Exceptional Liver Transplant Indications: History
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Contributor:
Teodor Cabel
,
Cristina Madalina Pascu
,
Catalin Stefan Ghenea
,
Bogdan Florin Dumbrava
,
Deniz Gunsahin
,
Andreea Andrunache
,
Livia-Marieta Negoita
,
Afrodita Panaitescu
,
Ecaterina Mihaela Rinja
,
Christopher Pavel
,
Oana-Mihaela Plotogea
,
Madalina Stan-Ilie
,
Vasile Sandru
,
Mariana Mihaila

Liver transplantation represents the definitive intervention for various etiologies of liver failure and encompasses a spectrum of rare indications crucial to understanding the diverse landscape of end-stage liver disease, with significantly improved survival rates over the past three decades.

  • liver transplantation (LT)
  • end-stage liver disease (ESLD)
  • rare indications (RI)

1. Introduction

Liver transplantation (LT) represents the elective treatment for all etiologies of liver failure [1][2]. The survival rates after LT have improved considerably in the last 30 years, achieving up to 94% one year after transplantation and 61% ten years after [3][4][5][6]. In centers with experience, this surgical procedure is performed routinely with favorable results and low mortality and morbidity rates [7]. Due to effective immunosuppression, improvement of surgical technique, and early diagnosis and management of post-transplant complications, the survival rate has increased significantly [2].
The most common indications for LT are decompensated cirrhosis and liver cancer, followed by acute liver failure. Other indications of LT are represented by metabolic and cholestatic diseases with liver involvement but with lower prevalence [8] (Table 1).
Table 1. Rare liver transplant indications.
Disease
Hepatic hemangiomatosis
Amyloidosis
Sarcoidosis
Severe hepatic trauma
Byler Disease
Caroli’s disease
HELLP syndrome
Graft-versus-host disease
Besides those common causes of LT, several rare diseases can lead to transplantation [9]. A rare disease is defined as when the incidence is below 1 per 10,000 [10]. Depending on the nature of the disease, rare causes can be neoplastic and non-neoplastic.

2. Rare Liver Transplants Indications

2.1. Hepatic Hemangiomatosis

Hepatic hemangiomas are among the most prevalent primary liver tumors classified as non-epithelial lesions [11]. Diffuse hepatic hemangiomatosis (DHH) is a rare, most frequently benign condition in which there is widespread substitution of liver tissue by hemangiomatous tumors and usually occurs in newborns [12].
The literature review by Shihua He et al. revealed that the most commonly reported symptoms were upper abdominal pain, dyspeptic symptoms, early satiety followed by dyspnea, and systemic symptoms such as high temperatures, excessive night sweats, and fatigue [13][14]. Physical examination findings consist of hepatomegaly in the majority of cases, together with jaundice, peripheral edema, and ascites [15][16][17].
The literature search revealed that DHH has an unclear prognosis due to its low incidence [18].
Surgery is not usually recommended if the margins of the tumor are unclear and there is a risk of bleeding [19]. Four people underwent right/left hepatectomy according to the available studies [17][20][21][22]. During follow-up, only one patient who underwent left hepatectomy was found to have tumor recurrence 6 years later after wedge biopsies [21].
Several research studies have described liver transplantation as a viable treatment option for patients with hepatic hemangiomatosis complicated with painful hepatomegaly, liver failure, portal hypertension, or heart failure due to hyperdynamic flow [23][24][25][26][27][28][29]. In a recent systematic literature review by Bhardwaj et al. (September 2022), two patients with DHH underwent living donor transplantation [29] and orthotopic liver transplantation [27], respectively, with good status after a follow-up period of at least 6 months [18].
Trans-arterial embolization, radiofrequency ablation, and radiation have been studied with various rates of effectiveness [28][30][31][32][33]. Studies found that radiotherapy was successful in only one in two patients, with the tumor disappearing three years later [13][34]. Radiotherapy could represent a viable therapy for DHH, but further studies are needed [13].
In addition, a therapy with anti-VEGF (anti-vascular endothelial growth factor) has been described, which was successful in liver tumors but had a negative effect on spleen lesions and led to the death of the patient [35].
The most prevalent complication of DHH is liver failure [16][22][36][37]. In reported cases, other complications such as Kasabach–Merritt syndrome, disseminated intravascular coagulation, and cardiac or various organic dysfunctions have also been noted, invariably leading to exitus [13][35].

