Liver disease predicts mortality in patients with X-linked immunodeficiency with hyper-IgM but can be prevented by early hematopoietic stem cell transplantation
2017; Elsevier BV; Volume: 141; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2017.06.036
ISSN1097-6825
AutoresVian Azzu, Lucinda Kennard, Beatriz Morillo-Gutiérrez, Mary Slatter, David Edgar, Dinakantha Kumararatne, William J. Griffiths,
Tópico(s)Pediatric health and respiratory diseases
ResumoX-linked immunodeficiency with hyper-IgM (XHIM) is a severe primary immunodeficiency disorder characterized by low levels of, or absence of IgG, IgA, and IgE, with normal to raised serum IgM concentrations.1Rosen F.S. Kevy S.V. Merler E. Janeway C.A. Gitlin D. Recurrent bacterial infections and dysgamma-globulinemia: deficiency of 7S gamma-globulins in the presence of elevated 19S gamma-globulins. Report of two cases.Pediatrics. 1961; 28: 182-195PubMed Google Scholar XHIM results from mutations in the CD40 ligand (CD40L) gene found on activated CD4 T cells2Etzioni A. Ochs H.D. The hyper IgM syndrome–an evolving story.Pediatr Res. 2004; 56: 519-525Crossref PubMed Scopus (111) Google Scholar; disruption of this gene results in aberrant interaction with CD40 on B-cell membranes, thus inhibiting B-cell proliferation and immunoglobulin class switching.3Hollenbaugh D. Grosmaire L.S. Kullas C.D. Chalupny N.J. Braesch-Andersen S. Noelle R.J. et al.The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity.EMBO J. 1992; 11: 4313-4321Crossref PubMed Scopus (498) Google Scholar CD40 is also found on other cells such as monocytes and endothelial and epithelial cells. Therefore, patients with XHIM have a combined immunodeficiency, resulting in recurrent bacterial and opportunistic infections. Sinopulmonary infections occur in approximately 80% of patients; gastrointestinal manifestations, including chronic diarrhea, affect approximately 50% of patients; and hepatic complications, which are principally biliary in nature, are reported to affect approximately 20% of patients with XHIM.4Winkelstein J.A. Marino M.C. Ochs H. Fuleihan R. Scholl P.R. Geha R. et al.The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003; 82: 373-384Crossref PubMed Scopus (330) Google Scholar, 5Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar The clinical presentation was broadly reflected in our cohort (see Table E1 in this article's Online Repository at www.jacionline.org). An appreciation of the true burden and nature of liver pathology in patients with XHIM has been limited; hence, we present a detailed characterization of liver pathology in a sizeable cohort of patients with XHIM from several United Kingdom (UK) centers. All UK centers submitting XHIM data to the UK Primary Immunodeficiency Network were asked to complete a standardized proforma. We collated data for 24 patients from 3 centers. Statistical comparisons were performed using Mann-Whitney test for continuous variables, Fisher exact test for categorical data, and log-rank test for survival data. Further methodology is included in this article's Online Repository at www.jacionline.org. We found a higher prevalence of liver disease (33%) in patients with XHIM compared with most other studies: approximately 20% in data from a European registry5Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar and a multinational study,6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long term outcomes of 176 patients with X-linked hyper IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and only 6% in 2 US registries.4Winkelstein J.A. Marino M.C. Ochs H. Fuleihan R. Scholl P.R. Geha R. et al.The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003; 82: 373-384Crossref PubMed Scopus (330) Google Scholar, 7Leven E.A. Maffucci P. Ochs H.D. Scholl P.R. Buckley R.H. Fuleihan R.L. et al.Hyper IgM syndrome: a report from the USIDNET Registry.J Clin Immunol. 2016; 36: 490-501Crossref PubMed Scopus (61) Google Scholar A small case series from Newcastle described liver disease in 3 of 8 patients with XHIM (37.5%) and there is likely to be a notable overlap with our patient population from Newcastle.8Khawaja K. Gennery A.R. Flood T.J. Abinun M. Cant A.J. Bone marrow transplantation for CD40 ligand deficiency: a single centre experience.Arch Dis Child. 