Laboratory Studies
These are oriented toward determining the etiology of the disease, excluding HIV and other infections that may compromise a successful LT, and screening for the presence of tumors. The following laboratory tests are those most commonly ordered during a LT evaluation:
* Liver function tests, total protein, albumin
* Hepatitis screen (A, B, C)
* Serologies - Cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), HIV
* Tumor markers
* Alpha-fetoprotein, cholinesterase
* Arterial blood gases
* Others (selective) - Carbohydrate antigen 19-9, cancer antigen 125
Evaluation and workup of prospective liver transplant recipients is as follows: The first step in the process of evaluating a potential candidate for LT is to determine the severity of the liver disease by clinical evaluation. In addition, an objective assessment, to include a comprehensive laboratory and radiological evaluation, is undertaken. The goal of this evaluation is 3-fold. First, it must establish a diagnosis of ESLD; second, it must exclude any absolute or relative contraindication to the proposed procedure; finally, it must assess the suitability and degree of illness of each patient to better allocate resources and optimize survival. The specific tests are outlined below. Once the results are received, specific consultations are sought to clear the patient for LT.
Mandatory consultations and clearances are as follows:
* Cardiopulmonary clearance
* Psychiatrist and social worker consultations
* Financial clearance
* Nephrologist, infectious diseases specialist, or dentist, as needed
One of the most important tools in this scheme is the Child-Turcotte-Pugh (CTP) scoring system, which is the system most widely used to grade the severity of liver disease. A patient is considered to be Child class A if he or she has fewer than 7 points, Child class B if he or she has 7-9 points, and Child class C if he or she has more than 10 points. For listing purposes, a patient must have at least 7 points (ie, be at least a Child class B), according to the minimal listing criteria consensus initially developed when the CTP score was the basis for organ allocation. Today, the CTP score is no longer the basis for organ allocation because this is now based on the Model for End-Stage Liver Disease (MELD) scoring system (see below).
CTP Scoring System for Assessment of Severity of Disease (with respect to listing)
Open table in new window
[ CLOSE WINDOW ]
Table
Parameter 1 Point 2 Points 3 Points
Encephalopathy None Grade 1-2 Grade 3-4
Ascites None Medically controlled Uncontrolled
Albumin, g/dL >3.5 2.8-3.5 <2.8
Bilirubin, mg/dL <2 2-3 > 3
International normalized ratio <1.7 1.7-2.3 >2.3
Parameter 1 Point 2 Points 3 Points
Encephalopathy None Grade 1-2 Grade 3-4
Ascites None Medically controlled Uncontrolled
Albumin, g/dL >3.5 2.8-3.5 <2.8
Bilirubin, mg/dL <2 2-3 > 3
International normalized ratio <1.7 1.7-2.3 >2.3
Although a good effort to grade severity of disease, this classification does not reflect the severity of disease in persons with cholestatic diseases, such as primary biliary cirrhosis or primary sclerosing cholangitis (PSC), because the bilirubin limits are significantly higher for these conditions and the other manifestations are not present until very late in the disease. Thus, recent developments in the allocation system are investigating the MELD scoring system as the new basis for organ allocation.
Because of the many factors (ie, increasing number of deaths while on liver waiting list, inability to accurately categorize liver patients according to severity of liver disease using the partially subjective CTP classification, reports suggesting that waiting time correlates poorly with death while on the waiting list), a consensus opinion emerged that a revised allocation scheme was needed. The new liver allocation system implemented by the Organ Procurement Transplantation Network in February 2002 is based primarily on the severity of liver disease as assessed by the MELD and Pediatric End-Stage Liver Disease (PELD) survival models for all patients with chronic liver disease.
The MELD score is based on 3 biochemical variables, (1) serum bilirubin, (2) serum creatinine, and (3) international normalized ratio, and has been shown in retrospective and prospective studies to be highly predictive of 3-month mortality in patients with chronic liver disease. Similarly, the PELD model for pediatric patients was developed based on analyses of data from the Study of Pediatric Liver Transplantation database and has been shown retrospectively to be predictive of waiting list mortality in pediatric patients.
