Indications for Liver Transplantation

Acetaminophen-induced ALF

Nonacetaminophen ALF

Arterial pH <7.3 irrespective of grade of encephalopathy or

INR >6.5 (PT >100 s), irrespective of grade of encephalopathy

PT >100 s

Or any 3 of the following:

Serum creatinine >3.4 mg/dL

INR >3.5 (PT >50 s)

Stage 3 or 4 encephalopathy

Age <11 or >40 years
Serum bilirubin >18 mg/dL
Time from onset of jaundice to coma development >7 days
Drug toxicity, regardless of whether it was the cause of the acute liver failure

Patients with subacute failure have a poor outcome with almost universal mortality if not transplanted. Timely referral is important in these patients because in the absence of transplantation, death may occur from sepsis and cerebral edema. Other scoring systems for listing a patient for urgent liver transplantation include Clichy criteria for acute viral hepatitis and Wilson’s prognostic index/revised Wilson’s prognostic index (Table 6.2) [47].

Table 6.2
Prognostic index in fulminant Wilson’s hepatitis (WPI)







Serum bilirubin (mg/dL)






Serum aspartate transaminase (IU/L)






Prothrombin time prolongation (INR)






Patients with a WPI score ≥7 need urgent liver transplantation

6.1.1 Indications for Transplantation Acute Liver Failure

  • Hepatitis A, acetaminophen, autoimmune hepatitis

  • Hepatitis B

  • Hepatitis C, cryptogenic

  • Drugs, hepatitis D

  • Wilson’s disease, Budd-Chiari syndrome

  • Hepatic trauma

  • Fatty infiltration—acute fatty liver of pregnancy, Reye’s syndrome Cirrhosis from Chronic Liver Disease

  • Chronic hepatitis B virus infection

  • Chronic hepatitis C virus infection

  • Alcoholic liver disease

  • Cryptogenic liver disease

  • Autoimmune hepatitis

  • Nonalcoholic fatty liver disease Liver Tumors

  • Hepatocellular carcinoma

  • Carcinoid tumor

  • Islet cell tumor

  • Epithelioid hemangioendothelioma

  • Cholangiocarcinoma Metabolic Liver Disorders

  • Wilson’s disease

  • Hereditary hemochromatosis

  • Alpha 1-antitrypsin deficiency

  • Glycogen storage disease

  • Cystic fibrosis

  • Glycogen storage disease I and IV

  • Crigler-Najjar syndrome

  • Galactosemia

  • Type 1 hyperoxaluria

  • Familial homozygous hypercholesterolemia

  • Hemophilia A and B Liver Vascular Diseases

  • Budd-Chiari syndrome

  • Veno-occlusive disease Cholestatic Liver Diseases

  • Primary sclerosing cholangitis

  • Primary biliary cirrhosis

  • Secondary biliary cirrhosis

  • Alagille syndrome

  • Biliary atresia

  • Byler’s disease Miscellaneous

  • Caroli’s disease

  • Amyloidosis

  • Polycystic liver disease

  • Nodular regenerative hyperplasia

  • Severe graft-versus-host disease

  • Sarcoidosis

  • Variant syndromes requiring liver transplantation

  • Intractable ascites

  • Diuretic resistant, nonresponsive to TIPS, or TIPS contraindicated

  • Hepatopulmonary syndrome

  • Shunt fraction >8 %, pulmonary vascular dilatation

  • Chronic hepatic encephalopathy

  • Persistent and intractable pruritus

6.1.2 Possible Contraindications to Liver Transplantation

  • Age >65 years.

  • Severe malnutrition (BMI <19–20 at time of transplantation). Malnutrition may be reversible with vigorous therapy.

  • Other organ failure.

  • Previous upper abdominal surgery.

  • Poor functional status.

  • Poor medical compliance.

  • Severe cardiopulmonary disease.

  • Irreversible cerebral injury.

  • Sepsis or active infection.


  • Extrahepatic malignancy (the disease-free period >2–5 years, depending on malignancy type).

  • Extensive portal and mesenteric vein thromboses.

  • Active alcohol or drug usage (abstinent <3–6 months).

  • Psychosocial issues—inability to understand the procedure.

  • Severe psychological disorders which will prevent medical compliance.

  • Lack of social support.

