Introduction

The liver plays an important role in the immune defense because of its central position adjacent to the gastrointestinal tract, representing the first line of defense against ingested or translocated pathogens and various antigens from diet.

There are two types of immune response: innate and adaptive. Innate immunity represents the first line of immune defense in which cells such as phagocytes, natural killer (NK) cells, and NK T-cells recognize highly conserved antigens from the invading microorganisms and provide a prompt non-specific inflammatory response. The principal intrahepatic defenders are Kupffer cells – resident macrophages, strongly supported by the action of NK cells, previously also known as Pit cells, which represent approximately 50% of the lymphocyte pool in a healthy liver. In contrast, the adaptive immune system is more phylogenetically advanced and includes highly specialized cells such as T- and B-lymphocytes, produced and differentiated in the lymphoid organs. On stimulation, these cells undergo sophisticated processes of immune diversification enabling them to mount specific immune responses to different invading antigens from the environment. These events are much slower and involve mechanisms such as cell-to-cell interaction, proliferation of B-cells, production of antibodies and cytokines, and activation of effector cytotoxic cells.

Conventionally, the adaptive immune response has been divided into two types: the humoral arm, mediated by B-cells capable of producing antibodies and responsible for mounting defense against bacterial and fungal infections, and the cellular arm, predominantly controlling viral, protozoan, mycobacterial, and other intracellular pathogens. In reality, this distinction is relatively artificial because the immune system, in order to control the infection, must have both of the components activated. This is achieved through a network of complex feedback mechanisms affecting both arms, orchestrated by CD4 T-cells via various co-stimuli on the lymphocyte surface and serine mediators such as acute phase proteins, cytokines, and complement components.

Role of the Liver in Immune Defenses

The main immunologic functions of the liver include participation in the acute inflammatory response, production of acute phase proteins, induction of tolerance to various antigens, tumor surveillance, and elimination of activated lymphocytes [1]. These are achieved through a complex interaction between macrophages, antigen-presenting cells, hepatocytes and effector cells of the innate and adaptive immune system trafficking through the liver. The portal vein is a principal supplier of the liver of massive amounts of lymphocytes and antigens from the intestine, which come into close contact with the endothelial cells through an extensive intrahepatic sinusoidal network. Kupffer cells control the influx of microorganisms and toxins from the gastrointestinal tract by ensuring that the majority of the pathogens are eliminated via phagocytosis before entering the systemic circulation. The hepatocytes are a major production site for components of the systemic inflammatory response, such as C-reactive protein, fibrinogen, α₁-antitrypsin, α₁-antichymotrypsin, mannose-binding lectin, amyloid, and ceruloplasmin [1]. These acute phase reactants assist in infection control and clearance of the pathogens. Finally, most of the activated lymphocytes, after fulfilling their immunologic duties, are destroyed by the hepatic elements of the reticuloendothelial system or via apoptosis. Consequently, the term “immunologic graveyard” has been coined for the liver [2].

An intriguing physiologic function inherent to the liver, encompassing elements from both innate and adaptive immunity, is immunologic tolerance. To distinguish between self- and foreign antigens, the immune system undergoes perpetual sophisticated mechanisms of T-cell clonal selection in the thymus and at the periphery. The key players in maintaining mechanisms of “central” and “peripheral” tolerance are T regulatory cells (Tregs). In addition, the intrahepatic antigen-presenting cells, including Kupffer cells, dendritic cells, sinusoidal endothelial cells and stellate cells, are heavily involved in the processes of induction and maintenance of immunologic tolerance [1–3]. This critical role of the liver may help in understanding its relatively immune-privileged position and the lesser degree of tissue compatibility required for successful liver transplantation. A variety of immunologic disturbances have been observed as a consequence of both acute liver failure [4] and chronic liver disease [5]. These include upregulation of various cytokines, such as interleukin (IL)-1, IL-6, tumor necrosis factor-α, and interferon-γ, and abnormal synthesis of acute phase reactants and complement components [6]. It is noteworthy that despite the frequent overproduction of immunologic components, the overall immune function remains impaired, suggesting a lack of cross-talk or immunologic coordination. This immune paresis often adds to the infection-related mortality in liver disorders, particularly in acute liver failure [4]. Conversely, inborn defects of the immune function per se can also contribute to both acute and chronic liver disorders, a fact particularly relevant from the pediatric perspective because these conditions tend to present in childhood.

