Liver and Hematopoietic Stem Cell Transplantation

Liver and hematopoietic stem cell transplantation (HSCT) have established their places in the ever-increasing number of individual indications in their respective fields of modern medicine. However, there is a group of overlapping conditions in immunology, hematology, metabolic medicine, and oncology where a combination of these two procedures could occasionally be considered as a potential cure. Some of these combined clinical scenarios requiring both procedures are urgent, for example, when a patient needs to be considered for emergency liver transplant (LT) owing to severe complications of already performed HSCT, such as chronic graft-versus-host disease (GvHD) or sinusoidal obstruction syndrome (SOS). Under these circumstances, the fast-evolving nature of the life-threatening liver injury leaves little time for discussions about the timing of LT. On the other side, some children may present with acute liver failure (ALF) and require urgent LT, with no time to fully investigate any possible underlying congenital immunological or hematological problems. The post-LT situation gives more time to plan HSCT if indicated, allowing clinical stabilization of the patient and establishing a good function of the liver graft. This then permits a search for the HLA-matched donor, preferably within the family, and the appropriate planning of required pre-HSCT conditioning. The examples of the latter scenario include primary immune deficiencies (PIDs), such as perforin deficiency or X-linked lymphoproliferative syndrome—both causes of primary or familial hemophagocytic lymphohistiocytosis (HLH), some very rare primary red cell membrane defects (such as spectrin deficiency or phosphoglycerate kinase deficiency), and severe aplastic anemia. Of course, the donor should be genetically confirmed not to be affected by the condition leading to HSCT.

In contrast with these acute scenarios, where the higher morbidity and mortality risks must be accepted with no clinical hesitation, elective combinations of LT and HSCT are more challenging. Classical examples for those are PIDs, where in about 25% of them, a long-standing immune deficit leads to a progressing degree of chronic liver disease—in about 60% of them diagnosed as chronic cholangiopathy and biliary cirrhosis. If LT is performed in isolation, the ongoing primary immune deficit will inevitably lead to the recurrent damage of the graft, possibly even more accelerated because of the added antirejection treatment, within a few months post-LT. Therefore correcting an underlying immune deficit through HSCT is mandatory for solving this complex clinical situation. A similar requirement for sequential liver and HSCT may be indicated in severe sickle cell disease hepatopathy, although hematological management of sickle cell disease only exceptionally requires HSCT. It is usually assumed that meticulous hematological treatment with frequent transfusions, hydroxyurea, and chelation is sufficient to prevent sickle cell disease–related injury of the liver graft post-LT, but that is not always the case. Chronic iron overload could also lead to a significant progressive liver injury in thalassemias and require consideration for the combination transplants. The morbidity risks associated with the dual procedures are clearly increased, and each patient scenario needs to be assessed on a strictly individual basis.

Liver and Hemopoietic Stem Cell Transplantation for Achieving Immunological Tolerance

Although for many years there have been attempts in solid organ transplantation to introduce HSCT as a possible facilitator of immune tolerance, most of the reported experience is anecdotal and limited. The concept is based on the idea that obtaining full donor chimerism would switch off antigenic capabilities of the graft and therefore preclude requirements for long-term immune suppression. Theoretically, organ donations from the living related donors (“haploidentical”) should be advantageous to achieve that goal. However, in the clinical setting, such relations are only exceptionally straightforward. Myeloablation before HSCT could lead to potentially better engraftment rates but also to a higher incidence of GvHD, although this can be variable. Furthermore, the aggressive preconditioning increases risks for the peri-HSCT liver complications, including infections, GvHD, SOS, or drug hepatotoxicity, particularly if the liver (or liver graft) function is a priori suboptimal. Nowadays, different sources of stem cells are available, including from unrelated human leukocyte antigen (HLA)-matched donors, haploidentical donors, autologous, HLA-matched umbilical cord, or peripheral blood stem cells, and they may all have different engraftment, complication, and outcome rates, making the elective procedures even more difficult to plan, assess, and eventually to compare.

There are reports of “incidental” stem cell transplants through LT or small bowel transplantation, where the donor chimerism has been observed and operational tolerance achieved presumably through passenger lymphocytes from the transplanted organ. Complete hematopoietic chimerism has been observed in a 9-year-old girl who received an LT for ALF and then achieved a full bone marrow engraftment through donor stem cells from the liver graft. The concept that for the immune tolerance, hematological chimerism needs to be established has been recently challenged by novel suggestions that more clinically relevant could be a skewing of the immunological balance to a predominantly T regulatory cell profile.

Mesenchymal stem cells (MSCs) could be potentially considered in achieving operational tolerance because they have the ability to promote T regulatory cells while reducing the proportion of effector T cells. One randomized, controlled phase I/II study investigated the clinical effects of infusing unrelated MSCs into 10 adult LT recipients on post-operative day 3 and found that the weaning of immune suppression was unsuccessful at 6 to 12 months post-LT. However, there were no discernible clinical effects on the number of episodes of rejection, peripheral lymphocyte profiles, or infection rates during the study, making the clinical application of MSCs in skewing the immunological balance post-LT possible but still experimental. The issues of different strategies to achieve operational tolerance after LT are discussed in more detail elsewhere in this book ( Chapter 45 ).

