liver is suitable for splitting should be made in the operating room.
Similarly, recipients should be selected carefully. Relatively stable patients
in Child class B or C tolerate split-related complications better.
Postoperative details:
Following
LT, the function of the new liver is monitored closely in an ICU setting.
Elevations of liver enzymes, notoriously transaminases (ie, aspartate
aminotransferase, alanine aminotransferase), early on are reflective of
preservation injury (cold preservation). On occasion, the enzymes rise sharply.
If they are higher than 2000, the overall viability function of the liver
should be monitored carefully to assess the need for retransplantation.
Usually, the liver enzyme levels normalize very quickly, typically within a
week of transplantation. The bilirubin level follows a similar pattern of early
rise and delayed clearing. However, if the preservation injury is severe, this
elevation can persist for 2-3 weeks and can be accompanied by a significant
rise in alkaline phosphatase levels.
Platelet
counts usually decrease in the first week after LT and recover during the
second week. This may be caused by platelet sequestration in the liver and
spleen due to preservation injury. Once the liver has recovered, as manifested
by the return of bilirubin to normal levels, the platelet count increases.
Recovery in a typical patient is rapid, as is discharge to the floor, usually
within 2-3 days. However, if the graft has suffered severe preservation injury,
return to normality may lag. Treatment is mostly supportive, with the goal of
maintaining stable hemodynamics while the liver recovers. In extreme cases,
termed primary graft nonfunction, the new liver never recovers and needs urgent
retransplantation.
After
the patient’s medical condition has stabilized and graft function is stable, he
or she is transferred from the ICU to the floor transplant unit. At this time,
tests are performed to assure adequacy of the new connections. A duplex Doppler
ultrasound helps check for patency of the vascular anastomoses and the presence
of abnormal fluid collections. If a tube is present, a T-tube cholangiogram is
performed to assure adequate biliary drainage and to exclude leaks.
During
the patient's stay on the floor unit, his or her laboratory studies, medications,
nutritional status, and exercise tolerance are monitored. As soon as patients
are able, discharge instructions begin to prepare them for going home. Most
patients with severe ESLD have a very low albumin level prior to
transplantation. After successful LT, the albumin level slowly rises to normal
levels. This explains the generalized edema that patients may experience
following transplantation, which begins to disappear once albumin levels start
to normalize.
Follow-up care: Upon
leaving the hospital, the patient receives a schedule of follow-up clinic
visits for laboratory tests and checkups. The idea is to track clinical
progress and to detect potential complications (eg, rejections, infections) as
early as possible. Patients are instructed to notify the transplant team if
they have any prolonged illness, fever, nausea, vomiting, or diarrhea or if
they experience any unusual symptoms or adverse effects potentially related to
the immunosuppressants.
Following
transplantation, all patients are placed on immunosuppressive drugs to prevent
rejection of the new liver. These medications are usually started in the
operating room and are continued thereafter. The dose of the immunosuppression
agent needed varies from patient to patient depending on the likelihood of
rejection.
Immunosuppression
must be balanced carefully against the patient's own immune system. Adjusting
the dose specifically for each patient helps avoid the risk of postoperative
infections, tumor development, and liver rejection. The dose of
immunosuppression varies between patients and may vary with time in a
particular patient. This explains the requirement of frequent blood drawing,
especially early after transplantation, because absorption, metabolism, and dose
requirements of these drugs can vary significantly from day to day in the early
posttransplant period. As time passes, the amount of immunosuppression needed
to prevent organ rejection usually decreases. Immunosuppression therapy is not
without risk and must be monitored closely. Immunosuppression management is
based on the following principles:
In-depth
discussion of the pharmacology of immunosuppressive medications is beyond the
scope of this article, although certain points are worth mentioning. Induction
immunosuppression is not commonly used after LT, although the recent
introduction of the newer IL-2 receptor-blocking antibody preparations,
daclizumab (Zenapax) and basiliximab (Simulect), may change this approach in
the future.
Maintenance
immunosuppression is usually based on a calcineurin inhibitor (ie, cyclosporine
A or tacrolimus) and corticosteroids. These may be combined with newer
antimetabolite compounds (eg, mycophenolate) or antiproliferative agents (eg,
Rapamycin) with the goal of decreasing steroid and/or calcineurin inhibitor
use. The most important toxicities are related to steroids (eg, osteopenia,
diabetes, cushingoid syndromes). Calcineurin inhibitor use is fraught mostly
with neurotoxicity and nephrotoxicity. Finally, the antimetabolites can cause
cytopenias, and Rapamycin has been associated with both cytopenias and severe
hyperlipidemia (see Image 15).
Cyclosporine
(Sandimmune, Neoral)
Cyclosporine
is a highly lipid-soluble drug that is extensively bound to plasma proteins. It
is metabolized in the liver by cytochrome P-450 enzymes. Excretion is mainly
biliary, with only trace amounts excreted unchanged in urine. Interactions with
other drugs generally arise from effects on the pharmacokinetic characteristics
of cyclosporine and from additive pharmacologic or toxic effects.
