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Liver Transplantation
GENERAL PRINCIPLES
Liver transplantation is treatment of
choice for :
Acute and chronic end-stage liver disease,
Hepatomas
Early cholangiocarcinoma
Some liver-based metabolic disorders
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Depending on the patient's condition
and organ availability, options
include:
whole-organ deceased donor
split-liver deceased donor
living donor transplantation.
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Liver transplantation currently
affords patients a survival
posttransplant of greater than
85% at 1 year and greater than
70% at 5 years.
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Indications for Liver Transplantation in Adults:
Etiologies of End-Stage Liver Disease
1. Fulminant Hepatic Failure
2. Alcoholic Liver Disease
3. Chronic Hepatitis C
4. Chronic Hepatitis B
5. Non-alcoholic steatohepatitis
6. Autoimmune Hepatitis
7. Primary Biliary Cirrhosis
8. Primary Sclerosing Cholangitis
9. Hepatic tumors
10. Metabolic anddrgenetic
disorders
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Indications for Liver Transplantation in Adults
Presence of irreversible liver disease and a life expectancy
of less than 12 months with no effective medical or
surgical alternatives to transplantation
Chronic liver disease that has progressed to the point of
significant interference with the patient's ability to work or
with his/her quality of life
Progression of liver disease that will predictably result in
mortality exceeding that of transplantation (85% one-year
patient survival and 70% five-year survival)
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Manifestations of End-Stage Liver Disease
Progressive jaundice
Intractable ascites
Spontaneous bacterial peritonitis
Hepatorenal Syndrome
Encephalopathy
Variceal bleeding
Intractable pruritus
Chronic fatigue (such as resulting in loss of
gainful employment)
Bleeding diathesis or coagulopathy
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Patient with liver failure
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Contraindications
All Recipients
Sepsis
Recent extra-hepatic malignancy
Irreversible cardiopulmonary disease
Active substance abuse
(HIV positive)Living donor recipients only
Re-transplant
Acute liver failure
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CARE OF PATIENT DURING
WAITING TIME
Required a regular follow-up
Every 2 to 4 weeks depending on severity of liver disease
Routine US doppler, surveillance of oesophagal varices,
management of ascites
This follow-up can be done:
• Directly by the transplant center
• By the referring general physician or specialist
•
All therapeutic decisions should be made in accordance with the
transplant physicians
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Expanding The Donor Pool
Age
Hepatitis B/C organs
High risk behavior
History of malignancy
Evaluate risk : benefit
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Living Donor: Liver Transplantation
Driven by:
Expansion in number of patients requiring
liver transplantation
Shortage of deceased donor organs
Increase in waiting list deaths
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Living Donor Transplantation
Recipient Advantages
• Elective surgery
• Scheduled (less uncertainty)
• Avoid long waiting time
Recipient Disadvantages
• Increased technical complications
• Arterial stenosis / thrombosis
• Biliary leak / stricture
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Living Donor Transplantation
Donor Advantages
• Emotional Gain
Donor Disadvantages
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Psychological stress to donor and family
Inconvenience / risk of evaluation process
Operative mortality ( 1/150 liver)
Major postoperative complications (2-10%)
Minor post operative complications (50%)
Possible long term morbidity
Unrecognized covert liver disease
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Living Liver Donor Evaluation
Donor Advocacy Team
• Age < 55yrs
• Compatible blood group
• History & physical
• Routine labs
• Ultrasound of liver
• Volumetric analysis by MRA
• R. lobe wt. = 1% recipient total wt
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Living Donor Evaluation
Decision to donate must be voluntary
Informed consent
Motivation to donate
Behavioral and psychological health
Donor recipient relationship
Diversity issues
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Preoperative management of complications
associated with hepatic failure & cirrhosis
Hepatic Encephalopathy
Cerebral Edema
Acute Renal Failure
Infection & Sepsis
Metabolic Derangements
Malnutrition
Coagulopathy
Portal Hypertension
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PRETRANSPLANT EVALUATION
The pretransplant evaluation has several
purposes and should be systematic,
covering all organ systems to ensure
that no major problems are overlooked.
