Review

Evaluation of living donors for hereditary liver disease

(siblings, heterozygotes)
Mureo Kasahara1,*, Johnny C. Hong2, Anil Dhawan3

Summary
Living donor liver transplantation (LDLT) is recognised as an alternative treatment modality to reduce waiting list mortality and
expand the donor pool. Over recent decades, there have been an increasing number of reports on the use of LT and specifically
LDLT for familial hereditary liver diseases. There are marginal indications and contraindications that should be considered for a
living donor in paediatric parental LDLT. No mortality or morbidity related to recurrence of metabolic diseases has been observed
with heterozygous donors, except for certain relevant cases, such as ornithine transcarbamylase deficiency, protein C deficiency,
hypercholesterolemia, protoporphyria, and Alagille syndrome, while donor human leukocyte antigen homozygosity also poses a
risk. It is not always essential to perform preoperative genetic assays for possible heterozygous carriers; however, genetic and
enzymatic assays must hereafter be included in the parental donor selection criteria in the aforementioned circumstances.
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction In 2014, the American Association for Study of Liver Dis-

The critical discrepancy between donor graft supply and de- ease, American Society of Transplantation, and the North
mand continues for paediatric liver transplant recipients, which American Society for Pediatric Gastroenterology, Hepatology,
has resulted in increased waiting list mortality of children and Nutrition published practice guidelines for paediatric LT,
awaiting liver transplantation (LT). This issue is particularly in which indications and contraindications for paediatric LT
problematic in small paediatric patients. For example, children recipients were described in detail.10 According to the
younger than two years of age in the United States have a more guidelines, absolute contraindications for paediatric LT are
than 1 in 10 risk of dying while waiting for a liver transplant those clinical circumstances that consistently lead to poor
compared to 1 in 20 for older children. To ameliorate the organ outcomes for recipients, such as hepatocellular carcinoma
shortage, partial graft LT utilising deceased (split LT) and living with extrahepatic disease progression, uncontrolled systemic
donors (LDLT) has been adopted since the early 1990s.1 infection, severe multisystem mitochondrial disease, and se-
Concurrently, the number of whole-organ and partial liver vere porto-pulmonary hypertension not responsive to medi-
grafts from deceased donors that are available for children has cal therapy.
steadily decreased in the last decade.2 Consequently, LDLT Among the indications for paediatric LT, hereditary meta-
has been increasingly recognised as an essential addition to bolic liver diseases present unique challenges in terms of pa-
deceased donor liver transplantation (DDLT) in mitigating tient management and liver graft options. Despite maximum
waiting list mortality and increasing the number of LT proced- medical and nutritional management, many inborn errors of
ures.3 Moreover, LDLT is particularly critical in countries where metabolism that affect the liver remain lethal and have a poor
DDLT has not been well established.4 prognosis. Metabolic decompensation can result in severe
In contrast to the practice in Western countries, where neurological sequelae and even mortality in some individuals
deceased donors are the primary organ source for LT, partial with inborn errors of metabolism.11 As such, timely LT has
liver grafts from living donors account for over 97.5% of become an important therapeutic modality and may offer a
paediatric LT procedures in Japan and are the predominant complete or partial cure for many metabolic disorders.12,13
form of paediatric LT in Southeast Asia and the Middle East Metabolic disorders have become the second largest indica-
region.5–7 In this regard, ensuring the safety of living donors tion for LT. The percentages of paediatric LT procedures per-
and excellent outcomes for recipients is paramount and re- formed for familial hereditary liver diseases increased over the
quires careful and methodical donor evaluation and optimal past three decades from 15.4% to 19.4% in the United States
donor-to-recipient matching.8,9 and from 8.0% to 14.2% in Japan.14,15

Keywords: Hereditary liver disease; Indication; Metabolic liver disease; Pediatric liver transplantation; Liver transplantation; Living donor liver
transplantation.
Received 24 August 2022; received in revised form 11 October 2022; accepted 12 October 2022
* Corresponding author. Address: National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan. Tel.:
+81-3-3416-0181, fax: +81-3-3416-2222.
E-mail address: [email protected] (M. Kasahara).
https://doi.org/10.1016/j.jhep.2022.10.013