Cyclosporine
can be administered by double-route therapy (PO and IV). Patients who have
undergone kidney transplants usually can be maintained on oral therapy alone.
Patients who have undergone LT, who sustain longer GI dysfunction after the
operation, are maintained on double-route therapy longer. The decision to
switch to oral therapy depends on the status of cyclosporine drug levels and
liver function. Oral cyclosporine is now available in an emulsified form
(Neoral), which has overcome many of the problems of absorption observed
initially. Capsules are available in 25-mg and 100-mg sizes.
Cyclosporine
toxicity is manifested by hypertension, tremulousness, hypertrichosis, gingival
hyperplasia, and nephrotoxicity with hyperkalemia and/or renal tubular
acidosis. A low serum magnesium level potentiates cyclosporine neurotoxicity
and may result in seizures. Liver function may also be impaired by
cyclosporine, but this is less common than nephrotoxicity. Cyclosporine can
produce acute and chronic nephrotoxicity. The most common cause of a rise in
BUN and creatinine levels after transplantation is cyclosporine toxicity, which
responds promptly to a reduction in dosage. Every effort is made to reduce
cyclosporine doses to the lowest levels possible.
Cyclosporine
levels are measured by the TDx monoclonal assay. Careful clinical assessment of
the patient for adverse effects of cyclosporine (eg, tremulousness,
hypertension, hyperkalemia, gum enlargement or soreness, elevated creatinine
level, liver dysfunction not attributable to other causes) remains the best
guide to dosage. In general, TDx 12-hour trough levels of 450-550 ng/mL for
liver recipients on triple therapy are expected during the early posttransplant
period, with decreasing levels in the weeks after transplantation.
Cyclosporine
also has toxic effects on the CNS. Intravenous cyclosporine may cause seizures.
The magnesium level must be kept greater than 2 to prevent adverse effects,
including paranoid delusions and hallucinations. Oral maintenance therapy has
also been found to produce mood depression.
Cyclosporine
is primarily eliminated from the body by hepatic metabolism, and potent
inducers and inhibitors of the cytochrome P-450 hepatic microsomal enzyme
system increase or decrease cyclosporine clearance. In general, enzyme-inducing
effects occur over a several-week period; when the inducing drug is withdrawn,
the effect takes a similar time to reverse. Enzyme inhibition has more rapid
clinical effects because drug accumulation begins immediately and may require a
reduction in cyclosporine dosage. LT recipients may need parenteral nutritional
support, including intravenous fat emulsions (Intralipid). Cyclosporine is
highly lipophilic and binds to serum lipoproteins. Cyclosporine levels should
be carefully monitored in patients receiving intravenous fat emulsions.
FK506/tacrolimus
(Prograf)
Tacrolimus
is a macrolide antibiotic that shares many characteristics with cyclosporine.
It inhibits IL-2, interferon-gamma, and IL-3 production; transferrin and IL-2
receptor expression; mixed lymphocyte reactions; and cytotoxic T generation.
Tacrolimus is metabolized by the same cytochrome P-450 system as cyclosporine,
and less than 1% appears in the urine after an oral dose. It is highly lipid
soluble; but, unlike cyclosporine, oral absorption is not dependent on bile
acids.
Tacrolimus
can be administered by both oral and intravenous routes, although the
intravenous route is used infrequently at present because of its greater
likelihood of toxicity, especially nephrotoxicity and neurological toxicity.
Because the absorption of tacrolimus is more efficient than that of
cyclosporine, it can be used as an oral agent very early following LT and does
not require clamping of the T-tube to provide adequate absorption and
maintenance of levels.
The
usual recommended oral dose of tacrolimus is 0.15 mg/kg, initially q12h. For
adults, the oral maintenance dose is usually in the range of 0.03-0.2 mg/kg/dose.
If an intravenous dose is required, it is usually 0.03 mg/kg, with a range of
0.01-0.05 mg/kg q12h as a continuous infusion. Like cyclosporine, tacrolimus
toxicity is manifested by nephrotoxicity, neurotoxicity, and hyperglycemia.
Nephrotoxicity seems to be as frequent and severe as that observed with
cyclosporine and is generally reversible with dosage reduction. Neurotoxicity
ranges from mild symptoms (eg, insomnia or somnolence, headaches, tremors) to
more severe symptoms (eg, obtundation, seizures, coma).
As
with nephrotoxicity, neurotoxicity appears to be related to high levels of the
drug and resolves with dosage reduction. Hyperglycemia requiring insulin
therapy has been reported, but the development of this hyperglycemia does not
appear to be dose dependent, and its cause is unknown. Other reported adverse
effects for patients taking tacrolimus include hypercalcemia, hyperlipidemia,
hypercholesterolemia, and alopecia. Low serum magnesium levels have been
reported, and the development of hyperkalemia in the face of stable renal
function has also been reported.