2001; 84: 508-511Crossref PubMed Scopus (39) Google Scholar Our study found that patients with XHIM without liver disease had normal liver biochemistry, normal imaging, and normal histology, where performed. However, patients with XHIM with liver disease had (1) statistically significant elevations in liver biochemistry excluding albumin (Table I; see Fig E1 in this article's Online Repository at www.jacionline.org); (2) abnormal liver imaging including splenomegaly, heterogeneous or cirrhotic appearing livers, and biliary dilatation or sclerosing cholangitis; and (iii) abnormal histology showing cholangiopathy/sclerosing cholangitis in 75% of those with liver disease, chronic hepatitis in 50%, and both features in 25% (see Table E2 in this article's Online Repository at www.jacionline.org).Table ICharacteristics of patients with XHIM with or without liver diseaseNo. of patientsNo liver disease(16 [67%])Liver disease(8 [33%])P valueALT (7-40 U/L)39187.0003GGT (U/L)151238.003ALP (30-130 U/L)212460.001Bilirubin (0-20 mg/L)675.0018PT (9.8-12.6 s)11.613.8.0329Albumin (35-55 g/L)4139NSImagingNot available (n = 7 of 16 [44%])Sclerosing cholangitis/cholangiopathy (n = 6 of 8 [75%])Normal (n = 9 of 16 [56%])Hepatomegaly (n = 2 of 8 [25%])Periportal echogenicity (n = 1 of 8 [13%])HistologyNormal (n = 2 [12.5%])Sclerosing cholangitis (n = 6 of 8 [75%])GvHD post-HSCT (n = 1 [6.25%])Chronic hepatitis (n = 4 of 8 [50%])Both (n = 2 of 8 [25%])Max IgM levels (0.23-2.6 g/L)∗Range includes newborn to adult.1.44.1.0286Min IgG levels (2.3-16 g/L)∗Range includes newborn to adult.4.53.9NSMin IgA levels (0.7-4 g/L)∗Range includes newborn to adult.0.180.18NSCMV infection3 of 16 (19%)1 of 8 (13%)NSCryptosporidium infection2 of 16 (13%)3 of 8 (38%)NSChronic diarrhea8 of 16 (50%)3 of 8 (38%)NSMean age of alive patients (y)18.439.1Mean age at death (y)4.513.2Crude mortality ratio1 of 16 (6%)3 of 8 (38%)Number receiving bone marrow transplant14 of 16 (88%)4 of 8 (50%)ALT, Alanine transferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transpeptidase; GvHD, graft versus host disease; max, maximum; min, minimum; PT, prothrombin time.∗ Range includes newborn to adult. Open table in a new tab ALT, Alanine transferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl transpeptidase; GvHD, graft versus host disease; max, maximum; min, minimum; PT, prothrombin time. Cryptosporidium and cytomegalovirus (CMV) infection have previously been associated with the development of cholangitis in patients with XHIM.5Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar, 9Hayward A.R. Levy J. Facchetti F. Notarangelo L. Ochs H.D. Etzioni A. et al.Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM.J Immunol. 1997; 158: 977-983PubMed Google Scholar In our case series, 38% of patients with liver disease tested positive for Cryptosporidium, and the prevalence was 3 times higher than in patients without liver disease (13%) (Table I). However, we did not find a statistically significant association between Cryptosporidium infection and the development of liver disease, or indeed, sclerosing cholangitis. CMV prevalence was not different between patients with XHIM with or without liver disease (Table I). Crude mortality was higher in the liver disease group (38%) compared with the group without liver disease (6%). Although the average age of patients was higher in the liver disease group (39.1 years vs 18.4 years), the standardized mortality ratio of 94 in those with liver disease versus 16 in those without supports this conclusion by correcting for this potential confounding factor (see Table E3 in this article's Online Repository at www.jacionline.org). Kaplan-Meier log-rank analysis shows decreased survival in patients with XHIM with liver disease, regardless of whether time 0 is plotted as birth (hazard ratio 4.5; P > .05) or as date of diagnosis of XHIM (hazard ratio, 6.9; P = .05) (Fig 