Therapeutic potential of living donor liver transplantation from heterozygous carrier donors in children with propionic acidemia

Propionic acidemia (PA; Online Mendelian Inheritance in Man [OMIM] #606054) is an ultrarare autosomal-recessive disorder of metabolism characterized by biallelic pathogenic variants on chromosome 13q32.3 (PCCA) or 3q22.3 (PCCB), resulting in the deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC) [1]. Dysfunction of PCC fails to convert propionyl-CoA to methylmalonyl-CoA, thereby leading to the chronic accumulation of propionic acid and propionyl-CoA-related metabolites. These circulating toxic metabolites continuously cause damage to various organs and tissues throughout the body [2]. Since compound heterozygotes in most patients result in undefined genotype–phenotype correlation, affected individuals present with a broad spectrum of clinical manifestations, and age of onset ranges from the neonatal period to adulthood [3]. Characteristic patients usually present in infancy with poor feeding and episodic vomiting within the first few hours to days of life. Without prompt diagnosis and treatment, the illness can progress rapidly to severe ketoacidosis, hyperammonemia, and hyperlactatemia, manifesting as lethargy, seizure, or coma that can result in early death [4, 5]. Despite good compliance with long-term conservative management consisting of individualized nutritional intervention, levocarnitine supplementation, and oral metronidazole, the overall prognosis of PA patients remains poor [6]. Patients surviving their initial metabolic decompensation episode may suffer frequent metabolic decompensations and disease-related long-term multiorgan sequelae such as growth impairment, neurocognitive deficits, cardiomyopathy, pancreatitis, or chronic kidney disease [7, 8]. Furthermore, PA patients' lifelong high-intensity medical and dietary management demands can severely affect family life and cause tremendous financial and psychosocial stress to patients' caregivers [9, 10].

Since replacing the enzyme-deficient liver with a metabolically normal liver could help regain partial PCC activity, after the first attempt in 1991, liver transplantation (LT) has emerged as a novel therapeutic option for selected PA patients who, despite strict dietary and medical intervention, still experience frequent metabolic decompensations or cardiomyopathy [11‐15]. In some centers, early LT has been offered as a preventative treatment for metabolically stable pediatric PA patients without metabolic decompensation and severe neurological or cardiac sequelae [13, 14, 16].

Living donors, especially in countries with limited availability of deceased donors, are an essential source of donor organs. And parents of liver transplant candidates are often the predominant and even sole source of living donors. Thus, living donor liver transplantation (LDLT) using an allograft from a heterozygous carrier donor in autosomal-recessive disorders is always inevitable. However, there remains a concern for the potentiality of the insufficient PCC activity in the donor remnant liver and the partial liver graft, and the current world experience of using obligate heterozygous carriers in LDLT for PA patients is limited. Here, we report our single-center experience with LDLT in 7 children with PA, of whom 6 received partial liver grafts from genetically proven heterozygous parental living donors.

To our knowledge, our series of 7 pediatric PA patients treated with LDLT is the largest to date from a single center. Of the 7 parental living donors, 6 were genetically proven obligate heterozygous carriers. In our report, all 7 recipients achieved satisfactory clinical outcomes with 100% patient and graft survival. There was no occurrence of metabolic decompensation, disease-associated long-term extrahepatic sequelae, or severe LT-related complications during a median follow-up period of 23.9 months. Meanwhile, all living donors recovered well after surgery, without metabolic acidosis or procedure-related complications during the immediate and long-term postoperative periods. More importantly, for the first time, we found that at the protein level, the hepatic expressions of PCCA and PCCB in the heterozygous donor were comparable to the healthy donor.

