Liver transplantation and heart transplantation

Liver transplantation and heart transplantationThe single most effective therapy for end stage liver failure (ESLF) is liver transplantation (LT).70.000 LT have been performed in 137 centres around Europe.

UK: currently 680 liver transplants are performed yearly.

More than 6000 patients have been transplanted

RO: about 30-50-60 LT/year

Unfortunately the supply cannot meet demand

Indications for LT - adultsCommon:

1. Alcoholic liver disease (ALD)

2. Cryptogenic cirrhosis

3. Primary biliary cirrhosis

4. Primary sclerosing cholangitis (PSC)

5. Hepatitis (B, C, non-A, non-B)

6. Hepatocellular carcinoma

7. Autoimmune hepatitis

Rare:

1. Haemochromathosis

2. Wilsons disease

3. 1-antitrypsin deficiency

4. Budd-Chiari syndrome

5. Polycystic disease

6. Hyperoxaluria, familial hypercholesterolaemia

7. Porphyrias, amyloidosis, neuroendocrine tumours (e.g. carcinoid)

Indications for LT in children Biliary atresia

Familial cholestasis syndromes

Metabolic disorders:

Cystic fibrosis

1-antitrypsin deficiency

Crigler-Najjar type 1

Wilsons disease

Unresectable tumours (e.g. hepatoblastomas)

Acute liver failure viral, drugs (e.g. paracetamol toxicity), autoimmune

Contraindications to liver transplantationAbsolute:

1. Infection

2. Malignancy outside the hepatobiliary system

3. Secondary hepatic malignancy

4. Active drug or alcohol abuse

5. Advanced cardiopulmonary disease

Relative:

1. Age over 65 years

2. Portal vein thrombosis

3. Renal failure not associated with liver disease

4. Intrahepatic sepsis

5. HIV

Emmergencies for LT Paracetamol poisoning

Diuretic-resistant ascites

Hepatopulmonary syndromes

Chronic hepatic encephalopathy

Persistent and intractable pruritus

Familial amyloidosis

Primary hyperlipidaemias

Polycystic liver disease

Work-up for liver transplantation Assessment for conventional deceased donor

1. Blood group

2. Conventional liver screen/liver biopsy for steatosis

3. Viral screening

4. HLA typing: HLA-A, B, DRB1

5. Tumor markers: AFP, CA 19-9, CEA, CA 125,

CA 15-3, 2-microglobulin, total and free PSA

Assessment for liver donation

1. Blood group

2. Conventional liver screen/liver biopsy for steatosis

3. Viral screening

4. HLA typing: HLA-A, B, DRB1

5. Tumor markers: AFP, CA 19-9, CEA, CA 125, CA 15-3, 2-microglobulin, total and free PSA

6. To exclude occult thromboembolic disorders: abnormalities for PT, protein C, protein S, antithrombine III, factor V Leiden, factor VIII, cardiolipin , antiphospholipinImmunology of liver transplantation in the recipient AB0 compatibility

Viral screening

Child Pugh score: A, B, C

MELD score (Model for End-stage Liver Disease)

3.8 x loge (bilirubin mg/dL) + 11.2 x loge (INR) + 9.6 loge (creatinine mg/dL) + 6,4 (aetiology: 0 if cholestatic or alcoholic, 1 otherwise)Immunology of liver transplantation in the recipient Histocompatibility testing plays little role in selecting an individual recipient for LT for a particular donor

Class I HLA matching may significantly improve patient graft survival.

In the liver tissue HLA class I antigens are to be found only on the biliar epithelium, but not on the hepatocytes

HLA class II antigens are present in Kupffer cells and endotelial cells.

Cytotoxic antibodies

Crossmatch a positive crossmatch is associated with a higher likelihood of early rejection episodes.

Liver transplantation for hepatitis C virus infection Hepatitis C virus (HCV) infection causes approximately 40 percent of all chronic liver disease in the United States, and HCV-associated cirrhosis is the most common indication for orthotopic liver transplantation (OLT) among adults . HCV infection remains a problem after transplantation, and recurrent hepatic infection is the leading cause of graft failure.

The major issues related to HCV following liver transplantation will be reviewed here. Similar problems arise in patients with HCV who undergo other forms of organ transplantation.

The natural history and treatment of HCV, as well as the selection of patients for liver transplantation, is discussed elsewhere.

EPIDEMIOLOGY Recurrence of hepatitis C virus (HCV) following orthotopic liver transplantation (OLT) occurs in more than 95 percent of patients. Nucleotide sequence studies of HCV demonstrate that the disease following OLT results from the same viral strain present before OLT. Virologic reinfection at the time of transplantation is not surprising since almost all patients are viremic at this time . Reinfection occurs during reperfusion of the allograft in the operating room, and viral titers reach pretransplant levels within 72 hours. Furthermore, peripheral monocytes may also harbor virus and act as a source for reinfection of the donor liver. De novo infection in previously HCV-negative patients can result from transfusion of blood products during OLT, but has become rare since 1992 due to blood product screening.