1, A and B, respectively). Our data reflect the survival curves in a highly powered recent study.6de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long term outcomes of 176 patients with X-linked hyper IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Hematopoietic stem cell transplant (HSCT) was performed in 89% of patients without liver disease (average age of HSCT, 3.1 years) compared with 50% in those with liver disease (average age of HSCT, 14.5 years). Early HSCT before age 10 years was performed in those without liver disease and survival was excellent. All patients with liver disease were transplanted as teenagers and liver disease at the time of HSCT conferred a poor prognosis, with the exception of a patient who was contemporaneously liver transplanted (see Fig 1, C, and discussion in this article's Online Repository at www.jacionline.org). A previous study has described the survival benefit in XHIM all-comers,10Mitsui-Sekinaka K. Imai K. Sato H. Tomizawa D. Kajiwara M. Nagasawa M. et al.Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan.J Allergy Clin Immunol. 2015; 136: 1018-1024Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar but we show that those with early HSCT do not develop liver disease despite an average follow-up of 11 years, and this confers a notable survival benefit (P = .0022). Multivariate analysis supports this conclusion and further discussion can be found in this article's Online Repository at www.jacionline.org. To date, this is the most detailed study of liver disease in XHIM. We conclude that liver disease in patients with XHIM is a later-occurring diagnosis, characterized histologically by sclerosing cholangitis and chronic hepatitis, which has a poorer outcome and may be preventable through early HSCT. Patients with XHIM should undergo annual monitoring of liver function tests, including gamma-glutamyl transpeptidase and clotting, liver imaging (especially in those without HSCT), and exclusion of pathogens such as Cryptosporidium and CMV via PCR even if patients are asymptomatic. The presence of liver disease confers a poor prognosis in these patients and we strongly advocate specialist hepatology input in their management. Early diagnosis is key and a multidisciplinary approach regarding HSCT and liver transplantation should be sought. We acknowledge authors whose work could not be cited in the main article because of reference limitations. We thank the reviewers and editors for their input on optimizing the manuscript. All UK centers submitting XHIM data to the UK Primary Immunodeficiency Network were asked to complete a proforma to standardize the data collection (details in Letter to the Editor). Three centers contributed data for 24 patients in total. Criteria for submission of patients included definitive genetic or mutational analysis confirming XHIM, functional analysis showing absent CD40L protein, probable diagnosis of XHIM based on X-linked inheritance, male sex, or clinical presentation diagnosed by participating clinicians. The proforma data included the patient's age, sex, whether XHIM was a de novo CD40L deficiency or whether there was a family history of the condition, genetic/mutation/molecular analysis, diagnosis date of CD40L deficiency, immunoglobulin maximum and minimum levels, medical history, allergies, current medications, and values of alanine transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase, bilirubin, albumin, and prothrombin time (PT). Data were collected regarding evidence of liver disease from histology or from imaging including ultrasound (US), computerized tomography (CT), magnetic resonance cholangiopancreatography (MRCP), and endoscopic retrograde cholangiopancreatography (ERCP). Information regarding formal hepatology review and HSCT was recorded. Questions were also asked about the presence of hepatotrophic viruses including CMV and the presence of Cryptosporidium and its management, with additional enquiry regarding symptoms of chronic diarrhea. Data were analyzed in Graphpad Prism using methods described in the main article. P values