Selection of patients for liver transplantation

Liver transplantation is indicated for patients with irreversible, progressive liver damage when alternative treatment methods are not available. The patient and his/her relatives should be aware of the complexity of the operation and be prepared for possible severe complications in the early postoperative period and for lifelong immunosuppressive therapy.

The selection of patients for surgery is particularly difficult due to the shortage of donors. It is carried out by the Transplant Patient Selection Committee. Potential recipients are divided into low, moderate and high risk groups based on the severity of their condition. Unfortunately, as the patient waits for surgery, their condition may worsen, which causes them to move into a higher risk group. Patients in the low-risk group (outpatients) have much better treatment outcomes and lower costs than patients in the high-risk group, who require intensive care while waiting.

In the United States, the number of patients requiring liver transplantation is increasing, but the number of donors is changing only slightly. The number of patients on the liver transplant waiting list now exceeds the number of surgeries performed in a year. Low-risk patients can wait 6-12 months for a donor organ. A patient with fulminant liver failure (FLF) can wait only 4 days. Patients with rare blood types in the ABO system - B(III) and AB(IV) - have to wait the longest. It is extremely rare to find a suitable donor for children, which has contributed to the development of the split liver transplant method.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ]

Potential recipients for liver transplantation

In Europe, absolute indications for liver transplantation are being revised. The main indication for surgery is cirrhosis, including primary biliary cirrhosis (PBC). Patients with acute and subacute liver failure and biliary atresia are being operated on more often, while transplantation is performed less frequently in patients with liver cancer.

Cirrhosis

Liver transplantation should be considered in all patients with end-stage cirrhosis. The optimal timing for surgery is difficult to establish. Patients who are dying have minimal chances of success, and patients who can lead relatively normal lives for a long time do not need surgery.

Indications for surgery are an increase in prothrombin time (PT) by more than 5 sec, a decrease in albumin levels to less than 30 g/l, and ascites resistant to therapy. An indication is bleeding from esophageal varices in the absence of an effect from conservative therapy, including sclerotherapy. The cost of liver transplantation is slightly higher than the cost of long-term conservative and surgical treatment of complications such as bleeding, coma, and ascites.

Surgery in these patients is associated with high risk due to disorders in the blood coagulation system and the presence of portal hypertension, which leads to significant blood loss. In liver cirrhosis, surgery is technically more complex, especially when the liver is small and difficult to remove. Survival in all types of cirrhosis is almost the same.

[ 7 ], [ 8 ], [ 9 ]

Chronic autoimmune hepatitis

Liver transplantation is performed at the stage of cirrhosis, as well as in cases of severe side effects of corticosteroid therapy, such as osteoporosis and recurrent infections. After transplantation, liver disease does not recur (see Chapter 17).

Survival among 9966 patients with liver cirrhosis, acute liver failure and liver cancer (data from the European Liver Transplant Registry, 1993)

Diagnosis	One-year survival rate, %	Two-year survival rate, %	Three-year survival rate, %
Cirrhosis	80	73	71
Acute liver failure	60	56	54
Liver cancer	64	42	36

Diseases that may require liver transplantation

Cirrhosis

• Cryptogenic
• Autoimmune
• Hepatitis B (HBV DNA negative)
• Hepatitis D
• Hepatitis C
• Alcoholic

Cholestatic liver diseases

• Primary biliary cirrhosis
• Biliary atresia
• Primary sclerosing cholangitis
• Secondary sclerosing cholangitis
• Graft versus host disease
• Chronic liver rejection
• Liver sarcoidosis with cholestasis syndrome
• Chronic drug reactions (rare)

Primary metabolic disorders

Fulminant liver failure

Malignant tumors

• Hepatocellular carcinoma
• Epithelioid hemangioendothelioma
• Hepatoblastoma

Other diseases

• Budd-Chiari syndrome
• Short bowel syndrome

[ 10 ], [ 11 ], [ 12 ], [ 13 ], [ 14 ], [ 15 ]

Transplantation in chronic viral hepatitis

Liver transplantation performed for acute fulminant hepatitis (A, B, D and E) is not accompanied by reinfection of the graft due to very low levels of viremia. However, in chronic hepatitis, the graft is very often susceptible to reinfection.