2.2. Amyloidosis

Amyloidosis is a systemic disease that commonly affects a wide variety of organs and can therefore lead to multiple organ failure and ultimately death. Amyloidosis can be classified as primary or secondary due to other diseases such as rheumatoid arthritis or multiple myeloma. Hepatic amyloidosis may be present in a wide variety of patients, but signs and symptoms caused by liver damage may rarely be seen [38].
The gastrointestinal tract and the liver are often affected by systemic amyloidosis, besides the most frequent localizations such as heart, kidney, and peripheral nervous system. It is very important to correctly diagnose this systemic disease because it can mimic other GI diseases, thus increasing the challenges for both the patient’s life and the diagnostic process [39]. The clinical and paraclinical manifestations of liver amyloidosis can vary drastically between patients with no symptoms at all or patients with very advanced liver disease. However, severe liver disease manifesting as jaundice and elevated cholestasis are rare, but with a high mortality rate [40]. Usually, the liver is involved in the later stages of amyloidosis only after the involvement of the heart and kidney, and this can represent a sign of poor prognosis for the patient [41].
The main goal of treatment in amyloidosis is to remove or decrease amyloid protein fibrils while maintaining minimal systemic toxicity. Thus, since 1972, various cytoreductive and immunosuppressive drugs have been introduced, as well as drugs and treatment methods used in multiple myeloma. Liver transplantation remains the last resort in the fight against amyloidosis for patients in advanced stages of the disease [42]. A study published in 2009 shows liver response in 69 patients with primary amyloidosis treated with high-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation. Hepatic response was present in 57% of patients, while hematological response was present in 53% of patients [43].
Hepatic amyloidosis is frequently associated with cardiac amyloidosis and can therefore lead to end stage heart and liver disease [44]. Nardo et al. published a study that included four patients who underwent combined heart and liver transplantation for familial amyloidosis between 1999 and 2003. Therefore, this method, although very difficult to perform, can be a solution for severely affected patients with both cardiac and hepatic amyloidosis [45].
Primary amyloidosis can, in rare cases, present as acute liver failure, as researchers will further detail through a case from the literature published by M Elnegouly et al. that presents a patient with primary amyloidosis who had been treated with Bortezomib, Dexamethasone, Melphalan, and autologous hematopoietic stem cell transplantation as a bridge to urgent liver transplantation. Eventually, the patient underwent liver transplantation with a very good outcome. Thirty-six months after the orthotopic liver transplantation, the patient is in complete remission [42].
The role of liver transplant in amyloidosis is controversial. Some data in the literature suggest that liver transplantation might be useful in patients with dominant hepatic involvement as they are not suitable for chemoimmunotherapy [46]. The first documented liver transplant for transthyretin amyloidosis was performed in 1990 with the purpose of removing the organ that had been producing this abnormal protein. The most favorable outcome from liver transplantation could be found in patients with the Val30Met mutation in the TTR gene [47]. A published study described the experience of liver transplantation in hepatic amyloidosis in a single center. Out of 11 transplanted patients, 6 had improvements in clinical symptoms. The study concluded that liver transplantation is the only therapeutic method for patients in which the liver is the primary site for amyloid protein synthesis [48]. In recent years, the criteria for liver transplantation have become more selective, and the new potential drugs (gene silencers and kinetic stabilizers) have the potential to start a new era in the treatment of transthyretin amyloidosis.
The criteria for liver transplantation have become increasingly stringent in recent years due to advancements in medical therapy such as genetic attenuators and kinetic stabilizers. These advancements have significantly reduced the necessity of liver transplants for amyloidosis. While a new treatment era is emerging to effectively manage this condition, the possibility of transplant remains an alternative option. Future evidence will clarify the benefits for patients and the necessity of liver transplantation in selected cases where medical therapy alone cannot effectively halt the disease progression [49].