The main theoretical concerns while considering HSCT and LT are the development of GvHD after introducing the third-party antigens, the ability of the liver graft to cope with conditioning regimens, and the possibility of inducing rejection of a previously successfully transplanted organ. Limited clinical experience so far has not been able to consistently observe these notions. In a recent literature review including all age recipients, the main indication for autologous HSCT post-LT was resistant post-transplant lymphoproliferative disease (PTLD), whereas for allogeneic HSCT, it was aplastic anemia. The reported medium-term survival rates were 75% (12/16) and 86% (12/14), respectively. It is possible that in the future, more consideration will be given to the possible HSCT from the living donor for establishing tolerance following the living donor solid organ transplant. However, at present, the attractive option of future immune suppression withdrawal does not justify and offset the higher risks of the additional transplant procedure.

We shall now review several clinical settings where combined LT and HSCT may be considered.

Liver and Hemopoietic Stem Cell Transplantation for Primary Immune Deficiencies

PIDs are inherited conditions with a typically progressive course involving different life-threatening end-organ damage, including the respiratory and gastrointestinal tracts and liver. To prevent those, HSCT is being increasingly performed electively, particularly in conditions where there are an established pattern and predictable timescale of the complications. Organ injury is almost universally attributed to uncontrolled opportunistic infections. In the context of the liver damage, two conditions known to result in chronic Cryptosporidium -related cholangiopathy are hyper-immunoglobulin (Ig)M syndrome and dedicator of cytokinesis 8 (DOCK-8) deficiency (previously known as hyper-IgE syndrome).

In the majority of these patients, the cholangiopathy progresses to chronic biliary disease. At present, it is not clear why some children respond well to anti- Cryptosporidial prophylaxis (boiling drinking water and paromomycin) while some do not, because there is no clear phenotype/genotype pattern established despite a multitude of different mutations. The current practice in hyper-IgM syndrome and DOCK-8 deficiency is that if the well-matched donor is available, the HSCT should be performed as early as practically possible, often in the first 3 to 5 years of life. The situation becomes more contentious when there is no appropriate donor and the liver disease starts to progress. In such circumstances, each case needs to be individually assessed, including liver biopsy, magnetic resonance cholangiopancreatography, and polymerase chain reaction–based studies for Cryptosporidium in the gastrointestinal tract. The role of hepatologists in assessing liver injury pre-HSCT is critical. If the cholangiopathy is more advanced, the likelihood of HSCT-associated complications, such as systemic infection, drug toxicity, and SOS, all contributing to consequent higher mortality, is increased several-fold. It is likely that emerging diagnostic modalities, including transient elastography and noninvasive scoring systems for the liver injury, would play an increasing role in the hepatological assessment. Some hyper-IgM patients with Cryptosporidium -induced mild cholangiopathy have undergone effective nonmyeloablative HSCTs with complete clearance of Cryptosporidium .

Immunological problems such as GvHD appear to be more related to the degree of pre-HSCT immune ablation (conditioning). Nonmyeloablative or reduced-intensity conditioning has been reported to achieve similar graft acceptance rates with less immunological complications in the setting of established other end-organ damage. Adding ursodeoxycholic acid to the peri-HSCT management also appears to reduce the incidence of the liver complications.

The most difficult scenario in the management of PIDs is when liver injury is very advanced. In the 1990s, some of these children would receive isolated LT, but the outcomes were invariably poor because of a prompt recurrence of the accelerated cholangiopathy in the liver grafts, likely worsened by the added anti-rejection medications. The overwhelming systemic infections were generally unresponsive to anti-infection treatment and have universally led to fatal outcomes. Therefore, a different approach was subsequently proposed, with sequential liver and then HSCT, as soon as the liver graft was deemed suitable to sustain nonmyeloablative conditioning. Despite the increased risks, this sequence has worked in selected patients but recently has been required only exceptionally owing to the generally accepted much earlier consideration for HSCT in PID children who had been deemed to be destined to develop the progressive cholangiopathy. The longest LT/HSCT survivor remains very well on minimal immune suppression after 20 years of follow-up (Hadžić, unpublished observation). There is no evidence to support the theory that the use of liver living related donors improves the outcome of these challenging procedures.

In Table 10.1 , we have summarized our suggestions for optimal management of children with PIDs and liver involvement.

Table 10.1

Suggested management of children with primary immune deficiencies and liver involvement

HLA-matched donor available/no liver disease	Elective HSCT
HLA-matched donor available/mild liver disease	Elective HSCT
HLA-matched donor available/severe liver disease	Sequential LT and HSCT
Suboptimal donor/no liver disease	Consider alternative HSC sources
Suboptimal donor/mild liver disease	High risks/strictly individual assessment
Suboptimal donor/severe liver disease	High risks/strictly individual assessment/palliation

HLA, Human leukocyte antigen; HSCT, hematopoietic stem cell transplantation; LT, liver transplantation.