6.2 Viral Chronic Hepatitis

Ranka Vukotic and Pietro Andreone4

Organisation Name, City, Country


Chronic hepatitis B virus (HBV)-related and hepatitis C virus (HCV)-related end-stage liver diseases lead to liver transplantation (LT). Nowadays, the availability of hepatitis B virus immunoglobulin (HBIG) and nucleos(t)ide analogues (NUCs) has allowed successful outcomes of most LTs for HBV-related end-stage liver disease. As far as HCV is concerned, post-LT recurrence is practically certain and has represented a great challenge in the IFN-based treatment era, which will probably soon be replaced by IFN-sparing regimens, radically changing the management and the long-term outcome of LT for HCV-related disease.

6.2.1 HBV and Liver Transplantation

In the last few years, in Western countries, the application of efficacious antiviral therapy has changed both the rate of transplants and the main indication for HBV-related LT which has become hepatocellular carcinoma rather than a very end-stage liver disease. Moreover, these therapeutic opportunities have allowed a significantly longer and better survival of the patients transplanted for HBV, since NUCs combined with HBIG protect the graft almost universally from HBV recurrence [8, 9]. At present, the 5-year survival rates in patients undergoing LT for HBV-related cirrhosis are around 80 %.

However, the patients transplanted for HBV are regularly monitored for HBV DNA and HBsAg in order to rapidly identify a possible, although extremely rare, recurrent HBV infection. If this occurs, liver histology is indicated to assess and monitor the presence and the stage of fibrosis. Currently, a severe fibrosing cholestatic onset is almost anecdotic and can be revealed by poorly expressed inflammatory features, high intrahepatic HBV DNA, presence of ballooning, and cholestasis [10]. A high level of HBV DNA at the time of LT is the most important index of the risk of hepatitis B recurrence [11], so the achievement of HBV DNA suppression is the goal in end-stage patients awaiting LT.

Lamivudine was the first nucleoside analogue approved for hepatitis B, offering epochal results in obtaining suppression of HBV viremia and ameliorating liver function, but hampered by a high resistance rate due to development of mutations in the YMDD locus of the polymerase gene (10–20 % at 1 year, around 60 % at 4 years). Adefovir showed satisfactory results in treating patients with lamivudine resistance but presented high rates of long-term treatment-related resistance and an important nephrotoxicity issue [12]. Fortunately, new oral antiviral agents (tenofovir and entecavir) were subsequently developed, showing greater efficacy, in terms of HBV DNA clearance and liver function improvement, and guaranteeing a higher resistance barrier [13, 14]. Of note, these agents require strict monitoring of renal function to exclude, as early as possible, any tubular injury which can provoke severe hypophosphoremia and/or lactic acidosis [15]. Post-LT Hepatitis B Prophylaxis

HBIG is burdened by its high costs and a suboptimal effectiveness in monotherapy. It has been demonstrated that beginning parenteral HBIG immediately after LT leads to a significant reduction in graft infection and an increase in 3-year survival [16]. Nevertheless, despite several solid immunological-acting pathways, HBIG should not be used in monotherapy since high rates of post-LT HBV recurrence have been reported in LT recipients treated with this strategy. On the other hand, lamivudine post-LT monotherapy leads to high rates of HBV recurrence, while the combination of HBIG and lamivudine has been seen to be an effective recurrence prophylaxis [17, 18]. Those patients who develop resistance to lamivudine during combined HBIG and lamivudine prophylaxis are commonly treated with tenofovir monotherapy rather than adefovir add-on, especially in view of the cost-effectiveness and safety issues. In short, if appropriately combined with available NUCs, HBIG use can be optimized in terms of costs and feasibility by administering lower doses and preferring intramuscular injections to intravenous regimens. As regards dose minimization or even prophylactic treatment withdrawal, this was prospectively explored in a study in which a gradual HBIG withdrawal was followed by antiviral discontinuation in patients not showing covalently closed circular HBV DNA in liver biopsy. At follow-up, more than 80 % of patients did not present HBV recurrence [19]. Recently, the efficacy of monotherapy with entecavir was examined in 80 subjects who underwent LT for HBV, showing cumulative rates of HBsAg clearance of 91 % after 2 years and almost 100 % of HBV DNA undetectable patients [20]. This approach might be taken into account in subjects who at the time of LT are HBeAg negative/HBV DNA undetectable. The vaccination strategy should be adopted since so far the studies including the use of adjuvanted vaccines are not encouraging [21]. Finally, the complete withdrawal of post-LT HBV prophylaxis in selected low-risk populations can be hypothesized, but is still debated and insufficiently explored. Post-LT Hepatitis B Recurrence

