National Medical Policy

Transcription

National Medical Policy
Subject:
Liver Transplantation
Policy Number:
NMP327
Effective Date*: March 2007
Updated:
March 2015
This National Medical Policy is subject to the terms in the
IMPORTANT NOTICE
at the end of this document
For Medicaid Plans: Please refer to the appropriate Medicaid Manuals for
coverage guidelines prior to applying Health Net Medical Policies
The Centers for Medicare & Medicaid Services (CMS)
For Medicare Advantage members please refer to the following for coverage
guidelines first:
Use
X
Source
National Coverage Determination
(NCD)
Reference/Website Link
Adult Liver Transplantation 260.1:
http://www.cms.gov/medicare-coveragedatabase/search/advanced-search.aspx
Pediatric Liver Transplantation 260.2:
http://www.cms.gov/medicare-coveragedatabase/search/advanced-search.aspx
X
National Coverage Manual Citation
Local Coverage Determination
(LCD)*
Article (Local)*
Other
Liver Transplantation Mar 15
MLN Matters Number: MM7908. June 21, 2012.
Liver Transplantation for Patients with
Malignancies: http://www.cms.gov/Outreachand-Education/Medicare-Learning-NetworkMLN/MLNMattersArticles/downloads/MM7908.pdf
MLN Matters. Number: MM8871 Revised Related
Change Request (CR) # 8871. Release Date:
November 19, 2014. Screening for Hepatitis C
Virus (HCV) in Adults:
http://www.cms.gov/Outreach-andEducation/Medicare-Learning-NetworkMLN/MLNMattersArticles/downloads/MM8871.pdf
1
None
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outside their service area when those MACs have exclusive coverage of an item
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Hyperlinks to Contents
Pre-Transplant Evaluation
Initial Policy Statement
General Patient Selection Criteria
Complications of Irreversible Cirrhosis
Variceal Bleeding
Hepatopulmonary Syndrome
Hepatic Encephalopathy
Portopulmonary Hypertension
Ascites
Pruritus
Spontaneous Bacterial Peritonitis
Hepatic Osteopenia
Hepatorenal Syndrome
Biochemical Criteria
Disease-Specific Criteria
Acute Fulminant Liver Failure
Chronic Noncholestatic Liver Disorders (Hepatocellular Diseases)
Alcoholic Cirrhosis
Autoimmune Hepatitis in Adults
Chronic Hepatitis C
Autoimmune Hepatitis in Children
Chronic Hepatitis B
Congenital Erythropoietic Protoporphyria
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HELLP Syndrome
Chronic Cholestatic Liver Diseases
Primary Biliary Cirrhosis
Nonsyndromic Paucity of the Intrahepatic Bile Ducts
Primary Sclerosing Cholangitis
Cystic Fibrosis
Extrahepatic Biliary Atresia
Familial Intrahepatic Cholestasis
Alagille Syndrome
Caroli's Disease
Metabolic Disorders Causing Cirrhosis
Alpha-1-Antitrypsin Deficiency
Crigler-Najjar Syndrome
Sickle Cell Hepatopathy
Hereditary Hemochromatosis
Wilson’s Disease
Neonatal Hemochromatosis
Nonalcoholic Steatohepatitis
Glycogen Branching Enzyme Deficiency
Cryptogenic Cirrhosis
Hereditary Tyrosinemia
Vascular Disorders
Budd-Chiari Syndrome
Veno-occlusive Disease
Inborn Errors of Metabolism
Type 1 Primary Hyperoxaluria
Branched-Chain Amino Acid Disorders
Hereditary Deficiency of Urea Cycle Enzymes
Hereditary Amyloidosis
Mass Occupying Lesions
Hepatocellular Carcinoma
Hepatoblastoma
Fibrolamellar Hepatocellular Carcinoma
Hepatic Metastasis of Neuroendocrine Tumors
Polycystic Disease of the Liver
Cholangiocarcinoma
Retransplantation
Absolute Contraindications
Investigational Procedures
Codes Related to this Policy
NOTE:
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The codes listed in this policy are for reference purposes only. Listing of a code in
this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and
medical necessity criteria. This list of codes may not be all inclusive.
On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and
inpatient procedures will be replaced by ICD-10 code sets. Health Net National
Medical Policies will now include the preliminary ICD-10 codes in preparation for this
transition. Please note that these may not be the final versions of the codes and
that will not be accepted for billing or payment purposes until the October 1, 2015
implementation date.
ICD-9 Codes
070.70
070.20
070.30
070.41
070.44
070.51
070.54
155.0
155.1
155.2
275.0
275.1
277.1
277.30
277.6
277.8
453.0
570
571.2
571.3
571.40
571.41
571.49
571.5
571.6
571.8
573.1
573.2
573.3
573.4
576.1
576.2
576.8
751.61
751.62
751.69
996.82
- 070.71 Unspecified viral hepatitis C
- 070.23 Viral hepatitis B with hepatic coma
- 070.33 Viral hepatitis B without mention of hepatic coma
Acute or unspecified hepatitis C with hepatic coma
Chronic hepatitis C with hepatic coma
Acute or unspecified hepatitis C without mention of hepatic coma
Chronic hepatitis C without mention of hepatic coma
Malignant neoplasm of liver, primary
Malignant neoplasm of intrahepatic bile ducts
Malignant neoplasm of liver, not specified as primary or secondary
Disorders of iron metabolism
Disorders of copper metabolism
Disorders of porphyrin metabolism
- 277.39 Amyloidosis
Other deficiencies of circulating enzymes
Other specified disorders of metabolism
Budd-Chiari syndrome
Acute and subacute necrosis of liver
Alcoholic cirrhosis of liver
Alcoholic liver damage, unspecified
Chronic hepatitis, unspecified
Chronic persistent hepatitis
Chronic active hepatitis
Cirrhosis of liver without mention of alcohol
Biliary cirrhosis
Other chronic non-alcoholic liver disease
Hepatitis in viral diseases, classified elsewhere
Hepatitis in other infectious diseases classified elsewhere
Hepatitis, unspecified
Hepatic infarction
Cholangitis
Obstruction of bile duct
Other specified disorders of biliary tract
Biliary atresia
Congenital cystic disease of liver
Other anomalies of gallbladder, bile ducts, and liver
Complications of transplanted organ, liver
ICD-10 Codes
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B16.0-B16.9
B17.10-B17.11
B18.0-B18.9
B19.0-B19.9
C22.0-C22.9
E80.0
E80.20-E80.29
E83.00-E83.09
E83.11-E83.119
E85.0-E85.9
I82.0
K70.0-K70.9
K71.0-K71.9
K72.00-K72.91
K73.0-K73.9
K74.0-K70.5
K75.0-K75.9
K76.0-K76.7
K76.81-K76.89
K77
K83.0
K83.1
K83.5
K83.8
Q44.1
Q44.2
Q44.3
Q44.4
Q44.6
T86.40
T86.41
T86.42
Acute hepatitis B
Acute hepatitis C
Chronic viral hepatitis
Unspecified viral hepatitis
Malignant neoplasm of liver and intrahepatic bile ducts
Hereditary erythropoietic porphyria
Other and unspecified porphyria
Disorders of copper metabolism
Hemochromatosis
Amyloidosis
Budd-Chiari syndrome
Alcoholic liver disease
Toxic liver disease
Hepatic failure, not elsewhere classified
Chronic hepatitis, not elsewhere classified
Fibrosis and cirrhosis of liver
Other inflammatory liver disease
Other diseases of liver
Other specified diseases of liver
Liver disorders in diseases classified elsewhere
Cholangitis
Obstruction of bile duct
Biliary cyst
Other specified diseases of biliary tract
Other congenital malformations of gallbladder
Atresia of bile ducts
Congenital stenosis and stricture of bile ducts
Choledochal cyst
Cystic disease of liver
Unspecified complication of liver transplant
Liver transplant rejection
Liver transplant failure
CPT Codes
00796
47133
47135
47136
47140
47141
47142
47143
Anesthesia for intraperitoneal procedures in upper abdomen including
laparoscopy; liver transplant (recipient)
Donor hepatectomy, with preparation and maintenance of allograft; from
cadaver donor
Liver allotransplantation; orthotopic, partial or whole, from cadaver or
living donor, any age
Liver allotransplantation; heterotopic, partial or whole, from cadaver or
living donor, any age
Donor hepatectomy (including cold preservation), from cadaver donor
Donor hepatectomy, with preparation and maintenance of allograft from
living donor; total left lobectomy (segments II, III, IV)
Donor hepatectomy, with preparation and maintenance of allograft, from
living donor; total right lobectomy (segments V, VI, VII and VIII)
Backbench standard preparation of cadaver donor whole liver graft prior
to allotransplantation, including cholecystectomy, if necessary, and
dissection and removal of surrounding soft tissues to prepare the vena
cava, portal vein, hepatic artery, and common bile duct for implantation;
without trisegment or lobe split
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47144
47145
47146
47147
with trisegment split of whole liver graft into two partial liver grafts (i.e.,
left lateral segment (segments II and III) and right trisegment (segments
I and IV through VIII)
with lobe split of whole liver graft into two partial liver grafts (i.e., left
lobe (segments II, III, and IV) and right lobe (segments I and V through
VIII)
Backbench reconstruction of cadaver or living donor liver graft prior to
allotransplantation; venous anastomosis, each
Backbench reconstruction of cadaver or living donor liver graft prior to
allotransplantation; arterial anastomosis, each
HCPCS Codes
S2152
Solid organs(s), complete or segmental, single organ or combination of
organs; deceased or living donor(s), procurement, transplantation, and
related complications; including: drugs; supplies; hospitalization with
outpatient follow-up; medical/surgical, diagnostic, emergency, and
rehabilitative services; and the number of days of pre- and posttransplant care in the global definition
Recipients for liver transplantation are growing in numbers, progressively outstripping the availability of organ donors. As there may be discrepancies in referral
practice and, therefore, inequity may exist in terms of access to transplantation,
there needs to be uniformity about who should be referred to transplant centers so
the system is fair for all patients. Evidence-based medicine forms the basis for
medical decision-making about accepting the patient as a transplant candidate.
These guidelines tackle the inter-related topics of the indications and optimal referral
practice to tertiary centers for liver transplantation. This guideline is based on the
two core questions: (1) which categories of patients should be considered for
transplantation, and (2) when in the course of their illness should possible candidates
be referred to specialist centers?
To answer the first question, liver transplantation (either cadaveric or live donor) is
the definitive treatment for adult and pediatric patients with end stage liver disease
(ESLD) secondary to decompensated cirrhosis. In general, this is heralded by a
Child-Turcotte-Pugh (CTP) score of > 7 (i.e., a less than 90 % chance of surviving
one year without a transplant), an episode of gastrointestinal hemorrhage related to
portal hypertension, or an episode of spontaneous bacterial peritonitis. Indications
for liver transplantation based upon quality of life include intractable ascites, severe
encephalopathy, intractable pruritus, severe osteoporosis, and recurrent biliary tree
infections. Children and adults with metabolic liver disease secondary to an enzyme
deficiency (inborn errors in metabolism) benefit from liver replacement to correct the
and halt progression of extra-hepatic organ damage. Based on the PELD and MELD
scoring systems, these patients would never have a score that would avail them of a
deceased donor organ. It is clearly recognized, however, that their need is urgent.
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Consequently, patients with enzyme deficiencies or compensated cirrhosis with
significant quality-of-life issues can be given priority for listing for deceased donor
organs, absent any absolute contraindications to liver transplantation. These patients
should be referred as early as possible to a transplant facility that performs a
reasonably high volume of liver transplantations because centers that have low
volumes (less than 20 transplants per year) have worse outcomes. Appropriate
patient selection is paramount to the overall success of liver transplantation.
To answer the second question, selecting an appropriate stage for a given illness for
liver transplantation is a complex issue. The more familiar physicians are with the
exact criteria for liver transplantation, the more likely they are to refer patients at an
appropriate stage. Early intervention and evaluation appear to play a positive role in
maximizing quality of life for the transplant recipient. Transplantation just prior to
death may significantly diminish the life-saving potential of the procedure since
hepatic decompensation in its latest stages poses a formidable surgical risk.
Transplantation early in the course of hepatic decompensation may deprive a patient
of an additional period of useful life. An ideally timed liver transplantation procedure
would be in a late enough phase of disease to offer the patient all opportunity for
spontaneous stabilization or recovery, but in an early enough phase to give the
surgical procedure a fair chance of success. Based on currently available knowledge
of the natural history of liver diseases, it appears that referral should be made when
a patient with cirrhosis begins to show evidence of synthetic dysfunction or
malnutrition or when the first complication of cirrhosis occurs. At this stage of
disease, most patients can be expected to survive the 1 to 2 years required for
acquisition of a donor organ. Patients with hepatocellular malignancies secondary to
cirrhosis should be referred as soon as the tumor is discovered. Because patients
with fulminant hepatic failure (FHF) can deteriorate quickly, they should also be
referred when a persistently elevated prothrombin time or the first alteration in
mental status is identified. Early referral of these patients is necessary to minimize
the risk of aspiration and other complications during transit.
Pediatric liver transplantation has been a major success and is now an established
therapeutic entity. The use of innovative surgical techniques has allowed the
application of liver transplantation to even very young infants with excellent results.
Selection criterion for adults is properly based on outcome measures. The major
driving force for this has been the mismatch between the number of donor organs
and potential recipients. While the same general principles apply to children there
are notable differences. The success of liver splitting allows many children to benefit
from liver transplantation with little net effect on the overall donor organ pool. Also
in some circumstances a smaller probability of long-term success may be a very
worthwhile outcome for some children and their families. The particularly high
mortality in children awaiting liver and intestinal transplantation has been recognized
by allocating this group a higher priority in the allocation sequence.
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Scientific Rationale Update - March 2014
The National Cancer Comprehensive Network (NCCN, Version 2.2013) notes the
following: “ Before biopsy, evaluate if patient is a surgical or transplant candidate. If
patient is a potential transplant candidate, consider referral to transplant center
before biopsy”.
Cirrhosis represents a late stage of progressive hepatic fibrosis characterized by
scarring, distortion of the hepatic architecture and the formation of regenerative
nodules. It is generally considered to be irreversible in its advanced stages at which
point the only option may be liver transplantation. Patients with cirrhosis are
susceptible to a variety of complications and their life expectancy is markedly
reduced secondary to these devastating complications. The quality of life and
survival of patients with cirrhosis can be improved by the prevention and treatment
of these complications. Once a patient develops complications of cirrhosis, they are
considered to have decompensated disease. Delays in referral and extended waiting
times for transplantation can allow unfavorable complications of advanced liver
disease to supervene, thereby jeopardizing the outcome.
Liver transplantation is the definitive treatment for patients with decompensated
cirrhosis. This policy addresses when the primary care MD should refer to the
specialist or the specialist based in a community hospital should refer to the liver
center. The center will do the evaluation in detail and previous MD’s need not repeat
procedures that will become necessary at the next level of care unless so directed by
that next level, i.e. tertiary care center asks the referring hospital to do blood testing
and send all results. Tertiary center may not consider radiological studies not
performed in their own hospital because of level of expertise or sophistication of
equipment issues. The selection of appropriate candidates out of a large number of
patients with liver disease combined with the relative scarcity of available organs
requires a strict individual assessment, which must to a certain extent be tailored to
the cause of liver failure. Exclusion of patients with contraindications to liver
transplantation allows the best use of scarce donor resources while maximizing
patient benefit. Potential transplant candidates should be assessed on the basis of:





The etiology of the liver disease
Profile of complications
Identification of absolute contraindications
Calculated prognosis
Quality of life
Scientific Rationale Update – March 2012
Artificial assist devices (bioartificial liver transplantation) used for a bridge
to transplantation until a suitable donor becomes available
Ding et al. (2011) Acute liver failure remains a significant cause of morbidity and
mortality. Bioartificial liver (BAL) devices have been in development for more than 20
years. Such devices aim to temporarily take over the metabolic and excretory
functions of the liver until the patients' own liver has recovered or a donor liver
becomes available for transplant. The important issues include the choice of cell
materials and the design of the bioreactor. Ideal BAL cell materials should be of good
viability and functionality, easy to access, and exclude immunoreactive and
tumorigenic cell materials. Unfortunately, the current cells in use in BAL do not meet
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these requirements. One of the challenges in BAL development is the improvement
of current materials; another key point concerning cell materials is the coculture of
different cells. The bioreactor is an important component of BAL, because it
determines the viability and function of the hepatocytes within it. From the
perspective of bioengineering, a successful and clinically effective bioreactor should
mimic the structure of the liver and provide an in vivo-like microenvironment for the
growth of hepatocytes, thereby maintaining the cells' viability and function to the
maximum extent. One future trend in the development of the bioreactor is to
improve the oxygen supply system. Another direction for future research on
bioreactors is the application of biomedical materials. In conclusion, BAL is, in
principle, an important therapeutic strategy for patients with acute liver failure, and
may also be a bridge to liver transplantation. It requires further research and
development, however, before it can enter clinical practice.
NCCN Guidelines Version 2.2012 Updates Hepatobiliary Cancers:
The pathway after UNOS criteria was revised and now includes the decision
points of “If ineligible for transplants” or “If eligible for transplants” . For
patients eligible for transplant, the recommendation. “Refer to liver transplant
center’ and “Consider bridge transplant as indicated”, were added.
Hepatocellular Transplantation
Early experience with liver transplantation in the setting of hepatocellular carcinoma
(HCC) was associated with a recurrence rate of up to 80 percent and dismal longterm survival. This resulted in HCC being considered a contraindication to liver
transplantation. However, better patient selection has permitted identification of
patients who have a good prognosis with transplantation. Patients with limited HCC
(one solitary lesion <5 cm or three lesions each <3 cm) have excellent long-term
outcomes, with a five-year survival rate of 70 percent and a recurrence rate below
15 percent. Many transplant centers use these criteria (sometimes referred to as the
"Milan" or "Mazzaferro" criteria) to determine candidacy for transplantation in
patients with HCC.
Ectopic or Auxiliary Transplantation
A liver transplant is usually positioned in the normal anatomical position (orthotopic)
following a total hepatectomy of the recipient. In auxiliary liver transplantation, a
second liver is implanted ectopically and the recipient's own liver remains in situ. A
major concern of ectopic transplantation is the recipient's diseased liver may harbor
bacterial, fungal or viral infection or cancer. At this time there is a paucity of peerreviewed literature to support this with no current ongoing studies noted.
Xenotransplantation
Copper et al. (2012) Cross-species transplantation (xenotransplantation) offers the
prospect of an unlimited supply of organs and cells for clinical transplantation, thus
resolving the critical shortage of human tissues that currently prohibits a majority of
patients on the waiting list from receiving transplants. Between the 17th and 20th
centuries, blood was transfused from various animal species into patients with a
variety of pathological conditions. Skin grafts were carried out in the 19th century
from a variety of animals, with frogs being the most popular. In the 1920s, Voronoff
advocated the transplantation of slices of chimpanzee testis into aged men whose
"zest for life" was deteriorating, believing that the hormones produced by the testis
would rejuvenate his patients. Following the pioneering surgical work of Carrel, who
developed the technique of blood vessel anastomosis, numerous attempts at
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nonhuman primate organ transplantation in patients were carried out in the 20th
century. In 1963-1964, when human organs were not available and chronic dialysis
was not yet in use, Reemtsma transplanted chimpanzee kidneys into 13 patients,
one of whom returned to work for almost 9 months before suddenly dying from what
was believed to be an electrolyte disturbance. The first heart transplant in a human
ever performed was by Hardy in 1964, using a chimpanzee heart, but the patient
died within 2 hours. Starzl carried out the first chimpanzee-to-human liver
transplantation in 1966; in 1992, he obtained patient survival for 70 days following a
baboon liver transplant. With the advent of genetic engineering and cloning
technologies, pigs are currently available with a number of different manipulations
that protect their tissues from the human immune response, resulting in increasing
pig graft survival in nonhuman primate models. Genetically modified pigs offer hope
of a limitless supply of organs and cells for those in need of a transplant.
Hepacytes, Lentivirus, Ex Vivo Transduction
Nguyen et al. (2009) Transplantation of hepatocytes, whether genetically modified or
not, has become an alternative to orthotopic liver transplantation for the treatment
of patients with metabolic disease. However, more than ten years after the first
clinical trial of ex vivo gene therapy to treat patients with familial
hypercholesterolemia, there are still a number of impediments to these approaches.
Simultaneous development of lentiviral vectors from different lentivirus species has
permitted the transfer of genes into mitotically-quiescent primary cells including
differentiated hepatocytes. Particularly third generation vectors derived from HIV-1
lentivirus are the most widely used and have significantly improved the safety and
efficiency of these vectors. Given the shortage of organs and problems related to
immunosuppression on one hand, and recent progresses in hepatocyte transduction
and transplantation on the other hand, ex vivo approach is becoming a real
alternative to allogeneic hepatocyte transplantation. We review the present
progresses and limits of the ex vivo liver gene therapy approach, emphasizing
clinically relevant procedures. Many of these studies are still being done on animals.
VanGeer et al. (2009) Human pancreatic tissue samples (malignant and normal)
were obtained from surgical specimens and processed immediately to tissue slices.
Tissue slices were cultured ex vivo for 1-6 d in an incubator using 95% O(2). Slices
were subsequently analyzed for viability and morphology. In addition the slices were
incubated with different viral vectors expressing the reporter genes GFP or DsRed.
Expression of these reporter genes was measured at 72 h after infection. With the
Krumdieck tissue slicer, uniform slices could be generated from pancreatic tissue but
only upon embedding the tissue in 3% low melting agarose. Immunohistological
examination showed the presence of all pancreatic cell types. Pancreatic normal and
cancer tissue slices could be cultured for up to 6 d, while retaining viability and a
moderate to good morphology. Reporter gene expression indicated that the slices
could be infected and transduced efficiently by adenoviral vectors and by adeno
associated viral vectors, whereas transduction with lentiviral vectors was limited. For
the adenoviral vector, the transduction seemed limited to the peripheral layers of the
explants. Although promising, many of the studies on adenoviral vectors were done
on animals.
Currently, lentiviral vectors for research and gene therapy are produced from 293-T
cells that are transiently transfected with plasmids encoding the vector and helper
functions. However, transiently transfected vectors as well as the presence of SV40
virus large T-antigen (T-Ag) cause serious technical and safety considerations. We
aimed to exploit single copy integration sites in the HEK293 genome supporting
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lentiviral vector production. We found that lentiviral vectors result in minimal
infectious particle production from single copy integrants in HEK293. Moreover, once
this cell line harbors single copy integrations of lentiviral vectors, its ability to
transiently produce lentiviral vectors becomes strongly impaired. T-Ag has a
dramatic effect on virus production. Low levels of constitutive T-Ag expression can
overcome the production restriction imposed by integrated lentiviral vectors copies.
Interestingly, T-Ag does not exert its role at the level of transcriptional activity of the
vector; rather, it seems to impose an indirect effect on the cell thereby enabling
lentiviral vector production. However, additional peer-reviewed studies are needed
regarding the use of lentiviral vectors for gene therapy used with liver transplants. At
this time there are currently no ongoing studies.
There is also a paucity of peer-reviewed literature regarding receptor-mediated gene
delivery and site-directed gene conversion for liver transplantation. In addition, there
are are no current clinical trials nor ongoing studies.
Policy Statement - Initial
Health Net, inc. considers referral for assessment, and hence either cadaveric or live
donor liver transplantation, medically necessary for carefully selected adults and
children with irreversible acute or chronic liver failure when all of the following are
met:
1. General patient selection criteria; AND
2. Clinical complications criteria; AND
3. Disease-specific criteria.
General Patient Selection Criteria Policy Statement
Adult Patients
Referral for evaluation of liver transplantation is medically necessary in adult patients
who meet all of the following:
1. Patient is < 75 years of age
2. Presence of irreversible, decompensated end stage liver disease (ESLD) and a
life expectancy of less than 12 months
3. Progression of liver disease will predictably result in mortality exceeding that of
transplantation (85% one-year patient survival and 70% five-year survival)
4. Patient has a greater than 50% probability of survival at 5 years after
transplantation with a quality of life that is acceptable to the patient
5. Patient does not have any absolute contraindications to liver transplantation
6. Because of liver disease, quality of life has deteriorated to unacceptable levels
significantly interfering with the patient's activities of daily living (e.g., no
longer able to work - the three clinical entities that have the greatest impact on
quality of life in end-stage liver disease are intractable ascites, with or without
spontaneous bacterial peritonitis; progressive hepatic encephalopathy; and
recurrent portal hypertensive bleeding); and
7. In patients with cirrhosis or sclerosing cholangitis, has developed evidence of
severe hepatic dysfunction as evidenced by a Child-Turcotte-Pugh (CTP)
Classification score* > 7 (Child's class B or C) or a Model of End-stage Liver
Disease (MELD) score** > 10 (a tool to calculate MELD score is available at the
following website: http://www.unos.org/resources/meldPeldCalculator.asp.)
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8. Absence of serious systemic illness or other medical conditions that may affect
immediate or long-term survival
9. No active alcohol or substance abuse for at least 6 months prior to the
transplant
10. Patient fully understands the transplant procedure, its limitations and expresses
willingness to comply with life-long follow-ups and medications.
11. Strong social support network
12. If patient HIV positive, all of the following are met to exclude active AIDS
infection:





Patient has been stable on antiviral therapy > 6 months; and
Patient has no other complications from AIDS such as opportunistic
infection (e.g. aspergillus, tuberculosis, coccidioidomycosis, resistant
fungal infections except esophageal candidiasis) Kaposi's sarcoma or other
neoplasm; and
Patient has a CD4 cell count > 200 cells/mm3 for > 6 months; and
Patient has a viral load < 1000 copies/ml or patient unable to tolerate
anti-HIV therapies due to the liver condition; and
A protocol HIV specialist must explicitly concur with the transplant and
determine that after transplantation the individual will be able to construct
an effective anti-HIV regimen that will result in maximal viral suppression.
* The Child-Turcote-Pugh (CPT) score determines short-term prognosis among
groups of patients awaiting liver transplantation and has been widely adopted for
risk-stratifying patients before transplantation.
NOTE: Per NCCN (Version 2. 2015 Hepatobiliary Cancers Updates), Patients with
Child-Pugh Class A liver function, who fit UNOS criteria** and are resectable could
be considered for resection or transplant. There is controversy over which initial
strategy is preferable to treat such patients. These patients should be evaluated by
a multidisciplinary team.
UNOS Criteria: Patient has a tumor <5 cm in diameter or 2-3 tumors <3 cm each,
no macrovascular involvement, no extrahepaic disease.
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Child-Turcote-Pugh Score of Severity of Liver Disease
Points
Encephalopathy
Ascites
Bilirubin (mg/dL)
For PBC/PSC, Bilirubin
Albumin (g/dL)
INR
PT (seconds prolonged)
1
None
Absent
<2
<4
> 3.5
< 1.7
<4
2
1–2
Slight
2–3
4 – 10
2.8 – 3.5
1.7 – 2.3
4-6
3
3–4
Moderate
>3
> 10
< 2.8
> 2.3
>6
The individual scores are summed and then grouped as a classification:
<7=A
7-9 = B
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> 9 = C (forecasts a survival of less than 12 months)
INR = International Normalized Ratio; PT = prothrombin time.
** The MELD score is a disease severity scoring system for adults with liver disease,
designed to effectively determine the prognosis of patients at various stages of
disease in order to improve organ allocation. It is based on the severity of liver
disease using only laboratory data in order to be as objective as possible. The
laboratory values used are a patient's serum creatinine, serum bilirubin, and
international normalized ratio (INR), which has been shown to be highly predictive of
3-month mortality and postoperative mortality in patients with chronic liver disease.
A similar model has been developed for pediatric endstage liver disease (PELD) that
includes: (1) age younger than 1 year; (2) serum albumin level; (3) serum bilirubin;
(4) INR and (5) growth failure.
Pediatric Patients
Referral for evaluation of liver transplantation is medically necessary when any of the
following is met:
1.
2.
3.
4.
5.
Anticipated length of life less than 18 months because of liver disease
Unacceptable quality of life because of liver disease
Growth failure or impairment due to liver disease
Reversible neurodevelopmental impairment due to liver disease
Likelihood of irreversible end organ damage (which may be renal, respiratory or
cardiovascular depending on underlying disorder)
6. There is an expectation that the child has a > 50% probability of survival at 5
years after transplantation with a quality of life acceptable to the child and their
families.
Complications of Irreversible Cirrhosis
Policy Statement
Health Net, Inc. considers referral for evaluation of liver transplantation medically
necessary for adult and pediatric patients who experience any of the following
complications of irreversible end-stage liver disease (ESLD), regardless of the
underlying disease etiology:











Portal hypertension with bleeding from esophageal varices or portal
gastropathy
Portal-systemic (hepatic) encephalopathy
Intractable ascites
Spontaneous bacterial peritonitis (recurrent)
Hepatorenal syndrome
Hepatopulmonary syndrome
Portopulmonary hypertension
Intractable pruritus associated with cholestasis (e.g., in patients with primary
biliary cirrhosis [PBC])
Ascending bacterial cholangitis (recurrent episodes) in primary sclerosing
cholangitis (PSC)
Hepatocellular carcinoma within defined criteria (no single lesion > 5 cm or no
more than three lesions, the largest 3 cm)
Progressive hepatic osteodystrophy
13







Progressive jaundice alone, in the absence of other signs of liver failure, is not
an absolute indication for transplant.
Rising INR (bleeding diathesis / coagulopathy) alone, in the absence of other
signs of liver failure, is not an absolute indication for transplant.
Malnutrition / hypoalbuminemia alone, in the absence of other signs of liver
failure, is not an absolute indication for transplant.
Intractable fatigue alone, in the absence of other signs of liver failure, is not
an absolute indication for transplant.
Growth failure or impairment due to liver disease
Reversible neurodevelopmental impairment due to liver disease
Likelihood of irreversible end organ damage (which may be renal, respiratory
or cardiovascular depending on underlying disorder)
Variceal Bleeding
Policy Statement
Referral for evaluation of liver transplantation is medically necessary for patients who
have had one or more episodes of variceal bleeding and does not have a
contraindication to liver transplantation, whether he/she has or has not responded to
therapy (e.g., vasoactive agents, sclerotherapy and band ligation, transjugular
intrahepatic portosystemic shunt (TIPS), surgical shunting)
Scientific Rationale
Variceal hemorrhage is a devastating complication that occurs in 25 to 40% of
patients with cirrhosis. Although survival has improved with modern techniques for
controlling variceal hemorrhage, mortality rates remain high. The outcome of an
episode of active hemorrhage depends upon the control of active bleeding and
avoidance of the major complications associated with bleeding and its treatment.
Clinically significant bleeding, defined by a transfusion requirement of two units of
blood or more within 24 hours of time zero together with a systolic blood pressure
below 100 mmHg, a postural systolic change of more than 20 mmHg, and/or a pulse
rate above 100 beats/min at time zero. Only 50% of patients with variceal
hemorrhage stop bleeding spontaneously. The greatest risk for rebleeding is within
the first 48 to 72 hours, and over 50% of all early rebleeding episodes occur within
the first 10 days. One-year survival in those who survive two weeks after a variceal
bleed is approximately 52%.
The goals of treatment of active variceal hemorrhage are hemodynamic
resuscitation, rapid arrest of initial bleeding, reduction of bleeding-related
complications, prevention of recurrent bleeding, and minimizing treatmentassociated morbidity and mortality. Several treatments are available for the
management of acute variceal hemorrhage. These can be broadly grouped into
treatments that address the local bleeding site and those that reduce portal pressure
directly. Examples of the former are esophageal sclerotherapy, band ligation, and
balloon tamponade. Treatments to reduce portal pressure include pharmacologic
agents (such as somatostatin, vasopressin and their analogues), surgically created
shunts, and TIPS. Endoscopic and pharmacologic treatment are first-line therapy for
active esophageal variceal hemorrhage. Endoscopic sclerotherapy or band ligation
can be performed at the bedside by practically all trained gastroenterologists and
achieves hemostasis in 80 to 90 % of subjects. Both methods decrease early
rebleeding and improve short-term survival. Pharmacologic therapy is also effective,
widely available, and can be used in combination with endoscopic therapy.
14
Transjugular intrahepatic portosystemic shunts (TIPS) have no role as first-line
therapy in acute variceal hemorrhage.
Approximately 10 to 20% of patients fail to stop bleeding with endoscopic treatment.
Other patients may rebleed in the first few days after cessation of the index bleed. A
second attempt to control hemorrhage with endoscopic treatment is sometimes
effective. However, when two attempts to control active hemorrhage fail, the risk of
mortality rises exponentially. While emergent surgery is extremely effective in
arresting hemorrhage and preventing rebleeding, it is associated with approximately
a 50 % mortality. Many patients die of liver failure and complications of surgery
despite achievement of hemostasis. Those with severe hemorrhage, tense ascites,
deep coma, aspiration pneumonia, renal failure or sepsis are at particular risk from
surgery.
TIPS involve creation of a low-resistance channel between the hepatic vein and the
intrahepatic portion of the portal vein (usually the right branch) using angiographic
techniques. The tract is kept patent by deployment of an expandable metal stent
across it, thereby allowing blood to return to the systemic circulation. TIPS has
primarily been used to treat the major consequences of portal hypertension (i.e.,
variceal hemorrhage and ascites). TIPS is not indicated for the primary prophylaxis
of variceal hemorrhage. Similarly, TIPS does not affect the outcome of liver
transplantation and is not indicated for preoperative portal decompression prior to
transplantation. TIPS is preferred to surgery in controlling acute bleeding from
varices that is refractory to medical therapy. Multiple series have demonstrated the
efficacy of TIPS for uncontrolled esophageal variceal hemorrhage despite emergent
endoscopic and pharmacologic treatment in patients who are poor-risk candidates for
urgent surgery. However, TIPS is inherently associated with a high rate of
complications.
All survivors of a variceal bleed should be evaluated for liver transplantation. Those
with Child class B or C should be listed for transplantation unless a contraindication
exists; listing for those with Child class A cirrhosis should be individualized, but
listing is certainly deserved if patient rebleeds.
Hepatic Encephalopathy
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in a patient who
has experienced hepatic encephalopathy and does not have an absolute
contraindication for transplantation, whether he/she has or has not responded to
therapy (e.g., correction of precipitating causes (see below), restriction of dietary
protein, measures to reduce the nitrogenous load from the gut [i.e., enemas, bowel
cleansing] with nonabsorbable disaccharides [lactulose or lactitol] and antibiotics
[e.g., neomycin], correction of hypokalemia and/or azotemia).
Hepatic (hyperammonemic) encephalopathy* (HE) describes the spectrum of
potentially reversible neuropsychiatric abnormalities seen in patients with liver
dysfunction and can range from subtle neurological dysfunction to frank coma
(important to exclude HIV-related dementia). The term implies that altered brain
function is due to metabolic abnormalities, which occur as a consequence of liver
failure. Disturbance in the diurnal sleep pattern (insomnia and hypersomnia) is a
common early feature that typically precedes overt neurologic signs. More advanced
15
neurologic features include the presence of asterixis, hyperactive deep tendon
reflexes, and less commonly, transient decerebrate posturing.
Laboratory abnormalities typically include evidence of hepatic biochemical and
synthetic dysfunction, and electrolyte disturbances (such as hyponatremia and
hypokalemia) that occur as a result of portal hypertension and use of diuretics. The
gastrointestinal tract is the primary source of ammonia, which enters the circulation
via the portal vein. Ammonia is produced by enterocytes from glutamine and by
colonic bacterial catabolism of nitrogenous sources such as ingested protein and
secreted urea. The intact liver clears almost all of the portal vein ammonia,
converting it into urea or glutamine and preventing entry into the systemic
circulation. The increase in blood ammonia in advanced liver disease is a
consequence of impaired liver function and of shunting of blood around the liver.
The initial management of acute hepatic encephalopathy involves two steps: (1)
correction of precipitating causes; and (2) measures to lower the blood ammonia
concentration. It is important to recognize that hepatic encephalopathy, acute and
chronic, is reversible and that a precipitating cause rather than worsening of
hepatocellular function can be identified in the majority of patients. In their classic
study, Fessel et al (1972) determined that over 80% of 100 cases were attributable
to such factors as gastrointestinal bleeding, increased protein intake, hypokalemic
alkalosis, infection, and constipation (all of which increase arterial ammonia levels),
or to hypoxia and the use of sedatives and tranquilizers (e.g., benzodiazepines,
narcotics, alcohol). Since elevations of ammonia are detected in 60 to 80% of
patients with HE and therapy aimed at reduction of the circulating ammonia level
usually results in resolution of the encephalopathy, treatment is aimed at either
reducing or inhibiting intestinal ammonia production or increasing the removal of
ammonia. Correction of hypokalemia, if present, is an essential component of
therapy since hypokalemia increases renal ammonia production. Removing the
source of the ammonia from the gastrointestinal tract can be an important step in
certain patients. Nasogastric lavage should be performed in patients with upper
gastrointestinal bleeding, while limiting protein intake and treating constipation may
be effective in patients with chronic encephalopathy. Both cleansing enemas and
dietary protein restriction are effective in patients with acute hepatic
encephalopathy.
Synthetic disaccharides (lactulose and lactitol) given orally are currently the
mainstay of therapy of hepatic encephalopathy. The rationale for treatment is due to
the absence of a specific disaccharidase on the microvillus membrane of enterocytes
in the human small bowel, thereby permitting entry into the colon. In the colon,
lactulose (beta-galactosidofructose) and lactitol (beta-galactosidosorbitol) are
catabolized by the bacterial flora to short chain fatty acids (e.g., lactic acid and
acetic acid) which lower the colonic pH about 5.0. The reduction in pH favors the
formation of the nonabsorbable NH4+ from NH3, trapping NH3 in the colon and
effectively reducing plasma ammonia concentrations. Cleansing of the colon is a
rapid and effective method to remove ammoniagenic substrates. It can be achieved
either by cathartics or by enemas. Antibiotics, particularly oral neomycin, have
generally been considered second-line therapy in patients who have not responded
to disaccharidases. Although neomycin has been used for many years to treat
hepatic encephalopathy, associated ototoxicity and nephrotoxicity limits long-term
use. Other antibiotics, such as metronidazole, vancomycin, and rifaximin, have been
found effective in limited clinical trials and are better tolerated than neomycin.
Continuous administration of lactulose can be given in patients with recurrent
encephalopathy or subclinical encephalopathy.
16
Ascites
Position Statement
has experienced hepatic encephalopathy and does not have an absolute
contraindication for transplantation, whether he/she has or has not responded to
therapy (e.g., 2 gram low sodium diet, aldosterone antagonists [e.g.,
spironolactone], loop diuretics [furosemide], repeat therapeutic large-volume
paracenteses)
Ascites is the accumulation of fluid within the peritoneal cavity. It is the most
common complication of cirrhosis. Nearly 60% of all patients with compensated
cirrhosis will develop ascites in 10 years. The two-year survival of patients with
ascites is approximately 50%. The first step leading to fluid retention and ultimately
ascites in patients with cirrhosis is the development of portal hypertension. Patients
without portal hypertension do not develop ascites or edema. Those with ascites
have several circulatory, vascular, functional, and biochemical abnormalities that
contribute to the pathogenesis of fluid retention. The onset of ascites is associated
with worsened quality of life, increased risk of spontaneous bacterial peritonitis, renal
failure and poor long-term survival. Ascites refractory to the maximal medical
therapy. Therefore, any patient who develops ascites should be a potential liver
transplant candidate; however, all subjects are not suitable candidates for liver
transplant and even those who are listed often have to wait for a long time before an
organ becomes available. These factors underscore the need for medical
management of ascites.
Spontaneous Bacterial Peritonitis
Policy Statement
Referral for evaluation of liver transplantation is medically necessary for survivors of
SBP who are otherwise good transplant candidates.
Spontaneous bacterial peritonitis (SBP) is a bacterial infection of preexisting ascitic
fluid without evidence for an intra-abdominal source such as a perforated viscus or
pancreatitis. SBP is a frequent and serious complication of cirrhotic patients with
ascites. The onset of SBP is characterized by an unexplained clinical deterioration,
sudden onset of fever, altered mental status (encephalopathy) of unknown origin,
abdominal pain and/or tenderness, renal failure, acidosis, an absolute neutrophil
count in the ascitic fluid of greater than 250/mm3 without a precipitating factor
and/or positive results from peritoneal fluid cultures. Without early treatment,
mortality is high. Patients who have severe enough liver disease to develop SBP have
a poor long-term prognosis. In-hospital, non-infection-related mortality may be as
high as 20 to 40 %, and one- and two-year mortality rates are approximately 70 and
80 %, respectively. Efforts to prevent SBP should be made in high-risk patients.
Treatment consist of IV antibiotics. SBP is associated with the development of
hepatorenal syndrome (HRS) in about 30% of the patients and carries a high
mortality. SBP recurs in 70% of subjects after 1 year of the first episode; therefore
prophylaxis with a quinolone antibiotic is recommended routinely to prevent the
recurrences and improve survival.
17
Hepatorenal Syndrome
Policy Statement
has experienced hepatic encephalopathy and does not have an absolute contraindication for transplantation, whether he/she has or has not responded to therapy
(e.g., vasoconstrictor agents, α-adrenergic agonists, TIPS).
Note: Liver transplantation is the only modality that is known to improve survival in
these patients.
Diagnosis of Hepatorenal Syndrome
MAJOR CRITERIA
1. Low glomerular filtration rate as indicated by serum creatinine greater than 1.5
mg/dL or 24-hour creatinine clearance less than 40 mL/min
2. Absence of shock, ongoing bacterial infection, and fluid losses, and current
treatment with nephrotoxic agents
3. Lack of sustained improvement in renal function on discontinuation of diuretics
and volume expansion by 1.5 L of a plasma expander
4. Proteinuria less than 500mg/d and no ultrasonographic evidence of obstructive
uropathy or parenchymal renal disease.
MINOR CRITERIA
1.
2.
3.
4.
5.
Oliguria (about two-thirds of patients have urine volume <500 mL/day at
diagnosis)
A very low rate of sodium excretion in the urine (< 10mEq/L)
Urine osmolality greater than plasma osmolality
Urine RBCs less than 50 per high power field
Serum sodium concentration less than 130 mEq/L
The hepatorenal syndrome (HRS) refers to the development of acute renal failure in
a patient who usually has advanced hepatic disease, due to cirrhosis or less often
metastatic tumor or severe alcoholic hepatitis. Rather than being a new disease, the
HRS usually represents the end-stage of a sequence of reductions in renal perfusion
induced by increasingly severe hepatic injury. The initial reductions in glomerular
filtration rate are often masked clinically since associated decreases in muscle mass
and hepatic urea production minimize elevations in the plasma creatinine concentration and blood urea nitrogen. HRS is caused by profound systemic vasodilation
and vasoconstriction in the renal circulation. This condition should be distinguished
from primary renal disease to predict potential for reversibility, or the need for
combined liver/kidney transplant.
Hepatopulmonary Syndrome
Policy Statement
has experienced hepatic encephalopathy and does not have an absolute contraindication for transplantation, whether he/she has or has not responded to therapy
Note: Patients who have Pa02 < 60 mm Hg, should be given priority on the list.
18
Estimates of the prevalence of hepatopulmonary syndrome (HPS)* among patients
with chronic liver disease range from 4 to 47 %, depending upon the diagnostic
criteria and methods used. Even in those without HPS, mild hypoxemia is common
and is presumably caused by ascites, with resulting diaphragmatic elevation and
ventilation/perfusion mismatch. HPS is characterized by the triad of severe portal
hypertension with or without cirrhotic liver disease complicated by arterial
hypoxemia caused by pulmonary vascular dilatations in both the pediatric and adult
age groups.
* For diagnosis, the patient must have all of the following:
1. Severe arterial hypoxemia (PaO2 < 70 mm Hg in supine or standing position)
2. Alveolar-arterial oxygen gradient > 15 mm Hg while breathing room air
3. Evidence for intrapulmonary vascular abnormalities, referred to as
intrapulmonary vascular dilatations (IPVDs), demonstrated by delayed “positive”
contrast-enhanced (CE) transthoracic echocardiography or abnormal brain uptake
(> 6%) after 99mTcMAA lung radionuclide perfusion scanning
4. If corrected by breathing 100% oxygen, then it is due to A-V shunting and
transplant will likely correct it.
Portopulmonary Hypertension
Policy Statement
Referral for evaluation of liver transplantation is medically necessary when
vasomodulating therapy (e.g., intravenous epoprostenol, bosentan, sildenafil)
successfully reduces mean pulmonary artery pressure (MPAP) to < 35 mm Hg and
PVR < 240 dyne/sec/cm−5 which indicates minimal post-transplant risk for mortality.
Patients who continue to have a MPAP between 35 and 50 mm Hg and a PVR
between 240 and 400 dyne/sec/cm−5 are at increased risk, with a perioperative
mortality approximating 50%; the decision to proceed with liver transplant is center
dependent.
Note: Patients who have a MPAP in excess of 50 mm Hg despite therapy are at
highest risk and would be excluded from consideration for liver transplant at most
major transplant centers.
Portopulmonary hypertension (POPH)* is characterized by the development of
pulmonary arterial hypertension in association with portal hypertension, with or
without hepatic disease. The prevalence in patients with cirrhosis is approximately 2
%. Neither the prevalence nor the severity of portopulmonary hypertension appears
to correlate with the degree of portal hypertension. Patients may present with
fatigue, dyspnea, peripheral edema, chest pain, and syncope. Diagnosis may be
suggested by transthoracic doppler echocardiography and confirmed by right heart
catheterization. Patients with moderate to severe portopulmonary hypertension are
difficult to treat with medical therapy and the perioperative mortality with liver
transplantation is high.
* Diagnostic criteria for portopulmonary hypertension includes all of the following:
19
1.
2.
3.
4.
Presence of portal hypertension (clinical diagnosis)
Increased mean pulmonary artery pressure (MPAP) > 35 mm Hg
Normal pulmonary artery occlusion pressure (PAOP) < 15 mm Hg
Increased pulmonary vascular resistance (PVR) > 240 dyne/sec/cm −5
Pruritus
Policy Statement
Referral for evaluation of liver transplantation is medically necessary when the
pruritus remains severe, incapacitating, and refractory, and there are no
contraindications for liver transplantation, even if the severity of liver disease may
not otherwise warrant liver transplantation. A functioning transplant cures the
underlying disease and produces rapid resolution of the pruritus.
Pruritus (itching) is a particularly troublesome symptom associated with cholestasis
caused by extrahepatic biliary obstruction and/or intrahepatic biliary disruption. It
can range in severity from mild, to moderate in which sleep is disturbed, to extreme
in which the lifestyle of the patient is completely disrupted. The treatment of choice
for pruritus associated with cholestasis is correction of the underlying hepatobiliary
disease. In cases of extrahepatic biliary obstruction in which definitive therapy is not
possible, biliary drainage is usually effective in eliminating pruritus. In cases of
intrahepatic cholestasis in which definitive therapy is not possible, several measures
can be attempted to relieve bothersome pruritus.
In mild cases, pruritus can often be controlled by nonspecific measures such as
warm baths and emollients. However, these measures often fail when the pruritus is
moderate to severe and often accompanied by excoriations. In such cases, the
following options are available. The bile acid resins cholestyramine (Questran) and
colestipol (Colestid) are effective first-line agents in the management of moderate or
severe cholestatic pruritus. They lower bile acid levels by inhibiting the reabsorption
of bile acids by approximately 90%. Opioid antagonists such as intravenous
naloxone, oral nalmefene and oral naltrexone are often associated with substantial
relief of cholestatic pruritus. Several reports have demonstrated improvement in
cholestatic pruritus with rifampin. For treatment of pruritus in patients with primary
biliary cirrhosis (PBC), treatment with ursodeoxycholic acid UDCA followed by the
addition of colchicine and then methotrexate in nonresponding patients is
recommended. If none of the above is helpful, rifampin may be indicated. Of note is
the fact that optimal therapy is uncertain for severe pruritus or pruritus refractory to
the above measures. Several measures described above have been effective in case
reports and can be tried in individual patients.
Hepatic Osteopenia
Policy Statement
patient has severe symptomatic bone disease that is refractory to medical
management, before hepatic encephalopathy or variceal hemorrhaging develops. It
is important to appreciate, however, that bone loss is accelerated for the first three
to six months after transplantation.
Metabolic bone disease (hepatic osteodystrophy) in the form of osteoporosis
(osteopenia) occurs in approximately 25% of patients with primary biliary cirrhosis
20
(PBC). It is a potential complication of long-standing hepatic disease and is
characterized by an absolute decrease in the amount of bone. It is directly related to
the duration and severity of PBC and to the intensity and duration of jaundice. This is
particularly true for post-menopausal women, patients with cholestatic disorders
such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC),
patients who have received prolonged corticosteroid therapy, and patients with
chronic hepatitis C and alcoholic cirrhosis. Osteoporosis is of particular concern in
patients being considered for liver transplantation because of the loss of bone
density and the risk for pathological fractures that can occur in the perioperative
period. However, the severe form associated with compression fractures of the spine
and bone pain is rarely seen now that there is effective medical treatment.
All patients with chronic liver disease should be screened for osteoporosis by DEXA
scan during evaluation for liver transplantation. In those with significant bone loss,
efforts to improve bone density and to prevent pathological fractures should be
pursued both before and after transplantation. Treatments may include calcium
supplementation, vitamin D, and alendronate.
Biochemical Criteria
1. For chronic hepatocellular disease:



Serum albumin < 3.0 g/dL
Prothrombin time > 3 seconds above control or INR > 1.3
Bilirubin > 2 mg/dL
2. For chronic cholestatic liver disease:




Serum bilirubin > 5 mg/dL
An increased serum alkaline phosphatase level
Protime prolonged > 5 seconds
Serum albumin level < 2.5 g/dL
3. For chronic noncholestatic liver disease:



Serum bilirubin > 3 mg/dL
Protime prolonged > 5 seconds
Serum albumin level < 2.5 g/dL
Disease-Specific Criteria
The major disease-specific conditions and their criteria that lead to the need for
transplantation in children and adults are:
Acute Fulminant Liver Failure
Policy Statement
Transfer to a facility capable of performing liver transplantation is medically
necessary for all patients with fulminant liver failure (FLF), as they need to be
managed in an intensive care unit.
Liver transplantation on an urgent basis is medically necessary in patients with FLF
when all of the following are met:
1. Patient is thought to be a candidate for liver transplantation
21
2. Hepatic encephalopathy (altered sensorium) occurs within 2 weeks (acute) or 8
weeks (subacute) of onset of jaundice in a previously normal person or in
patients who experience an acute decompensation of preexisting chronic liver
disease
3. Profound coagulopathy* (protime prolonged by 4 - 6 seconds, INR > 1.5)
4. One (1) of the following prognostic sets of criteria is met:

Clichy criteria for acute viral hepatitis secondary to A, B, non-A, non-B, D,
or E virus when all of the following are met:
 Stage III or IV coma***; and
 Factor V less than 20% (age less than 30 years) or factor V less than
30% (age greater than 30 years); or

King’s College Criteria in patients with acetaminophen (Tylenol,
paracetamol) toxicity:
Guidelines For Referral For Paracetamol Hepatotoxicity
Day 2
Day 3
Day 4
Arterial pH < 7.30*
Arterial pH < 7.30*
------
INR > 3
INR > 4.5
Any rise in INR
Encephalopathy
Encephalopathy
Encephalopathy
Creatinine > 200 μmol/l
Hypoglycemia
Day X, day after overdose; INR, international normalized ratio.
*Arterial pH < 7.3 that fails to correct with fluid resuscitation (results in a 90%
mortality rate without liver transplantation)