PA is a rare inborn error of mitochondrial metabolism with life-threatening consequences and multiorgan pathology. Despite following a strict protein restriction and pharmacological intervention, PA patients still suffer frequent metabolic decompensations and subsequent devastating long-term complications [6, 7, 18]. As a kind of enzyme replacement therapy, LT has been performed in 67 PA patients with 75 liver grafts to date [10, 11, 13‐15, 19‐34]. The overall patient and graft survivals were 80.6% and 72.0%, respectively (Table 3). In the present study, despite a relatively short follow-up of 23.9 months (13.9–40.2 months), our patients' survival outcomes were excellent, with 100% patient and graft survival rates, which were superior to previous data. These improvements may be attributed to the tremendous advances in surgical technology, medical management, and immunosuppressive agents since the 1990s. Hepatic artery thrombosis (HAT), one of the most life-threatening LT-related complications, is more frequent in pediatric LT, with an estimated rate of 4–8% [35]. However, the overall rate of HAT in historical PA cases was significantly high at 17.5% [11]. Therefore, it was once believed that patients with PA are more prone to develop HAT after LT [14, 15]. Contrary to previous results, none of our patients developed HAT post-transplant, and thus we could not confirm a propensity for developing HAT in the liver transplant recipients with PA. Regarding other LT-related complications, neither our study nor previous studies have found that patients with PA were at higher risk. Therefore, concerns about transplant-related complications should not be an obstacle for PA patients to choose LT as a treatment option.

Frequent metabolic decompensations are the most common complication of PA patients, leading to frequent hospitalizations and impaired quality of life, and even being life-threatening. Thus, poor metabolic control has become the main indication for LT. Previous studies have demonstrated that LT reduces the risk of metabolic decompensation and improves the quality of life of PA patients [13, 14, 22, 29]. In our study, 6 of the 7 recipients received LT due to frequent metabolic decompensations. Despite not all returning to normal levels, in the case of liberalized protein intake, propionate metabolites in our patients' blood and urine more or less decreased post-transplant. More importantly, no patients suffered further episodes of metabolic decompensation after LT. Therefore, it should be recognized that LT does bring metabolic stability to the already medically fragile PA patients, thereby largely protecting against metabolic decompensation and the need for frequent hospitalizations, which in itself leads to improved quality of life.

Cardiomyopathy, either dilated or hypertrophic, is another common and potentially lethal complication in PA, with an estimated incidence of 9–23% [4, 36]. It also contributes to one of the major causes of mortality in patients with PA [37]. The cardioprotective potential of LT for individuals with PA has been proved that reversal of cardiomyopathy is achieved in all previously reported 11 patients with pre-existing PA-associated cardiomyopathy [15, 20, 23, 25, 27, 29‐31]. In line with previous results, one of our patients with pre-existing mild dilated cardiomyopathy displayed a complete recovery of cardiac function after LT. Taken together, LT can be a viable therapeutic option for PA-related cardiomyopathy, and thus severe drug-resistant cardiomyopathy can remain as an indication for LT in patients with PA. Moreover, LT should not be contraindicated in PA patients with severely impaired cardiac function. Devices to stabilize the hemodynamic conditions, such as left ventricular assist device or extracorporeal membrane oxygenation, can be used as a bridge to LT [29, 30].

Neurodevelopmental sequelae are of particular concern in PA patients and the most crucial factor affecting the long-term quality of life. The poor neurocognitive and psychosocial development resulting from metabolic derangement was reported in 43–75% of PA patients [6, 38]. Previous studies suggested that almost all patients presented with neurodevelopmental delay prior to LT made some developmental progress after LT [13, 14, 22]. Our pretransplant neurodevelopmental assessment indicated that all individuals exhibited neurodevelopmental delay. However, LDLT has stabilized each patient's neurological impairment and even improved neurodevelopmental delay to some extent. Nevertheless, neurodevelopmental delay still exists in all surviving patients, and whether sustained neurological improvement could be expected requires more investigations in a longer follow-up.

Sufficient daily intake of essential and functional amino acids is necessary for normal body growth in children [39]. However, PA patients must follow a strict lifelong protein-restricted diet, resulting in severe amino acid deficiencies, so they are prone to develop body growth retardation [40]. A post-transplant liberalized protein diet means sufficient intake of essential and functional amino acids, which is crucial to correct chronic malnutrition and stimulate body growth in liver transplant recipients with PA. In turn, optimal growth leads to higher protein tolerance, which possibly helps further to reduce the risk of metabolic decompensation after transplantation [40]. In our series, in the case of no formal protein restriction, post-transplant mean height and weight Z scores were both improved compared with the pre-transplant levels. However, whether the present patients' physical growth would catch up to the standard growth curve warrants further long-term follow-up.