Model for End-Stage Liver Disease (MELD) scoring system:
* Serum creatinine (Loge value) 0.957
o The maximum serum creatinine considered within the MELD score equation is 4.0 mg/dL (ie, for candidates with a serum creatinine >4.0 mg/dL, the serum creatinine level is set to 4.0 mg/dL).
o For candidates on dialysis, defined as having 2 or more dialysis treatments within the prior week, or candidates who have received 24 hours of continuous venovenous hemodialysis (CVVHD) within the prior week, the serum creatinine level is automatically be set to 4.0 mg/dL.
* Serum bilirubin (Loge value) 0.378
* International normalized ratio (INR) (Loge value) 1.120
* Using these prognostic factors and regression coefficients, the UNetSM computerized system assigns a MELD score for each candidate based on the following calculation: MELD score = 0.957 x Log e (creatinine mg/dL) + 0. 378 x Log e (bilirubin mg/dL) + 1.120 x Log e (INR) + 0.643. Laboratory values <1.0 are set to 1.0 for the purposes of the MELD score calculation.2
* As an example, for a hypothetical candidate with cirrhosis caused by hepatitis C virus who has a serum creatinine concentration of 1.9 mg/dL, a serum bilirubin concentration of 4.2 mg/dL and an INR value of 1.2, the risk score would be calculated as follows: MELD score = (0.957 x Log e 1.9) + (0.378 x Log e 4.2) + (1.120 x Log e 1.2) + 0.643 = 2.0039.
* The MELD score for each liver transplant candidate derived from this calculation is rounded to the tenth decimal place and then multiplied by 10. The hypothetical candidate in the example described above, therefore, would be assigned a risk score of 20. The MELD score is limited to a total of 40 points maximum.
* Pediatric End-Stage Liver Disease (PELD) scoring system:
o Albumin (Log e value) -0.687
o Total bilirubin (Log e value) 0.480
o INR (Log e value) 1.857
o Growth failure (<-2 standard deviations [SD]) 0.667
o Age (<1 y) 0.436 (Scores for candidates listed for liver transplantation before the candidate’s first birthday continue to include the value assigned for age (<1 y) until the candidate reaches 24 months of age.)
o UNetSM assigns a PELD score for each candidate based on the following calculation: PELD score = 0.436 (age [<1 y]) – 0.687 x Log e (albumin g/dL) + 0.480 x Log e (total bilirubin mg/dL) + 1.857 x Log e (INR) + 0.667 (growth failure [<-2 SD present]). Laboratory values <1.0 are set to 1.0 for the purposes of the PELD score calculation.2 Growth failure is calculated based on age and gender using the current CDC growth chart.
o This is a much more precise method of ranking patients; therefore, patients most in need will be given the highest priority for donated livers, rather than simply allocating them to patients who have waited longer but who may be much more stable. The MELD policy replaced status 2A, 2B, and 3 with a continuous scale in February 2002 and is the current basis for liver allocation. Neither of these 2 scoring systems favors all patients, specifically patients with HCCs or exceptional cases.
Listing of candidates
* Once the workup is complete, the patient and all workup results are presented to the candidate selection committee for a decision about the suitability for transplantation. This committee consists of transplantation surgeons, hepatologists, psychiatrists, social work representatives, cardiologists, pulmonologists, anesthesiologists, and, occasionally, the patient's primary care physician.
* The following questions are posed to the committee before listing the patient for transplantation:
o Does the patient need LT as therapy for his or her disease?
o Have the indications and contraindications been properly assessed?
o What is the surgical risk?
o Is the patient's medical condition such that he or she will be able to tolerate the procedure and postoperative course?
o What are the chances of recurrent disease affecting graft and patient survival?
Imaging Studies
* Radiography (including chest radiography)
* Duplex ultrasonography
* Angiogram/magnetic resonance angiography (selective)
* Abdominal CT scanning
* Cardiopulmonary evaluation
* Stress thallium scanning, coronary angiography (as indicated)
* Echocardiography
Other Tests
* Electrocardiography
* Pulmonary function testing
Diagnostic Procedures
* During the workup of these patients, many tests may be ordered. Specific testing is performed on a case-by-case basis.