King’s College London criteria for patients without acetaminophen toxicity
(agents include chlorinated hydrocarbons, salicylates, methanol, isoniazid,
IV tetracycline, sodium valproate, Amanita mushroom poisoning and
anesthetic-induced [Halothane]**) when either of the following is met:
 A marked elevation of prothrombin time > 100 (INR > 6.5); or
 Any three of the following prognostic factors are present:
a. Age < 10 years or > 40 years
b. Non-A, non-B hepatitis
c. Halothane hepatitis or idiosyncratic drug reaction
d. Duration of jaundice before onset of encephalopathy greater than
7 days
e. Prothrombin time > 50, INR >3.5
f.
Serum bilirubin > 17.6 mg/dL
22
Note: Patients with non-paracetamol acute and subacute liver failure (defined by the
presence of encephalopathy, including fulminant Wilson’s disease) should be referred
to a transplant center. Patients with non-paracetamol liver failure and a progressive
coagulopathy, in the absence of encephalopathy, should be discussed with a
transplant center.
* Note: Replacement therapy for thrombocytopenia (platelet counts < 10,000 per
mm3) and/or prolonged prothrombin time is recommended only in the setting of
hemorrhage or prior to invasive procedures.
** Drugs / Toxins Associated With Fulminant Hepatic Failure
Alcohol
Methyldopa
Amiodarone
NSAIDs
Amoxacillin-clavulanate
Phenytoin
Carbon tetrachloride
Poison mushrooms (Amanita phalloides)
Dideoxyinosine
Propylthiouracil
Gold
Rifampin
Halothane
Sulfonamides
Isoniazid
Tetracycline
Ketoconazole
Tricyclic antidepressants
MAO inhibitors
Valproic acid
***Coma
Stage
Description
0
Minimal hepatic encephalopathy (previously known as subclinical hepatic
encephalopathy). Lack of detectable changes in personality or behavior.
Minimal changes in memory, concentration, intellectual function, and
coordination. Asterixis is absent.
1
Trivial lack of awareness. Shortened attention span. Impaired addition or
subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria,
depression, or irritability. Mild confusion. Slowing of ability to perform
mental tasks. Asterixis can be detected.
2
Lethargy or apathy. Disorientation. Inappropriate behavior. Slurred speech.
Obvious asterixis. Drowsiness, lethargy, gross deficits in ability to perform
mental tasks, obvious personality changes, and intermittent disorientation,
usually regarding time.
3
Somnolent but can be aroused, unable to perform mental tasks,
disorientation about time and place, marked confusion, amnesia, occasional
fits of rage, present but incomprehensible speech
4
Coma with or without response to painful stimuli
According to the so-called West Haven classification system
Fulminant liver failure (FLF), also known as acute fulminant hepatitis and acute liver
failure, refers to the rapid development of severe acute liver injury with encephalo-
23
pathy, impaired synthetic function leading to profound coagulopathy and
hypoglycemia in a person who previously had a normal liver or had wellcompensated liver disease. If symptoms occur within two weeks after onset of
symptoms, it is termed acute; if within eight weeks of the onset of symptoms in
patients without preexisting liver disease, it is termed subacute. In addition to those
previously mentioned, patients with FLF are susceptible to a wide variety of
complications including cerebral edema, renal failure, sepsis and multiorgan failure.
All patients with FLF should be managed in an intensive care unit at a facility capable
of performing liver transplantation. Although there is no specific therapy for FLF
(except for N-acetylcysteine in FLF due to acetaminophen intoxication), appropriate
critical care support in many patients will lead to spontaneous recovery. In these
instances, recovery typically is complete, with no evidence of residual liver injury.
The prognosis for spontaneous recovery depends on the patient's age, the underlying
etiology of disease, and the degree of encephalopathy.
The only therapy proven to improve patient outcome in FLF is orthotopic liver transplantation, which is associated with one-year survival rates of greater than 80%.
Thus, patients with liver failure should be transferred as early as possible to a
transplant center for expectant critical care management. Patients predicted to have
little chance of spontaneous recovery should undergo transplantation as soon as
possible. These patients can develop cerebral edema, multiorgan failure, or
cardiovascular collapse within days to weeks after clinical presentation. As a result,
any delay in obtaining a donor organ can have fatal consequences. To address this
urgency, a special category (status 1) was created to allow these patients to receive
first preference for any deceased donor organ.
The various causes of this devastating condition include acetaminophen overdose,
drug-induced liver injury* (idiosyncratic drug reactions), hepatitis A and B,
autoimmune hepatitis, ingestion of various hepatotoxins, Budd-Chiari syndrome
(hepatic vein thrombosis), veno-occlusive disease, acute fatty liver of pregnancy,
and Wilson disease. In many cases, the precise etiology is never discovered
(crytogenic).
Chronic Noncholestatic Liver Disorders
(Hepatocellular Diseases)
Alcoholic Cirrhosis
Policy Statement
Referral for evaluation of liver transplantation in patients with alcoholic liver disease
(also known as Laennec’s cirrhosis) is medically necessary when all of the following
are met:
1. Patient is in the terminal phase of the disease with evidence of progressive liver
failure despite medical treatment and abstinence from alcohol; and
2. The patient has developed a complication(s) of advanced portal hypertension
such as variceal hemorrhage, ascites, hepatic encephalopathy, etc. OR patient
has a CTP score of 11 or more (Child C disease), despite at least 6 months of
abstinence; and
3. There should be evidence of sufficient social support to assure assistance in
alcohol rehabilitation and immunosuppressive therapy following the operation;
and
4. There is no evidence of other major organ debility (e.g., cardiomyopathy).
24
Important Note: Referral for evaluation of liver transplantation is medically
necessary regardless of how long a patient has been abstinent of alcohol. However,
the actual liver transplantation must not occur until all of the following are met:

At least 6 months of sobriety has been achived as documented by random
surveillance of blood / breathilizer testing; and

Patient has been carefully evaluated by a health care professional experienced
in the management of patients with addictive behavior and the patient is
considered at low risk for continued alcohol abuse; and

Patient has evidence of ongoing participation in formal alcohol treatment
program or in a social support group like Alcoholics Anonymous.
Note: Patients who have alcoholic hepatitis are almost never transplanted because
the presence of this lesion implies recent alcohol abuse, and because the chronic
inflammatory state associated with this disorder may increase perioperative
complications.
Note: Patients who do not meet the above criteria at the time of referral may be
given the opportunity to fulfill these criteria and undergo re-evaluation.
At least 50% of the cases of cirrhosis in the United States are attributable to the
abuse of alcohol, and alcohol abuse is the leading cause of morbidity and mortality
(40%) from cirrhosis. Unfortunately, many alcoholics first become symptomatic only
when severe, life-threatening liver disease is already present. Abstinence is the only
effective treatment for most patients, but even among patients with decompensated
cirrhosis, it can be associated with a dramatic improvement in survival. Therefore, it
is prudent to delay transplantation for a minimum of 6 months during which time the
patient with far-advanced alcoholic liver disease is asked to abstain from alcohol to
avoid exposing patients who may not need transplantation to the risk of unnecessary
surgery. This is one of the reasons transplantation programs require six months of
abstinence and careful assessment by a health care professional experienced in the
management of patients with addictive behavior before transplantation.
Unfortunately, there is no effective means of predicting which patients will have such
a dramatic response. In addition, recent studies have shown that there may be a
benefit of delaying transplantation further in patients with milder disease. However,
patients who have CTP scores of 11 or more (Child C disease), despite at least six
months of abstinence, have improved survival with transplantation compared with
the natural history of disease predicted from prognostic models. Although alcohol
relapse rates vary considerably from center to center, graft loss as a consequence of
destructive drinking after transplantation is uncommon.
Chronic Hepatitis C
Policy Statement
Referral for evaluation of liver transplantation is medically necessary when one of
the following is met: (genotype and viral load should not influence transplant
assessment)
1. Patient has demonstrated impaired synthetic dysfunction (i.e., serum albumin
25
< 3.0 g/dL without alternative cause, prothrombin time > 3 seconds above
control INR > 1.3, or serum bilirubin > 2 mg/dL
2. Patient has hepatic decompensation with ascites, encephalopathy or variceal
hemorrhage
3. Patient has developed a hepatocellular carcinoma and meets the criteria below
in the Mass Occupying Lesions section
It is estimated that 15 % to 20 % of patients with chronic HCV infection develop
cirrhosis within 20 years of disease onset. Although morbidity and mortality due to
chronic hepatitis C virus (HCV) is low in childhood, ESLD secondary to chronic
hepatitis C virus infection in adults accounts for an estimated 4,500 in-hospital
deaths annually in the United States. As a result, cirrhosis due to HCV in adults is the
most common indication for liver transplantation in the United States. Although the
10-year survival rate of patients with well-compensated cirrhosis is more than 80%,
the 5-year survival decreases to less than 50% after the typical complications of
advanced liver disease develop including portal hypertension, hepatocellular failure,
and hepatic encephalopathy. Patients with cirrhosis secondary to chronic hepatitis C
also have a 2% to 8% annual risk of developing hepatocellular carcinoma (HCC).
Using strict criteria, patients can be identified who have almost no chance of survival
beyond 6 months and in such patients liver transplantation is often the only
therapeutic option. Five-year survival after transplantation is approximately 60 to 80
% in most series.
Hepatitis C is detected by the persistence of anti-HCV antibodies, serum viral
proteins, and HCV RNA. In contrast to hepatitis B, persistent viremia with HCV is
virtually universal (95%) after liver transplantation, and the majority of patients
develop some degree of recurrent liver injury. Postoperatively, active infection can
occur by one of two mechanisms: recurrence of preexisting disease, or, much less
commonly, from a new infection in a previously HCV-negative individual. Although
many patients have an indolent course with minimal liver damage despite
persistently high levels of circulating virus, a minority of patients develop rapidly
progressive fibrosis and cirrhosis within the first few years after transplantation.
Recurrent hepatitis C in the graft often follows an indolent course, and graft survival
is comparable to that seen with nonviral causes of hepatic failure. In addition,
emerging data suggest that preoperative treatment with interferon and ribavirin can
be quite effective in some patients with relatively well-compensated cirrhosis,
particularly those with genotype 2 and 3 infection. Furthermore, successful
treatment before transplantation usually prevents postoperative HCV infection.
Several studies have shown that treatment of hepatitis C with interferon alfa and
ribavirin after transplantation may be useful, but it is often poorly tolerated and no
significant benefits have been shown. However, there is no consensus on the optimal
strategies for administering this therapy. Although virological responses to treatment
have been well documented, the overall impact of antiviral therapy on histological
progression or patient and graft survival is not clear. Therefore, treatment of HCV
infection in the graft is not currently recommended.
The leading cause of death in all hepatitis C retransplanted patients is severe
recurrent HCV leading to liver failure. Hepatitis C is the leading indication for
orthotopic liver transplantation worldwide, and with nearly universal reinfection of
the graft, recurrent HCV disease is problematic clinically. HCV-related graft cirrhosis
26
has been reported as high as 30% at 5 years. At present, 40% of liver retransplants
in the United States are due to recurrent HCV disease. Studies have assessed
outcomes in patients undergoing retransplantation for HCV-related disease compared
with patients receiving a primary liver transplant. They found a significantly worse
survival outcome at 5 years (60% vs 28%) for patients undergoing retransplantation, with the leading cause of death after retransplant being recurrent HCV
disease leading to liver failure. Many reports suggest that more strict selection
criteria may be required when considering retransplantation in patients with
aggressive HCV recurrence, although considerable controversy still exists in this
arena.
Chronic Hepatitis B
Policy Statement
Referral for evaluation of liver transplantation is medically necessary when one of
the following is met: (genotype and viral load should not influence transplant
assessment)
4. Patient has demonstrated impaired synthetic dysfunction (i.e., serum albumin
< 3.0 g/dL without alternative cause, prothrombin time > 3 seconds above
control INR > 1.3, or serum bilirubin > 2 mg/dL
5. Patient has hepatic decompensation with ascites, encephalopathy or variceal
hemorrhage
6. Patient has developed a hepatocellular carcinoma and meets the criteria below
in the Mass Occupying Lesions section
Note: A patient should not proceed with the actual liver transplant until he/she is
rendered hepatitis B negative (HBV DNA negative) with antiviral treatment.
* Note: The majority of HBV DNA positive patients can be rendered HBV DNA
negative with antiviral treatment and should not be excluded from assessment.
Long-term passive immunization with hepatitis B immunoglobulin is an effective
strategy to prevent reinfection. Precore mutant HBV or hepatitis D virus (HDV) coinfection are not contraindications to transplantation.
An estimated 350 million persons worldwide and 1.25 million in the United States are
infected with HBV. HBV carriers, particularly those who acquire the disease at birth
or in early childhood, are at risk for the development of cirrhosis and hepatocellular
carcinoma (HCC). Hepatitis B virus (HBV) carriers with compensated cirrhosis have
an 84% 5-year survival rate and a 68% 10-year survival rate; however, patients
with decompensated cirrhosis have a 5-year survival rate of only 14%. Fulminant
hepatitis B is believed to be due to massive immune-mediated lysis of infected
hepatocytes. The only treatment for fulminant hepatitis is liver transplantation.
The early results of liver transplantation for hepatitis B were discouraging. Many
patients developed rapidly progressive recurrent disease (fibrosing cholestatic
hepatitis) that resulted in death within 12 to 18 months after the operation and a
patient survival of 50% compared to 80% in those transplanted for other types of
chronic liver disease. The high rate of HBV reinfection is probably due to enhanced
virus replication resulting from immunosuppression or from direct stimulatory effects
of steroid therapy on the glucocorticoid-responsive enhancer region of the HBV
27
genome. With these poor results and limited supply of donor organs, many centers
abandoned liver transplantation for patients with chronic hepatitis B. However,
dramatic improvements have occurred in the treatment of hepatitis B over the last
decade to prevent and treat reinfection. Particularly important is the development of
agents that are safe and effective both before and after liver transplantation.
Furthermore, highly effective vaccines now given routinely to newborns and children
have been developed that can prevent infection. The overall survival of patients
transplanted for HBV-related cirrhosis now exceeds 80 % at one year and 65 % at
three years.
Despite these advances, liver transplantation remains the only hope for many
patients with end-stage liver disease due to HBV. In a study of the natural history of
HBV-related cirrhosis, the five-year survival was 71% for the entire group of
patients, but only 14 % for those with decompensated disease. However, in the last
decade, perioperative treatment with lamivudine or adefovir has dramatically
reduced both the reinfection rate and the severity of recurrent hepatitis B after liver
transplantation. With routine use of these approaches, survival of patients
transplanted for chronic hepatitis B now exceeds that of patients transplanted for
many other conditions.
HBV reinfection is diagnosed by the reappearance of HBsAg in the serum. Most
reinfected patients are also HBeAg positive and have high levels of circulating HBV
DNA. There are multiple therapies for the treatment of HBV after transplantation and
these treatments are in evolution. Factors associated with a lower rate of graft
reinfection and improved survival include:
1.
2.
3.
4.
HBeAg negative
Lower levels of serum HBV-DNA negative
Fulminant hepatitis B
Coexistent hepatitis D virus (HDV) infection
Autoimmune Hepatitis in Adults
Policy Statement
patient is unable to undergo or fails to respond to corticosteroid / immunosuppressive therapy or who develop advanced decompensated disease despite
treatment. Therefore, failure of immunosuppressive therapy to arrest progression of
severe autoimmune hepatitis with the development of hepatic decompensation is an
indication to consider transplant (human leukocyte antigen (HLA)-DR3 is associated
with a lower likelihood of a therapeutic response to immunosuppression in
autoimmune hepatitis).
Indications For Corticosteroid / Immunosuppressive Therapy
Absolute
1. Serum aspartate aminotransferase level (AST) level = 10-fold of upper limit of
normal
2. Serum AST = 5-fold upper limit of normal and y-globulin level = twice normal
3. Bridging necrosis or multiacinar necrosis on histologic examination
Relative
1. Symptoms (fatigue, arthralgia, jaundice)
28
2. Serum AST and/or y-globulin less than absolute criteria
3. Interface hepatitis
Autoimmune hepatitis in adults is an unresolved inflammation of the liver caused by
autoantibodies circulating in the bloodstream that cause the immune system to
attack the liver. A prospective study has indicated that as many as 40% of patients
with untreated severe disease die within 6 months of diagnosis. Cirrhosis develops in
at least 40% of survivors, 54% develop esophageal varices within 2 years after
cirrhosis, and 20% of individuals with esophageal varices die from hemorrhage.
Treatment consists of corticosteroids and immunosuppressants (azathioprine and
mercaptopurine) to help reduce the inflammation. The 20-year life expectancy for all
treated patients exceeds 80%.
Autoimmune hepatitis can result in progressive inflammation and fibrosis of the liver
with subsequent cirrhosis and hepatic failure. Corticosteroid therapy is associated
with clinical remission of disease in 80% of patients, prolongs immediate survival,
and results in 10-year survival rates of 90% in adults. Nevertheless, some patients
who achieve biochemical and histological remission of disease develop intractable
portal hypertension and slowly progress to liver failure, despite medical therapy.
Excellent long-term survival is usual after transplant, with reported 5- and 10-year
survival rates of more than 75 % in adults. However, the autoimmune diathesis may
result in higher rates of acute cellular rejection. Recurrent disease can occur but is
usually mild and easily managed with higher maintenance doses of immunosuppression. Occasionally, recurrent autoimmune hepatitis results in graft loss;
however, these few cases have not had an appreciable impact on overall patient
survival after transplantation.
Autoimmune Hepatitis in Children
Policy Statement
decompensated patient with auto-immune hepatitis is unable to undergo or be
salvaged by medical therapy (corticosteroid, immunosuppressive therapy).
Autoimmune hepatitis in children is a mixture of type I (anti–smooth muscle
antibody positive, most common in older children) and type II (anti–liver kidney
microsomal antibody positive, more common in younger children). Children with type
II disease tend to have a more aggressive course that is less responsive to therapy,
with a higher %age requiring liver transplantation. Furthermore, posttransplantation
survival is lower in children with type II disease, most likely reflecting their
pretransplant morbidity entering the transplant. In contrast to autoimmune hepatitis
in adults, recurrence after transplantation occurs frequently in children and more
severe disease recurrence has been observed, and as a result, the outcome in
children seems to be less favorable than that in adults. Treatment is warranted in
most children at the time of diagnosis.
Congenital Erythropoietic Protoporphyria
Policy Statement
1. Referral for evaluation of liver transplantation is medically necessary in patients
with severe "hepatic" porphyria because it is potentially curative.
29
2. Referral for evaluation of liver transplantation is medically necessary in highly
selected patients who have the most severe and recalcitrant forms of hepatic
damage from excess protoporphyrin production in erythropoietic protoporphyria
(EPP). However, in the case of EPP the transplanted liver would eventually be
subject to the same damage, since the source of protoporphyrin production is the
bone marrow rather than the liver, and this will eventually cause recurrent
disease in the allograft.
The porphyrias are a group of inherited metabolic disorders characterized by the
excessive accumulation and excretion of porphyrins and their precursors caused by
specific enzyme defects in the heme synthetic pathway. Abnormalities in the
production of heme pigments (the base material responsible for hemoglobin, the red
blood cell pigment), myoglobin (reddish muscle cell pigment), and another group of
materials called cytochromes are primarily affected. The main clinical manifestations
of the porphyrias are cutaneous photosensitivity and neurologic dysfunction, most
often presenting as abdominal pain. Many patients with the enzyme defects do not
have clinical manifestations. Porphyric attacks can be fatal, so the early diagnosis of
carriers and affected individuals is important to be able to advise the avoidance of
precipitating factors for an acute attack: typically drugs, fasting, or alcohol which
result in the induction of aminolevulinic acid synthase (ALAS-N), the hepatic isoform
of the first enzyme in the heme pathway. If neurovisceral symptoms suggest an
acute porphyric attack, a rapid screening test for delta-aminolevulinic acid (ALA)
and/or porphobilinogen (PBG) should be performed because their increased
production are associated with neurovisceral complaints. If a cutaneous porphyria is
suspected, screening tests for increased erythrocytic porphyrins should be done (if
solar urticaria and acute photosensitivity suggest erythropoietic protoporphyria
[EPP]), or screening tests for urinary porphyrins (if vesiculobullous formation and
skin fragility suggest porphyria cutanea tarda [PCT], hereditary coproporphyria
[HCP], or variegate porphyria [VP]). Positive screening tests should be confirmed by
specific quantitative tests. Enzymic assays and DNA-based tests are useful for
kindred evaluation, genetic diagnosis, and the pinpointing of causative mutations but
are not needed for rapid diagnosis of symptomatic patients. Prevention is a central
component of management of patients with porphyria. Intravenous hematin, high
carbohydrate intake, and pain control are central in the treatment of acute
neurovisceral attacks. Sun avoidance and skin protection are important to reduce
cutaneous manifestations and complications.
Protoporphyria, also called erythropoietic protoporphyria or erythrohepatic
protoporphyria (EPP), is the commonest of the erythropoietic porphyrias and results
from a partial deficiency in the activity of the mitochondrial enzyme ferrochelatase,
the last enzyme in the heme biosynthetic pathway. This leads to accumulation of the
heme precursor protoporphyrin in the bone marrow, red blood cells, blood plasma,
skin, bile feces and liver. The clinical expression is highly variable. Photosensitivity is
the major clinical manifestation of EPP. EPP patients rarely (<10%) develop severe
liver disease with cirrhosis and acute cholestasis. The rate-limiting step is canalicular
excretion. If the hepatic load exceeds the excretion capacity, protoporphyrin
accumulates in the liver and causes liver damage, involving a vicious cycle of
worsening cholestasis and worsening accumulation. Only rarely do patients recover
after jaundice supervenes. Fortunately, the prognosis of EPP is good in the majority
of patients.
30
Treatment of hepatic complications must be individualized and the results are
unpredictable. Resolution of hepatic complications may occur spontaneously,
especially if another reversible cause of liver dysfunction, such as viral hepatitis or
alcohol, is a contributing factor. Cholestyramine and other porphyrin absorbents such
as activated charcoal should be considered in this situation. Other therapeutic
options include red blood cell transfusions, exchange transfusion, and intravenous
hematin to suppress erythroid and hepatic protoporphyrin production.
Some patients with EPP develop progressive liver disease requiring liver
transplantation. An excellent biochemical and clinical response has been noted in
patients following liver transplantation. Unfortunately, excessive production of
protoporphyrin by the bone marrow continues following liver transplantation,
eventually causing protoporphyrin-induced damage in the allograft in 65% of
patients surviving more than 2 months. Therefore, consideration for such treatment
should be reserved for highly selected patients with the most severe and recalcitrant
forms of this disorder. Although 5- and 10-year patient survival rates in those
receiving a liver transplant for EPP liver disease are reasonably high, the recurrence
of EPP liver disease appears to diminish long term graft and patient survival only.
Therefore, consideration for such treatment should be reserved for highly selected
patients with the most severe and recalcitrant forms of this disorder.
HELLP Syndrome
Policy Statement
Referral for evaluation of liver transplantation is medically necessary for patients
with complicated HELLP syndrome who have either ongoing, uncontrolled
hemorrhage or liver necrosis and failure.
HELLP syndrome is a group of symptoms that occur in pregnant women who have
Hemolysis, damage to liver cells causing Elevated Liver enzymes, and Low Platelets.
The diagnosis is based upon the presence of the characteristic laboratory findings in
patients of appropriate gestational age. These include:
1. Microangiopathic hemolytic anemia with characteristic schistocytes (helmet cells)
on blood smear. Other signs suggestive of hemolysis include an elevated indirect
bilirubin and a low serum haptoglobin concentration (25 mg/dL).
2. Platelet count <100,000 cells/microL.
3. Serum lactate dehydrogenase >600 IU/L or total bilirubin >1.2 mg/dL.
4. Serum aspartate aminotransferase (AST) >70 IU/L.
HELLP syndrome occurs in approximately 10% of pregnant women with preeclampsia or eclampsia. Severe cases involve pregnancy-induced high blood pressure
and protein in the urine and can progress to seizures (eclampsia). These findings
typically become apparent in the latter part of the third trimester and progress until
delivery. In some patients, however, symptoms begin in the latter half of the second
trimester, while other women have an onset that is delayed until delivery or even the
early postpartum period. Severe cases can be life-threatening to both mother and
fetus and may result in other hepatic manifestations including infarction, hematoma,
hemorrhage, and rupture. Imaging tests, particularly CT or MRI scanning, are useful
when these complications are suspected.
The initial steps in management are to stabilize the mother, assess the fetal
condition, and decide whether prompt delivery is indicated. Pregnancies 34 weeks of
31
gestation and those in which the mother is unstable should be managed in
consultation with a maternal-fetal specialist. There is a consensus of opinion that
prompt delivery is indicated for any of the following: (1) pregnancies > 34 weeks of
gestation; (2) non-reassuring tests of fetal status (e.g., biophysical profile, fetal
heart rate testing); and (3) presence of severe maternal disease: multiorgan
dysfunction, disseminated intravascular coagulation (DIC), liver infarction or
hemorrhage, renal failure, or abruptio placenta. Because liver rupture is a rare
perinatal complication with high maternal mortality, the main treatment is to deliver
the baby as soon as possible, since liver function in the mother rapidly deteriorates
in this condition, and this is harmful to both mother and child. In more severe cases,
the baby has to be delivered before its due date. If this is the case, a cesarean
section may be necessary. In less severe cases, the physician will monitor the
mother and wait as long as is possible to deliver the baby either through natural or
induced labor. The mother's liver may hemorrhage or permanent liver damage,
which can be fatal, may occur if delivery is delayed.
The outcome for mothers with HELLP is generally good. With treatment, maternal
mortality is about 1%. Maternal complications and gestational age at delivery are
strongly associated with fetal prognosis. Fetal complications may include prematurity
(70%), intrauterine growth restriction and abruptio placenta, and depend largely
upon the severity of the disease and the gestational stage. The overall perinatal
mortality is 7 to 20%. The rate of reoccurrence of this syndrome in subsequent
pregnancies is only 2 to 6%.
Chronic Cholestatic Liver Diseases
The clinical complications of cholestatic liver disease, such as intractable pruritus,
recurrent bacterial cholangitis, and progressive bone disease often warrant liver
transplantation before hepatic encephalopathy or variceal hemorrhaging develops.
Therefore, it is important to assess the patient's overall condition and not rely solely
on biochemical parameters when deciding who should be referred for possible liver
transplantation.
Primary Biliary Cirrhosis
Policy Statement
patient’s estimated six-month survival is less than 80% and one or more of these
findings is present:
1. The plasma bilirubin concentration is greater than 5 mg/dL (or exceeds 100
μmol/l) and increasing.
2. The serum albumin concentration is below 2.8 g/dL (28 g/L) and is decreasing.
3. Signs of end-stage liver disease develop, such as ascites, variceal bleeding,
coagulopathy, malnutrition, or encephalopathy.
4. The patient has severe, intractable pruritus with associated sleep deprivation and
emotional disturbance not responding to optimal medical therapy.
5. The patient has recurrent, debilitating nontraumatic bone fractures.
Note: The indolent course of primary biliary cirrhosis and the potential for
spontaneous improvement even in patients with advanced disease make
transplantation potentially suitable only in the final stages of liver failure or when the
quality of life has deteriorated to an unacceptable level. Earlier referral is justified if
symptoms or complications are prominent.
32
Primary biliary cirrhosis (PBC) is a chronic destructive disorder of interlobular bile
ducts that can progress to cirrhosis and liver failure and most commonly affects
women in the fourth to seventh decades of life. PBC is an excellent indication for
transplantation because of its indolent course and the potential for spontaneous
improvement with transplantation, even in patients with advanced disease. It is
potentially suitable only in the final stages of liver failure or when the quality of life
has deteriorated to an unacceptable level. The Mayo Clinic model states that serum
bilirubin levels above 3 mg/dL warrant referral for transplantation as well as
significant impairment of liver function (progressive jaundice, recurrent bacterial
cholangitis, ascites, rapidly progressive portal hypertension, malnutrition, or
progressive hepatic synthetic failure). Earlier referral is justified if symptoms or
complications are prominent. After liver transplantation, 70 % of patients with PBC
survive at least 10 years after the operation. Numerous studies using diseasespecific prognostic models have documented improved survival after transplantation
compared with estimated survival without surgery. Occasional patients with PBC and
good liver function have such severe, uncontrolled pruritus and associated sleep
deprivation and emotional disturbance that liver transplantation may be required.
However, every possible medical treatment should be explored before
transplantation is undertaken. Although recurrent PBC after transplantation has been
well documented, it has not had a major impact on long-term postoperative survival.
Liver transplantation is the only effective treatment for liver failure secondary to
primary biliary cirrhosis.
An important issue in the management of progressive PBC is to determine prediction
of prognosis and the optimal time to perform a liver transplant. Many groups have
developed models which use clinical variables to estimate patient survival. Two types
of models have been developed: one based upon initial data on entry into the study;
and one which uses both initial and follow-up data. Findings on physical examination,
laboratory data, and liver biopsy all may have predictive value. Among the factors at
entry into the study that have been found to correlate with prognosis are age, the
plasma bilirubin and albumin concentrations, hepatomegaly, a treatment variable
(whether or not azathioprine had been used), and on liver biopsy the presence of
cholestasis, portal fibrosis or cirrhosis. A model developed at the Mayo Clinic does
not require liver biopsy. They thought that survival could by predicted from the
patient's age, plasma bilirubin and albumin concentrations, the prothrombin time,
and the presence of edema. Cross-validation on 106 patients with PBC confirmed the
accuracy of this model in cohorts of PBC patients. Each of these models is time-fixed,
being designed to provide survival estimates based upon initial laboratory values and
physical findings. A separate study found that, if the third model were used
repeatedly with follow-up data, it was an accurate predictor of survival only if the
patient were doing well (survival greater than two years). The model was an
inaccurate predictor and overestimated survival if the patient was deteriorating at
the time of entry and survived less than two years.
Two time-dependent Cox regression models have been developed which use readily
available markers and follow-up data to predict survival. These models, therefore,
permit a change in the patient's condition to provide an updated prognosis. One uses
the plasma albumin and bilirubin concentrations, the presence of ascites, a history of
gastrointestinal bleeding, and age as important variables. The second uses the same
variables and adds plasma immunoglobulin measurements and the presence of
cirrhosis and central cholestasis. Both models were validated and were more
33
accurate than the time-fixed models in predicting survival, particularly in the shortterm. They suggest that liver transplantation be undertaken when the estimated sixmonth survival is less than 80 %. Six months is used as the cut-off since this is the
time when survival after transplantation becomes better than survival without
transplantation, assuming that a transplant is available within six months. The Mayo
model is most widely used, but because of individual patient variation does not
replace the input of an experienced physician.
Primary Sclerosing Cholangitis
Policy Statement
Early referral for evaluation of liver transplantation is medically necessary in all
patients with primary sclerosing cholangitis because of the risk of cholangiocarcinoma.
Liver transplantation is medically necessary when any of the following is met:
1. The patient has decompensated cirrhosis secondary to advanced PSC (i.e., a
Mayo model score of > 5 or a Child grade C score), indicating an estimated sixmonth survival < 80%; or
2. Recurrent episodes of ascending bacterial cholangitis; or
3. Patient is unresponsive to appropriate attempts at biliary tract diversion and/or
dilatation by endoscopic retrograde cholangiopancreatography (ERCP) using a
stent, and death from liver failure is imminent
4. Patient has an indication for liver transplant similar to those in other forms of
end-stage liver disease, including:






Hemorrhage due to esophageal varices or portal gastropathy
Intractable ascites
Recurrent bacterial cholangitis
Progressive muscle wasting
Hepatic encephalopathy
Jaundice alone, in the absence of other signs of liver failure, is not an
absolute indication for transplant
Primary sclerosing cholangitis (PSC) is a chronic progressive disorder of unknown
etiology that is characterized by non-suppurative inflammation, fibrosis, and
stricturing of medium size and large ducts in the intrahepatic and extrahepatic biliary
tree. This is usually accompanied by multiple episodes of bacterial cholangitis and
jaundice, with development of secondary biliary cirrhosis. The disease typically
occurs in young men, 70% to 75% of whom have underlying ulcerative colitis; the
incidence may be as high as 90 % when rectal and sigmoid biopsies are routinely
obtained. A subset of patients with PSC have a dominant extrahepatic biliary
stricture that is potentially amenable to endoscopic therapy. Thus, surgical therapies
employing various methods of biliary-enteric drainage, with or without intraoperative
stent insertion, other than transplantation should be avoided in patients with PSC.
The only exception may be in patients with isolated focal extrahepatic strictures and
early histologic stage disease. Eventually, PSC progresses to hepatic failure within 10
to 12 years. The most dreaded complication of sclerosing cholangitis is
cholangiocarcinoma, which is an absolute contraindication to liver transplantation.
Besides offering therapeutic benefits, ERCP with biopsy and brushing of the biliary
tract is the only proven screening tool for cholangiocarcinoma.
34
In an attempt to assist the clinician in deciding when patient survival is threatened,
the Mayo Clinic devised a model for predicting lifespan in primary sclerosing
cholangitis which included the serum bilirubin, age, the presence of splenomegaly,
and histologic staging by liver biopsy; this model (known as the Mayo Risk Score)
has subsequently been updated. The new model includes age, serum bilirubin, serum
albumin, serum AST, and a history of variceal bleeding, and no longer requires liver
biopsy, which often limited the use of the initial model. The models suggest that liver
transplantation be undertaken when the estimated six-month survival is less than 80
%; the six-month survival in the models is extrapolated from the predicted one-year
value. Six months is used as the cut-off since this is the time when survival after
transplantation becomes better than survival without transplantation, assuming that
a transplant is available within six months.
Liver transplantation is the only effective treatment for decompensated cirrhosis
secondary to advanced PSC (i.e., a Mayo model score of > 5 or a Child grade C
score) as the five-year survival after transplantation is as high as 85%, far superior
to that predicted for patients treated conservatively. Early referral for liver
transplantation should be considered in all patients with primary sclerosing
cholangitis because of the risk of cholangiocarcinoma. Recurrent cholangitis in
patients with PSC is a specific indication for transplantation. Transplantation
indicated when patient is unresponsive to appropriate attempts at biliary tract
diversion and dilatation by endoscopic retrograde cholangiopancreatography (ERCP)
using a stent. Ursodeoxycholic acid therapy may improve survival and delay the need
for transplantation. However, no specific medical treatment has been shown to
improve survival in patients with PSC. Although recurrent disease is common after
transplantation, this has not had a significant impact on long-term postoperative
survival. However, the discovery of cholangiocarcinoma before or during surgery
dramatically reduces survival. Furthermore, development of colorectal cancer can
adversely influence postoperative survival if regular screening is not performed in
patients with ulcerative colitis.
Extrahepatic Biliary Atresia
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in the young
infant when any of the following is met:
1. The diagnosis is delayed beyond 3 months; or
2. Hepatoportoenterostomy (Kasai procedure) is unsuccessful as manifested by
failure to thrive, recurrent cholangitis, and typical signs of ESLD; or
3. The development of progressive cholestasis, hepatocellular decompensation, or
intractable portal hypertension occur despite a successful Kasai procedure; or
4. Development of cirrhosis and progressive portal hypertension over a period of
years in children with successful Kasai procedures in order to assure long-term
survival.
* Note: Hepatoportoenterostomy (Kasai procedure) consists of anastamosis of bile
duct remnants in the porta hepatis to a loop of bowel by an experienced surgeon and
is usually performed within the first two months of life.
Note: In the absence of severe hepatic decompensation in these children, liver
transplantation should be delayed as long as possible to permit the child to achieve
maximum growth. In children with successful hepatoportoenterostomy, liver
transplantation should be deferred until progressive cholestasis, hepatocellular
35
decompensation, or severe portal hypertension supervene. Multiple attempts at
hepatoportoenterostomy or surgical porto-systemic shunting render eventual
transplant surgery technically more difficult and operationally more dangerous and
therefore should be avoided in favor of liver transplantation.
Biliary atresia is a destructive inflammatory process of unknown etiology that results
in fibrosis and obliteration of the extrahepatic bile ducts and variable involvement of
the intrahepatic ducts. If untreated, death usually results within the first one to two
years of life. There is no effective medical therapy for children with biliary atresia.
However, if the diagnosis can be established within the first few months of life, the
treatment of choice for most children, a Kasai portoenterostomy, can result in
prolonged survival in as many as 70% of infants. If the diagnosis is delayed beyond
three months after birth, successful results from hepatoportoenterostomy (Kasai
procedure)* are significantly reduced. Children who are not offered surgery because
of a delay in diagnosis, as well as those with unsuccessful Kasai procedures,
invariably die before their second birthday. There are no controlled studies directly
comparing liver transplantation with portoenterostomy. However, the advantages of
delaying transplantation from the first few months of life until 5 to 10 years of age
are considerable, the most important of which are increased opportunities for an
acceptable donor organ, diminished risk of primary nonfunction of the transplanted
donor organ, and decreased rates of rejection. Furthermore, if transplantation can be
delayed until the child is at least six years of age, both graft and patient survival are
greatly increased. These benefits must be weighed against the potential for
increased blood loss, longer operative time, and increased perioperative
complications of transplantation in children with a previous portoenterostomy.
However, recent surgical series do not suggest increased perioperative mortality in
such children. Overall, children with biliary atresia have the best posttransplant
outcome of any group of patients, with one-year survival of 93% and five-year
survival of more than 85%. Small children who need transplantation can be
successfully transplanted using a reduced-size deceased donor organ or a portion of
the liver from a living related donor.
Alagille Syndrome
Policy Statement
Referral for evaluation of liver transplantation is medically necessary when
preoperative assessment reveals no significant cardiovascular anomalies (e.g.,
complex congenital heart disease, intracranial bleeding) that would preclude
transplantation, and medical therapy* has failed to prevent or reduce health
problems resulting in any of the following:
1.
2.
3.
4.
Progressive hepatic dysfunction
Severe portal hypertension
Severe growth retardation
Intractable pruritus and osteodystrophy
* Medical therapy includes, but is not limited to, any of the following:
1. Special formulas made with medium chain triglyceride (MCT) oil to absorb enough
fat and the fat soluble vitamins (A, D, E and K) to correct deficiencies due to
inadequate levels of bile salts getting into the intestine, poor growth and
malnutrition in infancy
36
2. Ursodeoxycholic acid (ursodiol) to improve bile flow, reduce itching, reduce blood
cholesterol levels and jaundice
3. Antihistamines (such as diphenhydramine, hydroxyzine, Rifampin) to control
itching and improve sleep.
4. Cholestyramine and colesevelam to help remove bile salts from the body
5. In severe cases, surgery to remove excess bile (partial external biliary diversion
or ileal exclusion) to treat severe itching has failed.
Alagille syndrome (arteriohepatic dysplasia) is characterized by the paucity of
interlobular bile ducts and the following associated features:
1.
2.
3.
4.
5.
Chronic cholestasis (91%)
Cardiac anomalies, most commonly peripheral pulmonic stenosis (85%)
Butterfly vertebrae (87%)
Posterior embryotoxon (prominent Schwalbe line) of the eye (88%)
Dysmorphic facies, consisting of broad nasal bridge, triangular facies, and deep
set eyes (95%)
Other minor abnormalities seen in these patients consist of growth and mental
retardation, developmental delay, renal disease, and pancreatic insufficiency. The
syndrome is inherited in an autosomal dominant fashion. Diagnosis of Alagille
syndrome in the newborn with cholestasis depends upon detection of the associated
features and characteristic liver biopsy. In addition to direct hyperbilirubinemia,
serum aminotransferases are modestly elevated and GGTP is often disproportionally
increased. Liver biopsy demonstrates a reduced number of bile ducts, although the
progressive destruction of bile ducts may not be apparent in newborns.
Alagille syndrome is manifested as a syndrome that can affect the liver, heart, and
other systems of the body. Major contributors to morbidity arise from bile duct
paucity or cholestatic liver disease, underlying cardiac disease, and renal disease.
Approximately 90% of children develop chronic cholestasis, 20% develop cirrhosis,
and a greater number develop intractable drug-resistant pruritus. External biliary
diversion can provide relief from refractory pruritus. Although the number of
transplants performed for this condition is limited, the results seem to approximate
those seen for other chronic cholestatic conditions. Furthermore, in many children
growth is accelerated and quality of life is substantially improved after successful
transplantation. Mortality of children with Alagille syndrome is caused not only by
liver disease (25%) but also by intracranial bleeding (25%) and complex congenital
heart disease (15%). Consequently, the risk of these extrahepatic features of the
syndrome must be considered in the evaluation for transplantation.
Nonsyndromic Paucity of the Intrahepatic Bile Ducts
Policy Statement
Referral for evaluation of liver transplantation is medically necessary to significantly
prolong survival and improve quality of life by reducing pruritus.
Nonsyndromic paucity of the intrahepatic bile ducts may be an isolated and
unexplained finding in infants and children with idiopathic cholestasis. The structural
abnormality has also been referred to as intrahepatic biliary atresia or intrahepatic
biliary hypoplasia. However, these terms imply more insight into the pathogenesis of
ductular paucity than currently prevails. Cases may arise from true biliary dysgenesis
37
but more often result from active injury and loss of bile ducts. Bile duct paucity may
occur without associated developmental anomalies and without a documented
intrauterine infection or genetic disorder. However, this idiopathic form of
nonsyndromic bile duct paucity is likely to be heterogeneous in cause with extremely
variable clinical features and prognosis. Cholestasis typically develops early in
infancy and may be associated with progressive liver disease.
Cystic Fibrosis
Cystic fibrosis (CF) is the most common fatal autosomal recessive disease among
Caucasian populations, with a frequency of 1 in 2000 to 3000 live births. The usual
presenting symptoms and signs include persistent pulmonary infection, pancreatic
insufficiency, and elevated sweat chloride levels. Cystic fibrosis, which can cause
cholestatic liver disease resulting in extensive fibrosis, biliary cirrhosis, or sclerosing
cholangitis, accounts for 3 to 5% of pediatric liver transplants. However, many of
these children also have advanced restrictive lung disease, and most deaths after
liver transplantation are the result of pulmonary or septic events within the first few
years after the operation. Therefore, in evaluating patients with cystic fibrosis for
liver transplantation, careful assessment of lung disease should be performed.
Familial Intrahepatic Cholestasis
Policy Statement
Referral for evaluation of liver transplantation is medically necessary on an individual
consideration based on the morbidity of the polyneuropathy and whether or not it
involves the liver, causing cirrhosis and hepatic failure. Many patients may not be
candidates for liver transplant alone due to coexisting cardiac disease.
In familial intrahepatic cholestasis (Byler's disease), patients do not experience liver
disease per se, but develop polyneuropathy and cardiac amyloidosis due to the
production of a variant transthyretin molecule by the liver. The progressive familial
intrahepatic cholestasis (PFIC) disorders are a collection of autosomal recessive
defects of hepatocellular transport involved in bile salt formation. Infants with these
disorders develop progressive cholestasis and fibrosis within the first year of life,
which often progresses to cirrhosis with liver failure later in childhood. If the
diagnosis is established before the development of cirrhosis, partial external biliary
diversion can result in clinical, biochemical, and histological improvement in the
majority of patients. On the other hand, if cirrhosis has already been established or if
partial external biliary diversion is not successful, liver transplantation is usually
required for long-term survival, but the extrahepatic manifestations of these
conditions, such as short stature and diarrhea, are not always improved by
transplantation.
Caroli's Disease
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in patients who
have the complications of intractable biliary infection from repeated episodes of
cholangitis and end-stage liver disease with diffuse dilation of the intrahepatic bile
ducts unsuitable for lobectomy or extended hepatectomy.
Caroli's disease, characterized by segmental or diffuse (multifocal) dilation of the
intrahepatic biliary ducts, is a rare disease which is difficult to treat. The course of
38
the disorder is characterized by recurrent episodes of cholangitis and hospital stays,
with a consequent loss of quality-of-life and productive capacity, often ending in
death due to uncontrolled infection. Endoscopic drainage of the bile duct, percutaneously or surgically, is palliative and presents bad results in the follow-up of these
patients. Partial hepatectomy can offer a definite therapy, with an acceptable
morbidity and virtually no mortality in localized Caroli’s disease. In diffuse disease,
the use of extended resections or liver transplantation can provide good long-term
results.
The liver disease in autosomal recessive polycystic kidney disease (ARPKD) is related
to congenital malformation of the liver in which there are varying degrees of
periportal fibrosis, bile ductular hyperplasia, ectasia, and dysgenesis. This
malformation can manifest clinically as cystic dilation of the intrahepatic biliary tree
with or without congenital hepatic fibrosis (CHF). CHF is a malformation in which
there is fibrosis and enlargement of portal tracts, which contain variably dilated and
abnormally shaped bile ducts. The terms “Caroli's disease” and “Caroli's syndrome”
refer to the multifocal, segmental dilation of large intrahepatic bile ducts that is
associated with ARPKD. Rare cases have occurred in the setting of autosomal
dominant polycystic kidney disease (ADPKD). Caroli's disease is the rare variant that
is characterized by bile ductular ectasia without CHF; the dilated portions are in
continuity with the rest of the biliary tract. Caroli's disease may be limited to one
lobe of the liver, usually the left lobe. The biliary epithelium of the dilated bile ducts
is often lined by hyperplastic and ulcerated epithelial cells.
In both Caroli's disease and CHF, the dilated bile ducts lead to impaired bile flow,
formation of biliary sludge, and in some cases intraductal lithiasis. Patients may
complain of intermittent abdominal pain. Bacterial cholangitis occurs frequently and
may be complicated by septicemia and hepatic abscess formation. Pruritus is
common, and patients may develop end-stage liver disease after frequent bouts of
cholangitis. Cholangiocarcinoma is a complication in 5% to 10% of patients.
Treatment of Caroli's disease and CHF is largely supportive and is directed toward
treating biliary tract infection and the complications of portal hypertension. Bacterial
cholangitis should be treated aggressively with appropriate antibiotics. Because of
biliary stasis and the frequent occurrence of intrahepatic lithiasis, infection may be
difficult to eradicate and may require prolonged courses of antibiotics. Septicemia
and hepatic abscess formation can occur. Recurrent bouts of cholangitis may lead to
end-stage liver disease. Common duct stones may require endoscopic sphincterotomy and stone extraction. The management of stones within the dilated portions of
the intrahepatic biliary tree is problematic. Surgical removal of intra-hepatic stones
usually is not possible, but partial hepatectomy may be performed in patients who
have disease confined to one lobe of the liver. Extracorporeal shockwave lithotripsy
or intraductal electrohydraulic lithotripsy has also been used after endoscopic
sphincterotomy to clear intrahepatic stones. Ursodeoxycholic acid has been used to
treat intrahepatic lithiasis. Because the intrahepatic stones are pigmented, it is likely
that ursodeoxycholic acid acts primarily by improving bile flow and decreasing bile
stasis rather than by directly solubilizing the stones.
Patients who have CHF fibrosis with or without Caroli's disease develop portal
hypertension and are at risk of esophageal varices and development of ascites.
Variceal bleeding can be treated endoscopically by band ligation or sclerotherapy.
Prophylaxis against recurrent bleeding with a nonselective beta-blocker may be
useful. Because liver function in these disorders may be well preserved for a
prolonged period, a selective shunting procedure can provide relief from the
39
complications of portal hypertension. Liver transplantation is an option in patients
who have intractable biliary infection and end-stage liver disease.
Metabolic Disorders Causing Cirrhosis
If the source of the metabolic abnormality is primarily within the liver,
transplantation is curative; however, at present, it is indicated only if significant liver
disease is present. If the disease process is extrahepatic, liver replacement is not
always indicated, unless with the intention of modifying the effects of the disease.
Alpha-1-Antitrypsin Deficiency
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in patients with
end-stage hepatic disease from alpha-1-antitrypsin deficiency (AAT) when any of the
following is met:
1. In children with Pi ZZ phenotype, only when cirrhosis has developed and when
evidence of hepatic failure is present; or
2. In adults with phenotype Pi ZZ, MZ, or SZ, when hepatic failure occurs
Alpha-1-Antitrypsin disease is the most common inherited cause of liver disease for
which liver transplantation is performed in children. Severe deficiency of alpha-1antitrypsin (AAT) is associated with early onset pulmonary emphysema and with
several forms of liver disease, including cirrhosis, neonatal hepatitis, and
hepatocellular carcinoma. Features that should prompt suspicion by physicians that
their patient may be more likely to have AAT deficiency includes early-onset
emphysema (age of 45 years or less) or emphysema in the absence of a recognized
risk factor (smoking, occupational dust exposure, etc.). There are four recognized
clinical purposes for which testing for AAT deficiency might be undertaken: (1)
diagnostic testing (i.e., to identify symptomatic or otherwise affected individuals),
(2) predispositional testing (i.e., to identify asymptomatic individuals who may be at
high risk of having AAT deficiency), (3) assessment of carrier status in relation to
reproduction, and (4) population screening.
Liver disease is a complication of the intrahepatocytic accumulation of unsecreted,
polymerized in individuals with the Z allele. Most PI*ZZ AAT-deficient individuals are
clinically healthy throughout childhood but have liver enzyme abnormalities in early
life. The PI*ZZ phenotype is a common cause of neonatal cholestasis. Despite
spontaneous resolution in a majority of such individuals, AAT deficiency is a frequent
indication for liver transplantation in childhood. Cirrhosis in PI*ZZ AAT-deficient
individuals may become clinically apparent at any age, with the peak incidence
occurring in elderly never-smokers who have survived without developing severe
emphysema.
Although the prevalence of this genetic disorder is high, only 10 to 15% of
individuals with the PiZZ phenotype develop liver disease. Children with alpha-1antitrypsin deficiency often present with neonatal cholestasis. In most of these
children, the jaundice gradually resolves, but 25% develop cirrhosis within the first
decade of life. However, many children with cirrhosis remain stable for extended
periods and do not require transplantation. Cirrhosis secondary to alpha-1antitrypsin disease also can have its first presentation in adults of any age. Men with
alpha-1-antitrypsin disease have an increased risk for hepatocellular carcinoma
40
(HCC). In the evaluation of patients with liver disease, care must be taken not to
base the diagnosis of alpha-1-antitrypsin disease on the serum alpha-1-antitrypsin
level. With significant liver insufficiency from any cause, the serum level of this
protein can be low because of poor synthetic function and, because it is an acutephase reactant, the level can be artificially elevated in the setting of inflammation.
Paradoxically, lung disease is uncommon in either children or adults with liver
disease secondary to alpha-1-antitrypsin deficiency.
Population studies suggest a minimum plasma threshold of 11 µmol/L (corresponding
to 80 mg/dL), below which there is insufficient AAT to protect the lung, leading to a
risk of developing emphysema. Most patients below this threshold level have the PiZ
(protease inhibitor Z) phenotype. For other phenotypes that describe a range of
plasma levels that straddle the 11µmol/L "protective threshold," the plasma levels
should be used as a guide for considering augmentation therapy. The normal plasma
levels of AAT are 20 to 53 µmol/L (150 to 350 mg/dL).
Intravenous augmentation via the infusion of pooled human AAT (alpha-1
antiprotease) is currently the most direct and efficient means of elevating AAT levels
in the plasma and in the lung interstitium. for individuals with established airflow
obstruction from AAT deficiency. Evidence that augmentation therapy confers benefit
(e.g., slowed rate of FEV1 decline and decreased mortality) is stronger for individuals
with moderate airflow obstruction (e.g., FEV1 35 to 60 % predicted) than for those
with severe airflow obstruction. Augmentation therapy is not currently recommended
for individuals without emphysema, and benefits in individuals with severe (e.g.,
FEV1 35 % predicted) or mild (e.g., FEV1 50 to 60 % predicted) airflow obstruction
are less clear.
Liver transplantation is the only effective treatment for decompensated cirrhosis
secondary to alpha-1-antitrypsin disease. Other than liver transplantation for
individuals with advanced AAT deficiency-related liver disease, specific therapy for
liver disease is not currently available; notably, intravenous augmentation therapy
with alphpa1-antiprotease does not confer benefits for liver disease. Careful
assessment for lung disease should be performed before transplantation in patients
with cirrhosis secondary to alpha-1-antitrypsin deficiency, although coexistent
disease in uncommon. After transplantation, the donor alpha-1-antitypsin phenotype
is expressed and serum levels of alpha-1-antitrypsin return to the normal range
within weeks after the operation. Although reported series are small, the long-term
outcome of these patients after liver transplantation is excellent.
Sickle Cell Hepatopathy
Policy Statement
end-stage hepatic disease, which has only been infrequently described in patients
with sickle cell disease (SCD).
Sickle cell disease (SCD) encompasses a group of hemoglobinopathies characterized
by a single amino acid substitution in the ß-globin chain. The most frequently
occurring form of SCD is sickle cell anemia (HbSS), followed by HbSC and HbSßthalassemia. The liver can be affected by a number of complications due to the
disease itself and its treatment. In addition to the vascular complications from the
sickling process, patients with sickle cell disease have often received multiple
transfusions placing them at risk for viral hepatitis, iron overload, and (combined
41
with the effects of chronic hemolysis) the development of pigment gallstones, all of
which may contribute to the development of liver disease. The term "sickle cell
hepatopathy" has sometimes been used to reflect the overlapping causes of liver
dysfunction in these patients. Sickle cell hepatopathy occurs predominantly in
patients with homozygous sickle cell anemia, and to a lesser extent in patients with
HbSC disease and HbSß-thalassemia. Presentation is initially similar to that seen with
sickle hepatic crises, with right upper quadrant pain, nausea and vomiting, fever,
tender hepatomegaly, and leukocytosis. However, striking jaundice then develops,
accompanied frequently by renal impairment, a bleeding diathesis, and increasing
encephalopathy.
Acute hepatic crisis has been observed in approximately 10 % of patients with sickle
cell disease. Patients usually present with acute right upper quadrant pain, nausea,
low grade fever, tender hepatomegaly, and jaundice. The serum alanine and
aspartate aminotransferase concentrations are seldom > 300 IU/L (5.001 µkat/L),
although levels > 1000 IU/L (16.67 µkat/L) have been described. The serum total
bilirubin concentration is usually < 15 mg/dL (256.5 µmol/L). Liver histology may
reveal sickle cell thrombi in the sinusoidal space with engorgement by red blood
cells. Other features that have been described include Kupffer cell hypertrophy, mild
centrilobular necrosis, and occasional bile stasis. The pathogenesis is probably
related to ischemia caused by sinusoidal obstruction.
Patients with sickle cell disease may acutely sequester large numbers of red blood
cells in the spleen, the pulmonary vasculature, and less commonly the liver, often
leading to acute anemia, shock, and death. Although rare, intrahepatic cholestasis
may represent a severe variant of sickle cell hepatic crisis. It is due to widespread
sickling within the hepatic sinusoids leading to ischemia. Hypoxic damage leads to
ballooning of hepatocytes and intracanalicular cholestasis. Patients with hepatic
sequestration usually present with right upper quadrant pain, rapidly increasing
hepatomegaly, and a falling hematocrit. In various reports, serum ALT levels have
ranged from 34 to 3070 IU/L, serum AST levels from 100 to 6680 IU/L, and alkaline
phosphatase levels have ranged from normal to 860 IU/L. Total serum bilirubin levels
may be strikingly high; levels of up to 273 mg/dL have been observed. In most
cases the conjugated fraction exceeds 50 % of the total bilirubin. The extremely high
bilirubin levels are due to a combination of ongoing hemolysis, intrahepatic
cholestasis, and renal impairment. LDH levels are usually elevated in the range of
660 to 7760 IU/L. Prolongation of the prothrombin and partial thromboplastin time is
common. Elevations in blood urea, creatinine, and ammonia are also seen.
Hypofibrinogenemia, thrombocytopenia, and lactic acidosis may accompany the liver
failure
Treatment of hepatic sequestration crisis, as with splenic sequestration crisis,
involves prompt, aggressive restoration of blood volume and red cell mass, along
with attempts at reversing the sickling process, using such methodologies as
improved oxygenation (including hyperbaric O2), and transfusion with packed red
cells. Exchange transfusion may be necessary, especially if respiratory distress is
present.
Wilson’s Disease
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in any of the
following clinical scenerios:
42
1. Referral for liver transplantation for chronic Wilson’s disease is medically
necessary only for patients who have a complication of progressive,
decompensated liver disease (e.g., neurological dysfunction, renal involvement)
unresponsive to optimal medical therapy (adequate chelation therapy with
penicillamine, trientine, or oral zinc).
2. Urgent referral for liver transplantation and immediate placement on the
transplant list is medically necessary in children and young adults who present
with fulminant hepatic failure (Wilsonian crisis) because mortality is high before
liver transplantation can be performed and survival rates have ranged from 80 to
90% one year after transplantation. Although the reported series are small, longterm survival appears to be excellent.
3. Emergency referral for emergency transplantation and immediate placement on
the transplant list is medically necessary in patients with fulminant hepatic failure
from Wilson's disease who have an associated severe hemolytic anemia because
this has an ominous prognosis.
Note: According to a guideline from the American Association for the Study of Liver
Diseases (AASLD), the following features should be considered when the diagnosis of
fulminant hepatic failure due to Wilson's disease is suspected:
1. Coombs-negative hemolytic anemia with features of acute intravascular
hemolysis Coagulopathy unresponsive to vitamin K
2. Rapidly progressive renal failure
3. Serum aminotransferases typically less than 2,000 IU/L (AST often greater than
ALT)
4. Normal or markedly subnormal alkaline phosphatase (<40 IU/L)
5. Serum ceruloplasmin levels are decreased
6. Urinary copper and serum copper are increased
7. Kayser-Fleischer rings are present in approximately one-half of patients.
Note: Diagnosis in the setting of fulminant hepatic failure requires a high index of
suspicion, since many of these features can be seen in fulminant hepatic failure due
to viral or toxic causes. The relatively modest elevation in aminotransferases and low
serum alkaline phosphatase may provide clues. One series suggested that the ratio
of alkaline phosphatase (in IU/L) to total serum bilirubin (in mg/dL) is typically less
than two.
Note: Liver transplantation is not recommended as primary treatment for
neurological Wilson disease because the liver disease can be stabilized by medical
therapy in most of these individuals, and outcomes with liver transplantation are not
always beneficial.
Wilson's disease (hepatolenticular degeneration) is an autosomal recessive defect of
cellular copper excretion that can result in either acute or chronic hepatitis with liver
failure. Reduced biliary excretion leads to accumulation of copper, initially in the liver
and then in other tissues, particularly the brain. Tissue copper deposition causes a
multitude of signs and symptoms which reflect hepatic, neurologic, hematologic, and
renal impairment. Patients most often present with liver disease, which can range
from an asymptomatic elevations in the serum aminotransferase or bilirubin
concentrations to fulminant hepatic failure to chronic hepatitis, with or without
43
neuropsychiatric disease. The classical presentation (a patient who is between the
ages of 5 and 40 with a decreased serum ceruloplasmin and detectable KayserFleischer rings) represents only about one-half of patients ultimately diagnosed with
Wilson's disease. A serum ceruloplasmin concentration less than 20 mg/dL in a
patient who also has Kayser-Fleischer rings is considered to be diagnostic. In most
series of patients with Wilson's disease, approximately 85 to 90 % of patients have
serum ceruloplasmin concentrations below 20 mg/dL. Among patients with less
specific clinical manifestations, a serum ceruloplasmin level below 5 mg/dL should be
considered as highly suspicious for Wilson's disease. Complications of the disease
include neurological dysfunction, hemolytic anemia, and renal involvement. Although
most patients with chronic liver failure resulting from Wilson’s disease have low
serum ceruloplasmin values, this level can be elevated with inflammation or acute
liver disease or can be depressed by the presence of severe liver disease of any
etiology.
The prognosis in patients with Wilson's disease is excellent in all but those with
advanced disease and those who present with rapidly progressive liver failure and
hemolysis. The neurologic, psychiatric, and hepatic abnormalities gradually improve
with treatment, and liver function test results usually return to normal. Most patients
with chronic liver disease respond dramatically to treatment with D-penicillamine,
trientine, or oral zinc and have long-term sustained remission of the disease with
continued treatment. Multiple studies have demonstrated the effectiveness of
penicillamine in patients with Wilson's disease. Clinical improvement in patients with
advanced liver disease is usually observed during the first two to six months of
therapy, but can continue thereafter. Even advanced fibrosis or cirrhosis may show
reversibility following prolonged treatment; however, a repeat liver biopsy is not
necessary as long as there is a progressive improvement in symptoms and liver
biochemical tests. There does not appear to be an increased risk of hepatocellular
carcinoma.
The therapeutic approach is different in patients who present with fulminant hepatic
failure. Emergency liver transplantation must be considered. Initial treatment must
be aimed at the rapid removal of copper. Although hemodialysis, peritoneal dialysis,
and hemofiltration have been used, plasma exchange with fresh frozen plasma
replacement may be preferred since it can remove relatively large amounts of copper
in a short period of time. Most of these patients also have hemolytic anemia. Copper
ions leak from necrotic hepatocytes into the circulation and cause lysis of red blood
cells. Hemofiltration and albumin dialysis have also been described as temporizing
measures.
Liver transplantation for chronic Wilson disease is appropriate only for patients with
decompensated cirrhosis who fail to respond to medical therapy. However, patients
who present with fulminant hepatic failure usually die unless urgent liver transplantation can be performed. Whether or not liver transplant is indicated in patients
with exclusive or predominant neurologic manifestations is controversial. This may
be due in part to differences in the resolution of neurologic manifestations when the
recipient has extensive hepatic disease compared to those with neurologic
manifestations as the principal indication for transplantation. Survival appears to be
worse in patients with neurological involvement. Plasmapheresis, exchange
transfusion, hemofiltration or dialysis may be performed while transplant is being
awaited. Liver transplantation usually reverses all of the metabolic abnormalities
associated with Wilson’s disease. However, long-standing neurological dysfunction
may not improve in some patients. Survival rates have ranged from 80 to 90% one
44
year after transplantation. Although the reported series are small, long-term survival
appears to be excellent.
Copper chelation and zinc therapy are not necessary after transplantation in
asymptomatic patients. However, lifetime therapy is required in symptomatic
patients with Wilson's disease and treatment should be given in two phases:
removing the tissue copper that has accumulated and then preventing
reaccumulation. Copper removal is achieved by the administration of potent
chelators. The primary chelator that has been used is D-penicillamine. However,
approximately 30% of patients do not tolerate long-term therapy because of sideeffects and it may not be the treatment of choice in patients with neurologic
symptoms. Trientine has traditionally been used as a second-line agent but is also a
reasonable option for primary therapy. Oral zinc acts by preventing copper
absorption. Patients who stop taking chelating treatment may develop new
neurologic abnormalities. Rapidly progressive hepatic decompensation refractory to
treatment may also occur.
Nonalcoholic Steatohepatitis
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in selected
patients with decompensated cirrhosis secondary to nonalcoholic steatohepatitis
(NASH) who are at risk for eventually developing complications of cirrhosis (e.g.,
internal bleeding, fluid accumulation in the legs and abdomen, mental confusion, and
jaundice). The posttransplantation care of these patients should include metabolic
monitoring.
Nonalcoholic steatohepatitis (NASH), also known as nonalcoholic fatty liver disease
(NAFLD), is a condition characterized by inflammation and the accumulation of fat
and fibrous tissue in the liver in those who do drink little to no alcohol, but have liver
biopsy findings indistinguishable from alcoholic hepatitis. it is seen more frequently
in people with certain medical conditions such as hyperlipidemia, obesity, type II
diabetes, and insulin resistance. Many patients who have this constellation of medical
problems are believed to have a newly recognized condition called metabolic
syndrome. Given the increasing prevalence of obesity in North America, NAFLD is an
important public health problem. The diagnosis of steatohepatitis, as opposed to
fatty liver alone, and its grade and stage can only be made with precision by a liver
biopsy. This condition can lead to progressive scarring and cirrhosis in a small
number of patients. NASH may be an important underlying cause of cryptogenic
cirrhosis, particularly among older, diabetic women. At the present time, treatment
of NASH focuses on controlling some of the medical conditions associated with it
(such as diabetes and obesity) and monitoring patients for progression.
The following criteria have been proposed for the diagnosis of NASH:
1. A liver biopsy showing moderate to gross macrovesicular fatty change with
inflammation (lobular or portal) and with or without Mallory bodies, fibrosis, or
cirrhosis
2. Convincing evidence of negligible alcohol consumption (less than 40 g of ethanol
per week) including a detailed history obtained by three physicians independently
and interrogation of family members and local medical practitioners. Random
blood assays for ethanol estimation should be negative. If performed, assays for
45
the presence of desialylated transferrin in serum, a marker of alcohol
consumption, should also be negative.
3. Absence of serologic evidence of infection with hepatitis B or hepatitis C.
NASH is generally considered to be a clinically stable disorder and has a markedly
better prognosis than alcoholic hepatitis. In most patients, there is little change in
liver function tests throughout the course of the disease. A population-based study in
the United States found that patients with nonalcoholic fatty liver disease had slightly
lower overall survival than expected for the general population. No medical therapy
has yet been proven to be beneficial in patients with NASH. In a sizable minority,
however, histologic progression occurs and a small fraction of patients progress to
end-stage liver disease. A small number of patients, therefore, have required liver
transplantation. A number of cases of severe recurrent disease with progression to
cirrhosis have been reported after liver transplantation for NASH. Graft injury
apparently resulting from recurrent steatohepatitis has been observed following liver
transplantation. This suggests that the underlying metabolic defect may not be cured
by transplantation. In one study of 622 liver transplants, eight patients, all female,
had features consistent with NASH. At a median follow-up of 15 months, six
developed persistent fatty infiltration, three of whom had hepatic degeneration
consistent with NASH. In two patients, histologic progression from mild steatosis to
steatohepatitis with fibrosis occurred over a one- to two-year period. NASH may be
the underlying cause of many cases of cryptogenic cirrhosis, particularly among older
diabetic women. Patients who developed cirrhosis from NASH may also be at
increased risk for hepatocellular carcinoma.
Cryptogenic Cirrhosis
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in selected
patients with decompensated cryptogenic cirrhosis. These patients should be
screened for metabolic dysregulation because of the possibility of underlying
nonalcoholic steatohepatitis
End-stage liver disease from cryptogenic cirrhosis accounts for 7 to 14% of adults
who undergo liver transplantation in the United States and Europe. Five-year survival
rates in adults with cryptogenic cirrhosis who have undergone liver transplantation
range from 72 to 81%. Careful clinical-pathological correlation of liver biopsies
obtained before and after transplantation often reveals the underlying etiology,
which is most commonly NASH, autoimmune hepatitis, or alcoholic cirrhosis. After
transplantation, a number of patients with presumed cryptogenic cirrhosis have
developed aggressive NASH or autoimmune disease. Cryptogenic cirrhosis in children
often is an aggressive disease that progresses to liver failure, necessitating liver
transplantation. Disease recurrence is not uncommon after transplantation.
Crigler-Najjar Syndrome Type I / Type II
Policy Statement
I.
Referral for evaluation of liver transplantation is medically necessary at an early
age (before 15 months of age) in patients with Crigler-Najjar syndrome type I
because of the inevitability of central nervous system damage (enceph-alopathy
[kernicterus] from severe unconjugated hyperbilirubinemia) and the limitations
of phototherapy. Liver transplantation has resulted in long-term survival and is
46
the only curative therapy presently available. Despite its risks, some authorities
even advocate prophylactic liver transplantation to avoid the risk of kernicterus
which may not be fully reversible once it is established.
II. Referral for evaluation of liver transplantation may not be needed in patients
with Crigler-Najjar syndrome type II because they are much less likely to
develop neurologic consequences than those with type I disease. However, it
may be desirable to treat patients in whom jaundice has impaired quality of life.
This can be accomplished by the administration of phenobarbital, which reduces
serum bilirubin levels by at least 25%. A response should be expected within
two to three weeks. A similar benefit can be observed with clofibrate, which is
associated with fewer side effects.
Phototherapy is widely used for the treatment of hyperbilirubinemia in newborns.
Prior to the introduction of phototherapy and plasmapheresis to lower the serum
bilirubin concentration, almost all patients with Crigler-Najjar syndrome type I died
during the first 18 months of life due to kernicterus. Phototherapy acts by converting
a portion of bilirubin IX-alfa-ZZ into its geometric and structural isomers, which are
then excreted in the bile without the prerequisite for conjugation. The technique
involves exposure to an array of 140w fluorescent lamps for 12 hours per day with
devices for shielding the eyes. Plasmapheresis is the most efficient method for
rapidly reducing the serum bilirubin concentration during a crisis. Because bilirubin is
tightly bound to albumin, removal of albumin during plasmapheresis results in
equimolar clearance of bilirubin. Most patients treated with these methods survive
past puberty without significant brain damage but subsequently succumb to
kernicterus later in life. One of the reasons for treatment failure is thickening of the
skin, increased skin pigmentation, and decreased surface area in relation to body
mass, which renders phototherapy less effective.
Crigler-Najjar syndrome, also referred to as congenital nonhemolytic jaundice with
glucuronosyltransferase deficiency, is a rare, autosomal recessive disorder of
bilirubin metabolism. It has been divided into two distinct forms (types I and II)
based upon the severity of the disease:
1. Type I disease is associated with severe jaundice and neurologic impairment due
to kernicterus (bilirubin encephalopathy), usually before 15 months of age
2. Type II disease is associated with a lower serum bilirubin concentration and
affected patients survive into adulthood without neurologic impairment.
Crigler-Najjar syndrome type II (also known as Arias syndrome) is phenotypically
similar to type I disease but the unconjugated hyperbilirubinemia is usually less
marked (serum bilirubin < 20 mg/dL). Other liver function tests are normal. The
disease can be distinguished from Crigler-Najjar syndrome type I by its lower levels
of hyperbilirubinemia and often by its later age of onset. Since patients with CriglerNajjar syndrome type II are much less likely to develop neurologic consequences
than those with type I disease, specific treatment for the hyperbilirubinemia may be
unnecessary. However, it may be desirable to treat patients in whom jaundice has
impaired quality of life. This can be accomplished by the administration of
phenobarbital, which reduces serum bilirubin levels by at least 25%. A response
should be expected within two to three weeks. A similar benefit can be observed with
clofibrate, which is associated with fewer side effects.
47
Liver transplantation is considered the only definitive treatment for Crigler-Najjar
syndrome type I. It rapidly normalizes serum bilirubin levels. Despite its risks, some
authorities advocate prophylactic liver transplantation to avoid the risk of kernicterus
which may not be fully reversible once it is established. Liver transplantation has
resulted in long-term survival and is the only curative therapy presently available.
Hereditary Hemochromatosis
Policy Statement
Referral for evaluation of liver transplantation is medically necessary when any of
the following is met:
1. Patient has a complication of end-stage liver disease despite adequate ironreduction therapy (e.g., gastroesophageal bleeding, hepatic encephalopathy,
sepsis, congestive heart failure, arrhythmias)
2. The diagnosis of hepatocellular carcinoma (HCC) is being considered or if the
diagnosis is confirmed (patients should have a single tumor of 5 cm or smaller in
diameter. If multiple tumors are present, the acceptable number is 3 or less,
smaller than 3 cm - the 4-year survival rate can be approximately 90% if these
criteria are respected)
Hemochromatosis, also called genetic hemochromatosis, is an autosomal recessive
genetic disorder characterized by inappropriately high absorption of iron in the
intestines resulting in progressive iron overload in parenchymal organs (e.g., liver,
heart, pancreas, pituitary, joints, and skin), which in turn leads to organ toxicity. It
is a common genetic disease with a wide range of clinical expression: from no
symptoms to cirrhosis of the liver. Despite the frequency of the genetic abnormality,
liver failure requiring transplantation is quite uncommon. However, in some affected
individuals, chronic iron accumulation can result in decompensated cirrhosis,
cardiomyopathy, diabetes mellitus, arthritis, hypogonadism, and hepatocellular
carcinoma (HCC). If iron depletion can be accomplished before the development of
cirrhosis or diabetes mellitus, long-term phlebotomy results in a normal life
expectancy. Survival is diminished only in patients with cirrhosis or diabetes.
Furthermore, prevention of cirrhosis should prevent hepatocellular carcinoma.
However, if cirrhosis is present at the time of diagnosis, survival is diminished and
patients remain at high risk for HCC despite adequate iron depletion.
Measuring serum iron has no value in the diagnosis, but measuring transferrin
saturation is necessary. Transferrin saturation corresponds to the ratio of serum iron
and total iron-binding capacity. Similar to iron, it is influenced by liver disease (other
than hemochromatosis) and inflammation; therefore, it has limitations in the
diagnostic workup. Hemochromatosis is suggested by a persistently elevated
transferrin saturation in the absence of other causes of iron overload. It is the initial
test of choice. The screening threshold for hemochromatosis is a fasting transferrin
saturation of 45-50%. Approximately 30% of women younger than 30 years who
have hemochromatosis do not have elevated transferrin saturation. High transferrin
saturation is the earliest evidence of hemochromatosis. A value greater than 60% in
men and 50% in women is highly specific. Serum ferritin levels elevated higher than
200 mcg/L in premenopausal women and 300 mcg/L in men and postmenopausal
women indicate primary iron overload due to hemochromatosis, especially when
associated with high transferrin saturation and evidence of liver disease. Ferritin
concentration can be high in other conditions such as infections, inflammations, and
liver disease. Ferritin concentration higher than 1000 mcg/L suggests liver damage
with fibrosis or cirrhosis.
48
Ideally, treatment is initiated before the development of symptoms when serum
ferritin levels exceed 200 μg/L in premenopausal women or 300 μg/L in men and
postmenopausal women. Patients with manifestations of late disease should also
receive treatment because some of the sequelae are reversible. The simplest,
cheapest, and most effective way to remove iron is by therapeutic phlebotomy, also
known as venesection. Each 500 mL of whole blood removed contains 200 to 250 mg
of iron. The marrow, in providing replacement for the lost hemoglobin, mobilizes iron
from tissue stores, thereby reducing the degree of iron overload. Phlebotomy has a
variety of benefits including improvement in or resolution of varices, reversal of left
ventricular dysfunction, reversal of secondary hypogonadism in men, and reduction
in the degree of hepatic fibrosis. Most patients who have a clinical phenotype
consistent with hemochromatosis (regardless of their genotype) will benefit from
therapeutic phlebotomy. Possible exceptions include patients who have limited lifeexpectancy due to other diseases and those who do not tolerate phlebotomy, who
may require iron chelation therapy. Phlebotomy should not be withheld based upon
advanced age alone or in patients who are asymptomatic. Criteria for initiating
therapeutic phlebotomy have been proposed by a panel of experts who formed the
Hemochromatosis Management Working Group:
Criteria For Initiating Therapeutic Phlebotomy
Patient
Serum ferritin, ng/mL
Persons <18 years of age
> 200
Women, reproductive years, not
pregnant
> 200
Women, reproductive years, pregnant
> 500
Postreproductive years
> 200
Men
> 300
Chelation therapy is reserved for the forms of iron overload in which phlebotomy
cannot mobilize iron stores adequately or cannot be tolerated because of concurrent
anemia. Some experts believe that chelation therapy with desferrioxamine should
not be recommended for hemochromatosis. A standard chelation regimen of
subcutaneous deferoxamine is expensive, inefficient, cumbersome, and potentially
toxic. Patients with end-stage liver disease secondary to chronic hepatitis C, alcohol
abuse, or both can have elevated ferritin and transferrin saturation levels similar to
those seen in patients with hereditary hemochromatosis. However, only a few of
these patients have hepatic iron levels consistent with hemochromatosis and even
fewer have both increased hepatic iron stores and genetic abnormalities consistent
with hereditary hemochromatosis.
After liver transplantation, 1-year and 5-year survival rates are 58% and 42%,
respectively, which is significantly lower than for all other indications. Although liver
transplantation is the only effective treatment for patients with decompensated
cirrhosis secondary to hereditary hemochromatosis, there is considerable
controversy about the efficacy of the procedure. This condition has been associated
with poorer outcomes following liver transplantation than other forms of cirrhosis,
mainly because of a high rate of postoperative infections (mostly attributable to
bacterial and fungal infections), an increased risk of cardiac deaths resulting from
arrthymias, as well as occasional deaths from cardiac failure and recurrent HCC. Due
49
to the increased risk of cardiac complications, a pretransplantation cardiac evaluation
is essential. There are numerous reports of lower postoperative survival in patients
with hemochromatosis compared with patients transplanted for other conditions.
Furthermore, most, but not all, studies suggest that significant hepatic iron overload
from any cause is associated with decreased survival after trans-plantation. Iron
reaccumulation also occurs in the grafts of these recipients postoperatively and
continued iron depletion therapy may be required. It is uncertain whether this risk
can be reduced by aggressive phlebotomy before transplantation.
Neonatal Hemochromatosis
Policy Statement
Urgent referral for evaluation of liver transplantation is medically necessary for
infants with severe neonatal hemochromatosis because it is the only effective
treatment.
Neonatal hemochromatosis, also known as neonatal iron storage disease, is the
leading cause of liver failure in neonates. It is a rare disorder characterized by
extrahepatic iron accumulation and hepatic failure. The onset is intrauterine and has
recently been shown to be the result of maternal alloimmune injury analogous to
erythroblastosis fetalis. Newborns present with signs of severe liver failure within the
first few days of life, including coagulopathy, ascites, and hypoalbuminemia.
Hyperbilirubinemia typically is both conjugated and unconjugated, although
conjugated bilirubin levels may be only modestly elevated. The diagnosis may be
suggested by complete or nearly complete saturation of iron binding capacity,
elevated serum ferritin, or by demonstration of extrahepatic iron accumulation using
magnetic resonance imaging (MRI) or minor salivary gland biopsy. Treatment of
mothers with a previous pregnancy that resulted in an infant with neonatal
hemochromatosis with high dose intravenous immunoglobulin (IVIG) has been
shown to prevent recurrence of disease. Death usually occurs within months unless
liver transplantation can be performed. Although postoperative survival has been
poor, liver transplantation seems to be the only effective treatment for this
devastating condition.
Glycogen Branching Enzyme Deficiency
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in patients after
the initiation of effective dietary therapy when any of the following is met:
1. Poor metabolic control with specialized diet (i.e., an adequate nutrient intake and
a high-protein diet)
2. Multiple hepatic adenomas
3. Hepatocellular carcinoma (HCC)
4. Progressive liver failure.
Glucose is the principal circulating sugar in the blood and the major energy source of
the body. Any glucose that is not immediately used for energy is held in reserve in
the liver, muscles, and kidneys in the form of glycogen and released when needed by
the body. Glycogen is a complex carbohydrate that is converted into the simple
sugar glucose for the body's use as energy. Glycogen storage diseases (GSDs) - also
called glycogenoses - are characterized by deficiencies of certain enzymes involved
50
in the breakdown of glycogen to glucose, leading to an accumulation of abnormal
forms or amounts of glycogen in various parts of the body, particularly in the liver
and muscle. The disorder is rapidly progressive, leading to terminal liver failure
without transplantation. Children with these disorders can develop cirrhosis, ascites,
portal hypertension, HCC, liver failure, and renal insufficiency. Although early
diagnosis and initiation of effective dietary therapy (i.e., an adequate nutrient intake
to prevent hypoglycemia, maintain normoglycemia and to improve liver function and
reduce liver size; a high-protein diet to allow for growth and development, provide
increased muscle function and slow or arrest disease progression).
There are many different glycogen storage diseases, each identified by a roman
numeral. Some of these diseases cause few symptoms; others are fatal. The specific
symptoms, age at which symptoms start, and their severity vary considerably among
these diseases. For types II, V, and VII, the main symptom is usually weakness. For
types I, III, and VI, symptoms are low levels of sugar in the blood and protrusion of
the abdomen (because excess or abnormal glycogen may enlarge the liver). Low
levels of sugar in the blood cause weakness, sweating, confusion, and sometimes
seizures and coma. Other consequences for children may include stunted growth,
frequent infections, or sores in the mouth and intestines. Glycogen storage diseases
tend to cause the accumulation of uric acid, a waste product, in the joints (which can
cause gout) and in the kidneys (which can cause kidney stones). In type I glycogen
storage disease, kidney failure is common in the second decade of life or later.
GSD type IV - also known as Andersen’s disease, glycogenosis type IV, glycogen
branching enzyme deficiency (GBED) and polyglucosan body disease - is a rare
autosomal recessive disorder caused by a deficiency of the alpha-1,4-glucan
branching enzyme. The specific diagnosis is made by chemical examination of a
sample of tissue, usually muscle or liver, determining that this specific enzyme is
missing. As compared to other forms of GSD where there is an increased amount of
glycogen in the tissues, in GSD type IV the glycogen that does accumulate has very
long outer branches. This structural abnormality of the glycogen is thought to trigger
the body's immune system, causing the body to actually attack the glycogen and the
tissues in which it is stored. The result is tremendous scarring of the liver as well as
other organs, such as muscle. In most affected individuals, symptoms and findings
become evident in the first months of life. Such features typically include failure to
grow and gain weight at the expected rate (failure to thrive) and abnormal
enlargement of the liver and spleen (hepatosplenomegaly). In such cases, the
disease course is typically characterized by progressive hepatic cirrhosis and liver
failure, leading to potentially life-threatening complications of ascites, portal
hypertension, hepatocellular carcinoma (HCC), liver failure, and renal insufficiency.
Branching enzyme deficiency causes progressive liver cirrhosis and death in children
by the age of 5 years unless a liver transplant is performed. The perinatal form of
the disease invariably is fatal. Although several patients reportedly have experienced
decreased progression and systemic regression after hepatic allografting, long-term
prognosis for others depends on the extent, severity, and progression of this
multisystem disorder. Progressive accumulation of abnormal glycogen in other
organs may ultimately lead to death. As children with this condition can have a
variety of renal, cardiac (cardiomyopathy often developing into progressive heart
failure), or neurological abnormalities that may compromise the likelihood of survival
with good quality of life after liver transplantation, such factors must therefore be
considered during the evaluation for the operation. Patients with nonprogressive liver
disease usually retain some hepatic function and do not require liver transplantation.
51
An increased risk of hepatocellular adenoma and one case of hepatocellular
carcinoma has been reported.
Hereditary Tyrosinemia
Policy Statement
Referral for evaluation of liver transplantation is medically necessary when any of
the following is met:
1. Children with hereditary tyrosinemia type 1 who have hepatocellular carcinoma
(HCC) at presentation or develop HCC during treatment and who meet the
criteria for liver transplantation for HCC (should be high-priority candidates)
2. Children with tyrosinemia who are unresponsive to or have an incomplete
response to medical management (e.g., dietary restriction of tyrosine,
methionine and phenylalanine, and the provision of nitro-trifluoromethyl benzoyl
cyclohexanedione [NTBC])
3. Children with tyrosinemia and glycogen storage diseases unresponsive to medical
management
4. Patients with hereditary tyrosinemia type 1 involving the liver, causing cirrhosis
and persistent hepatic failure unresponsive to Orfadin (nitisinone) therapy, which
is indicated as an adjunct to dietary restriction of tyrosine and phenylalanine
Note: Consideration of extrahepatic complications of the underlying disease must be
carefully considered in potential transplant candidates.
Tyrosine is an aromatic amino acid that is important in the synthesis of thyroid
hormones, catecholamines, and melanin. Impaired catabolism of tyrosine is a feature
of several acquired and genetic disorders that may result in elevated plasma tyrosine
concentrations. Normal plasma tyrosine concentrations are 30 to 120 micromol/L.
Values >200 micromol/L are considered elevated. However, clinical manifestations
typically do not become apparent until plasma levels exceed 500 micromol/L.
Tyrosinemia is a hereditary genetic inborn error of the metabolism that causes
severe liver disease in infancy. Affected persons commonly develop cirrhosis of the
liver and will eventually require liver transplantation to survive. Even with therapy,
death frequently occurs within six to nine months of life for sufferers of the severe
form. Tyrosinemia is a genetic disorder characterized by elevated blood levels of the
amino acid tyrosine, a building block of most proteins. Tyrosinemia is caused by the
deficiency of one of the enzymes required for the multistep process that breaks down
tyrosine. If untreated, tyrosine and its byproducts build up in tissues and organs,
which leads to serious medical problems. Tyrosine restriction diet aims to decrease
tyrosine levels and formation of intermediate toxic metabolites, i.e., succinylacetone
and maleylacetoacetate, which are thought to cause liver damage and be oncogenic.
Diagnosis is confirmed by measuring decreased fumarylacetoacetate hydrolase
activity in red blood cells.
There are two main types of tyrosinemia: I and II. Type I tyrosinemia is the most
severe form of this disorder and is caused by a shortage of the enzyme
fumarylacetoacetate hydrolase. Symptoms usually appear in the first few months of
life and include failure to gain weight, failure to thrive, diarrhea, vomiting, jaundice,
and increased tendency to bleed (particularly nosebleeds). Type I tyrosinemia can
lead to an increased risk of liver cancer, liver and kidney failure and problems
52
affecting the nervous system resulting in irritability, rickets, or even liver failure and
death. Restriction of tyrosine in the diet is of little help. In previous days, early
transplantation was the only chance of long term survival in children with type I
tyrosinemia. A specific treatment has been introduced in the last decade which has
transformed the prognosis of the disease, although long term results are still to be
evaluated. Nitro trifluoromethyl benzoyl cyclohexanedione (NTBC) specifically inhibits
hydroxyphenylpyruvate dioxygenase, preventing further degradation of tyrosine in
its metabolic pathway. The result is absence of formation of the toxic compounds.
Provided that the patient is treated early, the evolution of the disease can be
completely stabilized, without progressive liver disease nor liver cancer. Tyrosine
restriction remains mandatory. Type II tyrosinemia is less common. Affected children
sometimes have mental retardation and frequently develop sores on the skin and
eyes. Unlike type I tyrosinemia, restriction of tyrosine in the diet can prevent
problems from developing.
The most common presentation is a systemic illness associated with liver dysfunction
in children a few months old. Cirrhosis and HCC are common at the time of
diagnosis. The underlying metabolic condition can be partially treated with dietary
restriction of tyrosine and phenylalanine, but the metabolism of protein results in
continued formation of the toxic metabolites succinylacetone and succinyl
acetoacetate. Formation of these metabolites can be reduced by providing nitrotrifluoromethyl benzoyl cyclohexanedione (NTBC). Although NTBC has significantly
improved longevity, with children achieving normal growth for up to 12 years in
some cases, the long-term benefit of this approach has yet to be determined.
Tyrosinemia, if it involves the liver, causes cirrhosis and hepatic failure.
Transplantation is still required in many children who have an incomplete response to
dietary restrictions and in those who have HCC at presentation or develop HCC
during treatment.
Vascular Disorders
Budd-Chiari Syndrome
Policy Statement
Urgent referral for evaluation of liver transplantation is medically necessary when
any of the following is met:
1. Patient has severe hepatic decompensation and is unresponsive to, or not a
candidate for, anticoagulation or appropriate surgery for portal venous
decompression (the possibility of later transplant surgery should not discourage
the use of portal decompression when otherwise indicated)
2. Patient has developed the Budd-Chiari syndrome as a result of thrombophilia
from protein S, protein C, or antithrombin III deficiency and may be cured of
their clotting tendency by liver transplantation, since the transplanted liver
produces normal amounts of these enzymes.
The Budd-Chiari syndrome (hepatic vein thrombosis) can be defined as any
pathophysiologic process that results in interruption or diminution of the normal
blood flow out of the liver. As commonly used, however, the Budd-Chiari syndrome
implies thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic
inferior vena cava. Patients with this condition can develop rapidly progressive liver
failure or a more chronic form, usually accompanied by intractable ascites as a
principal feature, provided underlying malignancy is excluded. Most cases of Budd-
53
Chiari syndrome result from an underlying hypercoagulable state. The most common
cause is a myeloproliferative disorder, such as polycythemia vera or essential
thrombocytosis. A number of inherited hypercoagulable states also have been
associated with hepatic vein occlusion. Among these, the factor V Leiden mutation
seems to be particularly important, accounting for 25 % of cases in recent series.
However, even in most cases of inherited hypercoagulable thrombophilia states,
Budd-Chiari syndrome typically occurs in combination with a myeloproliferative
disorder. Protein S, protein C, or antithrombin-III deficiency Another 10% of cases
are caused by malignancies that cause compression or direct invasion of the hepatic
veins or vena cava.
The Budd-Chiari syndrome is optimally managed in a center offering the four main
therapeutic options of decompressive surgery, transplantation, TIPS, and radiological
intervention. Medical approaches to management are disappointing and fail to retard
the often progressive natural history to liver failure and death. Liver biopsy may be
helpful in determining whether the therapeutic approach should be decompression
with a portosystemic shunt or liver transplantation. Good long-term results have
been described in patients who undergo prompt shunt surgery, but patients with
advanced fibrosis on liver biopsy should undergo liver transplantation.
A number of approaches have been used for treatment of patients with Budd-Chiari
syndrome. The three options that seem to be most effective in patients with severe
disease include the use of: (1) transjugular intrahepatic portosystemic shunts, (2)
surgical shunts to decompress the swollen liver, and (3) liver transplantation. Longterm survival has been documented with each approach; however, there also has
been considerable morbidity associated with each procedure. Survival after
transplantation depends on the severity of disease at the time of transplantation, the
extent of the thromboses, and the underlying cause of the condition. The best results
have been achieved in patients who have thrombosis limited to the hepatic veins, in
whom the underlying cause of the syndrome can be corrected by replacement of the
liver. In contrast, patients with an underlying malignancy and those with both
hepatic and portal vein thrombosis have more perioperative complications and a
lower long-term benefit. As a result, choosing the optimal treatment for patients with
this condition can be quite difficult.
Survival following liver transplantation depends upon the underlying cause of the
Budd-Chiari syndrome and the patients condition at the time of the transplant. In
one of the largest series (248 patients), overall survival was 76, 71, and 68% at one,
five, and ten years respectively. Most deaths (77%) occurred in the first three
months. The only predictor of mortality was impaired renal function and a history of
a shunt. Ten-year survival of 69% was reported in another series.
Veno-occlusive Disease
Policy Statement
1. Advanced Veno-occlusive disease (VOD), most commonly seen after bone
marrow transplantation (BMT)
2. Severe post-BMT graft-versus-host disease with predominantly hepatic
involvement.
54
Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome, is a
similar disorder manifested by necrosis of zone 3 hepatocytes and fibrous
obliteration of the central venule lumen. Most commonly seen after bone marrow
transplantation (BMT), VOD may lead to hepatic failure and death in up to 25% of
patients despite an otherwise successful BMT.
Although the experience with liver transplantation for hepatic complications of BMT is
limited, liver transplantation appears to be the only intervention that consistently
alters the course of advanced VOD - similarly, liver transplantation has been shown
to be effective in the management of severe post-BMT graft-versus-host disease with
predominantly hepatic involvement. Less commonly it occurs following use of
chemotherapeutic agents in non-transplant settings, ingestion of alkaloid toxins,
after high dose radiation therapy or liver transplantation. VOD is characterized by
hepatomegaly, right upper quadrant pain, jaundice, and ascites. Clinical and
laboratory features of veno-occlusive disease usually begin within the first three
weeks after hematopoietic cell transplantation. Not all features may be present, and
the severity of signs and symptoms can vary.
Pretransplant factors, and factors related to conditioning therapy or occurring during
the transplant course are associated with the development of VOD. The strength of
these associations varies among studies, and no factor alone or in combination
explains the variability in the risk of developing VOD among patients. Most cases of
VOD are diagnosed clinically. The otherwise unexplained occurrence of two or more
of the following events within 20 days of hematopoietic cell transplantation has been
proposed to establish the diagnosis: (1) serum total bilirubin concentration greater
than 2 mg/dL, (2) hepatomegaly or right upper quadrant pain, and (3) sudden
weight gain due to fluid accumulation (greater than 2% of baseline body weight.
However, other liver disorders are common during bone marrow transplantation, and
the sensitivity and specificity of the above criteria have not been well-defined. Thus,
additional testing may be required in patients presenting with clinical features of the
disease in whom the diagnosis is in question.
Inborn Errors of Metabolism
Important Note
Children and adults with inborn errors in metabolism for which liver transplantation is
performed to correct the enzyme deficiency and halt progression of extra-hepatic
organ damage have normally functioning livers in other respects. Based on the PELD
and MELD scoring systems, these patients would never have a score that would avail
them of a deceased donor organ. It is clearly recognized, however, that their need is
urgent. Consequently, these patients can be given priority for deceased donor
organs.
Type 1 Primary Hyperoxaluria
Policy Statement
1. Isolated liver transplantation in patients with rapidly progressive disease who still
have a glomerular filtration rate (GFR) > 30 mL/min per 1.73 m 2
55
2. Early liver transplantation when the glomerular filtration rate is < 20 mL/min to
minimize systemic oxalate accumulation. In this circumstance, aggressive
preoperative dialysis (as often as six days per week) to deplete the systemic
oxalate pool may be necessary.
3. Combined liver / renal transplantation for primary hyperoxaluria when all of the
following are met:





Progressive end-organ damage is confined to the kidney
The liver will provide the missing enzyme to lower oxalate production to the
normal range
Marked tissue oxalate deposition has not occurred
Liver biopsy confirms AGT deficiency
The glomerular filtration rate (GFR) is < 25 mL/min per 1.73 m 2
Oxalosis is defined as the widespread deposition of calcium oxalate crystals in the
kidneys, bones, arterial media, and myocardium, with increased urinary excretion of
oxalate. Primary hyperoxaluria (PHO) is a rare metabolic disorder with autosomal
recessive inheritance. Type 1 primary hyperoxaluria is characterized by inadequate
conversion of glyoxylate to glycine because of deficiency of hepatic alanine
glyoxylate aminotransferase. As a consequence, there is marked enhancement of the
conversion of glyoxylate to oxalate. Clinical manifestations of hyperoxaluria can first
become apparent at any age. Infants typically present with chronic renal failure and
massive parenchymal oxalosis, but do not develop renal calculi. In contrast, older
children and adults typically present with symptoms of urolithiasis, with subsequent
progression to renal failure.
Primary hyperoxaluria accounts for approximately 1% of all cases of end-stage renal
disease in children. If detected before the onset of significant renal disease, medical
management can be quite effective. Renal transplantation has historically been the
treatment of choice for patients with end-stage renal disease. However, the results
have been disappointing. Three-year graft survival has averaged only 20% because
of recurrent renal oxalosis. Improved patient survival has been documented in
patients who have undergone combined liver–kidney transplantation compared with
those who underwent kidney transplantation alone. If these results are confirmed,
combined liver–kidney transplantation may prove to be the treatment of choice for
patients with primary oxaluria and renal failure.
The efficacy of treatment in PHO is dependent upon early diagnosis. A number of
modalities may be effective in minimizing renal oxalate deposition before advanced
renal failure. These include:



Maintenance of a high urine output (above 3 L/day per 1.73 m2) as long as
the hyperoxaluria persists to decrease the tubular fluid oxalate concentration
and diminish intratubular oxalate deposition. A gastric tube may be necessary
in young children to maintain this high urine flow during night.
Avoidance of high oxalate foods, such as tea, chocolate, spinach, and
rhubarb.
A trial of high-dose pyridoxine, a coenzyme of AGT that promotes the
conversion of glyoxalate to glycine rather than to oxalate, to demonstrate or
exclude responsiveness.
56


Administration of neutral phosphate (orthophosphate, potassium citrate
and/or magnesium oxide for prevention of recurrent calcium stones) because
they are inhibitors of calcium oxalate precipitation
Thiazide diuretics in an attempt to diminish urinary calcium excretion.
Long-term therapy with pyridoxine and orthophosphate should probably be tried in
most patients with PHO. Orthophosphate should be discontinued if the patient
progresses to renal failure to prevent phosphate accumulation and exacerbation of
secondary hyperparathyroidism. A prospective study illustrated the potential efficacy
of long-term therapy if begun when renal function is still relatively normal. Twentyfive patients with types I and II PHO were treated with pyridoxine and
orthophosphate in the doses noted above. Oxalate excretion fell by about 10 %; this
effect plus the increase in excretion of inhibitors of crystallization led to a substantial
reduction in urinary calcium oxalate supersaturation. The mean fall in glomerular
filtration rate was only 1.5 mL/min per year and estimated renal survival was 89% at
10 years and 74% at 20 years. Although there was no control group, previous
reports suggested a 20-year renal survival of only 20% in untreated patients.
Intervention is required when stones obstruct the urinary tract. Percutaneous
surgery or nephrostomy are preferred, since surgical removal may precipitate acute
renal failure. Combined liver-kidney transplantation is probably the treatment of
choice for children with type 1 PHO with progressive renal disease. Since 1984, more
than 100 patients have undergone combined liver-kidney transplantation, resulting in
actuarial patient and liver graft survival at five years of 80 and 71%, respectively.
The liver provides the missing enzyme, thereby lowering oxalate production to the
normal range. This modality should be considered only after AGT deficiency has been
confirmed by hepatic biopsy. The outcome may be best if transplantation is
performed when the glomerular filtration rate (GFR) falls to 25 mL/min per 1.73 m2
and prior to marked tissue oxalate deposition. However, gradual resolution of tissue
oxalate deposits can be achieved even when transplantation is performed after a
relatively long period of dialysis. In this setting, increased urinary oxalate excretion
may persist for as long as two years due to mobilization of tissue stores rather than
enhanced production. The daily urine output should be maintained above 3 L/day per
1.73 m2 as long as the hyperoxaluria persists. Both citrate and magnesium
supplements should also be given during this period to inhibit crystallization.
Consideration of early transplantation when the glomerular filtration rate is less than
20 mL/min can be considered to minimize systemic oxalate accumulation. In this
circumstance, aggressive preoperative dialysis (as often as six days per week) to
deplete the systemic oxalate pool may be necessary. Isolated kidney transplantation
may be an option in patients who respond to pyridoxine and have minimal oxalate
deposition, and possibly adults with a late-onset form of the disease.
Isolated liver transplantation has been proposed for patients with rapidly progressive
disease who still have a glomerular filtration rate above 30 mL/min per 1.73 m 2. In a
case report, for example, the preemptive transplantation of a liver alone from a
living-related donor resulted in enhanced renal function in a 22 month old patient.
First liver then kidney transplantation may also be an option in infants and small
children in whom combined transplantation cannot be performed because of
anatomical reasons or who are too unstable for the combined procedure. The
preferential use of a living related donor reduces the risk of early acute renal failure,
which will lead to oxalate retention. Some physicians also try to avoid cyclosporine to
prevent the frequent nephrotoxicity associated with this drug.
Hereditary Deficiency of Urea Cycle Enzymes
57
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in children
when all of the following is met:
1. Child is not responsive to disease-specific medications or dietary modification
which may normalize ammonium levels and allow children with partial deficiency
to return to normality (i.e., a low protein diet, sodium benzoate administration to
promote nitrogen elimination via glycine conjugation to form hippurate which is
excreted in urine, arginine or citrulline to replace the secondary deficient amino
acid in the urea cycle)
2. Child has progressive liver disease and insufficiency or extra-hepatic injury
resulting in significant morbidity and mortality for which liver transplantation
would result in the reversal of the enzyme deficiency and metabolic derangement
Note: Because the major reason for liver transplantation is to prevent the
progression of neurological injury, the potential for functional health after
transplantation should be estimated to be good, based on the child's health, degree
of neurological injury before transplantation and the rapidity of decline at the time of
evaluation.
Note: Parent-to-child living-donor transplantation should be considered only if the
enzyme activity of the donor would satisfactorily reverse the deficiency of the
recipient, i.e., being autosomal recessive disorders, parents frequently have
reduction of enzyme activity, although to a lesser degree than their affected
offspring.
Note: In the United States, liver transplantation is considered for newborns with
carbamyl phosphate synthetase I (CPSI) or ornithine transcarbamylase (OTC)
deficiency who have not responded to medical therapy, and in argininosuccinate
lyase (ASL) deficiency associated with cirrhosis.
There are metabolic conditions that result in significant extrahepatic morbidity. The
urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion
from the body. Deficiency of an enzyme in the pathway causes a urea cycle disorder
(UCD). The urea cycle disorders are:






Ornithine transcarbamylase (OTC) deficiency
Carbamyl phosphate synthetase I (CPSI) deficiency
Argininosuccinate lyase deficiency (ASL, also known as argininosuccinic
aciduria)
Arginase deficiency
Argininosuccinate synthetase (ASS) deficiency (also known as classic
citrullinemia or type I citrullinemia, CTLN1)
N-acetyl glutamate synthetase (NAGS) deficiency
UCDs, except for arginase deficiency, result in hyperammonemia and life-threatening
illnesses. Survivors of the metabolic decompensation frequently have severe
neurologic injury. Prompt recognition and treatment are needed to improve outcome.
Mortality and morbidity is high in UCDs. Specific chronic complications include
developmental delay, mental retardation, learning problems, speech disorder,
attention deficit hyperactivity disorder, cerebral palsy, and seizure disorder. Because
58
of the high risk of mortality and neurologic morbidity, some patients with UCD may
be candidates for liver transplantation. The indications for liver transplantation are
relative. A careful analysis of the risks and benefits for individual patients should be
performed by a multi-disciplinary team of metabolic geneticists, transplant surgeons,
hepatologists, developmental pediatricians, psychologists, and social workers in
conjunction with the family.
Patients with urea cycle disorders may develop liver disease and insufficiency. They
have to follow a low protein diet. They can also benefit from sodium benzoate
administration (250 mg/kg/day) to promote nitrogen elimination via glycin
conjugation to form hippurate, excreted in urine. Similarly, phenylacetate is
conjugated to glutamine to form phenylacetylglutamine . In addition, arginine or
citrulline are given to replace the secondary deficient amino acid in the urea cycle.
These specific treatment may normalize ammonium levels and allow children with
partial deficiency to return to normality.
Branched-Chain Amino Acid Disorders
Policy Statement
when the patient has aggressive disease that is not satisfactorily treated with
standard dietary and pharmacological interventions (see treatment options below)
Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of
enzymes involved in their metabolism leads to accumulation of organic acids with
severe metabolic acidosis. In patients with hereditary deficiency of branched-chain
amino acid enzymes, proteinaceous meals or catabolism caused by normal childhood
illnesses result in profound hyperammonemia or metabolic acidosis, which can cause
progressive and additive central nervous system insult with intellectual decline.
Disorders of branched-chain amino acids and their treatment options are:

Maple syrup urine disease - acutely, treatment with peritoneal dialysis or
hemodialysis may be required, along with IV hydration and nutrition
(including high-dose dextrose). Long-term management is restriction of
dietary branched-chain amino acids; however, small amounts are required for
normal metabolic function. Thiamin is a cofactor for the decarboxylation, and
some patients respond favorably to high-dose thiamin

Propionic acidemia - Acute treatment is with IV hydration (including highdose dextrose) and nutrition; carnitine may be helpful. If these measures are
insufficient, peritoneal dialysis or hemodialysis may be needed. Long-term
treatment is dietary restriction of precursor amino acids and odd-chain fatty
acids and possibly continuation of carnitine supplementation. A few patients
respond to high-dose biotin because it is a cofactor for propionyl CoA and
other carboxylases.

Methylmalonic acidemia - treatment is similar to propionic acidemia except
that cobalamin, instead of biotin, may be helpful for some patients.