Given the shortage of available donor organs and low priority in the waiting list, LDLT has been a feasible choice for inborn errors of metabolism, in which the donor is almost always a blood relative of the patient, and parental donors are preferable [41, 42]. Since most monogenetic diseases are inherited in an autosomal recessive fashion, the parent who serves as a living donor is almost always an obligate heterozygous carrier. However, whether using a partial allograft from a heterozygous living donor contributes to sufficient metabolic correction in a homozygous recipient remains a concern. There is a possibility that the implanted partial liver graft may have low PCC activity, leading to persistent insufficient enzyme activity in the recipient, which will compromise the therapeutic value of LDLT in PA. There is also the possibility that the residual liver's PCC activity in the heterozygous donor is insufficient, which may put the donor in danger of disease-related symptoms and complications. Curnock et al. [13] hold the view that it should be preferential to use an unrelated LT donor in patients with PA. In contrast, previous studies suggested that no mortality or morbidity associated with the use of heterozygous carrier donors was observed in donors or recipients [16, 29, 33, 41]. Our study is believed to be the largest reported series of PA patients receiving partial liver grafts from genetically proven obligate heterozygous carriers. We demonstrated satisfactory clinical outcomes in all 6 recipients, with no negative impact on both donors' and recipients' clinical courses. More importantly, for the first time, our study demonstrated that the hepatic expressions of PCCA and PCCB at the protein level in one of the heterozygous parental living donors were equal to those of the healthy donor. These results clearly indicate that LDLT using obligate heterozygous carriers as donors is a viable therapeutic option for PA. An early LT (ideally within the first year of life) has been considered for younger children with non-severe PA [13‐15], and scheduled LT, according to the state of the disease, can almost only be performed in the setting of LDLT. Considering the promising therapeutic value of LDLT in the treatment of PA, LDLT using obligate heterozygous carriers as donors could be considered for selected PA patients, especially in countries with a limited deceased donor pool.

Although LT can theoretically provide a lifelong supply of PCC activity within the allograft, successful transplantation does not result in a cure in individuals with PA due to the ubiquitous enzyme deficiency throughout the body. Other extrahepatic tissues with remaining PCC deficiency, such as skeletal muscle, brain, heart, and kidneys, persistently produce pathognomonic propionate metabolites after LT [43]. These circulating toxic metabolites in turn cause damage to the central nervous system, heart, kidneys, and other organs throughout the body. Therefore, continued levocarnitine supplementation in the posttransplant period is advocated for all patients to enhance the excretion of propionate metabolites. Nevertheless, some liver transplant recipients with PA have been reported to develop metabolic decompensation, cardiomyopathy, and kidney dysfunction during long-term follow-up [13‐15, 20, 28, 33, 44]. Although our patients did not experience the above-mentioned PA-related complications, it is recognized that LT can only achieve partial clinical improvements of this devastating disease and delay the progression of the disease or complications but cannot completely change the natural history of PA. The possibility of post-transplant non-remission or even chronic progression of the disease, especially the occurrence of long-term disease-related complications, should always be kept in mind by transplant surgeons. And patients' parents or guardians should be fully informed of these potential risks before LT. Lifelong regular follow-up, including metabolic, cardiac, renal, and neurological monitoring and evaluation, is necessary for all individuals with PA post-transplant. An experienced interdisciplinary team consisting of metabolism physicians, pediatric hepatologists, pediatric neurologists, pediatric cardiologists, pediatric nephrologists, pediatric transplantation team, metabolic dieticians, and neurorehabilitation physicians is also essential for the long-term management of patients with PA.

This study's limitations included its single-center retrospective nature, small sample size, and relatively short-term follow-up. Nevertheless, we found for the first time that the hepatic expressions of PCCA and PCCB in the heterozygous parental living donor were equal to those of the healthy donor, which provides a solid foundation for the clinical use of LDLT from obligate heterozygous donors in patients with PA.

In summary, our study provides evidence that the hepatic expressions of PCCA and PCCB from the heterozygous donor are comparable to those of the healthy control at the protein level. LDLT using partial liver grafts from asymptomatic obligate heterozygous carrier donors is a viable therapeutic option for selected patients with PA, with no negative impact on both donors' and recipients' postoperative courses.