* In the author's experience, most patients undergo both upper and lower GI endoscopies to evaluate for the presence of esophageal or gastric varices or to exclude GI malignancy.
* Other common procedures may include paracentesis in patients with ascites, both for diagnostic purposes (eg, to exclude SBP) and for therapeutic intent (eg, alleviation of distention and hepatohydrothorax).
* Many patients undergo a TIPS procedure while awaiting LT because of complications that warrant this approach. These conditions include esophageal or gastric variceal bleeding, refractory ascites, and hepatorenal syndrome (HRS).
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.
Monday, February 1, 2010
liver transplantation (1)
History of the Procedure
Research into the possibility of 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, which led to improvements in rejection rates.
In 1983, the US National Institutes of Health 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, 4,500 procedures were performed, up from approximately 100 in 1982. Currently, approximately 16,000 patients are on the liver waiting list, and slightly more than 6,300 liver transplants were performed in 2008 (United Network for Organ Sharing [UNOS] data as of September 15, 2009).1
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 development 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 80-90% and 5-year survival rates of 62-80%.1 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.
Organ allocation has also evolved over time, with the current system based upon the Model for End-Stage Liver Disease (MELD), with a focus on maximizing transplant benefit.2,3 Further refinements of the model are always ongoing and aim to improve fairness in allocation and survival results. Hepatitis C virus, hepatocellular carcinoma (HCC), chronic renal dysfunction, and alcohol relapse continue to be major challenges, and continued research in these areas will undoubtedly lead to better outcomes for transplant recipients.
Problem
ESLD 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 transplantation because other criteria are also used to determine candidacy. Diagnoses indicating potential candidacy for LT include the following:
* 070 Viral hepatitis
* 1550-1552 Malignant neoplasm of liver and intrahepatic bile ducts
* 2115 Benign neoplasm of liver and biliary passages
* 2308 Carcinoma of liver and biliary system
* 2353 Neoplasm of uncertain behavior in liver and biliary passages
* 2390 Neoplasm of unspecified nature in digestive system
* 2710 Glycogenesis
* 2720 Pure hypercholesterolemia
* 2727 Lipidoses
* 2751 Disorders of copper metabolism
* 2770-2776 Cystic fibrosis, disorders of porphyrin metabolism, other disorders of purine and pyrimidine metabolism, amyloidosis, disorders of bilirubin excretion, mucopolysaccharidosis, other deficiencies of circulating enzymes
* 2860 Congenital factor VIII disorder
* 2861 Congenital factor IX disorder
* 4530 Budd-Chiari syndrome
* 570 Acute and subacute necrosis of liver
* 5710 Alcoholic fatty liver
* 5712 Alcoholic cirrhosis of liver
* 5714 Chronic hepatitis
* 5715 Cirrhosis of liver without mention of alcohol
* 5716 Biliary cirrhosis
* 5718 Other chronic nonalcoholic liver disease
* 5719 Unspecified liver disease without mention of alcohol
* 5728 Other sequelae of chronic liver disease
* 5758 Other specified disorders of gallbladder
* 5761,5762 Cholangitis, obstruction of bile duct
* 75161,75169 Biliary atresia, other anomalies of gallbladder, bile ducts, and liver
* 7744 Perinatal jaundice due to hepatocellular damage
* 7778 Other specified perinatal disorders of digestive system
* 864 Injury to liver
* 3483 Encephalopathy, unspecified
* 452 Portal vein thrombosis
The major constraint to meeting the demand for transplants is the availability of donated (cadaver) organs.4 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, the National Organ Donation Collaborative efforts, currently ongoing, and laws that require all deaths to be reported to organ procurement organizations have resulted in increased organ donations. 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, though these efforts still fail to meet the need for organs.
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. 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, UNOS personnel direct the organ to the recipient with the greatest need in another region. Organ recovery coordinators are on call 24 hours a day 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 27,013 deaths reported in 2004 and a death rate of nearly 9.2 cases per 100,000 persons.5 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.
Presentation
Patients present with signs and symptoms of ESLD, which is discussed in more detail in the next section.
Indications
Currently, any patient who has chronic or acute liver disease that leads to the 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.
Frequency of liver transplantation based on diagn...
Frequency of liver transplantation based on diagnosis.