Journal of Hepatology, June 2023. vol. 78 j 1147–1156

 Keypoints
 LDLT is increasingly being used for familial hereditary liver diseases, but there are marginal indications that should be considered for
living donors prior to performing paediatric parental LDLT.
 Most familial hereditary liver diseases have autosomal recessive traits, where living donors are generally blood relatives who are
obligate heterozygous carriers of the disease.
 Familial hereditary liver diseases pose the potential risk of the donor graft having inadequate metabolic function.
 Careful donor evaluation is necessary, including preoperative genetic assays, in the context of ornithine transcarbamylase deficiency,
protein C deficiency, hypercholesterolemia and protoporphyria, as well as in asymptomatic parental donors with a paucity of intrahepatic
bile ducts (for recipients with Alagille syndrome), and parental donors with human leukocyte antigen homozygosity.

Most familial hereditary liver diseases have autosomal Living donor evaluation for OTCD
recessive traits, where living donors are generally blood rela- OTCD—a urea cycle disorder of X-linked inheritance—is the
tives who are obligate heterozygous carriers of the disease. most common indication for LT among metabolic liver diseases
This poses the potential risk of the donor graft having inade- in children. The prevalence of OTCD is approximately 1 in
quate metabolic function. In the Japanese experience, mortality 50,000 births.20 OTCD can present as severe neonatal onset
or morbidity related to recurrence of such diseases has not disease or as late-onset disease. Affected hemizygous males
been observed with the use of heterozygous donors, except for usually present with the neonatal-onset type, with severe
relevant cases such as ornithine transcarbamylase deficiency manifestations during the first day of life. Late-onset OTCD can
(OTCD), protein C deficiency, hypercholesterolemia, proto- present from infancy to later childhood, adolescence, or
porphyria, and Alagille syndrome, while parental human adulthood and is frequently triggered by acute stress or illness,
leukocyte antigen (HLA) homozygosity also poses a chal- such as sepsis, surgery, trauma, drugs, or postpartum
lenge.16 Moreover, potential parental donor candidates for re- sequelae. It is often refractory to medical treatment, which
cipients with hepatorenal fibrocystic disease, such as Caroli consists of protein restriction combined with special formulas
disease and congenital hepatic fibrosis, are known to have to supplement essential amino acids, and sodium benzoate
morphological abnormalities (multiple liver cysts and peripheral and/or sodium or glycerol phenylbutyrate as alternative
bile duct dilatation).17 Recipients with primary sclerosing pathway therapies.21–23 LT can offer a complete cure for OTCD
cholangitis and autoimmune hepatitis receiving LDLT from as the metabolic defect is exclusively within the liver.24 LT for
close relatives have been shown to have a poor prognosis.18,19 OTCD has been applied clinically since the mid-1990s; the
With this background, and in the context of the increasing main purpose of LT for this and other congenital metabolic
use of LT and specifically LDLT for familial hereditary liver disorders would be to supply missing enzymes by replacing the
diseases, it is a necessary precaution to illustrate the marginal native liver with a normally functioning graft.25
indications or contraindications that should be considered for a The outcomes of employing heterozygous donors have
living donor in paediatric LDLT procedures. been excellent, with better long-term survival rates, although it
has been reported that OTCD LT recipients could experience
Marginal parental donors for paediatric LDLT hyperammonaemia following successful LDLT using heterozy-
Although LDLT has been indicated for a variety of metabolic gous maternal donor grafts, as the implanted graft obviously
disorders, there are several instances in paediatric LDLT where exhibits a low OTC activity, which may vary widely among
a parental donor transplant may be contraindicated (Table 1). different liver segments or even hepatocytes in heterozygous

Table 1. Relevant risks of using grafts from parental donors for paediatric LDLT.
Original liver disease Inheritance pattern Prevalence Marginal parental donors Risk associated with LDLT
Ornithine transcarbamylase deficiency X-linked 1 in 17,000–80,000 births Heterozygous mother Hyperammonaemia
Protein C deficiency Autosomal recessive 1 in 20,000 births Heterozygous parents Thromboembolic events
Familial hypercholesterolemia Autosomal dominant 1 in 160,000–300,000 births Heterozygous parents Hypercholesterolemia
Acute intermittent porphyria Autosomal recessive 1 in 20,000 births Heterozygous relatives Decrease in porphobilinogen
deaminase activity
Erythropoietic protoporphyria Autosomal recessive 1 in 50,000–75,000 births Heterozygous relatives Decrease in ferrochelatase
activity
Alagille syndrome Autosomal dominant 1 in 100,000 births Asymptomatic parental Cholestasis
donor with paucity of
intrahepatic bile duct
Hepatorenal fibrocystic disease Autosomal recessive 1 in 20,000 births Heterozygous relatives Multiple liver cysts connected
with intrahepatic biliary tract
(Cholangitis)
All living donors – 3.2% in Japan Homozygous HLA parental GVHD
donor
GVHD, graft-versus-host disease; HLA, human leukocyte antigen; LDLT, living donor liver transplantation.