Defects in the defense mechanisms can be divided into primary immunodeficiencies in which there is a genetic cause of the impaired immunity and secondary immunodeficiencies in which the presence of viruses, such as HIV, or some major medical intervention, such as chemotherapy or immunosuppressive medications, render the immune responses abnormal. Much of our current understanding of the physiology of the immune reactions originates from recognition of clinical patterns of immune dysfunction in immunodeficient patients and the identification of specific types of microorganisms isolated from them. Recent developments in immunogenetics have helped to define genotype/phenotype patterns and identify genetic loci for particular defects.

Primary Immunodeficiencies

Primary immunodeficiencies (PIDs) are rare but potentially fatal disorders of the innate and adaptive immune systems. More than 350 PIDs have been identified at a clinical or genetic level, with an estimated incidence of approximately 1 in 10,000 live births [7, 8].

Broadly speaking, PIDs can be divided into disorders of innate and adaptive immunity. Since the 1980s, the diagnosis and management of PIDs have been dramatically improved because of advances in immunogenetics, better anti-infectious strategies, and the earlier and more effective use of hematopoietic stem cell transplantation (HSCT) as a definitive treatment [7].

Secondary immunodeficiencies, related to HIV infection, chemotherapy, post-organ transplantation immunosuppression, or immune ablation, are also better controlled because of the use of modern anti-infectious strategies. In particular, progression of HIV infection has been significantly reduced by the advent of combination antiviral treatment [9].

The PIDs are inherited in either an autosomal recessive or an X-linked manner. Therefore, boys are more likely to be affected by PIDs. A simplified classification of PIDs is presented in Table 23.1. A majority of children with significant PIDs present early in infancy, when passive protection from transplacentally and breast milk-acquired immunoglobulins starts to wane. Life-threatening chest infections, often caused by Pneumocystis jiroveci, are a typical clinical presentation for children with severe combined immunodeficiency (SCID) or hyper-IgM syndrome. Milder forms of PIDs could be diagnosed following investigation into chronic diarrhea; recurrent chest, skin, or ear infections; or failure to thrive. Many children come from consanguineous families. Some have a positive family history of unexplained neonatal and infantile deaths in siblings or maternal relatives because of the X-linked pattern of inheritance in some PIDs [7, 8].

The main clinical problems in the management of immunodeficiencies are recurrent and opportunistic infections. In addition, these patients have an increased lifelong risk of developing malignancies and autoimmune disorders [7] (Figure 23.1). Frequently, the type of infection broadly indicates whether the problem affects the humoral (e.g., recurrent pyogenic pathogens: bacteria, fungi) or the cellular (e.g., opportunistic pathogens: viruses, atypical bacteria, protozoa) arm of the immune system. For example, isolation of protozoan Pneumocystis jiroveci from the bronchial aspirate suggests a likely problem in cellular immunity, while identification of Staphylococcus aureus from a liver abscess points to neutrophil dysfunction. However, in most immunodeficiencies, both cellular and humoral pathways are affected to some degree. For example, the X-linked form of hyper-IgM syndrome – CD40 ligand deficiency, an inborn immunoglobulin defect in class-switch recombination that renders the patients unable to produce other than IgM forms of immunoglobulin – is caused by abnormal interaction between activated lymphocytes and B-cells [10]. Consequently, early antibiotic prophylaxis, subcutaneous or intravenous immunoglobulin (IVIg) replacement therapy is indicated for the majority of PIDs. This therapeutic approach, by reducing the incidence of infections, has greatly improved the quality of life of children with PIDs.

Figure 23.1 Interaction between primary immune deficiencies and other immune-mediated conditions.