Isovaleric acidemia - Acute treatment is with IV hydration and nutrition
(including high-dose dextrose) and measures to increase isovaleric acid
clearance; glycine and carnitine may help increase excretion. If these
59
measures are insufficient, exchange transfusion and peritoneal dialysis may
be needed. Long-term treatment is with dietary leucine restriction and
continuation of glycine and carnitine supplements. Prognosis is excellent with
treatment.
In patients recognized to have aggressive disease that is not satisfactorily treated
with standard dietary and pharmacological interventions, liver transplantation has
been effective. However, a high rate of neurological complications after
transplantation has been observed in children with some of these conditions
categorized as the branched-chain amino acid disorders. In considering these
patients for liver transplantation, one must evaluate the reversibility of the enzyme
deficiency with whole or partial organ liver transplantation. This must be scrutinized
even more carefully if parent-to-child living-donor transplantation is being
considered, because these are usually autosomal recessive disorders in which
parents frequently have reduction of enzyme activity, although to a lesser degree
than their affected offspring. Additionally, because the major reason for liver
transplantation is to prevent the progression of neurological injury, the potential for
functional health after transplantation must be estimated, based on the child's health
at the time of evaluation and the rapidity of decline.
Hereditary Amyloidosis
Policy Statement
when all of the following are met:
1. Patient has aggressive disease that is not satisfactorily treated with standard
dietary and pharmacological interventions
2. Patient in whom the mutant amyloid precursor protein is produced by the liver
3. Mutations of the transthyretin, apolipoprotein A-1, and fibrinogen Aa amyloid
precursors are present
4. Transplant is being performed within the first year of symptoms and before the
development of severe cardiac, renal, gastrointestinal, or neurological end organ
damage.
Hereditary amyloidosis is a familial (inherited), autosomal dominant disorder in
which protein deposits (amyloid) accumulate in one or more organ systems in the
body. Hereditary amyloidosis is a relatively uncommon cause of amyloidosis. The
more common forms of amyloidosis are primary an secondary amyloidosis. However,
hereditary amyloidosis is found worldwide. It occurs in families of nearly every ethnic
background.
The protein deposits in hereditary amyloidosis are made up of the transthyretin or
TTR protein. The transthyretin protein is manufactured in the liver, and it is a
mutation of this protein that causes hereditary amyloidosis. More than 50 different
mutations in transthyretin are known in connection with this type of amyloidosis.
There are also other proteins which, when mutated, can cause familial amyloidosis,
but these situations are quite rare. In hereditary amyloidosis, the nervous system
and gastrointestinal tract are often involved. This can cause numbness and tingling
in the arms and legs, dizziness upon standing, and diarrhea. Each family with
hereditary amyloidosis has its own pattern of organ involvement and associated
symptoms.
60
Patients with hereditary amyloidosis die not from inherent liver disease per say, but
due to the production of a variant transthyretin molecule by the liver. The only
treatment that offers a potential cure for hereditary amyloidosis is liver
transplantation which prevents further deposition of amyloid and is often associated
with regression of symptoms and a decrease in the burden of amyloid. Preferably,
transplant should be performed within the first year of symptoms and before the
development of severe cardiac amyloidosis, renal, gastrointestinal, or neurological
involvement (polyneuropathy). Since the transthyretin protein is produced in the
liver, replacing this organ removes this mutant amyloid precursor protein. The
variants for which liver transplantation has been most successful include mutations
of the transthyretin, apolipoprotein A-1, and fibrinogen Aa amyloid precursors. An
example of this heterogeneous group of disorders is heritable neuropathic and/or
cardiomyopathic amyloidosis due to deposition of fibrils derived from transthyretin
(also referred to as prealbumin). Many patients may not be candidates for liver
transplant alone due to coexisting cardiac disease. Patients with sporadic or
undiagnosed hereditary amyloidosis who present with advanced end-organ damage
may benefit from combined hepatorenal or hepatocardiac transplantation.
Mass Occupying Lesions
Hepatocellular Carcinoma
Policy Statement
hepatocellular carcinoma (HCC) complicating cirrhosis when all of the following are
met: (referred to as the Milan criteria)





The patient is not a candidate for subtotal liver resection (e.g., cancer involves
two lobes or multifocal);
CT scan or MRI shows a solitary tumor nodule < 5cm in diameter or < 3
multiple nodules each < 3 cm in diameter*;
No gross vascular invasion by imaging studies (ultrasound) into the hepatic
vein(s); and
Patient has no radiologic evidence of extrahepatic tumor after thorough
evaluation, i.e., no advanced stage disease as defined by lymph node
involvement, metastatic disease to lungs, abdominal organs or bone or other
sites
Angiogram or dynamic imaging study shows contrast enhancement during the
arterial phase followed by a contrast washout (blush) in the delayed venous
phase corresponding to the area of suspicion
* Live donor transplants can use the expanded criteria of a single tumor of up to 6.5
cm or no more than 3 tumors with the sum of the diameters being 8 cm or less.
Note: Few candidates meet the criteria for successful and safe resection because
often they have decompensated cirrhosis, which contraindicates surgical resection. A
few centers are accepting patients for liver transplantation with so called “extended
criteria” or UCSF criteria that accept single tumors of up to 6.5 cm in diameter as
long as the cumulative diameters of all tumors does not exceed 8 cm. A nonsurgical
method to stabilize the disease while awaiting transplantation consists of TACE
(transarterial chemoembolization).
In order to give HCC patients enhanced priority for deceased donor organs, patients
with suspected HCC who met all of the criteria for transplantation were recently
given additional MELD points to be upgraded on the transplant waiting list:
61
1. The patient must undergo a thorough assessment to evaluate the number and
size of tumors, and to rule out extrahepatic spread and/or vascular involvement.
This can be accomplished by ultrasound, CT, or MRI, plus a chest CT scan.
2. Prelisting biopsy is not mandatory. However, such patients must have one of the
following:
 The patient must not be a resection candidate
 Tumor > 1 cm in size with a vascular blush
 An alpha fetoprotein (AFP) level > 200 mg/mL
 An arteriogram confirming a tumor
 A history of chemoembolization, RFA, cryoablation, or chemical tumor
ablation
3. Continued documentation of the tumor is required every three months by CT or
MRI to ensure continued eligibility for liver transplant
Note: Patients with AFP levels 500 mg/mL can also be listed even if there is no
evidence of tumor on imaging studies. However, these patients are assigned a lower
priority MELD score as compared to other patients with HCC.
Hepatocellular carcinoma (HCC) causes approximately 1 million deaths worldwide
each year and the incidence is expected to continue to increase over the next two
decades because of the epidemic of hepatitis C (HCV) in the United States which
started in the 1960s and peaked in the late 1980s and the fact that improvement in
the survival of patients with cirrhosis due to improved specialty care may further
increase the number of individuals at risk for developing HCC. It is an aggressive
tumor that often occurs in the setting of chronic liver disease and cirrhosis. It is
typically diagnosed late in its course, and the median survival following diagnosis is
generally dismal, averaging 8 months. It has been recognized that the highest risk
factor for the development of HCC is cirrhosis. HCV, hepatitis B (HBV) and
hemochromatosis are the major etiological agents that lead to the development of
HCC. In addition, almost all untreated children with tyrosinemia surviving to early
childhood develop HCC. The prognosis of patients with HCC is dependent both on the
stage of the tumor and the degree of liver function impairment. Although primary
hepatic resection has long been considered the treatment of choice for HCC, fiveyear tumor-free survival rates were less than 50%. Furthermore, most patients
referred for resection were rejected because the tumor is unresectable or because
hepatic reserve is considered inadequate. Even in patients with well-compensated
cirrhosis, perioperative mortality after surgical resection is extremely high if patients
have evidence of portal hypertension or elevated serum bilirubin values.
The early experience in liver transplantations for patients with unresectable HCC was
very discouraging. Although perioperative and short-term survival and quality of life
were much better than for patients who received transplantation for decompensated
cirrhosis, 90% of those transplanted for HCC developed recurrent disease within two
years. In contrast, patients with small tumors, especially those found incidentally at
the time of transplantation, did well. On the basis of these early results, HCC was
considered a contraindication to transplantation for a number of years. With
continued analysis of outcomes, a consensus has gradually emerged that optimal
results after transplantation can be achieved in patients with a single lesion 2 cm or
larger and less than 5 cm, or no more than three lesions, the largest of which is less
than 3 cm in size, and no radiographic evidence of extrahepatic disease. The
allocation policy for donor livers in the United States was recently modified to give
62
such patients enhanced priority for deceased donor organs. Since implementation of
this modification, the time on the donor waiting list for patients with HCC has
decreased from a mean of 2.3 years to 7 months.
In the setting of advanced liver disease, many patients with HCC are not candidates
for hepatic resection due to inadequate functional hepatic reserve and the risk of
postoperative decompensation. In these patients, liver transplantation offers curative
therapy, as well as amelioration of their underlying chronic liver disease. In part,
improved outcomes have been due to the application of the stringent Milan eligibility
criteria for patients undergoing liver transplantation for HCC. Excellent overall threeto four-year actuarial (75 to 85%) and recurrence-free survival rates (83 to 92%)
can be achieved, similar to patients undergoing liver transplantation for other
indications. The size and number of tumors plays an important role in determining an
individual patient’s candidacy for liver transplantation. However, patients on the liver
transplantation waiting list are at risk for tumor progression leading to ineligibility for
liver transplantation and death.
Since liver transplant surgeons have a responsibility to make the best use of scarce
donor organs, the landmark study of Mazzaferro in 1996 established deceased-donor
liver transplantation (orthotopic liver transplantation) as a viable option for the
treatment of HCC set the stage for patient selection. They showed that when
transplantation was restricted to patients with early HCC (defined as single lesion 5
cm, up to three separate lesions, none larger than 3 cm, no evidence of gross
vascular invasion, and no regional nodal or distant metastases), a four-year survival
rate of 75% could be achieved. These outcomes are similar to expected survival
rates for patients undergoing transplantation for cirrhosis without HCC. These criteria
have become known as the Milan criteria and have been widely applied around the
world in the selection of patients with HCC for liver transplantation. Extra-hepatic
metastatic disease and macroscopic vascular invasion are considered exclusion
criteria for liver transplantations due to the high rate of tumor recurrence. Evaluation
for extrahepatic metastases with CT and bone scans with radionuclide scintigraphy is
commonly performed. The most consistent association with prognosis following liver
transplantation is tumor size.
In contrast to other malignant tumors in which biopsy is required to guide management decisions, the diagnosis of HCC can usually be established by noninvasive
means. Practice guidelines by consensus recommend that patients with cirrhotic
stage liver disease be enrolled in surveillance programs with the aim of identifying
HCC at an early stage. Surveillance programs are typically based on ultrasonography
of the liver and measurement of serum alpha fetoprotein (AFP) at 6-month intervals.
Since HCC develops at a relatively high frequency among patients with cirrhosis, any
new liver mass identified in a cirrhotic patient should be considered to be HCC until
proven otherwise. The detection of a lesion suspicious for HCC in the setting of a
surveillance program should prompt further diagnostic and therapeutic evaluation.
HCC is characterized by a specific vascular pattern that in angiograms or dynamic
imaging studies results in contrast enhancement during the arterial phase followed
by a contrast washout in the delayed venous phase. When the detected nodule
exceeds 1 cm but is still less than 2 cm, a biopsy is technically more feasible and can
be considered if the dynamic imaging studies are indeterminate. HCC can be
confidently diagnosed in most instances if a nodule > 2 cm within a cirrhotic liver
demonstrates the characteristic imaging pattern (rapid arterial contrast enhancement
with washout during the delayed venous phase imaging studies) in a well-done
63
imaging study by computerized tomography (CT) or magnetic resonance imaging
(MRI).
Treatment options for HCC include those therapies with curative intent such as LT,
hepatic resection, and ablation, as well as palliative therapies such as transarterial
chemoembolization (TACE). Patients with well-compensated liver disease (ChildTurcotte-Pugh class A) and localized HCC may be managed with hepatic resection.
Among carefully selected patients, outcomes for hepatic resection for HCC are
satisfactory with reported 5 yr survival rates of over 50%. Identified risk factors for
postoperative hepatic decompensation in cirrhotic patients undergoing hepatic
resection for HCC are a serum bilirubin greater than 1.1 mg/dL and portal
hypertension > 10 mmHg as measured by hepatic venous pressure gradient). For
this reason, surgical resection should, therefore, be restricted to patients without
portal hypertension. The applicability of hepatic resection in this circumstances is low
(less than 5% of patients with HCC are candidates for hepatic resection), and the
main drawback of this therapeutic option is the development of tumor recurrence in
the remaining liver, as high as 50% at 3 yr and 70% at 5 yr. Transarterial
chemoembolization (TACE) is performed by selectively cannulating the hepatic artery
branch supplying the HCC lesion and injecting a chemoembolic mixture that occludes
the vessel. TACE is generally well tolerated and has been demonstrated in a
systematic review of randomized trials to provide a survival benefit in patients with
unresectable HCC. While there is a risk of causing further hepatic decompensation,
TACE does not appear to negatively impact the future operability of the patient.
Because of these reasons, TACE is frequently used to manage patients awaiting LT
for HCC.
Patients ineligible for hepatic resection due to decompensated liver disease who have
small lesions may undergo percutaneous ablative therapies. There are a variety of
ablative modalities, including percutaneous ethanol injection (PEI), cryoablation, and
radiofrequency ablation (RFA). RFA and PEI are effective in tumors smaller than 3 cm
but are far less successful for larger tumors. Percutaneous ablation is limited by the
number of tumors that may be treated (< 3) and technical limitations for tumors in
anatomically unfavorable positions (e.g., near the liver capsule, adjacent to the
gallbladder or other organs). Five-year survival rates of 50% have been reported for
percutaneous ethanol injection in tumors less than 2 cm in diameter, while RFA
achieves tumor necrosis rates of over 60% for tumors up to 3 cm in diameter. In
selected patients with otherwise untreatable tumors but relatively well-preserved
liver function, chemoembolization has been shown to improve survival; however,
these patients have much lower survival rates than those who are candidates for
surgical or ablative therapy.
Percutaneous ablative therapies, like hepatic resection, do not ameliorate the
underlying chronic liver disease and patients must be closely monitored for tumor
recurrence. The benefit of nonsurgical "bridging" therapy with radiofrequency
ablation (RFA) or chemoembolization has not been proven in controlled trials.
Nevertheless, it is suggested that immediate RFA at the time of listing, preferably
when the tumor is 3 cm in diameter or less, is indicated to reduce tumor size and
delay progression.
With the risk of dropout from the waiting list increasing with time, an adjustment to
the UNOS MELD score was necessary for patients awaiting LT for HCC. Upon the
adoption of the MELD system for organ allocation, patients with small HCCs (< 2 cm)
were allocated a priority score equal to a predicted 3-month mortality rate of 15%
64
(MELD = 24). Larger tumors were allocated a priority score equal to a predicted 3month mortality rate of 30% (MELD = 29). These adjusted scores led to a 2.4-fold
increase in the number of patients undergoing LT for HCC during the first yr after
MELD was adopted. Furthermore, over 85% of patients undergoing LT for HCC were
transplanted within 90 days of being placed on the waiting list. This disproportionate
prioritization of patients with HCC led to a significantly smaller number of patients
with HCC being removed from the waiting list compared to patients with chronic liver
disease. In response, UNOS made several adjustments to the priority scores for HCC.
From April 2004 forward, UNOS has restricted the assignment of additional priority to
patients with a solitary 2 to 5 cm HCC or up to 3 tumors each < 3 cm; the MELD
score for these patients is equivalent to a 15% probability of death within 3 months.
A prelisting biopsy is not obligatory but the lesion must meet the following imaging
criteria: an ultrasound of the candidate’s liver, a CT or MRI scan of the abdomen that
documents the tumor, and a CT of the chest plus a bone scan that rules out
metastatic disease. In addition, the candidate must have at least 1 of the following:
(1) a vascular blush corresponding to the area of suspicion seen on the above
imaging studies, (2) an AFP level of > 200 ng/mL, (3) an arteriogram confirming a
tumor, (4) a biopsy confirming HCC, (5) chemoembolization of the lesion, and RFA,
cryoablation, or chemical ablation of the lesion. Candidates with chronic liver disease
who have a rising AFP level > 500 ng/mL may be listed with a MELD score equivalent
to an 8% mortality risk without review even though there is no evidence of a tumor
based on imaging studies. Candidates will receive additional MELD points equivalent
to a 10% increase in mortality every 3 months until LT or delisting due to tumor
progression. Currently, an HCC lesion > 2 cm is assigned a MELD score of 22, with
tumors less than 2 cm in diameter no longer receiving additional priority. Every
3 months, the MELD score is increased to account for an additional 10% increase in
mortality risk for patients remaining on the waiting list.
Retrospective studies that adjust for disease severity suggest that survival following
liver transplantation is as good or better as with other alternative treatments for HCC
in carefully selected patients. However, a study from the UNOS in the United States
indicated that 30% of patients were understaged by imaging pre-transplant and 31%
of patients with a diagnosis of stage 1 HCC (single lesion < 2 cm in diameter) did not
have a tumor on the explant examination. Another study showed that washout of
arterially enhancing lesions is very sensitive and specific for a diagnosis of HCC.
The role of living donor transplantation in patients with HCC remains controversial.
However, if a suitable and willing donor is identified, and the patient is otherwise
eligible for transplantation, this approach is a reasonable alternative to waiting six to
12 months for a deceased donor graft. For patients who have undergone liver
transplantation for HCC, immunosuppressive therapy to reduce the risk of graft
rejection is associated with a risk of tumor regrowth. As a result, every effort should
be made to reduce doses to an effective minimum.
Fibrolamellar Hepatocellular Carcinoma
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in young adults
when the tumor is not resectable and there is no evidence of extrahepatic disease.
65
Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare primary malignant tumor of
the liver. Histologically, it is characterized by eosinophilic neoplastic hepatocytes
separated into cords by lamellar fibrous strands. FLHCC, also called fibrolamellar
oncocytic hepatoma, usually affects adolescents and young adults. If detected early,
this cancer is frequently resectable, with a much longer survival time than in classic
hepatocellular carcinoma. Fibrolamellar hepatocellular carcinoma has distinct
radiographic and pathologic features. Serum unsaturated vitamin B sub 12 binding
capacity and plasma neurotensin may be used as tumor markers.
It is important to distinguish fibrolamellar hepatocellular carcinoma from the classic
form of liver cancer, a malignant neoplasm with a very poor prognosis. Surgical
resection is possible in about 60% of patients with fibrolamellar hepatocellular
carcinoma. Survival time after resection is substantial, with a mean duration of 68
months. Most patients with FLHCC present with abdominal discomfort and malaise,
although some may be asymptomatic. The liver is usually enlarged. Serum
transaminase and alkaline phosphatase levels may be mildly or moderately elevated.
However, serum (alpha)-fetoprotein, which is often elevated in hepatocellular
carcinoma, is rarely elevated in the fibrolamellar form of primary liver cancer. The
carcinoembryonic antigen (CEA) level is elevated in the sera of some patients with
fibrolamellar hepatocellular carcinoma.
Two laboratory tests - serum unsaturated vitamin B sub 12 binding capacity and
plasma neurotensin - often show elevated values in patients with fibrolamellar
hepatocellular carcinoma, because the cells of this neoplasm may secrete vitamin B
binding proteins and neurotensin. These two tests may be used to monitor the
regression or recurrence of the tumor postoperatively. Computed tomographic (CT)
scanning often reveals a well-demarcated, homogeneous mass with a small, central,
calcified focus that is either stellate or nodular. In contrast, untreated hepatocellular
carcinoma rarely has areas of calcification that are visible radiographically. Ultrasonograms of patients with fibrolamellar hepatocellular carcinoma often show a
moderately echogenic, well-demarcated mass that is usually homogeneous. Focal
calcifications may be visualized. If the CT scan indicates the possibility of an atypical
cavernous hemangioma, a technetium red blood cell scintigram is necessary to rule
out hemangioma. On a technetium sulfur colloid liver scan, fibrolamellar
hepatocellular carcinoma appears as a cold nodule. The angiogram shows a
hypervascular lesion within the liver; in some cases, arteriovenous shunting can be
seen. The next step is to proceed with open biopsy of the liver.
Fibrolamellar hepatocellular carcinoma must be differentiated from hepatocellular
carcinoma, focal nodular hyperplasia of the liver, metastatic tumors to the liver and
hepatic adenoma. Since the management of hepatocellular carcinoma may not
involve aggressive surgical resection, FLHCC that simulates hepatocellular carcinoma
could potentially be undertreated. Patients with FLHCC have far better prognoses
than patients with HCC. In contrast to HCC, most patients with these tumors do not
have evidence of significant underlying liver disease. As a result, transplantation is
uncommonly required. However, in contrast to HCC, large tumors are not
contraindications to liver transplantation. Although experience is limited, the
prognosis for children with this tumor who have undergone transplantation remains
guarded.
Hepatic Epithelioid Hemangioendothelioma
Policy Statement
66
Referral for evaluation of liver transplantation is medically necessary in young adults
when any of the following is met:
1. Non-resectable epithelial hemangioendotheliomas (EHE) in young adults
2. Multifocal hepatic EHE
Note: Extrahepatic manifestation of the disease may not be a contraindication to
transplantation in EHE, although this varies from center to center.
Note: Epithelioid hemangioendothelioma (EHE) should be referred for expert histopathological and radiological opinion to exclude angiosarcoma
Primary hepatic epithelioid hemangioendothelioma (EHE) is a very rare tumor of
vascular origin with unknown etiology and a variable natural course. EHE mostly
affects females. The clinical course of hepatic epithelioid hemangioendothelioma
varies from favorable (benign hemangioma with protracted survival, perhaps without
treatment), to a low-grade malignancy, to that of rapidly progressive malignant
disease with fatal outcome depending on organs involved. Prognosis seems to be
worse if both liver and lung are involved. Neoplastic cells expressed the factor VIIIrelated antigen, CD31 or CD34. On imaging studies, the lesion has a solid
appearance and may mimic metastatic disease. As it is an intermediate entity
between well-differentiated hemangioma and angiosarcoma, low progression and
partial spontaneous regression might occur, especially in asymptomatic patients.
After diagnosis, the treatment of first choice appears to be anatomic radical liver
resection. Liver transplantation represents a potentially important option for patients
with a nonresectable tumor or in the case of diffuse tumor spread, both of which
show favorable long-term results. If metastases are identifiable, no surgery should
be attempted. Despite the long waiting time, its often unclear dignity, and a proven
progressive growth pattern, living related liver transplantation also plays a
potentially important role. The 5-year overall survival rate of patients with EHE in the
literature varies from 43% to 55%. Long-term survival of patients with EHE is
significantly higher compared to other hepatic malignancies. The role of adjuvant
therapy currently remains unclear.
A recent systematic review found that the most common clinical manifestations are
right upper quadrant pain, hepatomegaly, and weight loss. Most patients present
with multifocal tumor that involves both lobes of the liver. Lung, peritoneum, lymph
nodes, and bone are the most common sites of extrahepatic involvement at the time
of diagnosis. The most common management has been liver transplantation
(44.8%), followed by no treatment (24.8%), chemotherapy or radiotherapy (21%),
and liver resection (9.4%). The 1-year and 5-year patient survival rates were 96%
and 54.5%, respectively, after liver resection; 39.3% and 4.5%, respectively, after
no treatment, 73.3% and 30%, respectively, after chemotherapy or radiotherapy;
and 100% and 75%, respectively, after liver transplantation. Anatomic radical liver
resection has been the treatment of choice in patients with resectable EHE. However,
liver transplantation has been proposed as the treatment of choice because of the
hepatic multicentricity of EHE. In addition, liver transplantation is an acceptable
option for patients who have EHE with extrahepatic manifestation. Highly selected
patients may be able to undergo living-donor liver transplantation, preserving the
donor pool.
67
Cholangiocarcinoma
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in only a very
small subset of patients with a hilar location of the tumor and absence of nodal
involvement.
Note: Cholangiocarcinoma is not an indication for transplantation unless in
conjunction with an investigational trial and should be confined to a few centers with
well-designed clinical trials with approval by a local institutional review board and
informed consent of potential recipients.
Cholangiocarcinomas are rare malignancies arising from the epithelial cells of the
intrahepatic and extrahepatic bile ducts. In general, cholangiocarcinomas have an
extremely poor prognosis, with an average five-year survival rate of 5 to 10%.
Surgery provides the only possibility for a cure. Distal cholangiocarcinomas have the
highest resectability rates while proximal (particularly perihilar) tumors have the
lowest. In one large series, the resectability rates for distal, intrahepatic, and
perihilar lesions were 91, 60, and 56, respectively. The extent of cholangiocarcinoma
frequently is more extensive than suspected on pre-transplant imaging; often there
is local, lymphatic, and perineural spread. Even in patients who undergo potentially
curative resection, tumor-free margins can be obtained in only 20 to 40% of
proximal, and 50% of distal tumors. These numbers are even lower if a proximal
tumor-free margin of at least 5 mm is considered to constitute a curative procedure.
The addition of en bloc pancreaticoduo-denectomy has not resulted in improved
survival post-transplant. Other approaches to treatment include aggressive
preoperative irradiation and chemotherapy, with careful intraoperative tumor staging
followed by transplant, with encouraging results in a preliminary report from the
Mayo Clinic. The occasional patient with cholangiocarcinoma discovered incidentally
in the explant can have a good long-term survival.
Criteria for resectability include all of the following:




Absence of N2 nodal metastases or distant liver metastases
Absence of invasion of the portal vein or main hepatic artery (although some
centers support en bloc resection with vascular reconstruction)
Absence of extrahepatic adjacent organ invasion
Absence of disseminated disease
Additional criteria are specific to tumor location. For instance, radiographic criteria
that suggest local unresectability of perihilar tumors include bilateral hepatic duct
involvement up to secondary radicles bilaterally, encasement or occlusion of the
main portal vein proximal to its bifurcation, atrophy of one liver lobe with
encasement of the contralateral portal vein branch, atrophy of one liver lobe with
contralateral secondary biliary radicle involvement, or involvement of bilateral
hepatic arteries. However, as a general rule, true resectability is ultimately
determined at surgery, particularly with perihilar tumors. Due to their location within
the upper hepatoduodenal ligament, these tumors often extend into the liver and
major vascular structures, and preoperative evaluation of resectability is often
difficult. Thus, surgical exploration is the appropriate treatment for proximal bile duct
carcinomas whenever feasible. The main prognostic factors are histologic margin
status and lymph node involvement.
68
The outcome of liver transplantation for cholangiocarcinoma has been particularly
frustrating. Even small tumors with no evidence of local invasion almost invariably
recur within a few years after transplantation. Liver transplantation has also been
studied as a treatment for intrahepatic and central cholangiocarcinomas with mixed
results. In many cases, these were patients transplanted for primary sclerosing
cholangitis (PSC) who were found to have incidental cholangiocarcinomas in their
native liver. Despite favorable reports and long-term survival in some patients
(particularly with small peripheral tumors <1 cm), transplantation has fallen out of
favor for patients known to have cholangiocarcinoma since the disease recurs in
more than one-half of patients and because of the limited availability of organs.
The following represents the conclusions of a systematic review of published reports
of liver transplantation for cholangiocarcinoma performed on behalf of the Agency for
Healthcare Research and Quality:
“Median patient survival was 11.8 months when combining all studies
that included a minimum of 10 patients. Overall one-,three- and fiveyear patient survival rates were 63, 46, and 22%, respectively. For
comparison, one-, three-, and five-year patient survival following liver
transplantation for chronic hepatitis C is 79, 79, and 66%, respectively.
Recurrence was reported in 52 % of patients when combining all studies
that included a minimum of 10 patients (total 543 patients). The mean
follow-up was 53 months. Overall one-, three-, and five-year diseasefree survival rates for all patients were 58, 22, and 13%, respectively.
There were insufficient data to make firm conclusions regarding patient,
tumor, or transplant characteristics that were associated with a
favorable prognosis. However, limited data suggested that one-year
patient survival was better in patients with tumors diagnosed
incidentally compared with those in whom it was diagnosed
preoperatively. Prognosis was also better in those with negative lymph
nodes and no residual disease after surgery. Adjuvant and neoadjuvant
chemotherapy did not appear to improve survival. However, in a large
report from the Mayo Clinic that was not included in the systematic
review, a five-year survival rate of 82% was reported for patients with
initially unresectable disease or cholangiocarcinoma arising in the setting
of PSC. All of these patients underwent preoperative chemoradiotherapy
followed by exploratory laparotomy to exclude metastatic disease before
transplantation.”
Whether the prognosis is better in patients with underlying primary sclerosing
cholangitis (PSC) is unclear. Outcomes in patients with cholangiocarcinoma in the
setting of PSC were described in 13 reports with a total of 91 patients. When
combining results of the largest four studies, 53% recurred. A study of patients with
an incidental cholangiocarcinoma found in the setting of PSC found one- three- and
five-year patients survival rates of 65, 35, and 35%, respectively.
69
In conclusion and based on current outcomes, liver transplantation cannot be
considered a standard form of therapy for cholangiocarcinoma at present. It should
only be considered for selected patients with early stage disease as part of a clinical
research protocol approval by a local institutional review board and informed consent
of potential recipients.
Hepatoblastoma
Policy Statement
Referral for evaluation of liver transplantation is medically necessary when all of the
following are met:



Patient is not a candidate for subtotal liver resection; and
Patient's tumor is 5 cm or less in diameter or member has no more than three
tumors, each less than 3 cm in diameter (live donor transplants can use the
expanded criteria of a single tumor of up to 6.5 cm or no more than 3 tumors
with the sum of the diameters being 8 cm or less); and
There is no identifiable extrahepatic spread of tumor to surrounding lungs,
abdominal organs or bone.
Note: Spread of hepatoblastoma to veins and lymph nodes does not exclude
patient from a liver transplant.