A real de novo HBV infection post-LT is an extremely rare event. On the other hand, suboptimal adherence to the pharmacological prophylaxis and resistance phenomena might lead to HBsAg reappearance after an initial fade-out. If serum HBV DNA also becomes detectable, the antiviral therapy should be promptly started so as to avoid chronic liver injury development and progression, to prevent graft loss, and to reduce complication onset and mortality. The possible strategies should be tailored according to the virological and clinical characteristics of HBV recurrence. In particular, entecavir or tenofovir is used as an effective option if HBIG resistance occurs, taking into consideration that lamivudine resistance should be treated with tenofovir rather than entecavir, which might develop resistance as well. On the other hand, starting tenofovir should be evaluated carefully in patients with renal failure, especially considering proteinuria and previous tubular damage. When necessary, although there are no extensive data to support this approach, the combination of these two analogues can be considered if complex resistance features emerge [22]. De Novo HBV Infection Prophylaxis in Recipients of Anti-HBc-Positive Donor Livers

Over the years, the expansion of the donor pool has been proposed to allow greater LT access, and this was extended to HBsAg-negative/hepatitis B core antigen-antibody (anti-HBc)-positive donors, ideally allocating these organs to already HBsAg-positive liver recipients, previously undergoing immunoprophylactic HBV regimen [23]. In fact, an extensive review of the studies using livers from anti-HBc-positive donors in HBsAg-negative recipients revealed the probability of de novo HBV infection in recipients who did not receive immunoprophylaxis in anti-HBc-/anti-HBs-patients, of 15 % in anti-HBs+ and/or anti-HBc+, and of less than 2 % in anti-HBc–/anti-HBs+ recipients. In anti-HBc+ graft recipients, HBIG is not necessary, while lamivudine monotherapy seems to ensure satisfactory low rates of graft infection (<3 %).

In conclusion, the combination of antiviral drugs and low-dose HBIG can effectively prevent HBV recurrence in almost all LT recipients. HBIG discontinuation can be taken into consideration, maintaining the NUCs in those patients who do not have apparent risk factors for recurrence and who had low or undetectable HBV DNA levels before LT. These prophylactic and therapeutic approaches have drastically modified the natural history and the prognosis of both pre-LT and post-LT HBV-related settings. HCV and Liver Transplantation

Hepatitis C virus (HCV) infection can lead to cirrhosis and its complications and represents the main indication for LT, at least in the Western countries [24]. Unfortunately, in HCV RNA-positive patients, the recurrence of HCV infection after LT is universal [25, 26] and may lead to cirrhosis in approximately 30 % of recipients after 5 years [27]. The severity of the infection is unpredictable and often associated with additional clinical and histological features (e.g., cholestasis, de novo autoimmunity, coinfections), determining a more rapid progression versus advanced illness and possible graft loss. LT patients who undergo antiviral therapy have been shown to have a longer survival, better histological and hemodynamic long-term features, and a lower rate of decompensation [2831], especially when a sustained virological response (SVR) is achieved. However, dual antiviral therapy with pegylated interferon (PegIFN) and ribavirin (RBV) seems to be poorly effective in this population [32]. Direct-acting antiviral agents (DAA) such as protease inhibitors (PI) have been seen to ameliorate the rate of SVR in pre-LT genotype 1 patients, both treatment naive and experienced [33, 34]. Recently, several experiences have been reported regarding the use of the new antiviral agents in LT recipients, focusing not only on the likelihood of achieving higher SVR rates with the new antiviral regimens but also on the complex issue of immunosuppressant drug handling, drug interactions, and increase of renal and hematopoietic toxicity [3538]. These data confirmed that, also in post-LT hepatitis C settings, similar SVR rates to those of non-LT patients can be achieved by triple regimens with PI, peginterferon, and ribavirin. Moreover, satisfactory SVR rates have been obtained despite several adverse events such as anemia, neutropenia, rash, and renal failure. The worldwide growing experience with the use of telaprevir and boceprevir in LT recipients with HCV recurrence has significantly helped clinicians in the use of new DAAs, especially in awareness on the drug-drug interaction issue and the possible induction of plasma cell hepatitis during triple IFN-based regimens, sometimes with acute rejection-like onset resulting in graft loss or in fatal outcome [3941]. On the other hand, it is possible that the high costs of oncoming potent IFN-free regimens will be prohibitive for many developing countries which will continue to rely on PIs such as boceprevir and telaprevir [42]. Another issue which is still controversial is when to start treating the HCV recurrence [43]. The preemptive antiviral therapy after up to 6 months should be taken into consideration when rapidly progressive features emerge. The decision to treat post-LT HCV recurrence is often taken according to the histological characteristics (presence of fibrosis) at the 1-year liver biopsy, but at the same time, the individual patient’s predictive factors of response should be carefully evaluated. The positive predictive characteristics associated with SVR are genotypes 2 or 3, mild fibrosis, young donor age, low baseline level of viremia, early viral clearance, and both donor and recipient CC polymorphism of IL28B [4447]. The immunosuppressive regimen with cyclosporin has also been seen to be associated with SVR [48], but in triple regimens, especially those containing telaprevir, these data should be reviewed.