When LT is performed as a lifesaving emergency procedure for ALF, the cause remains unexplained in approximately 50% of the pediatric cases. Some children with PIDs may belong to this indeterminate category, but typically there is not enough time to perform sophisticated immunological and genetic tests to document the diagnosis. These children could present with the clinical syndrome of HLH, characterized by high fever, splenomegaly, hypertriglyceridemia, hyperferritinemia, and overexpression of soluble interleukin 2 (IL-2) receptor (CD25 ⁺ ) lymphocytes. This hyperinflammatory syndrome has often been underdiagnosed in clinical practice. HLH could be secondary to various infectious or immunologic stimuli, but in a proportion of younger infants, it could be the first manifestation of PID, such as perforin deficiency or X-linked proliferative syndrome (a primary or familial form of HLH). Immune activation markers in both ALF and HLH are quite deranged, but a clinical interpretation of the immunophenotyping profiles is not simple because of a significant overlap of the hyperinflammatory markers. ^34. For example, serum levels of soluble IL-2 receptor, one of the hallmarks of HLH syndrome, have been reported to have a prognostic value in pediatric ALF. There is only one case report suggesting that HSCT could be effective when performed after LT for ALF associated with unrecognized PID, but the generally accepted view is that LT is contraindicated in presence of primary HLH unless the PID is corrected by HSCT. Secondary HLH, when there is no verified underlying immune deficiency, was described to recur in 56% of children after LT and has a mortality rate of 33%, despite aggressive treatment with steroids, etoposide, and immune ablation.

Hematopoietic Stem Cell Transplantation for Aplastic Anemia After Liver Transplantation

ALF remains one of the most puzzling conditions in pediatric hepatology. Etiology of this rare syndrome remains unexplained in approximately 50% of children despite extensive diagnostic efforts. In these indeterminate cases, the occasional presence of some clinical pointers, such as prodromal diarrheal illness, mild fever, or nonspecific rash, could implicate a triggering role of infectious pathogens. In about one-third of children with indeterminate ALF, a bone marrow depression (BMD) is observed, and parvovirus B19 was identified in a small proportion of those. However, the majority of other affected children have no evidence of the presence of this or any other viruses by standard testing. The bone marrow injury usually follows ALF and develops within 1 to 3 months after ALF. This could possibly be further aggravated by the added immune suppression if LT had been required. This deterioration on immune suppressants would also indirectly support the presumed infectious etiology. However, exceptionally, the sequence could be the reverse, and the liver damage would follow the initial pancytopenia and BMD. For unclear reasons, the clinical course in the latter scenario is usually milder and rarely life-threatening.

The management of this rare clinical situation depends on the severity of the BMD, which ranges from mild pancytopenia to a very severe aplastic anemia (VSAA). Bone marrow and trephine examination with cell phenotyping and exclusion of myelodysplastic syndromes and malignancies are essential to guide further clinical management. They would often demonstrate multilineage cellular arrests, various degrees of bone marrow hypoplasia, and absence of respective precursor cells. Severe aplastic anemia (SAA) is defined as pancytopenia with at least two of the following abnormalities: an absolute neutrophil count of less than 500/mm ³ , a platelet count under 20/mm ³ , and a reticulocyte count of less than 60/m ³ , associated with a bone marrow cellularity of less than 30%. VSAA has a bone marrow cellularity of less than 15%.

Avoiding medications potentially aggravating BMD, such as acyclovir, cotrimoxazole, mycophenolate mofetil, or sirolimus, is advisable. Granulocyte colony–stimulating factor should be used sparingly post-LT because it could also mobilize immune cells facilitating the graft rejection. For SAA and VSAA, the current recommended treatment of choice is HSCT if a haploidentical donor is available. This approach removes the risks of late dysplastic and malignant complications that remain after the non-HSCT treatments. The reported success rate is exceeding 90% for haploidentical family donor HSCT. Based on presumed underlying immune pathogenesis of aplastic anemia (AA), in the absence of a well-matched donor, immunoablative treatment with anti-thymocyte globulin, combined with steroids and cyclosporin A, could be effective.

Box 10.1 provides some general guidance on the management of these patients. Very careful monitoring, intense supportive and symptomatic treatment, and early contact with the regional HSCT center are of paramount importance. Because these patients can become quite unwell very quickly, the management must be multidisciplinary, where the hepatologist must seek a considerable hematological input early. The outcome of post-LT HSCT can be surprisingly good, particularly if a sibling donor is available. A recent European study comparatively observed a lower graft failure rate (15% vs. 50%) and better survival (51% vs. 42%) 60 months after HSCT in 13 liver than in 12 kidney transplant recipients of mixed pediatric and adult age. The study, however, failed to identify a preferable source of hemopoietic cells or to validate any negative outcome parameters, suggesting that the assessment must continue to be strictly individualized.

Box 10.1

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