Liver Complications in Children with Immunodeficiencies

Hepatic complications in children with immunodeficiencies can be related to chronic infections unaffected by anti-microbial prophylaxis, drugs used to control the infections, or complications before or after HSCT. Approximately 25% of children with PIDs are estimated to have some form of liver involvement [11, 123]. By far the most common hepatic complication of the PIDs is sclerosing cholangitis (discussed in detail in Chapter 21) [11]. Typically, immunodeficient children with sclerosing cholangitis do not present with classical symptoms of cholangiopathy such as jaundice, fatigue, or pruritus. Elevation of liver enzymes (aspartate aminotransferase, gamma-glutamyl-transferase, or alkaline phosphatase) may be trivial or absent. Expert ultrasonography could indicate mild dilatation of the extrahepatic or, less frequently, intrahepatic bile ducts and splenomegaly. In the presence of biochemical or ultrasound changes, further evaluation with liver biopsy and cholangiography is indicated. The increased sensitivity of magnetic resonance cholangiopancreatography (MRCP) has reduced the requirement for the more invasive direct cholangiographic techniques, such as endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography. One study has reported a good concordance between MRCP and ERCP in diagnosing cholangiopathy when the disease is advanced [11] (Figure 23.2). However, subtle radiologic changes may be missed on MRCP.

Figure 23.2 MR cholangiopancreatography demonstrating advanced intrahepatic and extrahepatic cholangiopathy in a patient with combined immunodeficiency. Role of Opportunistic Infections in the Development of Sclerosing Cholangitis

Sclerosing cholangitis has been described in a number of immunodeficiencies, predominantly of the combined cellular and humoral type [12, 13, 124], including:

• 
  

  hyper-IgM syndrome

  
  
• 
  

  combined immunodeficiency

  
  
• 
  

  dedicator of cytokinesis-8 deficiency (hyper-IgE syndrome)

  
  
• 
  

  common variable deficiency

  
  
• 
  

  Wiskott–Aldrich syndrome

  
  
• 
  

  MHC class II deficiency

  
  
• 
  

  interferon-γ deficiency

  
  
• 
  

  DiGeorge syndrome

  
  
• 
  

  immunoglobulin subclass deficiency.

The most common association is with hyper-IgM syndrome [14]. In a significant proportion of these patients, Cryptosporidium spp. is identified, in particular with the use of more sensitive detection approaches, such as polymerase chain reaction-based assays [15]. Standard microscopy, following a modified acid-fast stain, can often overlook the focal presence of Cryptosporidium oocysts in the gastrointestinal tract, where the microbe usually resides in the intestinal and biliary epithelium. Rarely, Cryptosporidium can be identified in liver biopsy specimens at the surface of the biliary epithelium by light microscopy (Figure 23.3). There are ten Cryptosporidium species, with C. parvum representing the most common human pathogen. Two distinct genotypes of C. parvum relevant to humans – human type 1 and bovine type 2 – have been identified. In immunocompetent individuals, this ubiquitous organism can cause small waterborne outbreaks of diarrhea, but it has not been associated with cholangiopathy. The pathogenic role of C. parvum in immunodeficiency has not been fully elucidated, but animal models of Cryptosporidium-related cholangiopathy have been described [16]. Interferon-γ knockout mice appear to be particularly susceptible to Cryptosporidium infection, suggesting that this cytokine plays a critical role in the immune defense against this pathogen [16]. Biliary damage in humans appears to be caused by a direct cytopathic effect of C. parvum via apoptotic mechanisms [17]. In addition, C. parvum can induce cholangiopathy in HIV infection [18] and after organ transplant [19]. Other intracellular parasites such as Microsporidium spp., Mycobacterium avium intracellulare, and cytomegalovirus (CMV) have also been reported in association with cholangiopathy in adults infected with HIV [18]. It is possible that the particularly fast evolution of C. parvum cholangiopathy in immunodeficient patients results from the synergistic effect of multiple biliary infections [18].

Figure 23.3 Cryptosporidium oocysts (arrow) in the section of the liver biopsy of the patient with hyper-IgM syndrome and sclerosing cholangitis (hematoxylin and eosin, 150×).