Undoubtedly, the oncoming era of HCV treatment has begun with the approval of several DAAs with different viral targets [49]. These drugs will likely very soon guarantee simplified treatment schedules and high tolerability and might avoid the use of interferon. Sofosbuvir is a potent all-oral-dosing nucleotide analogue inhibitor of HCV polymerase activity, with excellent virological response rates obtained in randomized controlled studies employing combination schedules with RBV, with or without PegIFN, in both naive and experienced HCV patients [50]. Currently, sofosbuvir is becoming more and more available worldwide but, besides the cost-related limitations, it should be noted that in LT settings, the experience is still limited. The preliminary data of a compassionate US program, utilizing sofosbuvir in LT recipients with a severe recurrence of HCV infection, were recently presented [51, 52], showing good clinical outcomes, a global clinical and MELD improvement; however, the relapse rate was not negligible, indicating that the treatment regimen should be maximally optimized in this seriously ill LT population, probably by combining sofosbuvir with another potent DAA. No drug-drug interactions with calcineurin inhibitors are expected during SOF administration [53, 54], but in a single center experience, awareness of significant tacrolimus/cyclosporine trough level reduction when sofosbuvir is administered in LT recipients has already emerged [55].

Indeed, the future perspectives of HCV-related viral hepatitis in pre-LT and post-LT settings will soon drastically change, thanks to the rich pipeline of new antiviral agents. However, some issues not present until now will affect real clinical practice and will require expert dedication in this complex setting. Among these, in addition to the time to treat and the duration of treatment, the most important are cost-effectiveness, choice of one DAA rather than another, drug-drug interactions, patients’ eligibility for treatment, and viral resistance management. These features underline the importance of continuing to identify the predictive factors of good outcomes of antiviral treatment and of the global clinical outcomes in HCV-related viral hepatitis pre- and post-LT.

6.3 Liver Tumors

6.3.1 Hepatocellular Carcinoma

Fabio Piscaglia, Alessandro Cucchetti5, Anna Pecorelli5 and Luigi Bolondi5

Organisation Name, City, Country


Liver cancer is the fifth most common malignancy among men and the ninth among women. In the last few years, it has risen from the third to the second cause of death from cancer, accounting for nearly 746,000 deaths in 2012, with an overall ratio of mortality to incidence of 0.95 [56]. The most common primary liver cancer is hepatocellular carcinoma (HCC), which occurs in the setting of liver cirrhosis in up to 90 % of cases [57].

The primary risk factor for HCC is still represented by chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection [58]. However, the advent of new antiviral drugs, the vaccination for HBV, and, on the other hand, the increasing incidence of obesity and metabolic syndrome are expected to reduce the burden of HCC on chronic viral liver disease and to increase the appearance of HCC on other causes of liver cirrhosis, such as nonalcoholic fatty liver disease (NAFLD) [58, 59]. Liver transplantation is the only curative treatment potentially able to eradicate both the tumor and the underlying liver disease. According to the European Liver Transplant Registry, 14 % of liver transplantations in Europe are performed in patients with HCC [60]. The first experiences of liver transplantation for HCC addressed patients with advanced HCC, producing poor outcomes as a consequence of extremely high posttransplant tumor recurrence rates. These results together with the shortage of available grafts led many transplant centers to select patients with defined criteria more accurately in order to guarantee better survival outcome.