Tacrolimus
levels are monitored daily by obtaining trough levels while the patient is
hospitalized and at the time of their clinic follow-up visits. Tacrolimus is
usually administered at 8 am and 8 pm, with blood levels being drawn between 7
am and 8 am. These levels are measured by the florescent polarization
immunoassay analysis, with concentrations of 5-20 mg/mL representing
therapeutic levels that appear to avoid most adverse effects. However, careful
clinical assessment of the patient for adverse effects, even in the face of
what appears to be therapeutic levels, remains the most reliable method for
tacrolimus dosing.
Although
the extensive listing of drug interactions that have been defined for
cyclosporine have not been completely elucidated for tacrolimus, they likely
will have similar drug interactions. This is because both are metabolized by
the cytochrome P-450 hepatic microsomal enzyme system, and any medication that
induces or inhibits this system either increases or decreases tacrolimus
clearance. Drugs such as ketoconazole, fluconazole, and diltiazem may
significantly inhibit tacrolimus clearance; therefore, increase levels and
decrease the dosage requirement.
Corticosteroids
Corticosteroids
are used routinely as part of the maintenance protocol for solid organ
transplant recipients. Patients with brittle diabetes, advanced osteoporosis,
or refractory hypertension who are receiving conventional immunosuppression
with cyclosporine and prednisone may have their steroid doses reduced early.
Chronic steroid use is associated with many debilitating complications,
including refractory hypertension, diabetes, osteoporosis and fractures, hip
necrosis, cataracts, acne, and obesity; thus, weaning patients to the lowest
effective dose is highly desirable. One of the principal benefits of tacrolimus
is that it has permitted patients to be maintained on much lower doses of
prednisone than was possible with previous regimens. Steroids are also
important in the management of acute rejection (see Acute rejection).
Combination
therapy with azathioprine (Imuran) or mycophenolate (CellCept)
Azathioprine
(Imuran) or mycophenolate (CellCept) may be added to cyclosporine- or
tacrolimus-steroid therapy. This may be initiated to augment immunosuppression
or to permit reduced dosage of cyclosporine to control toxicity. Therapy is
usually started at low doses (~1 mg/kg for Imuran and 1 g bid for CellCept) and
is gradually increased as tolerated. Leukocyte counts (peripheral WBC count)
must be monitored daily because both drugs are bone marrow depressants.
Because
immunosuppressive agents have significant toxicities, other medications
frequently are added to the patients’ regimens to either prevent infections or
counteract some of these adverse effects. As such, prophylactic perioperative
antibiotics are routinely used for 48 hours post-LT. In addition, maintenance
antibiotic prophylaxis for infections frequently is instituted for 3-12 months
after transplantation, including agents such as trimethoprim-sulfamethoxazole
or dapsone (Pneumocystis carinii
pneumonia), acyclovir or ganciclovir (herpes viruses), and clotrimazole and/or
nystatin (fungal infections, candidal infections). Other commonly prescribed
medications include antacids, antiulcer medications, or both.
Acute
rejection
Acute
(cellular) hepatic allograft rejection, an attempt by the immune system to
attack the transplanted liver and destroy it, can occur in as many as 40% of
patients during the first 3 months posttransplant. Acute rejection normally
occurs 7-14 days after operation but can occur earlier or much later. Hyperacute
rejection of the liver, comparable to that observed in kidney transplantation,
is controversial and difficult to diagnose, but early accelerated rejection
certainly occurs. Liver biopsy may be required to distinguish between rejection
and viral infection.
Rejection
is most commonly manifested by malaise, fever, graft enlargement, and
diminished graft function. In patients who have undergone LT, a rise in
bilirubin and transaminase levels is observed and T-tube biliary drainage may
be thin and lighter in color. Acute rejection most commonly first occurs in the
second week after transplant but can occur earlier. Graft biopsy should be
performed, if safe, to document rejection. Adult liver biopsies are routinely
performed at the bedside with or without ultrasound guidance.
With
early suspicion and detection, most acute rejection episodes can be treated
successfully. Characteristic signs and symptoms of rejection include fatigue,
fever, abdominal pain or tenderness, jaundice, dark yellow or orange urine,
and/or clay-colored stools. In some instances, a patient may not have any
symptoms, but his or her liver function test findings may be abnormal,
suggesting that rejection is occurring. Rejection episodes are managed
sequentially by pulse steroids; OKT3; and/or the use of CellCept, tacrolimus
switch (if patient was on cyclosporine), or the addition of Rapamycin.
Retransplantation is the last resort when therapy fails and the patient
develops hepatic failure.
Chronic
rejection
The
characteristics of chronic rejection in recipients of LT are progressive bile
duct disappearance and obliterative arteriopathy (known as ductopenia) and
vanishing bile duct syndrome, which results in progressive jaundice and
allograft dysfunction. The ducts suffer direct immunological injury and
ischemia from the obliterative arteriopathy caused by antibody-mediated intimal
damage of hepatic arterioles. In the late phase of chronic rejection, diffuse
hepatic fibrosis occurs. Allograft function deteriorates, marked by cholestasis
and, ultimately, loss of synthetic function and portal hypertension. Heavy
immunosuppression with tacrolimus, mycophenolate mofetil, and/or sirolimus may
reverse chronic rejection in the early phases. Advanced chronic rejection is an
indication for retransplantation.