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 Review

OTCD female donors.26,27 It has been reported that a hetero- hypercholesterolemia have been reported, with both donors
zygous OTCD female donor showed increased urine orotic acid and recipients maintained on cholesterol-lowering drugs after
and orotidine levels following the allopurinol loading test.28 transplantation.38,39 LDLT using grafts from donors with het-
Moreover, hyperammonaemia can be precipitated by infec- erozygous familial hypercholesterolemia might lead to some
tion, anaesthesia, parturition, or surgery in up to 18% of het- alleviation of LDL-cholesterol levels but could induce prema-
erozygous OTCD female donors because of skewed X- ture atherosclerotic cardiovascular disease, either in the
inactivation, and it is more likely to be present in elderly pa- recipient or donor in the long term, although the potential risk to
tients.29 As donor safety should be mandatory in any LDLT the donor should be taken into consideration.
programme, women who are heterozygous for OTCD are not
suitable living donor candidates. On the other hand, LDLT Living donor evaluation for porphyrias
could be safely employed in other urea cycle disorders with Porphyrias are metabolic diseases that cause accumulation of
autosomal recessive inheritance, such as carbamoyl phos- intermediate compounds in the biosynthetic heme pathway,
phate synthetase-1 deficiency, citrullinemia, and arginino- where each disease represents a defect in one of the eight en-
succinic aciduria.15 zymes.40 Such diseases occur principally due to mutations in the
genes encoding the enzymes involved in heme production. Acute
Living donor evaluation for congenital deficiency of porphyrias present with immediate and severe abdominal pain,
protein C often accompanied by an over-activity of the sympathetic ner-
Congenital deficiency of protein C, a vitamin K-dependent vous system. The prevalence of porphyria is stated as 1 in 25,000
serine protease produced by the liver, is a rare and life- births.41 Although there are differences in the hereditary pattern,
threatening disorder with an autosomal recessive inheritance. LT may be required to prevent the recurrent and possibly life-
Patients with congenital protein C deficiency typically present threatening onset of acute intermittent porphyria, acute liver fail-
with various forms of thrombosis and haemorrhage in the ure, or end-stage chronic liver disease with erythropoietic pro-
neonatal period that can result in serious consequences, such toporphyria. LT in acute intermittent porphyria is classified as
as purpura fulminans, ophthalmic thrombosis, and cerebral corrective surgery; however, individuals with erythropoietic pro-
thrombosis.30 Protein C deficiency is an autosomal recessive toporphyria who are in need of LT should also be considered for
inherited disease with an estimated prevalence of approximately bone marrow transplantation to achieve complete disease
1 in 20,000 births, generated from a homozygous mutation in remission.42 The family history often reveals no other affected
the PROC gene.31 Treatment with protein C concentrate and a members due to the low penetrance of the clinical manifestations
vitamin K antagonist is effective; however, long-term manage- of porphyria, resulting in a significant proportion of heterozygotes
ment is uncertain due to the lack of an appropriate dosing remaining asymptomatic.43 It has been reported that porphobili-
regimen.32 LT is an established curative therapy for protein C nogen deaminase activity in individuals with heterozygous acute
deficiency; however, the use of a heterozygous parental donor intermittent porphyria decreased to 50% of the normal range.44
may induce thrombophilia in the recipient, donor, or both. In a One LDLT candidate with acute intermittent porphyria received
case report, a donor with heterozygous protein C deficiency a liver from an asymptomatic sibling and subsequently developed
required aggressive thromboprophylaxis and protein C a recurrence of acute porphyria 4 years after transplantation with
concentrate administration following the donor operation due to significant elevations in urinary porphobilinogen and amino-
borderline low clottable protein C activity levels.33 Based on the levulinic acid levels.45 Moreover, a decrease in ferrochelatase
significant risk of such thromboembolic events, heterozygous activity, the terminal enzyme of the biosynthetic heme pathway,
protein C deficiency in a parental donor should be considered a has been reported in erythropoietic protoporphyria heterozy-
contraindication for LDLT. gotes.46 Therefore, individuals with heterozygous porphyria
might not be suitable candidates for living donation. In the liter-
Living donor evaluation for familial hypercholesterolemia ature, three LDLT cases with erythropoietic protoporphyria were
reported. Although detailed information was not available from
Familial hypercholesterolemia is an autosomal dominant ge- the manuscripts, one patient died from cerebral herniation 58
netic disorder, resulting in elevated serum LDL-cholesterol and days after LDLT.46,47 Candidates with porphyria should therefore
a high frequency of cardiovascular disease.34 The reported not receive a living donor graft from relatives unless the same
prevalence ranges from 1 in 160,000 to 300,000 births.35 Early genetic porphyrin disorder was previously excluded by ge-
diagnosis, as well as prompt and aggressive treatment, are netic testing.
fundamental steps to prevent cardiovascular complications
and a high rate of premature mortality in children and adoles-
Living donor evaluation for Alagille syndrome
cents. The current medical therapy, including statins and eze-
timibe, does not ameliorate atherosclerosis in affected patients. Alagille syndrome is an autosomal dominant disorder caused
A recent report showed that the inhibition of angiopoietin-like by pathogenic variants in the JAG1 or NOTCH2 genes, which
protein 3 with evinacumab, a monoclonal antibody, halves encode fundamental components of the Notch signalling
LDL-cholesterol levels in individuals with homozygous familial pathway. Multiple organ systems (including hepatic, cardiac,
hypercholesterolemia via an LDL cholesterol-independent vascular, renal, skeletal, craniofacial, and ocular systems) are
mechanism; however, long-term effectiveness is not well affected.48 Alagille syndrome occurs in approximately 1 in
documented.36 LT offers the most effective treatment modality 100,000 live births. The most prominent hepatic manifestations
to reduce circulating levels of LDL-cholesterol and thereby the are cholestasis caused by a paucity of intrahepatic bile ducts,
risk of cardiovascular events.37 To date, three LDLT cases conjugated hyperbilirubinemia, and pruritus.49 End-stage liver
utilising grafts from donors with heterozygous familial disease is often the consequence. LT is typically indicated in up