Children with chronic cholangiopathy have been reported to have an increased number of gastrointestinal malignancies, including cholangiocarcinoma, lymphoma, and hepatocellular carcinoma. One multicenter study has reported that 55% of patients with hyper-IgM syndrome and sclerosing cholangitis had cryptosporidiosis [14]. One 18-year-old patient with hyper-IgM syndrome, eventually undergoing curative sequential liver and hematopoietic stem cell transplantation, was already found to have dysplastic biliary changes in the explanted liver (Figure 23.4) [20]. Similar histologic appearances have been noted in patients with HIV infection [18]. Therefore, it is conceivable that the failure of antimicrobials to clear C. parvum or other protozoans from the biliary tract could lead to chronic cholangiopathy, dysplastic changes, and, ultimately, biliary malignancies. The mechanisms for other described immunodeficiency-associated malignancies, such as lymphoma and hepatocellular carcinoma, however, remain less clear (Figure 23.1).

Figure 23.4 Dysplastic changes (arrow) in the biliary epithelium of the explanted liver of a patient with CD40 ligand deficiency and end-stage chronic liver disease (hematoxylin & eosin, 400×).

Hyper-IgM Syndrome

Hyper-IgM syndrome is a paradigm for immunodeficiency-associated sclerosing cholangitis, which, if not corrected, progresses to chronic biliary disease and cirrhosis in the majority of the patients. In addition, children with hyper-IgM suffer from neutropenia, opportunistic infections, chronic mouth ulcers, chronic diarrhea, failure to thrive, and poorly defined chronic encephalopathy [125, 126]. The estimated incidence is between 1 in 500,000 and 1 in 1000,000 live births [7, 10]. One study reported only 20% survival at 20 years of age in this condition, with life-threatening opportunistic infections and progressive hepatobiliary complications being the main cause of death [14, 127]. Hyper-IgM syndrome is caused by absence of CD40 ligand on activated lymphocytes and lack of interaction with CD40 molecules from B-cells in the X-linked form (CD40 ligand deficiency), or defective expression of activation-induced cytidine deaminase on B-cells in the autosomal recessive form of the disease [10]. Therefore, in both forms, B-cells are unable to direct physiologic IgM class switching to other immunoglobulin types. It is important to note that serum IgM levels are not always elevated in this condition. Recently, 50% of children with hyper IgM syndrome were found to have a striking presence of anti-MIT3 IgM antibodies, a serological hallmark of primary biliary cholangitis in adults, potentially offering some fresh pathogenetic insights into this poorly understood autoimmune condition [128].

In the past, the majority of children with hyper-IgM syndrome presented to the hepatologist with well-established signs of advanced liver disease, such as severe biochemical abnormalities and portal hypertension. An increased awareness of the hepatic involvement in PIDs among immunologists in recent years has led to earlier referrals and preventive measures, with a consequent reduction in presentations with severe liver involvement. Many children with hyper-IgM syndrome may remain clinically asymptomatic well into the second decade of life, when progression of the liver disease typically occurs. Therefore, pediatricians and parents alike have felt uneasy about considering mortality-associated transplantation options in children with hyper-IgM syndrome, who often have a near normal quality of life on immunoglobulin replacement and anti-infectious prophylaxis. Recently, a partial improvement in the immune function was observed following serial infusions of recombinant CD40 ligand in three children [22].