Diagnostic
tools for allograft dysfunction
As Image 16 shows, the etiology
of posttransplant allograft dysfunction is multifactorial and multietiological
in its origin. Anything, from technical factors to recurrent infections or drug
interactions, can ultimately cause allograft dysfunction. Thus, establishing
the diagnosis accurately is of prime importance because many of these
conditions have diametrically opposed management strategies. For example, if
the dysfunction is due to infection, appropriate antibiotics should be employed
and immunosuppression should be decreased. This is the wrong course of action
if the diagnosis were acute rejection.
The
complete workup of allograft dysfunction (see Image 17) in the adult LT
recipient must include all of the tests outlined in the slide. Serial
monitoring of liver function tests; pan cultures for bacteria, viruses, and
fungi; use of imaging tests (described below); and, ultimately, liver biopsy,
are essential for an accurate diagnosis. In terms of radiological imaging, the
transplant team may perform one or more of the following tests and procedures
to monitor a patient's transplant:
|
|
COMPLICATIONS |
Section
7 of 11 |
In
uncomplicated cases, recovery from the operation is surprisingly rapid and not
unlike that experienced by other general surgical patients. However, early
graft dysfunction suggests accelerated rejection, technical complications, or
primary graft failure.
Primary
graft failure occurs in approximately 7% of patients and is a very serious
complication. The patient decompensates quickly, and a desperate search for a
new graft must be initiated. Patients show markedly abnormal liver function,
coagulopathy, oliguria, and severe CNS changes (including seizures and status
epilepticus). Stage IV coma, alkalosis, hyperkalemia, and hypoglycemia
characterize the terminal phase of this acute hepatic decompensation.
In
these patients, management includes avoiding administration of any potassium,
transfusing FFP q4-6h (or as a continuous infusion when necessary), and keeping
the gastric pH greater than 5.0. FFP can be administered once the determination
of primary nonfunction has been made. A continuous 10% aqueous dextrose
solution (D10W) infusion may be needed to control hypoglycemia. Urgent
retransplantation is the solution to this complication if it can be performed
before pneumonia or irreversible coma occurs. Prostaglandin infusions may also
be used in the setting of primary nonfunction.
Technical
complications usually involve either biliary or arterial reconstruction.
Biliary complications are relatively frequent after LT and are thought to be
primarily of ischemic origin. Persistent jaundice with or without drainage of
bile through the drains warrants study. Ultrasound and/or abdominal CT scans
may show ductal dilation or bile collection. If the patient has a T-tube,
obtain a cholangiogram, preferably in the radiology suite. Reexploration is
required if a bile leak is present. Obstruction may require reexploration if it
cannot be dealt with by percutaneous interventional radiology.
Hepatic
arterial thrombosis should be considered in any patient who has a sudden high
fever and elevation in liver function study results. A positive blood culture
finding for Klebsiella species,
Escherichia coli, Pseudomonas
species, or enterococci in this setting is virtually pathognomonic. Doppler
ultrasound is an effective noninvasive method for evaluating hepatic artery
patency. If the vessel cannot be seen well or if clinical suggestion is high,
arteriography is indicated.
Hepatic
arterial thrombosis has 3 general patterns of presentation. The first is acute
hepatic gangrene with sepsis and fulminant liver failure. Urgent
retransplantation is required.
The
second is delayed bile leak or intrahepatic biloma or bile abscess resulting
from ischemic necrosis of the bile ducts. Retransplantation is usually
required, especially if the common bile duct is disrupted, but some patients
can be controlled, at least temporarily, with percutaneous drainage of
intrahepatic collections and antibiotic coverage.
The
third general pattern is relapsing bacteremia. Some patients, especially small
children, can be treated successfully with antibiotic therapy. A full course of
intravenous antibiotics is administered, followed by a course of oral
suppressive therapy. If the patient remains afebrile with good liver function,
retransplantation may be necessary only if chronic ischemic strictures of the
biliary tree develop. Other patients have persistent bacteremia and develop
liver abscesses, requiring eventual transplantation.
Because
of the danger of hepatic artery thrombosis, vigorously treating evaluated
prothrombin times or low platelet counts with FFP and platelet transfusions is
dangerous. Except in patients with active bleeding, platelet counts as low as
50,000/mm3 and prothrombin times less than 25 seconds are not
treated. In addition, at the discretion of the surgeon, patients may be started
on aspirin and Persantine.
Aggressively
evaluate all fever episodes in an immunosuppressed patient with the following
routine tests:
The
following tests may also be indicated if the above tests fail to identify the
source or if the clinical situation dictates:
Even
mild infections are a serious threat in immunosuppressed patients. As an
adjunct to therapy, immunosuppression must be reduced or even completely
stopped temporarily. Bacterial infections are better tolerated with
cyclosporine than with azathioprine (Imuran) but still must be treated
aggressively. Viral infections account for substantial morbidity and mortality.