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PRETRANSPLANT EVALUATION
A/Determine the etiology of liver disease and identify
patients with decompensated liver cirrhosis:
Spontaneous hepatic encephalopathy
Refractory ascites
Hepatorenal syndrome
Hepatopulmonary syndrome
Recurrent or refractory variceal bleeding
Recurrent infections such as cholangitis or spontaneous
bacterial peritonitis
Intractable pruritus
Severe malnutrition
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PRETRANSPLANT EVALUATION
B/Identify underlying medical problems that should
be dealt with to optimize the candidate's overall
condition before transplant
C/Identify and address psychiatric, chemical
dependency, and compliance issues and how they
impact a potential candidate's appropriateness for,
and timing of, transplant
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PRETRANSPLANT EVALUATION
D/Identify absolute contraindications:
Active extrahepatic sepsis
Extrahepatic malignancy
Acquired immune deficiency syndrome
Advanced cardiopulmonary disease
E/For patients with hepatic malignancy, order
preoperative imaging to detect extrahepatic spread
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PRETRANSPLANT EVALUATION
F/For acute (fulminant) liver failure (ALF) patients (generally
more ill than those with chronic failure), refer them early
to a transplant center
1/Poor prognostic indicators for spontaneous recovery
from ALF:
• Factor V level less than 30%
• pH less than 7.3
• International normalized ratio (INR) greater than 6.5
• Stage 3 or 4 encephalopathy
• Lack of response to medical therapy within 24 to 48 hours
2/More severe hepatic parenchymal dysfunction, manifested by
coagulopathy, hypoglycemia, and lactic acidosis
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PRETRANSPLANT EVALUATION
3/More infectious complications
4/Higher incidence of renal failure
5/Higher incidence of cerebral edema and neurologic
complications
a/Some centers use intracranial pressure monitoring to
monitor cerebral edema.
b/Mannitol, hyperventilation, and thiopental have been
used to prevent elevated intracranial pressure (>15 mm
Hg).
6/Multiple-organ dysfunction syndrome
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Implantation of liver transplantation after hepatectomy
Prasad, K R et al. BMJ 2001;322:845-847
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Removal of cirrhotic liver
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Implanting the new liver
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New liver
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Right lobe of
liver
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Vena Cava
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Left lobe of
liver
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Implantation in recipient
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INTRAOPERATIVE CARE
A/ Venous and arterial monitoring catheters
and large-volume infusion lines are placed
in the operating room and can be a source of
immediate morbidity (pneumothorax or
hemothorax, pericardial tamponade, arterial
pseudoaneurysm, air embolism) and
hemorrhage in the coagulopathic patient.
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INTRAOPERATIVE CARE
B/The transplant operation is divided into three phases:
1/Pre-anhepatic (mobilizing the recipient's diseased liver in
preparation for its removal)
2/Anhepatic, characterized by coagulopathy and decreased
venous return to the heart because of occlusion of the
inferior vena cava and portal vein
• Many centers routinely use a venous bypass system during this
time.
• After the native liver is removed, the donor liver is anastomosed to
the appropriate structures to place the new liver in an orthotopic or
piggyback (using a side-to-side cavoplasty technique) position.
3/Post-anhepatic, beginning after reperfusion.
Hemodynamic instability on reperfusion can result in
hypotension and serious arrhythmias due to acidosis,
electrolyte abnormalities, air embolus, and cardiac strain.
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Early Post-operative Management
Extubate early
Remove lines as soon as possible
Immunosuppression
Replace ascitic losses with albumin
Avoid FFP unless
• active bleeding
• Invasive intervention is required
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POSTOPERATIVE CARE
The postoperative course can range from
smooth to extremely complicated,
depending mainly on the patient's
preoperative status and the development of
any complications. Initial posttransplant
care should be in a critical care unit with
continuous invasive hemodynamic
monitoring and mechanical ventilation as
needed.