PATHOGENESIS Variables that influence the progression of recurrent hepatitis C virus (HCV) following orthotopic liver transplantation (OLT) are incompletely understood, but donor characteristics (donor type, age), viral characteristics (genotype, viral load), the inflammatory grade of the explanted liver, and the patient's immune status and immunosuppressive regimen may be important.

Overview of dermatologic problems following liver transplantation Liver transplantation recipients, like other solid organ transplantation recipients, have an increased risk of dermatologic problems due to their long-term immunosuppression and benefit from pre-and post-transplantation screenings, and management by a dermatologist and dermatologic care should be integrated into the comprehensive, multidisciplinary care of liver transplantation recipient. Cutaneous findings include aesthetic alterations, infections, precancerous lesions, and malignancies. The severity of skin alterations ranges from benign, unpleasant changes to life-threatening conditions . In addition to skin cancer diagnosis and management, visits with a dermatologist serve to educate and improve the patient's sun-protection behavior.

Among all solid organ transplantations, liver transplantation requires the least amount of immunosuppression, sometimes even permitting its complete cessation. As a result, patients who have undergone liver transplantation tend to have fewer dermatologic complications compared with other solid organ transplantation recipients. However, due to the large volume of the liver, patients undergoing liver transplantation receive more donor lymphocytes than kidney, heart, or lung transplantation recipients. Because of the immunosuppression, the transplanted lymphocytes proliferate and rarely trigger graft-versus-host-disease .

This topic will provide an overview of dermatologic disorders that may be seen following liver transplantation. A detailed discussion of skin cancer following solid organ transplantation and the general management of patients following liver transplantation are discussed separately.

EFFECT OF TRANSPLANTATION ON PREEXISTING DERMATOLOGIC DISORDERS Patients undergoing liver transplantation may have preexisting dermatologic disorders that are subsequently affected by transplantation. In many cases, the disorders improve either as a result of removal of the diseased liver or because of the immunosuppression patients receive.

Dermatologic manifestations of liver diseaseIn patients with dermatologic lesions related to cirrhosis or associated with specific forms of liver disease, transplantation often leads to improvement in the dermatologic findings .

Heart transplantation Indications adults

1. Coronary-related heart failure

2. Cardiomyopathies : valvular, mixt diagnoses, adult congenital, retransplantation

Indications paediatrics ( 25% rejection

HLA typing for A, B, DRB1

Crossmatch

Chronic transplant dysfunction in transplanted hearts remains the most common cause of graft loss after the first year postTx.

Acute cardiac allograft rejectionINCIDENCE AND OUTCOMES Acute rejection is a common problem after heart transplantation, particularly early after transplantation. Most cases are due to cellular rejection. Antibody-mediated (noncellular, vascular, humoral) rejection is a less well understood and less easily diagnosed process, but potentially produces morbidity .

The 2009 report from the Registry of the International Society for Heart and Lung Transplantation (ISHLT) of patients with one-year follow-up between July 2004 and July 2008 found that 21 to 30 percent were treated for rejection during the first year after transplantation. This represents an underestimate for overall rejection, since the Registry does not collect data on mild rejection episodes (grade 1 R) or on antibody-mediated rejection.

In the ISHLT report, among deaths occurring between January 1992 and June 2008, acute rejection accounted for 6 percent of deaths in the first 30 days, 12 percent from 31 days to one year, 10 percent from one year to three years, and less than 2 percent at more than five years. The contribution of rejection to post-transplant mortality has decreased over time. This is primarily due to improvements in maintenance immunosuppression and in the diagnosis and treatment of rejection. Nevertheless, acute heart allograft rejection remains an important clinical problem.

This topic will review the risk factors for and the clinical features and diagnostic evaluation of acute cellular rejection in the heart transplant recipient. The treatment of acute rejection is discussed separately.

RISK FACTORS Although acute cellular rejection is always a potential concern in a heart transplant recipient, the likelihood of a rejection episode is influenced by several factors, particularly the time after transplantation.

Treatment Despite the use of potent immunosuppressive agents both immediately after cardiac transplantation and during long-term maintenance, acute rejection remains an important problem. Cardiac transplant recipients have an average of two to three episodes in the first year after transplantation, with 50 to 80 percent of patients experiencing at least one rejection episode. Acute cellular rejection is most likely to occur in the first three to six months, with the incidence declining significantly after this time.

The diagnosis of acute cellular cardiac allograft rejection is generally made by endomyocardial biopsy performed either routinely or because of suggestive symptoms.

ISHLT grading systemThe endomyocardial biopsy is graded using the International Society for Heart and Lung Transplantation (ISHLT) nomenclature adopted in 1990 and revised in 2004.