Herpes infections are treated with a 10- to 14-day course of acyclovir (5-10
mg/kg q8h infused IV over 1 h). Candidal species in sputum, blood, urine, bile,
or drains are an indication for systemic therapy. The presence of candidal
species in peritoneal fluid strongly suggests a bile leak or bowel perforation.
Cytomegalovirus
CMV
status (positive or negative) of the donor must be recorded in the recipient’s
chart, and the CMV titer of the recipient must be ordered as part of the
pretransplant evaluation so the results are available immediately after
transplantation. CMV infection is usually observed 3 or more weeks after
transplantation and is one of the most common viral infections. CMV infection
is often characterized by fever, leukopenia, and malaise. Patients with
systemic CMV infections are treated with ganciclovir. The drug appears to be
most effective when started early in the course of CMV infection and may be
useful for CMV hepatitis, enteritis, and CMV pneumonia. A tissue diagnosis of
CMV should be sought, either by characteristic histological findings or by
biopsy cultures. Endoscopy is often successful in demonstrating CMV infection,
even in patients without GI symptoms.
Candidal
infections
Candidal
species (ie, Candida albicans, Candida tropicalis, Candida
parapsilosis, Torulopsis glabrata) can
cause severe locally or systematically invasive infections in heavily
immunosuppressed patients. As a general rule, if candidal species grow from 2
or more sites, even if not from blood (eg, urine, wound), the condition should
be treated and managed as a systemic infection. Traditional treatment for
systemic candidiasis has been intravenous amphotericin B. Amphotericin must be
administered intravenously and has synergistic renal toxicity with
cyclosporine.
Ketoconazole
is avoided because it can cause a dramatic increase in cyclosporine levels and
may be hepatotoxic. Another agent, fluconazole, appears to be promising. It can
be administered intravenously or orally and has less troublesome hepatic or
renal toxicity. The usual loading dose in patients with a serum creatinine
level less than 2 mg/kg is 400 mg followed by 200 mg/d. In patients with a
serum creatinine level of 2-4 mg/dL, the loading dose is 200 mg followed by 100
mg/d. If the serum creatinine level is greater than 4 mg/dL, administer a
100-mg loading dose and 100 mg qod.
Aspergillosis
Infections
with Aspergillus niger, Aspergillus flavus, or Aspergillus fumigatus may involve the lungs, the upper respiratory tract,
the skin, the soft tissues, and the CNS. The disease more commonly presents as
a diffuse pneumonia with patchy infiltrates rather than a fungus ball in the
lungs. Development of a brain abscess is insidious, and cure has been rare.
Treatment with amphotericin B should be initiated whenever the diagnosis of
aspergillosis is considered. A long course of systemic therapy (2-3 g) is
indicated if infection is confirmed.
Cryptococcosis
Cryptococcus neoformans may cause pulmonary, CNS, and disseminated cutaneous
infection in immunosuppressed patients. All patients with pulmonary
cryptococcus should have an examination of spinal fluid (lumbar puncture). In
addition to the traditional India ink stains, testing for cerebrospinal fluid
cryptococcal antigen and peripheral antibody should be performed. Systemic
treatment with amphotericin B (1-1.5 g) is indicated.
Phycomycetes
Infections
with Mucor and Rhizopus species are rarely encountered but can produce
destructive CNS or soft tissue infections that are difficult to eliminate.
Treatment includes local excision and a long course of systemic amphotericin B.
Legionella and Pneumocystis infections
These
infections are more common in immunosuppressed patients and must be treated
early. A patient who develops a pulmonary infiltrate of unknown etiology should
be started on erythromycin (1 g IV q6h) for Legionella infections and Bactrim (20 mg/kg/d in 4 divided
doses) for Pneumocystis
infections, which commonly present with dyspnea and hypoxemia before the chest
films show a significant infiltrate. Arterial blood gas measurements should be
obtained. Consultation with a pulmonologist for bronchoalveolar lavage should
be requested.
Posttransplant
lymphoproliferative disorders (PTLDs) may develop at any time, and these
lesions have been observed developing as soon as 1 month and as long as 14
years after transplantation, although most cases have developed within the
first year. These lesions are usually associated with EBV infection. PTLDs now
account for 41% of all tumors developing in immunosuppressed patients on
cyclosporine, compared to only 12% of patients treated with earlier regimens.
They may reflect the overall increased level of immunosuppression achieved with
current regimens including cyclosporine rather than a special property of
cyclosporine itself.
The
clinical presentation varies, but the head and neck and the GI tract have been
the most commonly involved. Presenting symptoms include lymphadenopathy, fever,
weight loss, abdominal pain, tonsillitis, night sweats, upper respiratory
infections, and diarrhea. Patients may present with a clinical syndrome
indistinguishable from mononucleosis, with fever and lymphadenopathy. Tonsillar
swelling may produce acute upper airway obstruction. An acute abdomen resulting
from intestinal obstruction or perforation may occur. Cases involving lymphoid
proliferation, mainly in the transplanted liver or kidney, which were detected
upon graft biopsy performed to exclude suspected rejection, have also been
observed. Other more unusual presentations have included lung lesions, renal
mass, prostatic obstruction, disseminated sepsis, and multiple organ failure.