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A B

Fig. 1. Imaging study of an asymptomatic heterozygous parental donor with Alagille syndrome. (A) MRCP in an asymptomatic heterozygous parental donor with
Alagille syndrome showed paucity of intrahepatic bile ducts (arrow). (B) Histopathological examination in this donor with Alagille syndrome demonstrated paucity of
intrahepatic bile ducts and cholestasis in the hepatocytes (cytokeratin 7 staining, arrow). MRCP, magnetic resonance cholangiopancreatography.

to 20% of cases, wherein it is associated with excellent out- with medical complications, such as cholangitis and biliary
comes.50,51 However, parental mosaicism of Jagged1 muta- calculi, either in the donor or recipient, even after successful
tions in families with Alagille syndrome has been documented; LDLT.59 If there is no connection between the cysts and the
intrahepatic bile duct paucity is mainly reported in the asymp- intrahepatic biliary tract in the preoperative imaging study and
tomatic heterozygous parental donor and is associated with a intraoperative cholangiogram, LDLT may still be appropriate
poor prognosis in the recipient due to insufficient biliary using grafts from parental donors with multiple cysts.
drainage (Fig. 1).52,53 Therefore, potential donor candidates
should be carefully evaluated with magnetic resonance chol- Donor-dominant one-way HLA matching in homozygous
angiopancreatography, liver biopsy, an intraoperative cholan- HLA parental donors
giogram, and genetic studies if appropriate. While rare, graft-versus-host disease (GVHD) is one of the most
feared complications of LT. It is characterised by fever, skin
Living donor evaluation for hepatorenal fibrocystic disease rash, diarrhoea, and pancytopenia with a poor prognosis.60 It
Hepatorenal fibrocystic disease is a heterogeneous disease, has been well documented that using a graft from a homozy-
mostly autosomal recessive, which involves increased hepatic gous HLA parental donor, who shows one-way HLA matching
fibrosis in association with cysts lined by biliary epithelium and with a haploidentical recipient, significantly increases the risk of
occurs at a prevalence of 1 in 20,000 births.54 Histopatholog- GVHD after LDLT. Therefore, LDLT using grafts from homozy-
ical characteristics are ductal plate malformations and peri- gous HLA parental donors should be avoided.61,62 The homo-
portal fibrosis. Resulting conditions include biliary zygous HLA entity occurs at a prevalence of 3.2% in Japan,
microhamartomas (von Meyenburg complexes), autosomal which is higher than in other countries, owing to its ethnically
dominant polycystic kidney disease, autosomal recessive homogenous population.63 Consequently, preoperative HLA-
polycystic kidney disease, congenital hepatic fibrosis, Caroli DNA typing, although it is time consuming, is strongly recom-
disease, and Caroli syndrome.55 Congenital hepatic fibrosis mended for combinations that could increase the risk of GVHD
and Caroli disease are the most common liver manifestations, in the LDLT setting.64 Transplant physicians may be better able
and the highly heterogenous clinical presentations involve to distinguish among HLA-subgroups and donor heterozy-
portal hypertension and cholangitis. The treatment is support- gosity with the increasing availability of gene analyses.
ive, aiming at management of portal hypertension and recurrent
cholangitis; LT is indicated in patients who are unresponsive to Other risk factors in parental LDLT
conservative treatment.56 In our experience, 67% of parental Several notable physiological changes during pregnancy in-
donors with hepatorenal fibrocystic disease show multiple he- crease the risk of liver dysfunction, such as steatosis and hy-
patic cysts without any histopathological abnormalities on liver percoagulability, as 3% of pregnant women showed liver
biopsy at the time of LDLT.57 Preoperative MRI has been dysfunction with spontaneous recovery in the puerperium.65
suggested to be more sensitive than computed tomography at Additionally, it has been reported that blood coagulation and
revealing irregularly delineated hyperintense nodules that fibrinolysis variables are affected during pregnancy and return to
demonstrate no communication with the intrahepatic biliary normal range by 21 days postpartum; the venous thromboem-
system (Fig. 2).58 Communicating ductal cysts have more bolism rates during the first through third weeks postpartum
clinical significance because they tend to present in association

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 Review

A B

Fig. 2. Imaging study of a parental donor with hepatorenal fibrocystic disease. (A) MRCP showed the presence of multiple cysts without any abnormal findings for
the biliary anatomy (arrow shows normal biliary anatomy). (B) Explanted left lateral segment graft with multiple cysts (arrows). MRCP, magnetic reso-
nance cholangiopancreatography.