In 1996, Mazzaferro and colleagues introduced the so-called Milan criteria. According to these criteria, initially documented by authors on pathological findings, patients with a single nodule <5 cm or up to three nodules <3 cm, with neither extrahepatic spread nor macrovascular invasion, could achieve a 5-year survival rate of 70 %, comparable to patients transplanted for nonmalignant liver disease [61], with tumor recurrence in less than 10 %. These criteria are still currently used in the Barcelona Clinic Liver Cancer (BCLC) HCC staging system, adopted in the majority of Western countries. This staging system stratifies patients according to liver function, tumor burden, and performance status, attempting to define, for each stage, the most effective treatment to adopt [62]. Patients within the Milan criteria correspond to the early HCC tumor stage.

Due to the excellent results achieved with use of the Milan criteria based on radiologic assessment, but also the clinical practice evidence of good outcome for some selected patients transplanted despite being beyond the Milan criteria, several transplant centers tried to expand the boundaries of liver transplantation for HCC in the last decade. In 2001, the University of California San Francisco (UCSF) group produced a prospective study to identify expanded criteria for liver transplantation for HCC. The outcome of patients inside UCSF criteria (one tumor ≤6.5 cm, or up to three nodules ≤4.5 cm, and total tumor diameter <8 cm) was comparable to that observed in other retrospective studies [63]. In 2009, a multicenter international retrospective study coordinated by Mazzaferro showed comparable 5-year survival rates between patients within Milan criteria versus patients outside Milan criteria but fitting the so-called up-to-seven criteria (UtS) on pathology and without microvascular invasion. According to UtS, the sum of the number of tumors and the diameter of the largest nodule should not exceed seven, with no macrovascular invasion or extrahepatic spread [9] to achieve acceptable results in terms of recurrence rates and overall survival. Another new tool, the Metroticket calculator, has been created. This tool predicts the 5-year survival of patients on the basis of tumor burden according to the number and size of nodules and presence or absence of vascular invasion [64]. The major criticism regarding this tool is that its most important variable, namely, microvascular invasion, can be assessed only in the pathological specimen, thus once the liver transplant has already been performed.

An alternative strategy to simply expand the listing criteria based on tumor burden is to assess the tumor biology, and hence the risk of recurrence, on the basis of tumor response to hepatic resection or locoregional treatments, whose aim is to bring selected intermediate (BCLC-B) stage HCCs back to the early (BCLC-A) tumor stage. Good results have recently been achieved by using this downstaging procedure. Up to 2014, only two perspectives studies have been carried out, one of which was conducted at the University of Bologna; this latter experience obtained comparable survivals between transplanted patients successfully treated with downstaging and patients who always met the Milan criteria [65]. In this study, criteria for downstaging were identified as a single nodule ≤6 cm, or two nodules ≤5 cm, or less than six nodules ≤4 cm, with the sum of diameters ≤12 cm without macrovascular invasion or extrahepatic spread. However, clear limits for size and number of lesions as eligibility criteria for starting the downstaging procedure are still lacking, with the exception of extrahepatic spread and macrovascular invasion. After a successful downstage, a minimum period of 3 months is recommended before considering liver transplantation [66]. An alternative option to select out patients with expected worse survival and high recurrence rate is to use tumor grading. This approach excludes patients with poor tumor differentiation according to the Edmondson and Steiner criteria (G4) but requires aggressive and numerous tumor biopsies and has never been validated outside the proposing center [67].

The imbalance between demand and donor organ supply still remains the main issue in liver transplantation. Since 2001, patients on the waiting list are ranked on the basis of the Model for End-Stage Liver Disease (MELD) score. This score is based on serum bilirubin, creatinine, and international normalized ratio and indicates the three-month mortality rate in cirrhotic patients [68]. As the neoplastic risk is not considered in the MELD score, patients with HCC are given additional MELD exception points, which increase over time. According to the 2013 United Network for Organ Sharing (UNOS) allocation system, patients with a single HCC <2 cm do not receive additional points, while patients with a single HCC of 2–5 cm or with three nodules each <3 cm receive 22 points in addition to the original MELD score with a 10 % point increase for every 3 months on the waiting list [69]. Despite additional points, the dropout rate from the waiting list due to tumor progression is common, being approximately 10–20 % per year. A regular follow-up with an imaging technique (CT or MRI) should therefore be performed every 3 months. An indirect measure of the tumor aggressiveness can be used to determine priority for transplantation. To date, there is growing evidence that cases with complete radiological response to pretransplant surgical and nonsurgical procedures will experience a lower dropout rate (tumor growth beyond transplantability criteria), and it is possible that in such cases, priority can be safely reduced, giving the remaining patients on the waiting list more chances of a transplant [70].