Most
lesions are polyclonal in nature. A fulminant course is uncommon, and the
appropriate management is reduction in immunosuppression and treatment with
acyclovir. Occasionally, an aggressive monoclonal monomorphous lesion may be
encountered that requires antilymphoma therapy. Unfortunately, diagnosis of
these lesions usually is made late in the course of the disease when the
patients are already moribund. Early recognition of PTLD with prompt reduction
in immunosuppression and antiviral therapy is associated with the best
prognosis.
Arterial
hypertension
This
may develop as a consequence of the natural aging process and as an adverse
effect of the immunosuppressive medications. Patients may need to take
additional medications for proper control of hypertensive states.
Diabetes
mellitus
Some
of the immunosuppressive medications may cause diabetes in the posttransplant
period. This may occur de novo or may be an exacerbation of a preexisting
condition. Patients are often placed on a diet and exercise program, oral
hypoglycemic agents, and even insulin for management. Symptoms of diabetes may
include increased thirst, increased frequency of urination, blurred vision, and
confusion.
Posttransplant
malignancies
Recipients
of solid liver transplants, as all transplant recipients, are at particular
risk for increased incidence of some malignant neoplasms after transplantation
as a consequence of the effects of immunosuppressive drug therapy.
Immunosuppressive therapy does not increase the frequency of most common
malignancies, but it does significantly increase the risk of lymphoma; skin
cancer; and some rare malignancies, including Kaposi sarcoma and carcinoma of
the cervix, external genitalia, and perineum.
These
malignancies can be virally induced, such as EBV-associated lymphoproliferative
disease (eg, PTLD), recurrence of preexisting cancers in recipients,
donor-transmitted neoplasms, or de novo malignancies. Development of de novo
and other malignancies is also related to the increased longevity of liver
transplant recipients. Certain cancers occur at distinct intervals after
transplantation, and immunosuppression facilitates the development of cancers
that occur relatively close to the actual transplant event.
A
great deal of the knowledge about malignancy after transplantation comes from
the Israel Penn International Transplant Tumor Registry (IPITTR), formerly the
Cincinnati Transplant Tumor Registry, founded by Israel Penn, MD, now deceased.
Since 1968, the IPITTR has collected and analyzed data on de novo cancers of
various organs from transplant centers worldwide. Much of the data in the
IPITTR have been collected on renal transplant recipients. Several reports and
analyses of the various incidences of different types of neoplasms have been
reported.
Another
database in wide use comes from a registry for data from transplant recipients
in Australia and New Zealand maintained by A.G. Shell, MD. However, these registries
are voluntary and thus may not accurately reflect the true risk of malignancies
or cancers in immunocompromised patients as compared with the general
population because not all neoplasms are uniformly reported. Similarly,
follow-up data such as survival after diagnosis and/or therapy are not known.
Thus, large data sets compiled from UNOS or large transplant centers with
longer follow-up periods may be preferable to evaluate the true risk of cancer
after LT. This is of particular interest in nonlymphoid cancers because they
generally present much later after LT than lymphoid cancers.
Some
malignancies are seen more frequently in certain subpopulations of transplant
recipients, according to preexisting risk factors or behaviors, such as
oropharyngeal and lung cancer in those with alcoholism and those who smoke, or
colon cancer in patients with preexisting inflammatory bowel disease
transplanted for primary sclerosing cholangitis (PSC). Directed screening in
these patients is thus desirable, with oropharyngeal examinations, chest
radiographs, and scheduled colonoscopies.
PTLD
is related to infection with EBV. It generally arises from B lymphocytes and is
most common in children, recipients who were seronegative for EBV receiving
seropositive donor organs, and patients who required the use of OKT3. PTLD is
frequently extranodal, arising in such places as the GI tract, lung, or CNS.
Therapy is multifactorial and involves decreasing immunosuppressive
medications, use of antiviral medications, and, sometimes chemotherapy or
radiotherapy.
Skin
cancer, including squamous cell carcinoma, melanoma, and basal cell carcinoma,
occurs up to 20 times more frequently in transplant recipients than in the
general population. It tends to run a more aggressive course in transplant
recipients. Because of this risk, recipients should avoid sun exposure and
undergo routine skin evaluations, with aggressive management of lesions, should
they develop. Kaposi sarcoma may present with cutaneous lesions or also may
affect the oropharynx, lung, or other viscera. Treatment involves decreasing
immunosuppression and may also involve chemotherapy or radiotherapy.
Recurrence
of HCC after LT is usually persistence rather than recurrence. The size and
number of nodules, the presence of capsular/vascular invasion, and lymph node
involvement predict the likelihood of recurrence. Options to treat the cancer
prior to or during surgery have had little impact on the rates of recurrence,
and careful candidate selection remains the most important tool.