Hepatitis B

The results of liver transplantation in patients with chronic hepatitis B are unsatisfactory, probably due to extrahepatic replication of the virus, especially in monocytes. The 1-year survival rate is 80%, but the 2-year survival rate is only 50-60%. Transplantation should be performed only when HBV DNA and HBeAg are absent from the serum. In HBV-positive patients, the post-transplantation period is usually severe, with a progressive course of the disease; after 2-3 years, cirrhosis of the liver or cirrhosis and cancer develop. With retransplantation, remission is even shorter and quickly gives way to relapse and liver failure.

Severe fibrosing cholestatic hepatitis with ballooning of liver cells and ground-glass hepatocytes may develop in the post-transplant period. This may be due to high expression of viral antigens in the cytoplasm against the background of immunosuppression. HBV may sometimes have a cytopathic effect. Attempts to prevent graft reinfection by interferon (IFN) therapy have been largely unsuccessful. Long-term use of HBV immunoglobulin reduces the likelihood of relapse in HBV DNA-positive patients if it is administered at the post-transplantation stage, then daily for a week, then monthly for 1 year and possibly longer. This is a very expensive method of prevention. Lamivudine administered before and after transplantation may prevent reinfection. Ganciclovir may reduce HBV replication. Hepatocellular carcinoma may develop in the transplanted liver.

Hepatitis D

After liver transplantation in hepatitis D, infection of the graft is almost always observed. HDV-RNA and HDAg can be detected in the transplanted liver, and HDV-RNA in the serum. Hepatitis develops only with co-infection or superinfection with HBV.

HBV is suppressed by HDV, and HDV infection may reduce the recurrence of hepatitis B. Overall, survival after liver transplantation in HDV-infected patients is high. One-year survival is 76%, and two-year survival is 71%.

Hepatitis C

Terminal hepatitis C is increasingly an indication for liver transplantation; currently, one third of patients undergo surgery specifically for this condition.

Almost all patients experience re-infection of the donor organ after transplantation. The source of reinfection is the host organism, since the genotype of viruses before and after transplantation is similar. Genotype 1b is one of the factors influencing the frequency of relapses. The disease can be transmitted from an anti-НСV-positive donor. Currently, this route of infection is observed less frequently due to donor screening for HCV. Despite massive blood transfusions, the probability of HCV-positive blood transfusion and the development of hepatitis C has not increased.

The one-year, two-year and three-year survival rates of patients with good transplant function are high and in patients with liver cirrhosis are 94, 89 and 87%, respectively.

After transplantation, even in the absence of histological signs of hepatitis, a 10-fold increase in the level of HCV-RNA in the serum is noted. More often, the activity of the process depends on the number of prescribed corticosteroids and other chemotherapeutic drugs.

Reinfection is more common after multiple episodes of rejection.

Transplant hepatitis has varying degrees of severity. It is usually mild and has a high survival rate. However, longer-term follow-up shows an increasing number of patients developing chronic hepatitis and cirrhosis. Persistence of HCV can cause severe graft damage, especially with the lb virus genotype.

Interferon treatment provides only a temporary effect and may increase the incidence of transplant rejection. Combined treatment with interferon and ribavirin appears to be more effective; the histological picture of liver tissue improves and the incidence of donor organ rejection decreases.

Neonatal hepatitis

This disease of unknown etiology is accompanied by jaundice, the development of giant cell hepatitis and, in rare cases, liver failure, requiring liver transplantation, which leads to a cure.

Alcoholic liver disease

In Western countries, these patients make up the majority of those who require liver transplantation.