[ CLOSE WINDOW ]
Frequency of liver transplantation based on diagn...
Frequency of liver transplantation based on diagnosis.
The red portion 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 portion 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:
* Recurrent variceal hemorrhage
* Intractable ascites
* Spontaneous bacterial peritonitis
* Refractory encephalopathy
* Severe jaundice
* Exacerbated synthetic dysfunction
* Sudden deterioration
* Fulminant hepatic failure
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.6 Portal hypertension can manifest either silently (ie, decreased platelet count, WBC count, or both) or overtly, with variceal bleeding. Other manifestations include the development of hepatocellular carcinoma (HCC), which is common in patients with hepatitis B and hepatitis 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 treatment 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 transplantation) 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.
Contraindications
Currently accepted absolute contraindications to LT by most programs include HIV positivity, spontaneous bacterial peritonitis (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 count in the peritoneal fluid. The absolute criteria for a diagnosis of SBP are the presence of more than 200-250 polymorphonuclear leukocytes, the identification of bacteria in the fluid by light microscopy, subsequent positive bacterial culture results in the appropriate clinical setting, or a combination thereof. 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 transplantation.
Secondary liver malignancies are not indications for hepatic replacement because of the 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 a liver transplant, these are red flags, which, if multiple or if manifesting 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 transplantation may be required), advanced cachexia, large HCCs (more advanced than stage II, as described by the UNOS-modified American Joint Committee on Cancer [AJCC] classification), medication-resistant hepatitis B virus (HBV) cirrhosis, portal and mesenteric vein thrombosis, history of prior cancer not meeting full AJCC cure criteria, 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. In cases of mesenteric thrombosis, cavoportal hemitransposition may offer a chance of successful liver engraftment in these patients.
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-sided heart function, treatment with vasodilators, prostaglandin, or both allows safe LT.
A history 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 or adefovir 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 or prevent recurrence. As a rule, single-lesion HCCs smaller than 5 cm or 3 or fewer lesions (the largest <3 cm), ie, AJCC stages I and II, are associated with less chance of recurrence and survival rates equal to those of patients undergoing transplantation because of nonmalignant conditions. Protocols using chemoembolization have shown promising early results for larger tumors. Finally, the widespread use of chemoembolization protocols while on the waiting list and aggressive radiofrequency ablation may change the indications and therapeutic approaches in the immediate future.
Research into the possibility of 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, which led to improvements in rejection rates.
In 1983, the US National Institutes of Health 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, 4,500 procedures were performed, up from approximately 100 in 1982. Currently, approximately 16,000 patients are on the liver waiting list, and slightly more than 6,300 liver transplants were performed in 2008 (United Network for Organ Sharing [UNOS] data as of September 15, 2009).1
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 development 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 80-90% and 5-year survival rates of 62-80%.1 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.
Organ allocation has also evolved over time, with the current system based upon the Model for End-Stage Liver Disease (MELD), with a focus on maximizing transplant benefit.2,3 Further refinements of the model are always ongoing and aim to improve fairness in allocation and survival results. Hepatitis C virus, hepatocellular carcinoma (HCC), chronic renal dysfunction, and alcohol relapse continue to be major challenges, and continued research in these areas will undoubtedly lead to better outcomes for transplant recipients.