Locoregional treatments are commonly performed on patients awaiting liver transplantation as “bridge therapy” to prevent dropout. Currently, EASL-EORTC guidelines suggest bridge therapy if the waiting list time exceeds 6 months; however, there are no recommendations about the type of treatment [71]. The choice should be taken by a multidisciplinary team and tailored on the basis of tumor burden, liver function, and patient characteristics. In most countries, the expected waiting time exceeds 6 months for HCC, and all patients are aggressively treated for HCC, liver function permitting, in the prospect of transplantation, to prevent dropouts. Transcatheter arterial chemoembolization (TACE) is the most common bridge therapy, usually performed in patients with a single nodule >3 cm or multifocal HCCs. In the presence of decompensate liver function, TACE is contraindicated, and percutaneous ablative therapies, such as radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI), are preferred. However, RFA or PEI efficacy is limited to small HCCs (<2–3 cm). Liver resection should be the first-line therapy in the case of resectable HCCs in a setting of preserved liver function, normal portal pressure, and normal bilirubin. In the case of postoperative liver failure or HCC recurrence, liver transplantation can be reconsidered as “salvage transplantation,” with outcomes comparable to primary liver transplantation [72]. However, clinically significant portal hypertension should not be considered an absolute contraindication but taken into account in the final decision, which has to consider liver function, usually in terms also of MELD score, and the extent of resection [73].

Another strategy to overcome deceased organ shortage and long waiting times is to use grafts from healthy living donors (LDLT). Although survival rates between LDLT and DDLT (deceased donor liver transplantation) are comparable, a high recurrence rate has been observed in LDLT. This could be due to the different waiting time, inherently longer in patients awaiting a DDLT, during which a tumor with a more aggressive behavior can be detected. Some authors suggest a 3-month period of observation to avoid transplantation of a more aggressive tumor [74, 75]. According to EASL guidelines, LDLT is an alternative option in patients with a waiting list time exceeding 6–7 months [68].

After liver transplantation, the main complication is the risk of HCC recurrence, which affects 8–20 % of the recipients. Recurrence is associated with poor outcome and a median survival less than 1 year after the diagnosis [74]. According to recent recommendations for liver transplantation for hepatocellular carcinoma, patients should be followed up with CT or MRI imaging and alpha-fetoprotein every 6–12 months after LT. HCC recurrence could be treated by surgery, locoregional therapy, and also systemic therapy, while retransplantation is not appropriate. As regards immunosuppression, mTOR inhibitors, in particular sirolimus, should be used due to their antineoplastic properties [76].

6.4 Cholestatic and Autoimmune Disease

Maria Cristina Morelli

UO Internal Medicine for the Treatment of Severe Organ Insufficiency, Organ Insufficiency and Transplantation, Bologna, Italy


6.4.1 Autoimmune Liver Diseases

The group of cholestatic and autoimmune disease usually includes autoimmune hepatitis (AH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Even if these diseases are infrequent, they represent a considerable proportion of patients in need of transplantation. The estimated prevalence of AH in the general population is 10–20/100,000, of PBC it is 40–60/100,000, and of PSC it is 10–30/100,000. The difficulty to reach a diagnosis and the need to exclude other causes of liver disease, such as hepatotropic infection but also systemic inflammation or drug-induced toxicity, are common in the context of autoimmune disease. Autoimmune liver disease may also overlap. The concomitant presence of PBC and AH features is a frequent finding, as is, although to a lesser extent, the overlap between PSC and AH. Another important issue is that overlap features may also change over time, and the patient may acquire other features many years after the first diagnosis; this is a very important aspect to consider as regards therapeutic implications. To date, there is no definitive treatments that can cure autoimmune disease; as a consequence, a considerable proportion of patients progressively develops liver failure requiring liver transplantation. In addition, all three autoimmune diseases can recur after liver transplantation and represent a greater risk of organ rejection.