Patient is not a candidate for subtotal liver resection; and

The patient meets UNOS criteria for tumor size and number; and

There is no identifiable extrahepatic spread of tumor to surrounding lungs,
abdominal organs, bone or other sites.
Hepatoblastoma is the most common malignant tumor of the liver in the pediatric
population, affecting mostly young boys age < 3 years and accounting for 75% of
primary liver tumors in childhood. Even though diagnosis is usually at a late stage,
the introduction of chemotherapy with cisplatin and doxorubicin has changed the
treatment success of hepatoblastoma substantially, and despite a large tumor mass
at presentation, a combined surgical and chemotherapeutic approach has yielded a
5-year survival rate of approximately 80%. Initial management consists of surgical
resection; adjuvant chemotherapy is indicated for metastatic disease. This tumor
usually is locally invasive with a better long-term prognosis than for HCC. As a
result, successful results from transplantation can be achieved in children with much
larger tumors. Liver transplantation should be considered for children in whom
hepatoblastoma is confined to the liver and is not completely resectable after
appropriate chemotherapy. Even children with nonresectable hepatoblastoma have
an excellent prognosis for long-term tumor-free survival if liver transplantation
follows chemotherapy. However, these children usually do not have underlying liver
disease, and consequently the PELD scoring system does not adequately capture
their need for transplantation. Accordingly, the transplantation center may submit a
request for enhanced prioritization for deceased donor organs, which is then
reviewed through a regional peer review system.
Hepatic Metastasis of Neuroendocrine Tumors
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in a few highly
selected young patients when all of the following are met:
70
1. Carcinoid tumor(s) is confirmed by histology
2. Primary tumor originates from the gastrointestinal tract (e.g., carcinoid tumors,
islet cell tumors, apudomas, gastrinomas, glucagonomas) and produces a
hormone (e.g., serotonin, insulin, gastrin, glucagon, etc.)
3. Symptoms have persisted (e.g., flushing, diarrhea) despite optimal medical
therapy (systemic somatostatin or radioactive metaiodobenzylguanidine therapy)
4. Tumors not accessible to curative resectional surgery or major tumor reduction
(debulking)
5. The primary tumor has been previously removed surgically and controlled for at
least 6 months after surgical resection or interventional therapy (e.g.,
radiofrequency ablation, chemoembolization, cryoablation, either alone or in
conjunction with surgical debulking) without signs of extrahepatic metastases,
which would be a contraindication to transplantation.
Note: An additional indication for surgery are tumors causing life-threatening
hormonal symptoms.
Carcinoid tumors, or carcinoids, originate in hormone-producing cells of the
gastrointestinal (GI) tract (i.e., esophagus, stomach, small intestine, colon), the
respiratory tract (i.e., lungs, trachea, bronchi), the hepatobiliary system (i.e.,
pancreas, gallbladder, liver), and the reproductive glands (i.e., testes, ovaries). The
most common site of origin is the GI tract and carcinoid tumors often develop in the
appendix, the rectum, and the lower sections of the small intestine (i.e., the jejunum
and the ileum). According to the American Cancer Society, approximately 5,000
carcinoid tumors are diagnosed each year in the United States. According to the
National Cancer Institute (NCI), approximately 74% of these tumors originate in the
GI tract and 25% occur in the respiratory tract. Carcinoids are rare in children and
are more common in patients older than the age of 50. They are twice as common in
men. Carcinoid tumors of the appendix usually are benign and often occur between
the ages of 20 and 40.
Carcinoids are classified as neuroendocrine tumors (also referred to as apudomas).
They release hormones in response to signals from the nervous system. Excessive
amounts of these hormones cause a condition called carcinoid syndrome in
approximately 10% of patients with carcinoid tumors. Even after metastasizing,
these tumors often remain slow growing so that approximately one-third of the
patients survives for 5 years after the development of liver metastases. Because of
the somewhat indolent nature of their liver metastases, these patients are
considered appropriate candidates for liver transplantation. Symptoms of carcinoid
tumors depend on the site of origin, on whether or not the tumor has metastasized,
and on which hormones are produced by the tumor. Carcinoid tumors that are
confined to the GI tract may be asymptomatic because the hormones produced by
these tumors are released into the bloodstream and destroyed by the liver. Tumors
that originate in or metastasize to areas other than the GI tract (e.g., liver, lungs,
pancreas) produce hormones that are not destroyed in the liver. Common sites of
carcinoid metastases include lymph nodes, liver, lungs, and bone. When carcinoid
tumors produce excessive amounts of hormones that circulate throughout the body,
a condition called carcinoid syndrome can occur. This syndrome, which develops in
71
approximately 10% of patients, is more common in carcinoids of the midgut, the
foregut, and in those that have metastasized (especially to the liver). Symptoms of
carcinoid syndrome depend on which hormones are produced by the tumor. During
the course of the disease, approximately 70% of carcinoid syndrome patients
experience a sudden red rash that usually develops on the face and neck and is
accompanied by feelings of warmth and itching (called flushing). Diarrhea is another
prominent feature.
The diagnosis of carcinoid tumors involve urine, blood, and imaging tests. When a
carcinoid is suspected, the levels of serotonin or its by-products (usually 5hydroxyindoleacetic acid [5-HIAA]) in the patient's urine are measured over a 24hour period. High levels of other peptides (e.g., neuropeptide, neurotensin, secretin)
may indicate a carcinoid tumor as well. Blood tests also may be used to measure the
plasma level of these substances. In some cases, physicians administer a drug (e.g.,
calcium gluconate, pentagastrin, alcohol) to provoke flushing and help in the
diagnosis. Imaging tests include x-rays, CT scan, MRI, and PET scan. Because most
carcinoids have receptors for the hormone somatostatin, angiography and
radionuclide scan can be used to detect approximately 90% of tumors. These tests
involve injecting a radioactive form of somatostatin into the bloodstream and using
nuclear scanning to locate the tumor and determine its growth.
Surgical resection of the tumor is the preferred method of treatment for carcinoid
tumors. If the entire tumor cannot be removed, treatment may include removing as
much of the tumor as possible (debulking), chemotherapy, biological therapy, and
radiation therapy. In cases of metastatic disease, chemotherapy and/or radiation
may be used to relieve symptoms. Surgical treatment depends on the size and
location of the tumor and whether or not the tumor has metastasized. Surgical
options may include local excision, removal of the tumor and part of the organ,
fulguration, or cryosurgery. Carcinoid tumors that have metastasized to the liver
may be treated using hepatic artery ligation or hepatic artery embolization. Hepatic
artery ligation involves cutting and tying off the hepatic artery to slow tumor growth.
Hepatic artery embolization uses drugs or radiation to reduce or block the flow of
blood to the tumor.
Polycystic Disease of the Liver
Policy Statement
Referral for evaluation of liver transplantation is medically necessary in patients who
do not develop liver failure but may require transplantation due to any of the
following anatomic complications of a massively enlarged liver, which can only be
treated by liver transplant:
1. Enlargement of liver impinging on respiratory function
2. Extremely painful enlargement of liver
3. Enlargement of liver significantly compressing and interfering with function of
other abdominal organs
Polycystic liver disease may manifest in childhood as an autosomal recessive disorder
that is usually rapidly fatal as a consequence of the associated (autosomal recessive)
polycystic kidney disease (ARPKD). A proportion of the patients maintain renal
function into adulthood, however, and complications of the associated liver disease
then predominate. The liver cysts are microscopic, rather than macroscopic, and
72
present a clinical picture indistinguishable from that of congenital hepatic fibrosis.
Complications of portal hypertension are the usual hepatic manifestations of the
disease. More commonly, multiple cysts of the liver are diagnosed in adulthood. They
present either in association with autosomal dominant polycystic kidney disease
(ADPKD) or as isolated polycystic liver disease.
ADPKD carries a better prognosis than that for the recessive variety. Polycystic
kidney disease has a more deleterious effect on kidney function than that of
polycystic liver disease on hepatic function and largely determines the outcome.
Hepatic cysts, which manifest later in life than do the renal cysts, usually are
diagnosed in the fourth or fifth decade of life. The size and number of cysts correlate
with the patient's age, severity of renal disease, and worsening renal function.
Women tend to have larger and more numerous cysts, and a correlation with the
number of pregnancies has been found. The use of exogenous female sex hormones
may accelerate the rate of growth and size of the cysts. In the autosomal dominant
variety, cysts also may be present in the pancreas, spleen, and, less often, other
organs. In addition, autosomal dominant polycystic liver disease may coexist with
the other fibropolycystic liver diseases, such as congenital hepatic fibrosis (in which
the patient is likely to present with portal hypertension), Caroli's disease, or von
Meyenburg complexes, as well as other conditions such as berry aneurysms, mitral
valve prolapse, diverticular disease, and inguinal hernias.
The hepatic cysts in polycystic liver disease, whether or not they occur in association
with renal cysts, rarely cause morbidity, and many affected patients are
asymptomatic. The livers of these patients contain only a few cysts or cysts smaller
than 2 cm in diameter. With the more widespread use of hepatic imaging,
asymptomatic cysts are being discovered more often now than in the past.
Symptoms occur in patients with more numerous and larger cysts (10% to 15% of
patients, almost always women), usually as abdominal discomfort or pain,
postprandial fullness, awareness of an upper abdominal mass, a protuberant
abdomen, and shortness of breath. Severe pain may be experienced with rupture or
infection of a cyst, bleeding into a cyst, or torsion of a pedunculated cyst. The liver is
enlarged in approximately 80% of patients. The associated polycystic kidneys also
often are palpable. Jaundice is evident in approximately 5% of patients and is caused
by compression of the major intrahepatic or extrahepatic bile ducts. Ascites, if
present, is the result of portal hypertension, which generally is caused by the
associated congenital hepatic fibrosis but occasionally by compression of the hepatic
veins by the cysts. A raised right hemidiaphragm may be evident on a plain
radiograph of the chest in severe polycystic liver disease. The diagnosis of polycystic
liver disease is confirmed by ultrasound examination or CT. Hepatic arteriography
shows multiple avascular lesions with displacement of the vessels.
The cysts range in diameter from a few millimeters to 10 cm or more. They contain
clear, colorless, or straw-colored fluid and are lined by a single layer of cuboidal or
columnar epithelium, resembling that of bile ducts. On the rare occasions when a
cyst requires treatment, fenestration (unroofing) should be performed. Cyst
fenestration originally was done at laparotomy but is now performed
laparoscopically. A high recurrence rate is observed for cysts treated in this way.
Cysts also have been treated by percutaneous injection of sclerosing substances such
as alcohol or doxycycline, but most patients have too many cysts of small size to
warrant this approach. Patients who fail to respond to cyst fenestration may be
considered for partial hepatic resection or liver transplantation (sometimes combined
with renal transplantation). Liver failure is uncommon in patients with polycystic
disease. However, occasional patients are so debilitated by abdominal pain, anorexia,
73
or fatigue that consideration for liver transplantation is requested. The published
experience with liver transplantation is quite limited. Patients with severe symptoms
also may be considered for transarterial embolization.
Retransplantation
Policy Statement
We consider retransplantation medically necessary if the initial transplant was
performed for a medically necessary indication and any of the following is met:
1. Nonfunction of the grafted organ
2. Surgical complications such as ischemia, hepatic artery thrombosis and/or
biliary stricture
3. Rejection refractory to immunosuppressive therapy
4. Recurrent disease
Given the critical organ shortage, one of the most controversial questions is whether
hepatic retransplantation, the only chance of survival for patients with a failing first
organ, should be offered liberally despite its greater cost, worse survival, and the
inevitable denial of access to primary transplantation to other patients due to the
depletion of an already-limited organ supply.
In the setting of lack of donor organ availability, increasing death rates on the
waiting list for primary orthotopic liver transplantation, and the difficulties with
recurrent disease, significant debate continues surrounding the issue of
retransplantation. There is higher associated morbidity and mortality with
retransplantation; however, at present, 4% of patients listed for liver transplantation
are retransplant candidates with no other option. Pedersen and colleagues[8]
assessed the applicability of the MELD score to assess wait-list mortality in
retransplant candidates compared with primary transplant candidates. They
extracted data from the UNOS (United Network for Organ Sharing) database and
found that patients relisted had higher MELD scores (22 vs 14), but when adjusted
for equivalent MELD scores, short-term wait-list mortality was slightly lower in the
retransplant candidates than in the primary candidates. The study authors concluded
that MELD score is an important determinant of wait-list mortality, and that patients
listed for retransplant have equivalent wait-list mortality. The continuing controversy
will concern not only predicting how soon a patient needs retransplantation based on
the MELD score but also determining whom we should be transplanting.
Retransplant operations account for approximately 10% of all liver transplants. Most
times, they are the only means of prolonging life in patients whose initial graft has
failed, make an important contribution to overall survival. Retransplantation should
be considered in selected patients with primary graft failure, hepatic artery
thrombosis, severe allograft rejection, or recurrent disease. Retransplantation should
be considered before patients develop severe hepatic and renal failure, should be
used with discretion in the emergency setting and should be avoided in subgroups of
patients with little chance of success. The outcome for retransplantation is
significantly lower than for primary transplantation with one-, three-, and five-year
survival rates approximately 20% lower than for primary transplantation. Patients
who undergo retransplantation also have significantly longer hospital and intensive
care unit stays and higher total hospital charges than those who receive only one
transplant.
74
Studies have shown that survival after retransplantation is excellent (80% 2-year
survival) when performed on a nonurgent basis in patients with relatively stable liver
and renal function in contrast to 40% when performed in patients with decompensated liver disease and renal failure. Risk factors associated with “worse”
retransplantation outcome include total bilirubin over 10 mg/dL, creatinine level over
2.0 mg/dL, creatinine clearance of less than 40 mL/min, recipient age over 55 years,
early recurrence with development of cirrhosis at less than 1 year, and donor age
over 40 years.
Hepatitis C is the leading indication for orthotopic liver transplantation worldwide,
and with nearly universal reinfection of the graft, recurrent HCV disease is
problematic clinically. HCV-related graft cirrhosis has been reported as high as 30%
at 5 years. At present, 40% of liver retransplants in the United States are due to
recurrent HCV disease and liver failure from recurrent hepatitis C has been
associated with particularly poor survival. The leading cause of death in all hepatitis
C retransplanted patients is severe recurrent HCV leading to liver failure.
A number of groups have attempted to develop prognostic models for patients
undergoing retransplantation. It appears that retransplantation in the setting of
rapidly recurrent HCV infection is a matter of timing and should be considered early
after identification of the process. Studies have assessed outcomes in patients
undergoing retransplantation for HCV-related disease compared with patients
receiving a primary liver transplant. They found a significantly worse survival
outcome at 5 years (60% vs 28%) for patients undergoing retransplantation. The
urgency of retransplantation, serum bilirubin and creatinine levels, CTP score of 10
or more, and MELD score of more than 25 all are associated with a poor prognosis
after retransplantation. Many reports suggest that more strict selection criteria may
be required when considering retransplantation in patients with aggressive HCV
recurrence, although considerable controversy still exists in this arena.
HCV-related cirrhosis is still a valid indication for liver transplantation, despite the
frequency of recurrence. As this segment of the liver transplantation-recipient
population grows, the transplantation hepatologist needs to consider the challenge of
preventing aggressive recurrence and considering the value of retransplantation in
this patient group. Current treatment options for HCV offer limited chance of longterm success. There is ample room for investigation into the most beneficial regimen
and duration of treatment, the time at which one should start, and how all the
factors over which the clinician and patient have control will be manipulated to
achieve the highest possible disease- and symptom-free survival.
Absolute Contraindications for Transplant Recipients
We do not cover liver transplantation when any of the following absolute
contraindications is present:





When other effective medical or surgical options have not been tried to reverse
or prevent further hepatic decompensation
The history of a demonstrated behavior pattern (e.g., not adhering to current
medical recommendations) or psychiatric illness considered likely to
significantly hinder compliance with disciplined life-long pre- and posttransplant regimens which might place the organ at risk
Child-Turcotte-Pugh score < 7 or MELD score < 10
Active alcoholism or illicit drug abuse
Alcoholic cardiomyopathy
75




Irreversible brain damage
Chronic hepatitis B with cirrhosis and HBV DNA positivity, despite antiviral
therapy
Fulminant hepatic failure with sustained intracranial pressure (ICP) > 50 mm
Hg or cerebral perfusion pressure (CPP - equals the mean arterial pressure
minus ICP) < 40 mm Hg
HIV positivity unless all of the following are met:



















CD4 count > 200cells/mm3 for > 6 months
HIV-1 RNA undetectable
On stable anti-retroviral therapy > 3 months
No other complications from AIDS (e.g., opportunistic infection,
including aspergillus, tuberculosis, coccidioidomycosis, resistant fungal
infections, Kaposi’s sarcoma or other neoplasm)
 Patient meets all other criteria for liver transplantation
Multiple uncorrectable life-threatening congenital anomalies
Morbid obesity (BMI > 40)
Total thrombosis of porto-mesenteric venous system when radiographic studies
do not support the possibility of simple reconstruction above the level of the
pancreas, or by vein graft to the base of the superior mesenteric vein
Anatomic abnormality precluding liver transplantation
Ongoing or recurrent infections or sepsis outside the biliary tract that have not
been effectively treated (e.g., endocarditis) - cholangitis does not disqualify the
patient for transplant
Chronic infectious disease - chronic suppurative infections (e.g., osteomyelitis,
sinusitis) or chronic fungal disease
Active pulmonary tuberculosis, unless patient has been treated for at least 3
months prior to transplant
Some rheumatic diseases (e.g., scleroderma with gastrointestinal/pulmonary
involvement)
Patient has a non-hepatic cancers (other than neuroendocrine tumors
metastatic to the liver and skin cancers) who are actively receiving treatment
(chemotherapy, radiation therapy) or have a life expectancy of < 5 years
Intrahepatic malignancies other than those listed as medically necessary above
(e.g., unresectable colon cancer metastatic to the liver)
Patient has an intrahepatic malignancy that extends beyond the margin of the
liver or extrahepatic metastasis
Cholangiocarcinoma, unless transplant is being performed in a specialized
center enrolling patients for an investigational trial
Hemangiosarcoma
Presence of life limiting co-existing organ system failure other than kidney, liver
or small bowel, that create an inability to tolerate transplant surgery, for
example:
 Advanced heart disease (severe valvular disease complicated by severe
pulmonary hypertension; aortic stenosis with LV dysfunction;
uncorrected coronary artery disease or residual LV dysfunction)
 Severe progressive primary lung disease whose pulmonary functions are
irreversibly compromised
 Severe pulmonary hypertension (mean pulmonary pressure > 50-55
mm Hg) found on Doppler and confirmed by right heart catheterization
not effectively controlled with medical therapy
Patient has other serious condition(s) that is unlikely to be improved by
transplantation as life expectancy can be finitely measured
76




Children with persistent uremia
The need for prior transplantation of a second organ, such as a lung, heart,
kidney or marrow, if this represents the coexistence of significant disease
Combination of extensive prior hepatobiliary surgery, associated with
uncorrectable severe coagulopathy (prothrombin time consistently > 22
seconds)
Potential complications from immunosuppressive medications are unacceptable
to the patient
Investigational Procedures
Health Net, Inc. consider any of the following investigational because there is
inadequate scientific evidence to validate their effectiveness:




Artificial assist devices (bioartificial liver transplantation) used for a bridge to
transplantation until a suitable donor becomes available
Xenotransplantation
Hepatocellular transplantation
Hepatocyte transplantation
Not Medical Necessary
Health Net, Inc. considers any of the following not medically necessary because
there is a paucity of peer-reviewed literature and no current ongoing clinical trials or
studies. In addition, many of the current studies involve animals:








Ectopic or auxiliary liver transplantation
Gene therapy
Ex vivo gene transduction
Vector-mediated gene delivery
Adenoviral vectors
SV40 and lentiviruses
Receptor-mediated gene delivery
Site-directed gene conversion
Review History
March 2007
February 2008
April 2011
March 2012
March 2013
March 2014
March 2015
Medical Advisory Council initial approval
Revised - Under General Patient Selection Criteria, revised
MELD score from > 12 to >10 as per AASLD recommendations
for transplant referral for adults. Under Absolute
Contraindications for Transplant Recipients, 3rd bullet, revised
Meld score <12 to <10.
Update. Added Medicare Table with link to NCDs. No Revisions
Update. No Revisions.
Update – no revisions. Code Updates
Update – no revisions. Code Updates.
Update – no revisions. Code Updates
This policy is based on the following evidence-based guidelines:
1. National Institutes of Health Consensus Development Conference Statement Liver
Transplantation. June 20-23, 1983.
2. Agency for Health Care Policy and Research. Assessment of Liver Transplantation
1990.
77
Murray KF, Carithers RL Jr. AASLD practice guidelines: evaluation of the patient
for liver transplantation. Hepatology 2005 Jun;41(6):1407-32.
3. Devlin J, O'Grady J. British Society of Gastroenterology. Indications for Referral
and Assessment in Adult Liver Transplantation: A Clinical Guideline. Available at:
http://www.bsg.org.uk/pdf_word_docs/adult_liver.pdf
4. Runyon BA. AASLD Practice Guidelines. Management of adult patients with
ascites due to cirrhosis. Hepatology 2004 Mar;39(3):841-56.
5. Jalan R, Hayes PC. British Society of Gastroenterology. UK guidelines on the
Management of Variceal Haemorrhage in Cirrhotic Patients. June 2000. Available
at: http://www.bsg.org.uk/pdf_word_docs/vari_hae.pdf
6. Boyer TD, Haskal ZJ. The role of transjugular intrahepatic portosystemic shunt in
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99. Alsina AE, Bartus S, Hull D, et al. Liver transplant for metastatic neuroendocrine
tumor. J Clin Gastroenterol. 1990;12(5):533-537.
100. Makowka L, Tzakis AG, Mazzaferro V, et al. Transplantation of the liver for
metastatic endocrine tumors of the intestine and pancreas. Surg Gynecol
Obstet. 1989;168(2):107-111.
101. Arnold JC, O'Grady JG, Bird GL, et al. Liver transplantation for primary and
secondary hepatic apudomas. Br J Surg. 1989;76(3):248-249.
102. O'Grady JG, Polson RJ, Rolles K, et al. Liver transplantation for malignant
disease. Results in 93 consecutive patients. Ann Surg. 1988;207(4):373-379.
Important Notice
General Purpose.
Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering
plan benefits and determining whether a particular procedure, drug, service or supply is medically
necessary. The Policies are based upon a review of the available clinical information including clinical
outcome studies in the peer-reviewed published medical literature, regulatory status of the drug or device,
evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select
national health professional organizations. Coverage determinations are made on a case-by-case basis
and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract,
including medical necessity requirements. Health Net may use the Policies to determine whether under the
facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically
necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not
constitute coverage. The member's contract defines which procedure, drug, service or supply is covered,
excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current
criteria that have been approved by Health Net’s National Medical Advisory Council (MAC). The clinical
criteria and medical policies provide guidelines for determining the medical necessity criteria for specific
procedures, equipment, and services. In order to be eligible, all services must be medically necessary and
otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all
cases, final benefit determinations are based on the applicable contract language. To the extent there are
any conflicts between medical policy guidelines and applicable contract language, the contract language
prevails. Medical policy is not intended to override the policy that defines the member’s benefits, nor is it
intended to dictate to providers how to practice medicine.
Policy Effective Date and Defined Terms.
The date of posting is not the effective date of the Policy. The Policy is effective as of the date determined
by Health Net. All policies are subject to applicable legal and regulatory mandates and requirements for
prior notification. If there is a discrepancy between the policy effective date and legal mandates and
regulatory requirements, the requirements of law and regulation shall govern. * In some states, prior
notice or posting on the website is required before a policy is deemed effective. For information regarding
the effective dates of Policies, contact your provider representative.
The Policies do not include
definitions. All terms are defined by Health Net. For information regarding the definitions of terms used
in the Policies, contact your provider representative.
Policy Amendment without Notice.
Health Net reserves the right to amend the Policies without notice to providers or Members.
states, prior notice or website posting is required before an amendment is deemed effective.
In some
No Medical Advice.
The Policies do not constitute medical advice. Health Net does not provide or recommend treatment to
members. Members should consult with their treating physician in connection with diagnosis and
treatment decisions.
No Authorization or Guarantee of Coverage.
86
The Policies do not constitute authorization or guarantee of coverage of particular procedure, drug, service
or supply. Members and providers should refer to the Member contract to determine if exclusions,
limitations, and dollar caps apply to a particular procedure, drug, service or supply.
Policy Limitation: Member’s Contract Controls Coverage Determinations.
Statutory Notice to Members: The materials provided to you are guidelines used by this plan to authorize,
modify, or deny care for persons with similar illnesses or conditions. Specific care and treatment may vary
depending on individual need and the benefits covered under your contract. The determination of
coverage for a particular procedure, drug, service or supply is not based upon the Policies, but rather is
subject to the facts of the individual clinical case, terms and conditions of the member’s contract, and
requirements of applicable laws and regulations. The contract language contains specific terms and
conditions, including pre-existing conditions, limitations, exclusions, benefit maximums, eligibility, and
other relevant terms and conditions of coverage. In the event the Member’s contract (also known as the
benefit contract, coverage document, or evidence of coverage) conflicts with the Policies, the Member’s
contract shall govern. The Policies do not replace or amend the Member’s contract.
Policy Limitation: Legal and Regulatory Mandates and Requirements
The determinations of coverage for a particular procedure, drug, service or supply is subject to applicable
legal and regulatory mandates and requirements. If there is a discrepancy between the Policies and legal
mandates and regulatory requirements, the requirements of law and regulation shall govern.
Reconstructive Surgery
CA Health and Safety Code 1367.63 requires health care service plans to cover reconstructive surgery.
“Reconstructive surgery” means surgery performed to correct or repair abnormal structures of the body
caused by congenital defects, developmental abnormalities, trauma, infection, tumors, or disease to do
either of the following:
(1) To improve function or
(2) To create a normal appearance, to the extent possible.
Reconstructive surgery does not mean “cosmetic surgery," which is surgery performed to alter or reshape
normal structures of the body in order to improve appearance.
Requests for reconstructive surgery may be denied, if the proposed procedure offers only a minimal
improvement in the appearance of the enrollee, in accordance with the standard of care as practiced by
physicians specializing in reconstructive surgery.
Reconstructive Surgery after Mastectomy
California Health and Safety Code 1367.6 requires treatment for breast cancer to cover prosthetic devices
or reconstructive surgery to restore and achieve symmetry for the patient incident to a mastectomy.
Coverage for prosthetic devices and reconstructive surgery shall be subject to the co-payment, or
deductible and coinsurance conditions, that are applicable to the mastectomy and all other terms and
conditions applicable to other benefits. "Mastectomy" means the removal of all or part of the breast for
medically necessary reasons, as determined by a licensed physician and surgeon.
Policy Limitations: Medicare and Medicaid
Policies specifically developed to assist Health Net in administering Medicare or Medicaid plan benefits and
determining coverage for a particular procedure, drug, service or supply for Medicare or Medicaid
members shall not be construed to apply to any other Health Net plans and members. The Policies shall
not be interpreted to limit the benefits afforded Medicare and Medicaid members by law and regulation.
87

National Medical Policy

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