Liver transplantation has been attempted for end-stage biliary disease in hyper-IgM syndrome, but fatal cholangiopathy recurs within months after the operation [23]. The recurrence may well be accelerated by the effect of post-transplant immunosuppression on quiescent infections of the gastrointestinal tract. It has become clear that correction of the immune defect is essential for patient and graft survival. Although HSCT is able to correct the immunodeficiency [24], associated hepatic complications such as sinusoidal obstruction syndrome (veno-occlusive disease), drug hepatotoxicity, and graft-versus-host disease significantly reduce survival [25]. Therefore, a reduced intensity conditioning (RIC) approach that avoids irradiation and uses less hepatotoxic chemotherapeutics with a smaller amount of infused cells has been introduced for HSCT in the presence of significant pre-existing organ (lungs, liver, or heart) damage. This modified gentler approach has been termed non-myeloablative or “mini” HSCT [26, 27]. Effective sequential approach with combined liver and “mini” HSCT has been described in children with decompensated biliary cirrhosis secondary to hyper-IgM syndrome [20, 129]. Some children with less advanced liver disease can survive isolated non-myeloablative HSCT, but generally patients with hyper-IgM should be identified and screened for a matched donor for HSCT early, while the liver involvement is absent or minimal [130, 131]. The use of umbilical cord grafts has expanded the availability of donors for the correction of this and other immune defects.

Miscellaneous Immunodeficiencies and Liver Disease

Several rare metabolic liver-based conditions have been associated with immunodeficiency, including adenosine deaminase deficiency [33], lysinuric protein intolerance [34], and propionic acidemia [35]. Their immune phenotype may vary from SCID in adenosine deaminase deficiency to a slightly increased frequency of infections in propionic acidemia. The hepatic damage is thought to be inflicted by accumulation of toxic metabolites and appears to improve with pegylated-adenosine deaminase supplements in adenosine deaminase deficiency [33]. Another rare association is SCID and multiple intestinal atresia with ensuing parental nutrition-induced liver damage [36]. In this often fatal genetic condition, tetratricopeptide 7 A (TTC7A) is absent from the thymic epithelium [135]. One report suggested amelioration of the immune phenotype following a liver–small bowel transplant, possibly related to the accidental transfer of the peripheral stem cells into the heavily immunosuppressed host during the operation [37].

A recent study has described an intriguing association between common variable immunodeficiency, which typically presents outside pediatric age group, and nodular regenerative hyperplasia associated with portal hypertension [38]. The authors have postulated autoimmune etiology, as these patients often had low-titer serum autoantibodies and 90% had intrasinusoidal lymphocytic infiltrate in the liver histology. They have also confirmed the presence of epitheloid granulomas, known to be associated with various forms of immunodeficiencies, in 43% of their patients [38]. Nodular regenerative hyperplasia has also recently been described complicating malignancy treatment with pembrolizumab, a novel IgG4 antibody targeting the anti-programmed death-1 receptor on the lymphocytes, which physiologically serves as an immune checkpoint blocker and proposed to be possibly related to aberrant immune responses [130].

Some rare monogenetic PIDs, including autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), immune dysregulation polyendocrinopathy-enteropathy X-linked syndrome (IPEX), heterozygous CTLA4 mutation and GATA2 mutation syndromes can present with autoimmune hepatitis-like features. A proposed overlapping clinical spectrum between different groups of immune disorders is presented in Figure 23.1.

Chronic Viral Hepatitis in Patients with Immunodeficiencies

Immunodeficient patients often have abnormal responses to viral pathogens. Given their common long-term requirements for blood products, they may have been exposed to hepatotropic viruses despite the much improved safety of such products. Moreover, these patients are less likely to mount an adequate immune response to vaccines, when they are available, as is the case for hepatitis B virus (HBV). Longer term, chronic viral infections in immunodeficient patients could have a more aggressive clinical course, particularly in the setting of co-infection. One study from Italy found evidence of HBV and hepatitis C (HCV) in six of 11 children with PIDs and liver disease, with a five-year survival of 60% [39].

Recently, genotype 3 hepatitis E virus (HEV) infection was described in European liver transplant recipients, mimicking the liver graft dysfunction [136]. It has been suggested that this zoonosis could be transmitted through eating contaminated uncooked pork meat and shellfish. Of note, there was also an observed significant HEV prevalence in healthy blood donors and many European countries have now moved to routine HEV testing [137]. Reducing immune suppression often helps HEV seroconversion, but ribavirin was proven effective if that fails [136].