6.4.2 Primary Biliary Cirrhosis (PBC)

Primary biliary cirrhosis is a chronic cholestatic liver disease characterized by immune-mediated destruction of small and medium intrahepatic bile ducts leading to cholestasis and cirrhosis. Primary biliary cirrhosis affects women in 90–95 % of cases and is often associated with other autoimmune diseases such as rheumatoid arthritis, scleroderma, and Sjogren’s syndrome. A recent epidemiologic study reported that the lowest and highest incidences for PBC were both found in Newcastle-upon-Tyne in 1997 with 0.9 per 100,000 inhabitants per year in 1977 and 5.8 per 100,000 inhabitants per year in 1994, respectively. The highest prevalence for PBC is reported in a North American study published in 1995 with 40.2 per 100,000 age- and sex-matched inhabitants. Looking at the most recent epidemiological studies, the mean proportion of female patients was 92 % (76–100 %). Increasing trends of both incidence and prevalence of the disease are highlighted in studies from the United Kingdom, the United States, and Australia, but it is not clear whether the increase is true or just represents earlier recognition of the disease due to greater awareness and improved diagnostic workup [77].

Clinical presentation is often nonspecific, and symptoms include signs of cholestasis such as fatigue, skin pigmentation, jaundice, itching skin, and weight loss. Fatigue, the main symptom in patients with PBC, is usually characterized as excessive daytime somnolence and can impair quality of life. In a recent study, fatigue in woman with PBC was found to be independently associated with an increased risk of cardiac death [78]. Pruritus is reported by 20–70 % of patients and, in some cases, could be very disabling and, when intractable, may become an indication for liver transplantation. Diagnosis is based on clinical and biochemical features of cholestasis, highly specific antimitochondrial antibodies (AMAs) detection, and high IgM levels. A reduction in bone density is common in patients with PBC, with features of osteopenia and osteoporosis. Most patients with PBC have elevations of alkaline phosphatase, mild elevations of aminotransferases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) activity, and increased levels of immunoglobulin M; serum cholesterol levels are also often elevated. A rise in serum bilirubin and gamma globulins, with a fall in serum albumin and platelet count, is the early indicator of the development of cirrhosis and portal hypertension [79, 80]. Antimitochondrial antibodies in serum are highly sensitive and specific for PBC: their presence is detectable in nearly 95 % of PBC patients. Follow-up data from AMA-positive individuals without signs of liver disease suggest that autoantibodies arise several years before the onset of symptoms and have a high predictive value. Histology is characterized by a lymphocytic cholangitis and classically divided into four stages. Stage I is characterized by normal-sized triads with portal inflammation and subtle bile duct damage; granulomas are often detected. Stage II is characterized by the increase of periportal inflammation extending into the hepatic parenchyma and periportal fibrosis. Stage III is characterized by a distortion of the hepatic architecture with numerous fibrous septa. Stage IV is defined by a cirrhotic evolution. Liver biopsy is not always needed in patients with AMA positivity and typical biochemical profile since the additional information obtainable by histology is quite small. Histology is otherwise useful in patients who have high levels of antinuclear antibodies in order to assess the presence of an overlap syndrome that will require substantial modification of the therapeutic approach.

PBC is a chronic and a progressive disease, but the clinical features may vary greatly between patients. Patients can remain symptom-free for years with a low progressive disease or, conversely, can progress rapidly to a symptomatic and evolving disease. Presence of symptoms at diagnosis is an important determinant of disease progression and survival [81]. Many therapeutic agents have been proposed for primary biliary cirrhosis on the basis of different views of disease pathogenesis. The only currently established treatment for primary biliary cirrhosis is ursodeoxycholic acid (UDCA) 13–15 mg/kg a day, which can be subdivided into two or three doses [82]. A meta-analysis of randomized placebo-controlled studies of UDCA concluded that about 20 % of patients treated with UDCA will have no histological progression over 4 years, and some will have no progression over a decade or longer [83]. This agent has the potential to reduce liver damage and, consequently, to prevent the development of portal hypertension and the need for transplantation. Survival free from liver transplantation seems to be improved in patients treated with UDCA compared with patients originally assigned to placebo, in particular in medium- and high-risk groups of patients (serum bilirubin level, 1.4–3.5 or >3.5 mg/dL and histological stage IV subgroup) [84].