of less than .05 were considered statistically significant. Multivariate analysis was performed in ClustVis (http://biit.cs.ut.ee/clustvis/). All 24 patients were males and about half had an X-linked pattern family history of XHIM. All had missing CD40L expression and 67% had genetics or mutational analysis performed (Table E1). There were no T-cell abnormalities in our patient cohort, in keeping with diagnostic guidelines. We documented minimum and maximum immunoglobulin levels, corresponding to preintravenous and postintravenous immunoglobulin therapy. Although there was a lack of association with IgA and IgG levels, patients with liver disease had statistically higher maximum IgM levels (Table I). The clinical phenotype of our patients was sinopulmonary disease in 83%, gastrointestinal disease in 54%, liver disease in 33%, hemaopoietic disorders in 33%, central nervous system disorders in 13%, and skin manifestations in 8% (Table E1). Eight patients (33% of the XHIM cohort) demonstrated convincing biochemical liver disease with confirmatory radiological and histological evidence. One patient developed graft versus host disease after HSCT. This patient was not considered to have XHIM-related liver disease (see discussion below). Patients with XHIM with liver disease had statistically significant elevations in alkaline phosphatase, gamma-glutamyl transpeptidase, alanine transaminase, bilirubin, and PT when compared with those without liver disease. However, there was no statistical difference in the albumin level (Fig E1). Hepatotrophic viruses were routinely checked in clinical practice—hepatitis B and C were absent in the current cohort. Nine of the 16 patients without liver disease had abdominal imaging available, all of which were reported as normal (Table I). All patients with liver disease showed imaging abnormalities on various modalities such as US, CT, MRCP, or ERCP. The most common abnormalities were splenomegaly, a heterogeneous or cirrhotic appearing liver, and biliary dilatation or sclerosing cholangitis. Typical findings for those with liver disease are listed in Table E2. All patients with abnormal liver biochemistry and radiology underwent liver biopsy. Histological cholangiopathy/sclerosing cholangitis was the most common liver abnormality, seen in 6 patients (75%), followed by chronic hepatitis in 4 patients (50%) or both features in 2 patients (25%). Granulomatous hepatitis was also observed in 1 patient (13%) who also had chronic hepatitis. There was no secondary cause of granuloma formation in this patient. All patients with histological sclerosing cholangitis had a dilated biliary tree, cholangiopathy, or overt sclerosing cholangitis on their imaging. Histological chronic hepatitis could not be identified from imaging alone (Table E2). CD40L mutation pattern did not correlate with the development of liver disease. Chronic diarrhea was present in 50% of those without liver disease and 38% of those with liver disease (not statistically significant). Cryptosporidium infection was identified in 2 of 16 (13%) patients without liver disease and 3 of 8 (38%) patients with liver disease; this trend did not reach statistical significance (Table I). Asymptomatic Cryptosporidium infection was present only in the liver disease group (25%). Cryptosporidum was diagnosed by microscopy in 5 patients with supplementary PCR testing in 2 patients. CMV rates of 19% (3 of 16 patients) in the group without liver disease were not significantly different from 13% (1 of 8 patients) in the liver disease group (Table I). All patients were tested by PCR. Diarrhea manifested in half of the affected patients. There was no correlation between mutation type (deletion, frameshift, premature stop codon) or the CD40L domain affected, and the clinical phenotype, consistent with previous findings.E1de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, E2Hayward A.R. Levy J. Facchetti F. Notarangelo L. Ochs H.D. Etzioni A. et al.Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM.J Immunol. 