Cholangiocarcinomas are very difficult to detect prior to transplantation and
are rarely cured, although aggressive multimodality approaches with surgery,
chemotherapy, and brachytherapy have been associated with a good outcome in
highly selected patients at the Mayo Clinic. The only secondary cancers, which
may be indications for LT, are the symptomatic endocrine tumors, for which
worthwhile palliation can be achieved.
Recurrent
liver disease
Liver
transplant recipients may be susceptible to recurrence of their original
disease. Liver transplant recipients may develop recurrence of hepatitis C,
hepatitis B, HCC, alcoholic liver disease, or one of the autoimmune
hepatitides. The severity of recurrence varies from mild to development of
progressive allograft failure.
Hepatitis
A may recur to infect the graft, but, in the few cases reported, no significant
consequences have been described. As for HBV, until recently, recurrent HBV
infection indicated that those who were positive for HBV DNA prior to transplantation
were contraindicated for transplantation. Those who were negative for HBV DNA
were treated with hepatitis B immunoglobulin (HBIg). Now, patients are treated
with lamivudine for 6 weeks prior to transplantation until their HBV DNA is
reduced to less than one million copies per milliliter. Follow-up after
transplantation is with both lamivudine and HBIg; the dose and duration of HBIg
treatment is not firmly established, but some centers aim to maintain levels
higher than 100 U/mL forever or offer vaccination. Development of resistant
mutants is an increasing problem. The role of other antiviral therapies, such
as ganciclovir, adefovir, or famciclovir, is uncertain at this time.
HCV
recurrence after transplantation is almost universal, but the extent of the
graft damage is variable. The survival in the short term is not significantly
affected, but concerns exist regarding long-term recurrence because the rate of
developing cirrhosis at 5 years can be as high as 8-25%. Several factors have
been variably implicated in recurrence, including genotype (1b), viral load,
HLA match, degree and type of immunosuppression, quasispecies, and recipient
age. Recent studies have implicated higher viral load as a factor in HCV
recurrence.
Genotype
1 has also been cited as a marker in more severe recurrent hepatitis C in
European studies, but this has not been confirmed by North American centers. An
important concern has been whether specific primary immunosuppression with
tacrolimus results in more frequent and severe HCV recurrence in contrast to a
cyclosporine-based regimen (as based on retrospective analysis). However, when
studied prospectively, no deleterious effect of tacrolimus was noted.
Earlier
studies implicated treatment of apparent steroid-resistant rejection with the
monoclonal antibody OKT3 in exacerbating the consequences of recurrent HCV
infection. Distinction of graft injury due to recurrent HCV infection from
acute rejection may be extremely difficult, even for experienced transplant
pathologists. Justifiable caution is now warranted when aggressively treating
LT recipients with HCV infection for presumed acute cellular rejection,
generally employing a strategy of repeated liver biopsy before initiating the
typical steroid cycle.
Patients
grafted more recently for HCV appear to develop graft fibrosis more quickly.
The reasons for this are not clear. The role of interferon and/or ribavirin is
uncertain; concerns about inducing chronic rejection must be balanced against
any therapeutic benefit.
Other
complications
In
those with alcoholic liver disease, a return to alcohol use leads to recurrent
alcoholic liver disease in a small proportion of cases. However, overall 1-year
and 5-year survival is no different in this cohort of patients. Pretransplant
abstinence, often necessary to determine if the liver will recover enough to
avoid the need for transplantation, is a relatively poor indicator of future
abstinence.
Nonalcoholic
steatohepatitis (NASH) occasionally is an indication for transplantation. Recurrence
of NASH has been identified after transplantation and may be associated with
progress fibrosis in the graft. This is more common when the underlying cause
of NASH (eg, obesity, jejunoileal bypass) has not been altered.
Budd-Chiari
syndrome once was a major indication for transplantation. However, this is less
common due to the introduction of other methods of treatment. The probability
of further thrombosis despite the use of anticoagulation is 30-40%. The
presence of an underlying disorder affects the need for transplantation.
Metabolic
liver disease
If
the metabolic abnormality is primarily within the liver, transplantation is
curative; however, at present, it is indicated only if significant liver
disease (eg, hemophilia with end-stage HCV infection from multiple blood
transfusions) is present. Such indications include alpha-1 antitrypsin
deficiency, antithrombin-III deficiency, protein C deficiency, protein S
deficiency, Wilson disease, tyrosinosis, Byler disease, galactosemia,
hemophilia A and B, and Crigler-Najjar syndrome. If the disease process is
extrahepatic, liver replacement is not always indicated, unless with the
intention of modifying the effects of the disease, such as in hemochromatosis
and congenital erythropoietic porphyria.
