National Medical Policy Subject:
Effective Date*: March 2007 Updated:
This National Medical Policy is subject to the terms in the IMPORTANT NOTICE
at the end of this document
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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
National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other
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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-Network-
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Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under “Reference/Website” and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance.
Hyperlinks to Contents Liver Transplantation 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)
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Alcoholic Cirrhosis Autoimmune Hepatitis in Adults Chronic Hepatitis C Autoimmune Hepatitis in Children Chronic Hepatitis B Congenital Erythropoietic Protoporphyria 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
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Investigational Procedures Codes Related to this Policy NOTE: 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 have been replaced by ICD-10 code sets.
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 Liver Transplantation Mar 16
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 (Deleted in 2016. to report, use 47399). 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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47146 47147 47399
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; 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) 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; 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 Unlisted procedure, liver
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
Liver Transplantation 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 Liver Transplantation Mar 16
deceased donor organ. It is clearly recognized, however, that their need is urgent. 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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Pre-Transplant Evaluation 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”.
Scientific Rationale Update – March 2016 The National Cancer Comprehensive Network (NCCN, Version 1.2016) for Hepatocellular Carcinoma notes:
Patients should be evaluated as to weather or not they are a candidate for transplant, either cadaveric or living donation. The UNOS/Milan Criteria under Surgical Assessment includes: Patient has a tumor < 5cm in diameter or 2-3tumors 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
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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 1. 2016 (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 6
The individual scores are summed and then grouped as a classification: 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. Anticipated length of life less than 18 months because of liver disease 2. Unacceptable quality of life because of liver disease 3. Growth failure or impairment due to liver disease
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4. Reversible neurodevelopmental impairment due to liver disease 5. 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 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)
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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. 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
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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).
Scientific Rationale 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 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
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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.
Ascites Position 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., 2 gram low sodium diet, aldosterone antagonists [e.g., spironolactone], loop diuretics [furosemide], repeat therapeutic large-volume paracenteses)
Scientific Rationale 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
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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.
Scientific Rationale 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.
Hepatorenal Syndrome 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., 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.
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1. 2. 3. 4. 5.
Oliguria (about two-thirds of patients have urine volume 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.
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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.
Scientific Rationale 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: 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.
Scientific Rationale 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.
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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
Referral for evaluation of liver transplantation is medically necessary when the 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.
Scientific Rationale Metabolic bone disease (hepatic osteodystrophy) in the form of osteoporosis (osteopenia) occurs in approximately 25% of patients with primary biliary cirrhosis (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
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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 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
Arterial pH < 7.30*
Arterial pH < 7.30*
INR > 3
INR > 4.5
Any rise in INR
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Creatinine > 200 μmol/l
Creatinine > 200 μmol/l
Creatinine > 250 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
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
Poison mushrooms (Amanita phalloides)
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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.
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.
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.
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
Coma with or without response to painful stimuli
According to the so-called West Haven classification system
Scientific Rationale 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 encephalopathy, 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.
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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). 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.
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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 < 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
Scientific Rationale 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.
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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 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
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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.
Scientific Rationale 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 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:
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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 Referral for evaluation of liver transplantation is medically necessary when the 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) 2. Serum AST and/or y-globulin less than absolute criteria 3. Interface hepatitis
Scientific Rationale 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;
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however, these few cases have not had an appreciable impact on overall patient survival after transplantation.
Autoimmune Hepatitis in Children Policy Statement Referral for evaluation of liver transplantation is medically necessary when the decompensated patient with auto-immune hepatitis is unable to undergo or be salvaged by medical therapy (corticosteroid, immunosuppressive therapy).
Scientific Rationale 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. 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.
Scientific Rationale 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
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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 (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 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
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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 Referral for evaluation of liver transplantation is medically necessary when the 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.
Scientific Rationale 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
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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 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
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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
Scientific Rationale 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. 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
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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 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.
Scientific Rationale 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 Liver Transplantation Mar 16
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 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.
Scientific Rationale 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
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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.
Scientific Rationale 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 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.
Scientific Rationale In familial intrahepatic cholestasis (Byler's disease), patients do not experience liver disease per se, but develop polyneuropathy and cardiac amyloidosis due to the Liver Transplantation Mar 16
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.
Scientific Rationale 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 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.
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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 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
Scientific Rationale 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)
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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 (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
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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 Referral for evaluation of liver transplantation is medically necessary in patients with end-stage hepatic disease, which has only been infrequently described in patients with sickle cell disease (SCD).
Scientific Rationale 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 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
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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: 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 (