1997; 158: 977-983Crossref PubMed Google Scholar, E3Khawaja K. Gennery A.R. Flood T.J. Abinun M. Cant A.J. Bone marrow transplantation for CD40 ligand deficiency: a single centre experience.Arch Dis Child. 2001; 84: 508-511Crossref PubMed Scopus (44) Google Scholar, E4Leven E.A. Maffucci P. Ochs H.D. Scholl P.R. Buckley R.H. Fuleihan R.L. et al.Hyper-IgM syndrome: a report from the USIDNET Registry.J Clin Immunol. 2016; 36: 490-501Crossref PubMed Scopus (69) Google Scholar, E5Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar We noted that maximum IgM levels are higher in the liver disease group, but the clinical significance of this finding is unclear. It has previously been reported that IgM levels may increase with age,E5Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar and our findings may simply reflect an older cohort in the group with liver disease. Patients with biopsy-proven liver disease had elevated liver function tests (except for albumin) and prolonged PT compared with those without liver disease (Table I and Fig E1). All patients with liver disease had abnormal liver imaging in the form of US, MRCP, or ERCP (Table I and Table E2). Sclerosing cholangitis/cholangiopathy was the most common presentation and could be predicted from the biliary dilatation seen on various imaging modalities (US, CT, MRCP, ERCP). Chronic hepatitis was not easily predicted from imaging (Table E2). We consider it of paramount importance that patients with XHIM are screened annually for liver disease with blood tests including liver function and clotting, with a low threshold for consideration of abdominal imaging if any abnormalities are detected. Hepatotrophic viruses should be excluded in all patients with abnormal liver function test results and we recommend early hepatology input to manage liver disease burden. Previous studies have suggested a role of persistent Cryptosporidium infection leading to biliary disease in this group of patients.E2Hayward A.R. Levy J. Facchetti F. Notarangelo L. Ochs H.D. Etzioni A. et al.Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM.J Immunol. 1997; 158: 977-983Crossref PubMed Google Scholar, E5Levy J. Espanol-Boren T. Thomas C. Fischer A. Tovo P. Bordigoni P. et al.Clinical spectrum of X-linked hyper-IgM syndrome.J Pediatr. 1997; 131: 47-54Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar Studies looking at CD40 agonist antibody use in CD40L deficiency have shown suppression of Cryptosporidium ooyst shedding into the stool with this therapy.E6Fan X. Upadhyaya B. Wu L. Koh C. Santin-Duran M. Pittaluga S. et al.CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome.Clin Immunol. 2012; 143: 152-161Crossref PubMed Scopus (19) Google Scholar In a previous case series of 79 patients, it was demonstrated that in 5 patients with sclerosing cholangitis, 4 had Cryptosporidium infection,E7Winkelstein J.A. Marino M.C. Ochs H. Fuleihan R. Scholl P.R. Geha R. et al.The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003; 82: 373-384Crossref PubMed Scopus (403) Google Scholar whereas in a more recent study, Cryptosporidium was present in 25% of patients with XHIM with liver disease and 7% in the overall cohort.E1de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar In our case series, 38% of patients with liver disease tested positive for Cryptosporidium, and the prevalence was 3 times higher than in patients without liver disease (13%) (Table I). We could not find a statistically significant association between Cryptosporidium infection and the development of liver disease, or indeed, sclerosing cholangitis. Our methodological preference is to test for Cryptosporidium using PCR because previous studies have shown microscopy to be less sensitive and less specific than PCR analysis for Cryptosporidium infection.E8Morgan U.M. Pallant L. Dwyer B.W. Forbes D.A. Rich G. Thompson R.C. Comparison of PCR and microscopy for detection of Cryptosporidium parvum in human fecal specimens: clinical trial.J Clin Microbiol. 1998; 36: 995-998PubMed Google Scholar, E9Rahman M. Chapel H. Chapman R.W. Collier J.D. Cholangiocarcinoma complicating secondary sclerosing cholangitis from cryptosporidiosis in an adult patient with CD40 ligand deficiency: case report and review of the literature.Int Arch Allergy Immunol. 