Autoimmune
liver disease
Most
autoimmune liver diseases recur in the allograft but have little impact in the
short and medium term. Primary biliary cirrhosis recurs in the allograft in 20%
of patients at 5 years and in 45% at 51 years. Some have found that recurrence
is greater in those on tacrolimus compared with cyclosporine. The role of
ursodeoxycholic acid in this situation is unclear. Autoimmune hepatitis may
recur, especially if corticosteroids are withdrawn, but usually responds
rapidly to reintroduction of steroids with no adverse long-term impact. PSC
also may recur in the allograft. Making the diagnosis of recurrence is
difficult because differentiation of recurrent primary disease from de novo
secondary disease may be hard. PSC recurs in approximately 45% of patients at 5
years and may lead to cirrhosis, requiring retransplantation.
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OUTCOME AND PROGNOSIS |
Section
8 of 11 |
LT
is a standard proven therapy for ESLD and should be offered to any patient who
needs it. Careful selection of both donors and recipients maximizes usage by
optimizing outcomes. This requires a dedicated multidisciplinary team of health
care providers, usually concentrated in a transplant center. Living-related LT
may be one of the solutions to the donor shortage.
Overall
patient survival rates at 1 and 3 years are 85.6% and 75.9%, respectively (UNOS
data as of June 28, 2000), with corresponding graft survival rates of 79.8% and
68.8%, respectively. In addition, patients are surviving longer with improved
quality of life, as compared to pretransplant status. However, this prolonged
longevity has brought about new concerns, such as the long-term effects of
immunosuppression, as they relate to effects on the cardiovascular system,
infections, and propensity for malignancy. Thus, the search for newer
immunosuppressive strategies to minimize these adverse effects continues today.
Occasionally,
improvement in quality of life does not bring a parallel increase in the
employment capabilities of the patient. Much social mistrust and misconceptions
about liver disease still exist because it is frequently perceived as
self-inflicted. Further education of the population in this respect should
alleviate this problem in the future.
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FUTURE AND CONTROVERSIES |
Section
9 of 11 |
A
possible solution to the chronic shortage of allografts is xenotransplantation,
ie, the use of tissue from an animal donor. Most experts believe that the pig
will provide the most suitable solid organs for use in human beings. Animal
organs are rapidly rejected by a process called hyperacute rejection (HAR). In
addition, increasing evidence indicates that other barriers besides HAR, both
immune and nonimmune, might exist to limit the survival of xenografts. New strategies
to overcome these barriers are needed if long-term xenograft survival
equivalent to, or better than, that of allografts is ever to be achieved.
Xenografts
may also offer potential benefits over allografts because they offer the
possibility of manipulating donor organs before transplantation, which would
help develop graft-specific immunosuppressive treatments and thus reduce the
need for systemic immunosuppressive therapy and its risks.
Other
concerns may limit the widespread application of xenotransplantation,
notoriously the threat of transmissible zoonosis. These fears have been
heightened by data showing that coculture of porcine and human cell lines
allows endogenous porcine retroviruses to begin replication. The potential
risks of disease transmission must be examined carefully before clinical trials
can proceed. However, addressing every concern will be difficult until after
clinical xenotransplantation has begun.
Other
future directions under consideration today include hepatocyte cell transplantation
and use of bioartificial liver devices (ie, extracorporeal liver-assist
devices). Although promising, great development in these devices is still
needed, as with xenotransplantation, to bring them to the clinical arena.
Once
the realm of science fiction but now within reach, the future of organ
availability ultimately may depend on the cautious development of organ-cloning
techniques.
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PICTURES |
Section
10 of 11 |
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Caption: Picture 1. Liver Transplantation. United Network for
Organ Sharing regional map. |
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Caption: Picture 2. Frequency of liver transplantation based on
diagnosis. |
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Caption: Picture 3. Timing of liver transplantation. |
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Caption: Picture 4. Challenges and controversies of liver
transplantation. |
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Caption: Picture 5. Liver transplantation. Organ allocation and
transplantation. |
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Caption: Picture 6. Liver transplantation. Retractors in place aid
exposure in this case of polycystic liver disease with a very large liver. |
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Caption: Picture 7. Liver transplantation. Hilar dissection begins
with exposure of the undersurface of the liver. |
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Caption: Picture 8. Liver transplantation. Venous bypass. |
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Caption: Picture 9. Liver transplantation. Upper caval
anastomosis. |
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Caption: Picture 10. Liver transplantation. Lower caval
anastomosis. |
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Caption: Picture 11. Liver transplantation. Piggyback dissection. |
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Caption: Picture 12. Liver transplantation. Liver resection. |
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Caption: Picture 13. Liver transplantation. Living-related donor
liver after splitting. |
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Caption: Picture 14. Liver transplantation. Split liver. |
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Caption: Picture 15. Liver transplantation. Common adverse effects
of immunosuppression. |
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Caption: Picture 16. Liver transplantation. Etiology of
posttransplant liver dysfunction. |
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Caption: Picture 17. Liver transplantation. Workup of
posttransplant allograft dysfunction. |
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BIBLIOGRAPHY |
Section
11 of 11 |
eMedicine
Journal, June 12 2002, Volume
3, Number 6