Human Immunodeficiency Virus Infection

Opportunistic Infections and Human Immunodeficiency Virus Cholangiopathy

During the pre-HAART era, HIV-related cholangiopathy associated with Cryptosporidia, Microsporidia, and CMV was frequently reported from both adults and children [45]. This condition, clinically and radiologically similar to sclerosing cholangitis in PIDs, is still the most common hepatic feature of HIV infection, although it is less frequent, with a better preserved immunocompetence of the HIV-infected patients achieved through HAART [9]. Clinical symptoms include abdominal pain, scleral icterus, hepatomegaly, and diarrhea. Mild to moderate elevation of serum alkaline phosphatase, gamma-glutamyl-transferase, aspartate aminotransferase and bilirubin is common. Abdominal ultrasonography often demonstrates a mild dilatation of the bile ducts, enlarged gallbladder, and abnormal echo pattern of the liver with minimal splenomegaly [46]. MRCP is usually sufficient to document the cholangiopathy, although ERCP may exceptionally be required for bile sampling to identify the pathogens or therapeutic biliary stenting and papillotomy in the presence of distal biliary stricture or papillary stenosis, respectively [45].

Management of HIV-related hepatic involvement in children is limited. A range of liver disorders has been described in association with HIV infection (Table 23.2). Often, presence of the liver complications simply reflects the general clinical condition of the patient. Therefore, it is hoped that the routine use of effective antiretroviral treatment will arrest their development. By analogy to prevention of cholangiopathy in PIDs, where protozoans such as C. parvum or Microsporidium spp. are also frequently implicated, it is prudent to initiate antiprotozoal prophylaxis with azythromycin or paromomycin as soon as a decline in peripheral CD4 cell count is observed. At present, however, there are no controlled data to endorse this suggestion. Choleretic treatment with ursodeoxycholic acid (20 mg/kg/day) may be of benefit when evidence of cholangiopathy is present [32].

Some research indicates that HAART treatment per se may be hepatotoxic [47, 48]. In addition to the liver involvement, affected patients may develop profound lactic acidosis, myopathy, hypercapnia, organic aciduria, anemia, and a range of neurologic symptoms. The underlying mechanism for these symptoms appears to be mitochondrial injury resulting in depletion of mitochondrial DNA in the liver and muscle. On withdrawal of nucleoside analogues, the clinical symptoms have been reported to reverse, with normalization of mitochondrial DNA content in the muscle [47, 48].

Following the success of HAART, HIV infection has ceased to be a contraindication for liver transplantation. Short-term transplant results in adults are comparable to other indications, partially related to effective treatment of HCV infection. Post-transplant, integrase strand transferase inhibitors-based anti-HIV regimens are preferred due to the lack of interactions with calcineurin and mTOR inhibitors. Of note, despite the more potent immunosuppression, rejection rates exceed those found in HIV-uninfected recipients [49, 139].

Co-Infection with Human Immunodeficiency Virus and Other Hepatotropic Viruses

Evolution of chronic liver disease caused by hepatotropic viruses (HBV and HCV) in the presence of HIV infection appears to be accentuated [50–52]. The prolonged survival of co-infected children requires tailored therapeutic strategies. It has been suggested that children with HIV and HCV co-infection need to be treated early, while immune competence of the host is preserved [52]. However, this is less clear for children co-infected with HIV and HBV. It is conceivable that impaired cytotoxic, HBV-specific, T-cell function may result in a lesser degree of hepatocyte damage despite ongoing HBV replication. Whether HIV infection-related decline in immune competence is associated with reduced liver injury is possible, but unproven. In HBV/HIV co-infected adults there is an increased risk of HBV-related acute liver failure [51] and of hepatitic flare-ups (“immune reconstitution syndrome”) in 20–25% on initiation of HAART [140]. Early studies in individuals co-infected with HIV and HCV showed that combination therapy with pegylated interferon and ribavirin was safe, but that the response was less good than in patients infected with HCV alone [52]. However, HIV/HCV co-infected adult patients respond similarly well – with sustained viral response rates above 93% – to modern combination treatments [141].