2012; 159: 204-208Crossref PubMed Scopus (12) Google Scholar On the basis of our data showing that some patients had asymptomatic Cryptosporidium infection, we would also advocate testing for this pathogen in all immunodeficient patients because early treatment (eg, with nitazoxanide) may delay/prevent the development of cholangiopathy.E10Sparks H. Nair G. Castellanos-Gonzalez A. White Jr., A.C. Treatment of Cryptosporidium: what we know, gaps, and the way forward.Curr Trop Med Rep. 2015; 2: 181-187Crossref PubMed Scopus (74) Google Scholar As we do in clinical practice, we recommend advising patients with XHIM to boil or filter tap water to reduce their risk of infection; there is limited data that rates of endemic Cryptosporidium transmission may be higher in immunocompromised individuals.E11Perz J.F. Ennever F.K. Le Blancq S.M. Cryptosporidium in tap water: comparison of predicted risks with observed levels of disease.Am J Epidemiol. 1998; 147: 289-301Crossref PubMed Scopus (64) Google Scholar In addition to cryptosporidiosis, CMV has been implicated in the pathogenesis of cholangiopathy in various immunodeficiencies including HIV infectionE12Benhamou Y. Caumes E. Gerosa Y. Cadranel J.F. Dohin E. Katlama C. et al.AIDS-related cholangiopathy: critical analysis of a prospective series of 26 patients.Dig Dis Sci. 1993; 38: 1113-1118Crossref PubMed Scopus (95) Google Scholar and XHIM.E13Gilmour K.C. Walshe D. Heath S. Monaghan G. Loughlin S. Lester T. et al.Immunological and genetic analysis of 65 patients with a clinical suspicion of X linked hyper-IgM.Mol Pathol. 2003; 56: 256-262Crossref PubMed Scopus (33) Google Scholar, E2Hayward A.R. Levy J. Facchetti F. Notarangelo L. Ochs H.D. Etzioni A. et al.Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM.J Immunol. 1997; 158: 977-983Crossref PubMed Google Scholar However, we found no significant difference in CMV prevalence between those with or without liver disease (Table I). Interestingly, the pathophysiology of CD40L deficiency and sclerosing cholangitis suggests a role for TNF-α. In mouse models, infection of CD40L-deficient mice with Cryptosporidium leads to chronic infection and cholangitis.E14Stephens J. Cosyns M. Jones M. Hayward A. Liver and bile duct pathology following Cryptosporidium parvum infection of immunodeficient mice.Hepatology. 1999; 30: 27-35Crossref PubMed Scopus (63) Google Scholar, E15Ponnuraj E.M. Hayward A.R. Requirement for TNF-Tnfrsf1 signalling for sclerosing cholangitis in mice chronically infected by Cryptosporidium parvum.Clin Exp Immunol. 2002; 128: 416-420Crossref PubMed Scopus (18) Google Scholar Furthermore, CD40L knockout mice showed increased mRNA for Tnfrsf1a (TNF-α) and Tnfrsf1b (TNF-β). In addition, TNF-α production was seen in areas of inflammation of biliary epithelium on microscopy.E15Ponnuraj E.M. Hayward A.R. Requirement for TNF-Tnfrsf1 signalling for sclerosing cholangitis in mice chronically infected by Cryptosporidium parvum.Clin Exp Immunol. 2002; 128: 416-420Crossref PubMed Scopus (18) Google Scholar Triple knockout mice for CD40L/Tnfrsf1a/Tnfrsf1b did not develop sclerosing cholangitis of biliary tree or gall bladder in the context of chronic Cryptosporidium infection.E15Ponnuraj E.M. Hayward A.R. Requirement for TNF-Tnfrsf1 signalling for sclerosing cholangitis in mice chronically infected by Cryptosporidium parvum.Clin Exp Immunol. 2002; 128: 416-420Crossref PubMed Scopus (18) Google Scholar Speculatively, therefore, TNF-α may be an important pathway in sclerosing cholangitis in patients with XHIM. Several studies have reported that curative HSCT improves outcomes and survival of patients with XHIM and that younger age was optimal for the timing of transplantation because persistent infections and severe organ damage were frequently observed in older patients.E16Allewelt H. Martin P.L. Szabolcs P. Chao N. Buckley R. Parikh S. Hematopoietic stem cell transplantation for CD40 ligand deficiency: single institution experience.Pediatr Blood Cancer. 