were 14 times higher than in non-pregnant, non-postpartum recipients showed marked improvement after LDLT using
women.66 There are serious medical and ethical considerations if grafts from heterozygous donors.75 LDLT using grafts from
a pregnant or postpartum mother insists on undergoing partial heterozygous donors is safe and effective, and is associated
hepatectomy to save her child with end-stage liver disease. LT with an excellent survival rate (75.8% in 30 years) which is
physicians and their patients confront distinctive ethical chal- comparable to that of patients receiving the liver from a
lenges, given that a defining feature of such interventions is that deceased, unrelated donor.15
beneficence-based ethical obligations to the postpartum mother
can conflict with ethical obligations to the neonatal patient.67 LDLT for organic acidaemia
There are several reports of successfully utilising grafts from Recently, the efficiency of LT for organic acidaemia has been
pregnant and postpartum maternal living donors for LT; how- increasingly recognised.76,77 Organic acidaemias are a het-
ever, given the potential medical and ethical risks involved, LT erogeneous group of inborn errors of metabolism caused by
should be undertaken only when there is absolutely no other disruption of normal amino acid metabolism that result in the
donor and the recipient is in urgent need.68,69 accumulation of toxic intermediary metabolites. Methylmalonic
acidaemia (MMA) and propionic acidaemia (PA) are the most
Applicable parental donors for paediatric LDLT frequent organic acidaemias with prevalences of 1:69,000 and
LDLT for Wilson’s disease 1:240,000 births, respectively.78 Implanted liver grafts produce
Wilson’s disease (WD) is a rare autosomal recessive disorder deficient enzymes in patients with organic acidaemia, hence
characterised by copper accumulation in several organs the procedure only partially corrects the biochemical defects,
caused by mutations in the ATP7B gene; historically, it was as the enzymes are expressed in most cells and surgery may
the most common indication for LT among the metabolic liver not prevent the development of progressive renal and neuro-
diseases.70 The prevalence of WD was reported to be logical deterioration. However, the Japanese LDLT registry
1:40,000 births.71 LT is used for patients with chronic liver demonstrated that the use of LDLT for organic acidaemia was
failure and the fulminant form of WD. However, conventional associated with acceptable patient survival (85.2% at 10
medical treatment with copper-chelating agents (D-penicilla- years).79 We analysed MMA-CoA mutase activity in liver bi-
mine, trientine hydrochloride) and zinc salt, combined with opsy specimens from a recipient and heterozygous paternal
early diagnosis, can improve a patient’s condition.72 Hence, donor at the time of LDLT, which revealed 0.0 and
more patients can now be maintained on medication without 2,351.3 pmol succinyl-CoA/min/mg protein, respectively.
LT, and the percentage for whom LT is indicated has However, further validation is necessary. The heterozygous
decreased from 43.9% to 12.7% in the past 10 years.15 It has donor demonstrated acceptable MMA-CoA mutase activity in
been reported that LDLT using a heterozygous donor has the liver. Post-LDLT with a heterozygous donor, the recipient’s
been safely applied for WD.73,74 We demonstrated that the serum methyl-malonic acid level was significantly reduced with
serum copper and ceruloplasmin levels were below the conventional medical treatment.80 Regarding individuals with
normal range in 50% of heterozygous donors, and urinary PA, it has been reported that the metabolite levels, such as
copper was above the normal range in 40% of heterozygous urine methyl citrate, serum-free carnitine level, and serum
donors. All heterozygous donors were asymptomatic for WD propionyl carnitine, are stabilised following LDLT using grafts
with normal liver function, and liver biopsies obtained from the from heterozygous parental donors.81 The benefits of an
liver graft showed no changes suggestive of WD. Serum improved quality of life associated with the elimination of ep-
ceruloplasmin, serum copper, and urinary copper levels in isodes of metabolic decompensation and improved protein