For acute cellular rejection:

Grade 0 no rejection

Grade 1 R, mild Interstitialand/orperivascular infiltrate with up to one focus of myocyte damage

Grade 2 R, moderate two or more foci of infiltrate with associated myocyte damage

Grade 3 R, severe diffuse infiltrate with multifocal myocyte damage, with or without edema, hemorrhage, or vasculitis

Grade 1 R includes grades 1A, 1B, and 2 in the 1990 system; grade 2 R was grade 3A; and grade 3 R was grades 3B and 4

Indications and contraindications for cardiac transplantation Cardiac transplantation is the treatment of choice for many patients with end-stage heart failure (HF) who remain symptomatic despite optimal medical therapy. Risk stratification of patients with end stage HF is pivotal for transplant candidate selection. The primary indications for cardiac transplantation along with the specific inclusion and exclusion criteria are discussed here.

Prognosis after cardiac transplantation and treatment of refractory HF are discussed separately.

WAITING LIST AND ALLOCATION The Registry of the International Society for Heart and Lung Transplantation reported 4196 heart transplants worldwide in 2012.This is probably an underestimate, as reporting to the registry is voluntary outside of the United States. In the United States, where reporting to the United Network Of Organ Sharing (UNOS) has been mandatory for the past two decades, the number of United States heart transplants performed has been stable at approximately 2300 cases annually .The majority of centers perform between 10 and 19 heart transplants per year.

The number of transplant centers has decreased from 243 in 1996 to 204 in 2007. The ongoing organ donor shortage has been the major limitation to the growth of this therapy. Due to this critical organ shortage, the recipient selection process and donor allocation system have involved both clinical and ethical issues.

Donor allocationIn an effort to ensure equitable distribution of donor hearts, UNOS (a private organization under contract to the federal government) has created and regularly updates an organ allocation system (Organ Procurement and Transplantation Network). This system delineates prioritization rules that take into account the clinical severity of illness, time accrued on the wait list, blood type compatibility, and geographic distance. With heart procurement, the duration of ischemic time for the donor heart is a limiting factor in organ retrieval, with ischemic times greater than four hours associated with a higher rate of primary graft failure. Accordingly, geographic distance between the donor hospital and the transplant center is measured in 500 nautical mile circular concentric zones.

Prospective HLA matching of donor and recipient is not usually performed for heart and heart-lung transplants. In a multi-centre study statistically significant improved survival with the better-matched heart grafts was found. In a small series of heart grafts it was also found that the improvement with HLA matching was confined to male recipients who were not blood group O.

Heart graft recipients with wide panel reactive antibody had worse graft survival one year after transplant than the unsensitized. In several studies patients with a positive cross-match had a significantly lower survival rate than those with a negative cross-match.

It is suggested that, minimally, pre-transplant screening and prospective cross-matching of highly sensitised patients is necessary.

Prevention and treatment of cardiac allograft vasculopathy Cardiac transplantation is the definitive therapy for eligible patients with end-stage heart failure. The major limitations to survival in the early post-transplant period (first year) are nonspecific graft failure, multiorgan failure, acute rejection, and infection . Beyond the first year, cardiac allograft vasculopathy (CAV, also called transplant coronary artery disease or cardiac transplant vasculopathy) is among the top three causes of death. Approximately 30 percent of patients have angiographic coronary artery disease at five years and 50 percent at 10 years, with the incidence increasing progressively with time.

The pathogenesis of CAV will be reviewed here. The diagnosis, prevention, and treatment of this disease are discussed separately.

PATHOLOGY Cardiac allograft vasculopathy (CAV) is a panarterial disease confined to the allograft and is characterized by diffuse concentric longitudinal intimal hyperplasia in the epicardial coronary arteries and concentric medial disease in the microvasculature . In contrast, traditional atherosclerosis is focal, noncircumferential, and most often observed proximally in the epicardial vessels.

Transplant recipients also frequently develop proximal coronary artery disease. However, these lesions more closely resemble traditional atherosclerosis pathologically and probably evolve from pre-existing disease in the donor heart that is accelerated by the plethora of cardiac risk factors after transplantation.

Serial intravascular (intracoronary) ultrasound testing has shown that most of the intimal thickening occurs during the first year after transplantation. Lumen loss is also due to arterial remodeling, with early expansion and late constriction of the external elastic membrane area

Basics of Stem Cell Transplant Background First successful transplantslate 1960s

30,000-40,000 transplants performed yearly worldwide

>20,000 patients have survived >5 years

Graft Sources Allogeneic: from another person

Syngeneic: from an identical twin

Autologous: from the patient

Choice of graft is based on disease type, patient condition, donor compatibility and health

Autologous Transplant

No evidence of disease in the blood or bone marrow

Transplant related mortality (TRM) lowest with autos (