2015; 62: 2216-2222Crossref PubMed Scopus (17) Google Scholar, E17Gennery A.R. Khawaja K. Veys P. Bredius R.G. Notarangelo L.D. Mazzolari E. et al.Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a survey of the European experience, 1993-2002.Blood. 2004; 103: 1152-1157Crossref PubMed Scopus (113) Google Scholar, E18Mitsui-Sekinaka K. Imai K. Sato H. Tomizawa D. Kajiwara M. Nagasawa M. et al.Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan.J Allergy Clin Immunol. 2015; 136: 1018-1024Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar In our cohort, 75% of patients underwent HSCT, compared with other studies reporting rates ranging from 6% to 52%.E1de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, E18Mitsui-Sekinaka K. Imai K. Sato H. Tomizawa D. Kajiwara M. Nagasawa M. et al.Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan.J Allergy Clin Immunol. 2015; 136: 1018-1024Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, E4Leven E.A. Maffucci P. Ochs H.D. Scholl P.R. Buckley R.H. Fuleihan R.L. et al.Hyper-IgM syndrome: a report from the USIDNET Registry.J Clin Immunol. 2016; 36: 490-501Crossref PubMed Scopus (69) Google Scholar, E7Winkelstein J.A. Marino M.C. Ochs H. Fuleihan R. Scholl P.R. Geha R. et al.The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients.Medicine (Baltimore). 2003; 82: 373-384Crossref PubMed Scopus (403) Google Scholar Eighty-nine percent (16 of 18) of patients in the group without liver disease were transplanted at an average age of 3.1 years, with a mean follow-up time of 11 years. One patient developed graft versus host disease in the liver post-HSCT, but underwent successful liver transplantation without further abnormalities in liver function. One patient died of severe graft versus host disease post-HSCT (Table E3). No XHIM-related cholangiopathy or hepatitis has occurred in these patients despite an average of 11 years of follow-up post-HSCT. In comparison, only 50% (4 of 8) of patients in the liver disease group underwent HSCT at an average age of 14.5 years. Higher age and liver disease at HSCT conferred a poor prognosis (Fig 1, C). The cause of death in 3 of these patients was liver failure (while awaiting liver transplantation), multiorgan failure secondary to hemophagocytic syndrome, and severe cryptosporidiosis. HSCT was performed alongside liver transplantation in 1 patient, who, of note, has not had liver disease recurrence despite a follow-up of more than 17 years. Two patients with liver disease who have not undergone HSCT have end-stage liver disease requiring liver transplantation and are currently undergoing assessment. In clinical practice, having treated XHIM- and other immunodeficiency-related liver diseases, we find that receiving liver transplantation without correction of the immunodeficiency confers an extremely poor prognosis (V. Azzu, W. J. H. Griffiths, unpublished data, 2017). Indeed in this study and elsewhere, we find that patients undergoing HSCT have far worse outcomes if they have liver disease that remains uncorrected (ie, without undergoing liver transplantation). Two previous reports support better outcomes in those undergoing both HSCT and liver transplantation. One case study indicates that HSCT shortly after liver transplantation prevented recurrence of liver disease in 1 patient.E19Hadzic N. Pagliuca A. Rela M. Portmann B. Jones A. Veys P. et al.Correction of the hyper-IgM syndrome after liver and bone marrow transplantation.N Engl J Med. 2000; 342: 320-324Crossref PubMed Scopus (88) Google Scholar Another study suggested that 2 patients who received liver transplantation after HSCT did well, compared with a patient receiving a liver transplant without HSCT, who went on to die.E1de la Morena M.T. Leonard D. Torgerson T.R. Cabral-Marques O. Slatter M. Aghamohammadi A. et al.Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.J Allergy Clin Immunol. 