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POSTOPERATIVE CARE
A/Stabilization and recovery of major organ systems
functions
B/Evaluation for continual improvement in graft function
1/Normalizing mental status
2/Normalizing coagulation profile
3/Resolution of hypoglycemia
4/Clearance of serum lactate
5/Serum transaminase levels usually rise during the first 24 to 48 hours
secondary to reperfusion and preservation injury and then fall rapidly
over the next 48 to 72 hours. Serum bilirubin and alkaline phosphatase
levels may take several days longer to normalize.
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POSTOPERATIVE CARE
C/Provision of adequate immunosuppression
D/Prevention along with vigilant monitoring for, and
expeditious management of, complications in the
immediate posttransplant period, to minimize morbidity
and mortality
1/Avoid oversedation with benzodiazepines or morphine.
2/Avoid hypotension (systolic blood pressure below 100 mm Hg) to
avoid renal dysfunction and graft thrombosis. Provision of adequate
preload is paramount.
3/Limit central venous pressure to 8 to 12 cm H2O to
• optimize portocaval pressure gradient and graft perfusion
• minimize liver graft congestion/edema and bleeding risk from caval
anastomoses
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POSTOPERATIVE COMPLICATIONS
A/Surgical complications
1/Hemorrhage.
- Bleeding is common and can be compounded by deficits
in coagulation factors, fibrinolysis, and platelet function.
- Blood loss should be monitored by serial measurements
of hemoglobin and detection of changes associated with
acute hypovolemia (e.g., decreased central venous
pressure and urine output).
If bleeding persists despite correction of coagulation
deficiencies, surgical exploration is indicated
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POSTOPERATIVE COMPLICATIONS
2/Vascular complications. The overall incidence of vascular
complications is reported to be 8% to 12%. Thrombosis is
the most common early event; stenosis and
pseudoaneurysm formation occur later.
Doppler ultrasound evaluation is the initial investigation of choice,
with more than 90% sensitivity and specificity for thrombosis.
a/Hepatic artery thrombosis (HAT) has a reported incidence of approximately
2% in adults and 10% in children. If detected early, up to 70% of grafts can be
salvaged with urgent exploration, thrombectomy, or revision of the
anastomosis.
b/Thrombosis of the portal vein or hepatic veins is far less frequent. Liver
dysfunction, tense ascites, and variceal bleeding can occur. If thrombosis is
diagnosed early, operative thrombectomy and revision of the anastomosis may
be successful. If thrombosis occurs late, liver function is frequently preserved
because of the collateral veins; a retransplant is usually not necessary
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POSTOPERATIVE COMPLICATIONS
3/Biliary complications. Biliary complications occur
in 15% to 35% of cases.
a/Leak (early)
• (1) Clinical symptoms: fever, abdominal pain, and peritoneal irritation.
• (2) Diagnosis: Bilious output from surgical drains; ultrasound may demonstrate a
fluid collection; hepatobiliary scintigraphy (e.g., HIDA [hepatobiliary
iminodiacetic acid] scan) may demonstrate extravasation of radioactive tracer;
cholangiography] or ERCP [endoscopic retrograde cholangiopancreatography])
• (3) Management: Endoscopic stent placement and biloma drainage, or operative
repair hepaticojejunostomy).
b/Stricture (later)
most common at the anastomotic site, likely related to local ischemia
• (1) Clinical symptoms: cholangitis or cholestasis, or both
• (2) Diagnosis: Ultrasound, magnetic resonance cholangiopancreatography,
cholangiography
• (3) Management: balloon dilatation or stent placement across the stricture, or both.