2.3. Sarcoidosis

Sarcoidosis is a multiorgan disease that can therefore affect the hepatic parenchyma. Sarcoidosis is classified as an inflammatory disease. Microscopically, it is characterized by the presence of non-caseating granulomas in the affected organs. The etiology is unknown but a multifactorial etiology is thought to exist, involving genetic, environmental, and immunological causes. Most patients with liver sarcoidosis are asymptomatic. Among patients with systemic sarcoidosis, about 50–70% have specific changes for sarcoidosis in the liver, while only 10–30% of them have altered liver tests [50].
Most frequently, patients present elevated liver cytolysis markers and alkaline phosphatase levels. The diagnosis of sarcoidosis is challenging, with a crucial role attributed to liver biopsy as an indispensable step in confirming and distinguishing this condition [51].
The study by M Sedki et al. analyzed 286 patients with sarcoidosis, of whom only 9.4% also had liver sarcoidosis and only 37% had clinical symptoms. In addition, a quarter of patients with liver sarcoidosis also had cirrhosis at the time of identification of sarcoidosis. The progression of liver sarcoidosis to cirrhosis is highly variable [52].
A study published in 2019 by S Ghoneim et al. included three patients with systemic sarcoidosis and liver sarcoidosis, of whom two patients eventually developed liver cirrhosis. Mortality in sarcoidosis is between 1–5%, not due to liver insufficiency but rather due to cardiac and pulmonary insufficiency and also from the lesions in the central nervous system [53].
Liver transplantation is the last-resort treatment for patients with end-stage liver disease. The most common type of surgery chosen is combined lung and liver transplantation for patients with both pulmonary and liver sarcoidosis [54].
A study published in 2020 by AJ Thuluvath and al. compared patients with sarcoidosis who underwent liver transplantation with patients with primary biliary cirrhosis and with patients with primary sclerosing cholangitis who also underwent liver transplantation between 1985–2016. The patients were compared according to the 5-year survival rate and the graft viability rate. Thus, the study concluded that patients with sarcoidosis undergoing liver transplantation have a lower survival rate, both of themselves and the graft, compared to the other two groups of patients, but approximately 66% of liver-transplanted sarcoidosis patients still had a good survival rate after 5 years of follow-up [55].
Between 1988 and 2004, EJ Lipson and al. assessed 2117 patients who underwent liver transplantation, and hepatic sarcoidosis was an indication in only seven patients (about 0.3%). The survival rate at 1 year for patients and grafts was 100%, and at 5 years, the survival rate was 86%. These survival rates are good and comparable with those of other patients who underwent liver transplantation with other indications. Researchers must keep in mind that end-stage liver disease due to advanced sarcoidosis is a rare indication for liver transplantation when considering all other indications for this specific therapeutic method [56].
The incidence of sarcoidosis tends to be higher in African Americans and white Americans. However, liver failure due to sarcoidosis as an indication for liver transplantation is rare in the United States, accounting for only 0.12% of all liver transplants performed between 1987 and 2007. Although liver failure in sarcoidosis is very rare, the outcome of patients who have undergone liver transplantation is satisfactory. The differences in survival rates between patients with sarcoidosis and other cholestatic diseases (primary biliary cirrhosis and primary sclerosing cholangitis) can be explained by the systemic nature of sarcoidosis and the use of high-dose corticosteroids [57].

This entry is adapted from the peer-reviewed paper 10.3390/diagnostics14020226

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