Hepatitis B Virus and Primary Immunodeficiency

Chronic HBV infection is rarely diagnosed in children with PIDs. There are two primary reasons for this: (1) the countries where PIDs are predominantly diagnosed have a lower incidence of HBV; and (2) to inflict hepatocellular injury to HBV-infected hepatocytes, cytotoxic T-lymphocytes, sensitized against cells expressing HBV-related peptides, need to be fully operational, which is often not the case in children with PIDs. Therefore, their HBV DNA titers and amount of HBVe antigen could be high, but the liver damage remains minimal because of the lack of host immune response required to cause injury to the hepatocytes.

No published data on the long-term outcome of HBV-positive patients with PIDs are available, but some analogy can be drawn from HBV/HIV co-infected adults who, despite the earlier postulate, appear to have an accelerated course of HBV [53]. In a study of adults co-infected with HBV and HIV dating from a pre-HAART era, the histologic features of hepatitis were less advanced as HIV infection progressed [51]. More recent studies indicate reduced rates of anti-HBe antigen and anti-HBs antigen seroconversion, with a higher incidence of decompensated end-stage cirrhosis [53]. Antiretroviral treatment can trigger anti-HBeAg and anti-HBsAg seroconversion and enhance immune control of HBV replication by restoring T-cell integrity, but may also induce flares of hepatitis [140]. Combination of tenofovir with the nucleoside analogues lamivudine or emtricitabine has been proposed as potentially effective treatment for both viruses [54].

If immunity is restored, for example after successful HSCT, there is a danger of overwhelming hepatitis B. Therefore, the use of lamivudine or adefovir is recommended for the HBV-positive patients undergoing HSCT. It has been reported that using donors positive for anti-HBV core antigen may lead to a transfer of adoptive HBV immunity after HSCT [55]. This approach should minimize the likelihood of post-HSCT acute hepatitis B.

Hepatitis C Virus and Primary Immunodeficiency

Evidence of HCV infection in patients with PIDs should be sought by measuring serum HCV RNA because of the patients’ frequently assumed deficiency in producing antibodies. Nevertheless, one study suggested that eight of 18 adults with various primary impairments of antibody production, such as common variable immunodeficiency, hyper-IgM syndrome, and IgG subclass deficiency, were able to produce anti-HCV antibodies [56].

Chronic hepatitis C has an accelerated course in individuals with immunodeficiencies [57]. When compared with immunocompetent individuals, immunodeficient patients have significantly higher HCV RNA titers during acute hepatitis. Before 1990, there were several well-documented outbreaks of HCV infection in patients with immunodeficiencies caused by contaminated immunoglobulins and leading to progressive liver disease, often requiring liver transplantation [57, 58]. The results of transplantation were largely disappointing with prompt recurrence and fatal infectious complications [58]. It is likely that post-transplant immunosuppression played a significant contributory role in these adverse outcomes [59]. Advent of effective combination nucleos(t)ide anti-HCV treatment has changed the outcome of these patients, including preparatory bridging treatment facilitating a successful liver transplantation [142].

It would appear logical that immunodeficient patients should be treated early with the emerging more efficient anti-HCV combinations, as well as children perinatally co-infected by HIV and HCV in view of the available HAART.

Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by high fever, pancytopenia, hypercytokinemia, and coagulopathy [60, 61]. Cardinal clinical features are hepatosplenomegaly, ascites, respiratory failure, skin infiltrates, and central nervous system involvement. Frequent laboratory findings are hypofibrinogenemia, hyperferritinemia, hypertriglyceridemia, and elevated serum lactate dehydrogenase [61]. Hallmark of the disease is the presence of hemophagocytosis in activated macrophages in the bone marrow, ascitic fluid, or cerebrospinal fluid (Figure 23.5). This diagnostic feature may not be seen at presentation and cytologic examination of the bone marrow or ascitic fluid may need to be repeated if clinically indicated. At autopsy, the hemophagocytic infiltrates can be found in the liver, lungs, skin, kidneys, and brain [60, 61]. This systemic disease is often triggered by infection and may progress to hepatic and renal failure. The microorganisms reported in association with HLH include viruses (Epstein–Barr virus (EBV), herpes simplex and zoster, CMV, HIV, avian flu), bacteria, and fungi, but often no organism is identified [60, 62]. Children with HLH who present with liver involvement and multi-organ failure have a high mortality rate [62]. The clinical diagnostic criteria are presented in Box 23.1. To diagnose HLH either a molecular genetic confirmation or fulfillment of five out of the eight clinical criteria listed are required [63].