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tolerance must be weighed against potential neurological LDLT for primary hyperoxaluria type 1
injury in individuals with organic acidaemias, but LDLT can be Primary hyperoxaluria type 1 (PH1) is an autosomal recessive
safely employed.82 inherited disorder of glyoxylate metabolism which is caused
by a deficiency of liver-specific peroxisomal alanine-
LDLT for alpha 1 antitrypsin deficiency glyoxylate aminotransferase (AGT); overproduction of oxalate
Alpha-1 antitrypsin (A1AT) deficiency is an autosomal recessive leads to urolithiasis and subsequently renal failure.98 The
disorder that predisposes individuals to the development of prevalence of PH1 is 1:120,000 births.99 Liver and kidney
lung and liver disease due to insufficient secretion of glyco- transplantation has been applied to correct the metabolic
protein A1AT from the liver. Although geographical and racial defect and end-stage renal failure and is associated with
disparities exist, its prevalence is 1:5,000 births.83,84 The excellent outcomes.100 The efficacy of LDLT using a graft from
classical form of severe A1AT deficiency is due to a homozy- a heterozygous PH1 donor has not been well documented. We
gous point mutation in the SERPINA gene that leads to mis- measured the AGT catalytic activity of graft livers that were
folding of the mutant protein, intracellular polymerisation, and genetically characterised as heterozygous PH1. AGT activity
consequent accumulation of protein aggregates in the endo- levels in graft livers were available for three cases, and were
plasmic reticulum of hepatocytes. This toxic gain of function 30.9%, 35.0%, and 77.2% of control activity levels. Although
can induce chronic endoplasmic reticulum stress, development the AGT activities were lower compared to the normal control,
of fibrosis, and in some cases progression to cirrhosis, hepa- none of the donors and recipients showed any clinical
tocellular carcinoma, or both.85 LT for A1AT deficiency, which symptoms or abnormal laboratory findings related to PH1, and
was first reported in 1977, is associated with an excellent pa- excellent recipient survival was achieved.101 A previous report
tient survival rate of 89.1% at 20 years.86,87 It has been re- showed that the mean AGT activity in individuals with PH1
ported that LDLT using a heterozygous donor for A1AT was 3.3% and that AGT activities of PH1 heterozygous car-
represents a complicated post-transplant course owing to riers were intermediate at 30%-50%.102 It is unclear how to
acute cellular rejection and massive ascites.88 Even though interpret the relatively low AGT catalytic activity of the graft
heterozygous living donors demonstrated lower serum A1AT livers in the previous series. However, liver grafts from het-
concentrations compared to normal controls, biopsy of the erozygous carriers of PH1 can be safely used for LDLT in
allograft pre-reperfusion demonstrated normal liver histopath- most cases.
ological findings with no evidence of cholestasis, steatosis, or
inflammation, and no cytoplasmic globules on periodic acid- LDLT for primary maple syrup urine disease
Schiff staining.89,90 As the post-transplant A1AT levels reach Maple syrup urine disease (MSUD) is an autosomal recessive
the normal range within a few months following LDLT in the disorder associated with impaired metabolism and accumula-