Problem
ESLD 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 transplantation because other criteria are also used to determine candidacy. Diagnoses indicating potential candidacy for LT include the following:
* 070 Viral hepatitis
* 1550-1552 Malignant neoplasm of liver and intrahepatic bile ducts
* 2115 Benign neoplasm of liver and biliary passages
* 2308 Carcinoma of liver and biliary system
* 2353 Neoplasm of uncertain behavior in liver and biliary passages
* 2390 Neoplasm of unspecified nature in digestive system
* 2710 Glycogenesis
* 2720 Pure hypercholesterolemia
* 2727 Lipidoses
* 2751 Disorders of copper metabolism
* 2770-2776 Cystic fibrosis, disorders of porphyrin metabolism, other disorders of purine and pyrimidine metabolism, amyloidosis, disorders of bilirubin excretion, mucopolysaccharidosis, other deficiencies of circulating enzymes
* 2860 Congenital factor VIII disorder
* 2861 Congenital factor IX disorder
* 4530 Budd-Chiari syndrome
* 570 Acute and subacute necrosis of liver
* 5710 Alcoholic fatty liver
* 5712 Alcoholic cirrhosis of liver
* 5714 Chronic hepatitis
* 5715 Cirrhosis of liver without mention of alcohol
* 5716 Biliary cirrhosis
* 5718 Other chronic nonalcoholic liver disease
* 5719 Unspecified liver disease without mention of alcohol
* 5728 Other sequelae of chronic liver disease
* 5758 Other specified disorders of gallbladder
* 5761,5762 Cholangitis, obstruction of bile duct
* 75161,75169 Biliary atresia, other anomalies of gallbladder, bile ducts, and liver
* 7744 Perinatal jaundice due to hepatocellular damage
* 7778 Other specified perinatal disorders of digestive system
* 864 Injury to liver
* 3483 Encephalopathy, unspecified
* 452 Portal vein thrombosis
The major constraint to meeting the demand for transplants is the availability of donated (cadaver) organs.4 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, the National Organ Donation Collaborative efforts, currently ongoing, and laws that require all deaths to be reported to organ procurement organizations have resulted in increased organ donations. 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, though these efforts still fail to meet the need for organs.
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. 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, UNOS personnel direct the organ to the recipient with the greatest need in another region. Organ recovery coordinators are on call 24 hours a day 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 27,013 deaths reported in 2004 and a death rate of nearly 9.2 cases per 100,000 persons.5 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.
Presentation
Patients present with signs and symptoms of ESLD, which is discussed in more detail in the next section.
Indications
Currently, any patient who has chronic or acute liver disease that leads to the 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.
Frequency of liver transplantation based on diagn...
Frequency of liver transplantation based on diagnosis.
[ CLOSE WINDOW ]
Frequency of liver transplantation based on diagn...
Frequency of liver transplantation based on diagnosis.
The red portion 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 portion 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:
* Recurrent variceal hemorrhage
* Intractable ascites
* Spontaneous bacterial peritonitis
* Refractory encephalopathy
* Severe jaundice
* Exacerbated synthetic dysfunction
* Sudden deterioration
* Fulminant hepatic failure
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.6 Portal hypertension can manifest either silently (ie, decreased platelet count, WBC count, or both) or overtly, with variceal bleeding. Other manifestations include the development of hepatocellular carcinoma (HCC), which is common in patients with hepatitis B and hepatitis 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 treatment 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 transplantation) 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.
Contraindications
Currently accepted absolute contraindications to LT by most programs include HIV positivity, spontaneous bacterial peritonitis (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 count in the peritoneal fluid. The absolute criteria for a diagnosis of SBP are the presence of more than 200-250 polymorphonuclear leukocytes, the identification of bacteria in the fluid by light microscopy, subsequent positive bacterial culture results in the appropriate clinical setting, or a combination thereof. 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 transplantation.
Secondary liver malignancies are not indications for hepatic replacement because of the 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 a liver transplant, these are red flags, which, if multiple or if manifesting 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 transplantation may be required), advanced cachexia, large HCCs (more advanced than stage II, as described by the UNOS-modified American Joint Committee on Cancer [AJCC] classification), medication-resistant hepatitis B virus (HBV) cirrhosis, portal and mesenteric vein thrombosis, history of prior cancer not meeting full AJCC cure criteria, 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. In cases of mesenteric thrombosis, cavoportal hemitransposition may offer a chance of successful liver engraftment in these patients.
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-sided heart function, treatment with vasodilators, prostaglandin, or both allows safe LT.
A history 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 or adefovir 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 or prevent recurrence. As a rule, single-lesion HCCs smaller than 5 cm or 3 or fewer lesions (the largest <3 cm), ie, AJCC stages I and II, are associated with less chance of recurrence and survival rates equal to those of patients undergoing transplantation because of nonmalignant conditions. Protocols using chemoembolization have shown promising early results for larger tumors. Finally, the widespread use of chemoembolization protocols while on the waiting list and aggressive radiofrequency ablation may change the indications and therapeutic approaches in the immediate future.
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