Figure 23.5 Phenomenon of hemophagocytosis demonstrated by a large histiocyte (center) engulfing two smaller cells in the bone marrow aspirate.

Despite its recognition more than 50 years ago [64] and recent progress in understanding its pathogenesis [65], HLH remains underdiagnosed, probably because of its non-specific clinical features and often fulminant progression. Its incidence is estimated to be approximately 1 in 50,000 live births [60, 61].

Most patients with HLH will have abnormal NK cell function, with evidence of impaired granule-dependent cytotoxic pathways. Perforin is a 60 kDa polypeptide secreted by cytoplasmic granules of NK cells and cytotoxic lymphocytes. Its physiologic role, on stimulation, is to form “pores” or perforations in the membrane of the target cells, allowing other mediators of cell death (i.e., granzyme) to enter the cell and facilitate osmotic cell lysis [60, 65]. The ongoing yet inefficient stimulation of the immune system via various complex pathogenic mechanisms results in overexpression of pro-inflammatory cytokines, such as tumor necrosis factor-α, IL-6, IL-8, IL-12, IL-18, interferon-γ, and macrophage inhibitory protein 1α, but also of a number of hemopoietic growth factors released by the overstimulated lymphocytes and macrophages [65]. Consequently, the physiological contraction of the immune response does not occur.

Approximately 70–80% of the patients with HLH, predominantly presenting in infancy, have an autosomal recessive primary immune defect (primary or familial form of HLH (FHL)), often unmasked by an acute infection [60]. Only 20–30% of these children have documented mutations affecting perforin [60, 61], and it is speculated that other modifiers or yet unrecognized defects of cytotoxicity could play a role in the remaining patients. In older patients with HLH, the “overstimulation” of the immune system may also be triggered by a microbial stimulus (secondary form). Consanguinity is not a common feature, but this sporadic form of HLH can be seen in association with malignancy, autoimmune disorders, or after organ transplant [66]. “Macrophage activation syndrome” is an alternative term sometimes used in rheumatology to describe a phenomenon similar to HLH. A diagnostic score was recently proposed to clinically differentiate these two conditions, as their initial clinical features typically are quite different [143].

Familial HLH is a heterogeneous syndrome with possibly different degrees of clinical severity. There are now at least five variants of familial HLH for which a number of mutations in the genes involved in the intracellular perforin- and granzyme-related intracellular killing homeostasis have been identified in children from various ethnic groups, with some preliminary suggestions of genotype–phenotype correlations (Table 23.3) [67–71]. The best documented are the defects in perforin synthesis (FHL2) in which absence of perforin-1 in the cytotoxic granules of NK cells can also be demonstrated immunohistochemically [68]. Expression of perforin in peripheral lymphocytes using a fluorescence activated cell sorter technique can be used as a simple and rapid screening test for confirmation of perforin deficiency in a child with clinically suspected HLH [72]. Some laboratories have recently broadened this “fast track” flow cytometry testing by screening for markers of other forms of impaired cytotoxicity (Munc and syntaxin) and X-linked proliferative syndromes, which could have clinical presentation similar to FHL2 [7].

Table 23.3 Genetic Variants of Familial Hemophagocytic Lymphohistiocytosis

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Chapter 5 – Cirrhosis and Chronic Liver Failure in Children Chapter 13 – Familial Hepatocellular Cholestasis Chapter 14 – Alagille Syndrome Chapter 26 – Cystic Fibrosis Liver Disease in Children Chapter 32 – Lysosomal Storage Disorders in Children Chapter 43 – Liver Transplantation in Children: Indications and Surgical Aspects

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