recipient and adequate liver synthetic function occurs in both tion of branched-chain amino acids (BCAAs), such as leucine,
donors and recipients post-transplant, grafts from heterozy- isoleucine, and valine. Children with MSUD suffer from meta-
gous A1AT donors can be safely utilised for LDLT. bolic decompensation, which may lead to neurological
sequalae and even death as a result of brain swelling despite
LDLT for Crigler-Najjar syndrome type 1 nutritional and medical treatment. MSUD occurs in 1:185,000
Crigler-Najjar syndrome (CNS) type 1, which was first reported live births.103 Approximately 10% of branched-chain alpha-
in 1952 as a congenital familial non-haemolytic jaundice with ketoacid dehydrogenase complex (BCKDH) enzyme activity is
kernicterus, is an extremely rare autosomal recessive mono- in the liver and LT is a therapeutic option for MSUD in those
genic disease with a prevalence of 1:1,000,000 births.91 Clinical with poor metabolic control and poor quality of life; LT is
manifestations include bilirubin conjugation caused by hepatic associated with excellent patient survival for this indication.104
uridine 50 -diphosphate (UDP) glucuronyl transferase deficiency, Selecting a related donor for MSUD is challenging, because the
which can provoke the accumulation of neurotoxic unconju- parental donor is inevitably a carrier of a genetic mutation.
gated bilirubin and subsequently result in irreversible neuro- However, it has been reported that BCKDH activity was in the
logical consequences and mortality.92. LT has been indicated normal range in a genetically proven parental donor, and 100%
for patients not responding to conventional medical treatment activity of whole-body BCKDH is not necessary for metabolic
(phototherapy, phenobarbital, and ursodeoxycholic acid) and is improvement in recipients with MSUD.105 Heterozygous liver
associated with excellent long-term results.93,94 To the best of segments may effectively provide steady-state BCAAs and
our knowledge, eight parental LDLT procedures have been branched-chain ketoacid homeostasis.106 Twenty-four parental
reported worldwide, with the recipient age ranging from 4 LDLTs for MSUD have been reported, and 22 patients are
months to 13 years. Although one patient died from aspiration doing well at the time of publication.15,105–109 One patient died
pneumonia 10 months following successful LDLT, others were from sepsis due to intestinal perforation 86 days following
alive with an excellent graft function at the time of publica- LDLT, and the other experienced acute metabolic crisis 5
tion.15,95,96 It has been reported that heterozygotes of CNS months after LDLT. The latter developed encephalopathy with
type 1 showed relatively low UDP-glucuronyl transferase ac- progressive lethargy and seizures after an episode of gastro-
tivity in the liver without clinical manifestations relevant to CNS enteritis with dehydration. Plasma levels of leucine, isoleucine,
type 1.97 Heterozygotes of CNS type 1 may exhibit some de- and valine were markedly elevated and alloisoleucine was
fects in bilirubin metabolism; however, they do not exhibit any detected. This case suggests that some recipients of LT from a
physical findings of CNS type 1 and can therefore be consid- haploidentical parent possess limited capacity to oxidise
ered as potential donors for LDLT. BCAAs at the time of catabolic stress and remain at risk of