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POSTOPERATIVE COMPLICATIONS
4/Wound complications
a/Superficial wound infection, hematoma, and seroma
(early)
• (1) Diagnosis: drainage, increasing pain, erythema, fluctuance
• (2) Management: (Re)incision and drainage, allowing for healing
by secondary intention (serial open wound dressing changes)
,antibiotics
b/Incisional hernias (later), associated with malnutrition,
attenuated fascia, and immunosuppression
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POSTOPERATIVE COMPLICATIONS
5/Primary nonfunction
a/Incidence: 3% to 5%
b/Mortality rate is more than 80% without a retransplant
c/Definition: poor or no hepatic function from the time of transplant
d/Associated donor factors.
•
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•
•
(1) Donor age greater than 49 years
(2) Macrosteatosis greater than 30%
(3) Donor intensive care unit stay greater than 3 days
(4) Cold ischemia time greater than 18 hours
(5) Reduced-size grafts
e/Diagnosis: rule out HAT, severe preservation injury, accelerated acute
rejection, and severe infection, because they can mimic primary nonfunction.
The diagnosis is usually based on clinical parameters; graft biopsy may be
helpful in some cases.
f/Treatment
• (1) Intravenous prostaglandin E1
• (2) Early relisting for retransplantation
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POSTOPERATIVE COMPLICATIONS
B/Medical complications
1/Neurologic
most commonly related to drugs or a poorly functioning graft
• a/Symptoms:
• (1) Decreased level of consciousness
• (2) Seizures
• (3) Focal neurologic deficits
• b/Other neurologic complications:
•
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(1) Hypoxic ischemic encephalopathy
(2) Central pontine myelinolysis
(3) Cerebral edema
(4) Intracranial hematomas
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POSTOPERATIVE COMPLICATIONS
2/Pulmonary
in up to 75% of recipients
a/Noninfectious complications (first postoperative week):
•
•
•
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(1) Pulmonary edema
(2) Pleural effusions
(3) Atelectasis
(4) Acute respiratory distress syndrome (ARDS)
• (a) incidence less than 5%, but mortality greater than 80%
• (b) most common when underlying bacterial infection is present, multiple transfusions,
hypertension, aspiration, and antilymphocyte therapy
b/Infectious complications (after the first week):
• (1) Bacterial
• (2) Fungal
• (3) Viral
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POSTOPERATIVE COMPLICATIONS
3/Renal
affecting almost all liver recipients. Renal failure increases the mortality rate.
Causes of renal failure:
a/Pretransplant
• (1) Hepatorenal syndrome
• (2) Acute tubular necrosis
b/Postoperative
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(1) Hypovolemia
(2) Ischemic acute tubular necrosis
(3) Drug nephrotoxicity (calcineurin inhibitors)
(4) Preexisting subclinical or overt renal disease (e.g., diabetic
nephropathy, hepatitis ,membranoproliferative glomerulonephritis)
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POSTOPERATIVE COMPLICATIONS
4/Immunosuppressive:
a/Posttransplant diabetes
b/Hyperlipidemia
c/Viral and fungal infections
d/Squamous and basal cell skin cancers and lymphoma
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POSTOPERATIVE COMPLICATIONS
5/Recurrence of primary liver disease
may require treatment and can significantly impact graft and patient
survival
a/Hepatitis B (Highly effective peritransplant and posttransplant longterm prophylaxis protocols that include lamivudine and/or hepatitis B
immune globulin [HBIg] prevent hepatitis B recurrence.)
b/Hepatitis C (~20% cirrhosis rate from recurrent hepatitis C at 5 years
posttransplant; no evidence-based recommendations on posttransplant
treatment and efficacy of prophylaxis with pegylated interferon and
ribavirin available)
c/Autoimmune liver diseases (Recurrence rates of clinically significant
autoimmune hepatitis, primary sclerosing cholangitis, and primary
biliary cirrhosis are low and controversial; long-term posttransplant
immunosuppression that includes steroids may offer theoretical [but
not evidence-based] added benefits with regard to autoimmune disease
recurrence prevention.)