[ 16 ], [ 17 ], [ 18 ], [ 19 ], [ 20 ]

Cholestatic liver diseases

The terminal stage of biliary tract diseases, usually occurring with damage to small intrahepatic bile ducts, is a favorable indication for liver transplantation. Hepatocyte function is usually preserved for a long time, and it is easy to choose the optimal time for surgery. All patients have signs of widespread biliary cirrhosis in the liver, often in combination with the disappearance of the bile ducts (vanishing bile duct syndrome).

[ 21 ], [ 22 ], [ 23 ], [ 24 ], [ 25 ], [ 26 ], [ 27 ]

Primary biliary cirrhosis

The one-year survival rate after liver transplantation exceeds 75%. An observation is described where a three-organ transplant (liver, lung, and heart) was performed for primary biliary cirrhosis and primary pulmonary hypertension with a good result over 7 years.

Atresia of the extrahepatic bile ducts

This disease is an indication for liver transplantation in children in 35-67% of cases. The results of the operation are good, and with a high survival rate, normal physical and mental development is observed.

According to the Pittsburgh researchers, the follow-up periods for 12 of 20 children after liver transplantation ranged from 1 to 56 months, with 19% of them requiring retransplantation and 37% requiring various reconstructive surgeries. According to the results of another study, in a group of 36 children, whose average age at the time of liver transplantation was 30 months, the 3-year survival rate was 75%.

A previous Kasai operation complicates the transplant and increases the number of complications.

[ 28 ], [ 29 ], [ 30 ], [ 31 ], [ 32 ], [ 33 ], [ 34 ], [ 35 ]

Alagille syndrome

Liver transplantation is performed only in cases of severe disease. Concomitant cardiopulmonary disease can be fatal, so careful preoperative examination is necessary.

[ 36 ], [ 37 ], [ 38 ], [ 39 ], [ 40 ], [ 41 ], [ 42 ], [ 43 ]

Primary sclerosing cholangitis

Sepsis and previous bile duct surgery make liver transplantation difficult. However, transplantation results are good, with a 1-year survival rate of 70% and a 5-year survival rate of 57%. Cholangiocarcinoma is a complication that significantly reduces life expectancy. The most common cause of death is colon cancer.

Langerhans cell histiocytosis accounts for 15-39% of cases of sclerosing cholangitis. Liver transplantation results for this disease have been good.

Other terminal cholestatic diseases

The transplant was performed on a bone marrow recipient who developed cirrhosis due to graft-versus-host disease (GVHD). Other rare indications for surgery include liver sarcoidosis with cholestasis syndrome and chronic drug reactions (e.g., chlorpromazine toxicity).

Primary metabolic disorders

The transplanted liver retains its inherent metabolic activity. In this regard, liver transplantation is performed in patients with liver function defects that lead to congenital metabolic disorders. In patients suffering from these liver diseases, transplantation gives good results. When selecting patients, the prognosis of the disease and the likelihood of developing primary liver tumors in the remote period are taken into account.

Indications for liver transplantation in metabolic disorders:

1. end-stage liver disease or precancerous conditions,
2. significant extrahepatic manifestations.

Overall survival over a follow-up period of more than 5.5 years is 85.9%.

Alpha-1 antitrypsin deficiency

This is the most common metabolic disorder that is an indication for liver transplantation. Severe liver damage is observed in only a small number of patients, but large-nodular cirrhosis develops in approximately 15% by the age of 20. Hepatocellular carcinoma is a complication. After liver transplantation, the plasma alpha-1 antitrypsin level is normalized and lung damage is stabilized. Severe changes in the lungs are a contraindication to surgery unless a lung transplant is planned simultaneously with the liver transplant.

Wilson's disease

Liver transplantation should be performed in patients with clinical signs of fulminant hepatitis, in young patients with severe decompensated liver cirrhosis and no effect from 3-month adequate therapy with penicillamine, as well as in patients effectively treated with penicillamine in case of development of severe decompensation of the disease after drug withdrawal. One-year survival after liver transplantation is approximately 68%. Copper metabolism is normalized.