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 Review

Table 2. Donor evaluation for paediatric LDLT for hereditary liver diseases.
Item Requirements
Age 18–65 years
Absence of major medical issues Diabetes, hypertension, or hepatic, cardiac, renal, or pulmonary disease
General blood test ABO-Rh typing, complete blood count, coagulation test, renal and liver function test
Serologic test Hepatitis B, C virus, human immunodeficiency virus, Human T-cell leukaemia virus type 1,
syphilis, cytomegalovirus, Epstein-Barr virus
HLA test To exclude homozygous parental donor
Routine imaging study Chest X-ray, dynamic liver CT with volumetry, ultrasonography
Heart and lung work-up Electrocardiography, echocardiography, pulmonary function test
Psychosocial evaluation Assess the psychological fitness of the donor including the ability to understand and
accept the risks and benefits of donation
Indication for LDLT Additional inspections for potential donor candidates
Urea cycle disorder Genetic analysis to exclude heterozygous OTCD mother
Congenital deficiency of protein C Genetic analysis to exclude heterozygous donor
Familial hypercholesterolemia Genetic analysis to exclude heterozygous donor
Porphyrias Genetic analysis to exclude heterozygous donor
Alagille syndrome Assessment of intrahepatic bile ducts on MRCP or liver biopsy and/or genetic analysis for asymptomatic donors
Hepatorenal fibrocystic disease MRCP to detect multiple liver cysts and determine whether they are connected with intrahepatic biliary tract
Wilson’s disease None
Organic acidaemia None
Alpha 1 antitrypsin deficiency None
Crigler-Najjar syndrome type 1 None
Primary hyperoxaluria type 1 None
Maple syrup urine disease None
LDLT, living donor liver transplantation; MRCP, magnetic resonance cholangiopancreatography; OTCD, ornithine transcarbamylase deficiency.

severe metabolic crises.109 Most individuals with MSUD are potential contraindications for LDLT, namely, heterozygous
doing well with an unrestricted diet after LDLT; however, careful mothers with OTCD, heterozygous parents with protein C
metabolic monitoring may still be required if the donor was deficiency, hypercholesterolemia, or protoporphyria, asymp-
heterozygous for MSUD. tomatic parental donors with a paucity of intrahepatic bile ducts
in Alagille syndrome, and homozygous HLA parental donors. It
Conclusion is not always essential to perform preoperative genetic assays
LDLT is an attractive option for paediatric patients awaiting LT for possible heterozygous carriers according to the latest evi-
as it can effectively reduce transplant waiting time and allow dence; however, genetic and enzymatic assays must be
candidates to undergo LT with excellent results. The funda- included hereafter in the parental donor selection criteria under
mental goals of LDLT are to ensure an adequate preoperative the aforementioned circumstances. Table 2 summarises po-
donor evaluation, and safe, planned donor surgery for the tential donor evaluation for paediatric LDLT for hereditary liver
recipient. To minimise surgical risks in otherwise healthy living disease. To validate the findings discussed herein, larger case
donors and maximise post-transplant outcomes in recipients, it series are required to confirm the efficacy of heterozygous
is essential to determine which medical and metabolic abnor- parental donors, the indications for LT, and the long-term
malities are acceptable for both donor and recipient liver prognosis for both donors and recipients, in the context of
function after LDLT.110,111 Based on the experience of more expanding the donor pool to save the paediatric patients who
than 4,000 paediatric LDLT procedures, we have discussed the are in dire need of LT.

Affiliations
1
Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan; 2Division of Transplant Surgery, Department of Surgery, Medical
College of Wisconsin, Milwaukee, USA; 3Paediatric Liver GI and Nutrition Center and MowatLabs, King’s College Hospital, London, UK

Abbreviations Conflict of interest

A1AT, alpha 1 antitrypsin; AGT, alanine-glyoxylate aminotransferase; BCAAs, The authors declare no conflicts of interest that pertain to this work.
branched-chain amino acids; BCKDH, branched-chain alpha-ketoacid dehydro- Please refer to the accompanying ICMJE disclosure forms for further
genase complex, DDLT, deceased donor liver transplantation; GVHD, graft- details.
versus-host disease; HLA, human leukocyte antigen; LDLT, living donor liver
transplantation; LT, liver transplantation; MMA, methylmalonic acidaemia; OTCD, Authors’ contributions
ornithine transcarbamylase deficiency; MSUD, Maple syrup urine disease; PA,
propionic acidaemia; PH1, primary hyperoxaluria type 1; UDP, uridine 50 - MK designed and wrote the manuscript. JH and AD prepared the final version.
diphosphate; WD, Wilson’s disease.
Supplementary data
Financial support Supplementary data to this article can be found online at https://doi.org/10.1016/
The authors received no financial support to produce this manuscript. j.jhep.2022.10.013.

Journal of Hepatology, June 2023. vol. 78 j 1147–1156 1153

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