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Post-operative complications &
management of liver transplant patients
Right pleural effusion
• May affect ventilation, necessitating drainage.
Hepatic edema secondary to aggressive
resuscitation & increased intravascular
volume.
• Goal CVP 6-10. Minimize increased hepatic vein pressures
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Post-operative complications &
management of liver transplant patients
Renal failure
• Elevation of creatinine & BUN observed in
nearly all transplant patients secondary to ATN,
hepatorenal syndrome. Usually self-limiting.
May necessitate therapy with loop diuretics, renal
replacement therapy.
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Post-operative complications &
management of liver transplant patients
Electrolyte Derangements
• Recovering graft increases demand for magnesium &
phosphorous.
• Transfusion of citrate rich blood products results in
decreased serum magnesium & calcium.
• Rapid correction of chronic hyponatremia with isotonic
solution can have severe neurological consequence.
Judicious use of hypotonic solutions with goal of serum
Na 125-130 advised.
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Post-operative complications &
management of liver transplant patients
Thrombocytopenia
• Preoperative portal hypertension results in
splenomegaly & platelet sequestration. Generally
improves as graft recovers. May necessitate
replacement if bleeding is encountered or invasive
procedures are planned. Splenectomy is rarely
indicated.
• Platelet dysfunction secondary to renal & hepatic
failure may be improved acutely with DDAVP.
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Post-operative complications &
management of liver transplant patients
Biliary leak
• RUQ pain, fever, persistent elevation of bilirubin, liver enzymes.
Biloma on CT.
• Treated with endoscopic stent, percutaneous drainage. Possible
surgical revision if duct is ischemic.
Hepatic artery thrombosis
• Persistent elevation or increasing liver enzymes, poor
graft function. Diagnosed with U/S, CT angiography,
MRA.
• Treated with immediate revascularization.
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Induction of Immunosuppression
Triple therapy
Initiated immediately following transplantation.
• Calcineurin inhibitor (tacrolimus, cyclosporine)
• anti-proliferative agent (mycophenolate)
• corticosteroid taper.
Agents vary according to etiology of liver disease
• Thymoglobulin & Hb Ig utilized in hepatitis patients along with
viral replication & to avoid coritocsteroid usage.
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Allograft rejection
Hyperacute rejection
• Secondary to preformed Ab to graft antigen.
• Extremely rare
• Necessitates retransplantation.
Acute Cellular Rejection
• 70% of patients 5 to 14 days following transplant.
• Heralded by fever, jaundice, elevation of liver enzymes.
• Diagnosed by liver biopsy. Demonstrates endothelialitis
& non-suppurative cholangitis.
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Classification of Complications
Graft dysfuntion or non-function
Technical
Immunological
Infective
Extrahepatic
Drug effects
Medical
Recurrent Disease
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Technical Complications
Bleeding
Hepatic artery thrombosis / stenosis
Portal vein thrombosis / stenosis
Biliary complications
• Leak
• Stricture
• Sludge
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Immunological
Acute Rejection
5-10 days post transplant but may occur at any time
Clinical
Elevated LFTS
Liver Biopsy Portal tract inflammatory infiltrate
Endothelialitis
Destruction of biliary epithelium
Treatment
Steroids
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Infective
Bacterial < 15 days
• Commonly lines /chest /urine
Fungal > 15 days
•
•
•
•
Prolonged hospitalization
Broad spectrum antibiotics
Re transplant
Roux loop
Viral
> 4 weeks
• CMV – recipients of CMV + organs
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Extra-hepatic
Cardiac failure / infarction
Pulmonary
Neurological
Renal
Endocrine
• Diabetes (33%)
Drug effects
Recurrent disease
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When to contact the transplant
program:
Sooner rather than later
New medications
Fever
Abnormal liver functions tests
Vomiting / diarrhea
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?
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