Neurological manifestations resolve with varying frequency

Liver transplantation for metabolic disorders

End-stage liver disease or precancerous conditions

• a1-antitrypsin deficiency
• Wilson's disease
• Tyrosinemia
• Galactosemia
• Glycogen storage diseases
• Protoporphyria
• Neonatal hemochromatosis
• beta thalassemia
• Cystic fibrosis
• Byler's disease

Significant extrahepatic disorders

• Primary oxaluria type I
• Homozygous hypercholesterolemia
• Crigler-Najjar syndrome
• Primary disorders of the blood coagulation system (factors VIII, IX, protein C)
• Defects of the urea synthesis cycle
• Mitochondrial respiratory chain defects
• Primary familial amyloidosis

Glycogen storage diseases

Liver transplantation is successfully performed in glycogenosis types I and IV; patients survive to adulthood.

[ 44 ], [ 45 ], [ 46 ], [ 47 ], [ 48 ], [ 49 ]

Galactosemia

A small number of patients with late diagnosis of the disease have progressive development of cirrhosis in childhood and young adulthood. Such patients are recommended for liver transplantation.

Protoporphyria

This disease can lead to terminal cirrhosis, which is an indication for liver transplantation. In the postoperative period, high levels of protoporphyrin in erythrocytes and feces persist, i.e. the disease is not cured.

Tyrosinemia

Liver transplantation is a radical treatment method and should be performed in the early stages of the disease, before the development of hepatocellular carcinoma.

Neonatal hemochromatosis

Neonatal hemochromatosis can be rapidly fatal. It is a manifestation of several diseases. Transplant results are mixed.

Beta thalassemia

There is a report of combined heart and liver transplantation in an adult patient with homozygous beta-thalassemia in end-stage organ failure due to iron overload.

[ 50 ], [ 51 ], [ 52 ], [ 53 ], [ 54 ], [ 55 ]

Cystic fibrosis

Liver transplantation is indicated when liver disease is predominant. Complications may include infection with Pseudomonas spp. and Aspergillus spp. Improvement of lung function is possible after transplantation.

[ 56 ], [ 57 ], [ 58 ], [ 59 ], [ 60 ], [ 61 ], [ 62 ]

Byler's disease

This familial disorder, characterized by intrahepatic cholestasis, leads to death from cirrhosis or heart failure. Liver transplantation performed in cirrhosis normalizes the decreased serum apolipoprotein A1 concentration.

Oxalaturia

Primary oxaluria type I, caused by deficiency of the peroxisomal enzyme alanine glycosyl aminotransferase, is corrected by simultaneous liver and kidney transplantation. Cardiac function is restored. Liver transplantation may be necessary before kidney damage develops.

Homozygous hypercholesterolemia

Liver transplantation results in an 80% reduction in serum lipid levels. Heart transplantation or coronary artery bypass grafting is usually also necessary.

Crigler-Najjar syndrome

Liver transplantation is indicated to prevent neurological complications when serum bilirubin levels are very high and not controlled by phototherapy.

Primary disorders of the blood coagulation system

Liver transplantation is performed in the terminal stages of cirrhosis resulting from viral hepatitis B or C. As a result, normal levels of factors VIII and IX in the blood are maintained and hemophilia A is cured. Protein C deficiency is corrected.

Urea Cycle Enzyme Deficiency

The transplantation was performed in case of ornithine carbamoyltransferase deficiency, since the enzymes of urea synthesis are localized mainly in the liver. It is not easy to decide on the need for a liver transplantation, since in some diseases associated with a violation of the urea synthesis cycle, a normal quality of life is maintained.

[ 63 ], [ 64 ], [ 65 ], [ 66 ], [ 67 ], [ 68 ]

Mitochondrial respiratory chain defects

These defects underlie a neonatal liver disease characterized by postprandial hypoglycemia and hyperlactacidemia. Liver transplantation has cured these children.