Liver transplantation is a definite therapeutic option in patients with PBC not only when patients decompensate as a cause of cirrhosis development but also in other condition such as treatment-resistant itching. Liver transplantation has been proved to improve fatigue and pruritus; the bone disease can worsen initially but improves in the subsequent periods. Surprisingly, the increase trend of incidence and prevalence of PBC is in contrast with the decrease of liver transplantation burden for this indication, despite an increase in total liver transplants [85]. The explanation for this trend is not clear but may be associated with a more efficacious therapy or a changing disease phenotype. Primary biliary cirrhosis after transplant has been described in 15–30 % of recipients, but only a low percentage evolved into graft failure. The Birmingham study reported a 2–3 % rate of graft loss for PBC recurrence over 15 years. Autoantibodies AMA may persist after liver transplantation but do not seem to be associated with recurrence of the disease.

6.4.3 Primary Sclerosing Cholangitis (PSC)

Primary sclerosing cholangitis is characterized by progressive inflammation of the intra- and extrahepatic bile ducts with progressive stenosis and obliteration of ducts leading to the development of secondary biliary cirrhosis, portal hypertension, and, finally, toward liver failure. It is characterized by a strong association (75–80 % of cases) with inflammatory bowel disease (IDB), mainly ulcerative colitis. Immunological mechanisms are involved in the pathogenesis of this disease, and consistent data show that PSC is an immune-mediated inflammatory disease rather than an autoimmune disease by itself. In favor of this hypothesis is the male prevalence, the failure to identify specific autoantigens, and lack of response to immunosuppressive therapy. It is currently accepted that, in an immunologically predisposed patient, antigens derived from bacteria may migrate into the portal circulation due to increased permeability of the colonic wall. Activation of Kupffer cells leads to cytokine and chemokine release with recall of inflammatory infiltrate (granulocytes, lymphocytes, macrophages, and fibroblasts) into the portal and peri-biliary space, resulting in fibrosis and, finally, in secondary biliary cirrhosis.

Primary sclerosing cholangitis is a relatively rare disease. Epidemiological studies published so far are few and are mainly derived from tertiary hospitals resulting from IBD prevalence rates. The first epidemiological study in the general population was conducted in Norway and published in 1998 [86]. This study reported an incidence of 1.3/100,000/year and a prevalence of 8.7/100,000. In 71 % of cases, there was an association with IBD; the male/female ratio was 3.3/1, and the mean age at the onset of the disease was 40 years [10]. At diagnosis, the majority of PSC patients are asymptomatic, and studies published in recent years reveal an increasing proportion of cases diagnosed in the asymptomatic phase. Most asymptomatic patients develop symptoms after 5–7 years. Symptoms are frequently nonspecific including fatigue, jaundice, pruritus, and weight loss; fat-soluble vitamin deficiency, steatorrhea, and osteoporosis are rarer. Bacterial cholangitis and gallstones are specific symptoms related to development of biliary stenosis. Finally, patients can develop liver cirrhosis with hepatic failure; in addition, PSC has to be considered a preneoplastic condition with a high risk of cholangiocarcinoma development (100 times higher than the general population) and a higher risk of colorectal cancer in patients with coexistent ulcerative colitis than in patients with isolated ulcerative colitis. Thus, these aspects have to be considered from a transplantation perspective. The cholangiographic features of alternate extra- and intrahepatic bile duct stenosis and dilatation are the gold standard for the diagnosis of PSC. Because of its noninvasive nature, magnetic resonance imaging (MRI) may have advantages over invasive cholangiography when diagnosis is the major goal of the procedure, showing in recent studies 88 % sensitivity and 99 % specificity. In the presence of specific radiological features, liver biopsy is not considered essential because of the low diagnostic accuracy; furthermore, the typical histological lesions such as periductal “onion skin” fibrosis are detectable only in 13 % of cases. Histological examination is useful in suspected overlap syndrome and in the diagnosis of PSC involving only small ducts.

Only gold members can continue reading. Log In or Register to continue

Oct 6, 2016 | Posted by in GASTROENTEROLOGY | Comments Off on Indications for Liver Transplantation
Premium Wordpress Themes by UFO Themes