[ 69 ], [ 70 ], [ 71 ], [ 72 ], [ 73 ], [ 74 ], [ 75 ], [ 76 ]

Primary familial amyloidosis

Liver transplantation is performed in cases of incurable polyneuropathy. The degree of improvement in neurological symptoms after surgery varies.

Fulminant liver failure

Indications for liver transplantation include fulminant viral hepatitis, Wilson's disease, acute fatty liver of pregnancy, drug overdose (eg, paracetamol), and drug-induced hepatitis (eg, isoniazid and rifampicin).

Malignant tumors

Transplant outcomes in patients with malignant liver tumors are poor, despite careful preoperative exclusion of extrahepatic tumor spread. In cancer patients, surgical mortality is low, but long-term survival is the worst. Carcinomatosis is the usual cause of death. The tumor recurs in 60% of cases, possibly due to the use of immunosuppressants to prevent rejection.

Perioperative survival is 76%, but 1-year survival is only 50% and 2-year survival is 31%. Regardless of the type of tumor for which the liver transplant was performed, 5-year survival is 20.4%. Such results justify transplantation.

Hepatocellular carcinoma

The tumor size should not exceed 5 cm. In case of multifocal lesions, transplantation is performed in the presence of up to three tumor foci no larger than 3 cm. At the time of transplantation, laparoscopy plays an important role, specifying the stage of the disease [118]. The presence of even microscopic vascular invasion by the tumor increases the frequency of relapses and mortality. Preoperative chemotherapy or chemoembolization can delay the occurrence of relapse.

The 2-year survival rate is 50%, while for diseases other than malignant tumors it is 83%. This raises the question of whether donor liver transplantation is justified in patients with malignant tumors.

Transplantation may be preferable to resection when small tumors are incidentally discovered in a patient with compensated cirrhosis.

Fibrolamellar carcinoma

The tumor is localized in the liver and there is no cirrhosis. These patients are the most suitable "candidates" for transplantation among all patients with malignant liver tumors.

[ 77 ], [ 78 ], [ 79 ], [ 80 ], [ 81 ], [ 82 ]

Epithelioid hemangioendothelioma

This tumor is represented by multiple focal lesions of both lobes of the liver, developing against the background of unchanged parenchyma. The course of the disease is unpredictable, and the probability of relapse is 50%. The presence of metastases is not a contraindication to surgery and does not correlate with survival. Liver transplantation can be successful.

[ 83 ], [ 84 ], [ 85 ], [ 86 ]

Hepatoblastoma

As a result of transplantation, 50% of patients survive for 24-70 months. Poor prognostic signs are microscopic vascular invasion and epithelial anaplasia with extrahepatic spread.

Liver apudomas

Transplantation is sometimes performed as a palliative intervention even in the presence of secondary tumor foci.

Transplantation of complex abdominal organs for malignant tumors in the right upper quadrant of the abdomen

Most of the organs derived from the embryonic foregut, including the liver, duodenum, pancreas, stomach, and small intestine, are removed. By using potent immunosuppressants, donor lymphoreticular cells circulate without causing clinical signs of GVHD and become self-associated with the recipient; rejection is thus prevented. Complex organ transplantation is unlikely to be justified, since patients usually die from tumor recurrence.

Cholangiocarcinoma

The results of transplantation for this disease are unsatisfactory, since the tumor usually recurs, and life expectancy does not reach 1 year.

[ 87 ], [ 88 ], [ 89 ]

Budd-Chiari syndrome

Despite cases of successful liver transplantation, the recurrence of thrombosis is high, especially in Budd-Chiari syndrome, which develops as a result of myeloproliferative disease.

[ 90 ], [ 91 ], [ 92 ]

Short bowel syndrome

Complex small intestine and liver transplantation is performed on patients with short bowel syndrome with secondary liver failure.

Liver transplantation is also indicated for cystic fibrosis with concomitant liver cirrhosis and for Niemann-Pick disease in adults.