2017; 139: 1282-1292Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar We will therefore be approaching the transplant assessment of the aforementioned patients with a view to contemporaneous HCST because this likely confers a survival advantage. There are several potential variables affecting survival in this data set (eg, HSCT timing and liver disease); early HSCT and no liver disease cluster closely to explain survival multivariate analysis (not shown). Although we cannot prove causality, these factors covary intimately, thereby hinting that early HSCT may confer a survival benefit by preventing liver disease onset. The benefits of our study include detailed investigation of liver disease in a complex primary immunodeficiency as well as the inclusion of data from more than 1 center with a cross-sectional look at practice in the United Kingdom. Limitations include data gathered from a single country and less than full recruitment of all UK centers.Table E1Hereditary, genetic, functional, and clinical phenotypes of patients with XHIMIDFH/DNCD40L protein absenceMutation typeProtein domain affected by mutationBody system affected1FHY—Sinupulmonary, GI2DNY—Skin, neutropenia3DNYc.164 delAECU domainSinopulmonary, neutropenia, GI, CNS4FHYc.289 G>AECU domainSinopulmonary5DNYGene deletion/no amplification by PCRNASinopulmonary, FTT6FHYc.798 delTNFH domainSinopulmonary, neutropenia, skin, FTT7DNY—Sinopulmonary, neutropenia8DNY—Neutropenia, GI9FHYUnspecified exon 5 nucleotide deletionTNFH domainSinupolmonary, GI, CNS10DNYc.516 T>ATNFH domainSinopulmonary, GI11FHY—Sinopulmonary, GU12DNYc.289 G>AECU domainSinopulmonary, GI, GU13DNYc.680 delTNFH domainSinopulmonary, GI, FTT14DNYc.540 delTNFH domainSinopulmonary, GI15DNYNovel mutation in TM domain∗Unpublished mutation (courtesy of Dr E. Staples and Dr D. S. Kumararatne).TM domainSinopulmonary, GI, CNS16FHYPoint mutation affecting amino acid E76ECU domainSinopulmonary, anemia, GI17FHY—Sinopulmonary, GI, liver18FHY—CNS, liver19DNYGene deletionNASinopulmonary, GI, liver20FHYUnspecified exon 5 point mutationTNFH domainSinopulmonary, neutropenia, skin, liver21FHY—Liver22DNYc.163 T>GECU domainSinopulmonary, GI, liver23DNYM99Cfs1 amino acid point mutationECU domainSinopulmonary, liver24FHYNovel mutation in TM domain∗Unpublished mutation (courtesy of Dr E. Staples and Dr D. S. Kumararatne).TM domainSinopulmonary, leukemia, GI, CNS, liverCNS, Central nervous system; DN, de novo (diagnosis of XHIM); ECU, extracellular unique domain; FH, family history (of XHIM); FTT, failure to thrive; GI, gastrointestinal; GU, genitourinary; NA, not applicable/available; TM, transmembrane domain; TNFH, tumor necrosis factor homology domain.∗ Unpublished mutation (courtesy of Dr E. Staples and Dr D. S. Kumararatne). Open table in a new tab Table E2Imaging and histological findings in the 8 patients with XHIM with liver diseasePatient IDImagingHistology17Sclerosing cholangitis & dilated CBD on ERCP; hepatomegaly & splenomegaly on USSclerosing cholangitis, periportal fibrosis18Increased periportal echogenicity on USChronic hepatitis, interface hepatitis, portal fibrosis19Sclerosing cholangitis on ERCPSclerosing cholangitis, mild chronic hepatitis20Cholangiopathy & dilated ducts on US & ERCPSclerosing cholangitis, CBD inflammation, minimal portal tract inflammation21Sclerosing cholangitis & ascites on USSclerosing cholangitis22Heterogeneous liver, cholangiopathy with duct dilatation, splenomegaly on US/CT/MRCPCholangiopathy, chronic hepatitis, ductopenia23Heterogeneous liver, cholangiopathy with duct dilatation, cirrhosis on US/CT/MRCPCholangiopathy, perisinusoidal & biliary fibrosis, cirrhosis24Heterogeneous liver, marked hepatomegaly, normal ducts on US/CT/MRCPChronic active hepatitis, fibrosis, granulomatous diseaseCBD, Common bile duct; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancretography; US, ultrasound. Open table in a new tab Table E3Age-adjusted mortality, crude mortality, and standardized mortality ratio in patients with XHIM with or without liver diseaseAge (y)XHIM, No liver diseaseXHIM, liver diseaseUK male populationDeathTotalDeath rateDeathTotalDeath rateDeath rate0-91∗Cause of death in the group without liver disease: severe GvHD post-HSCT.50.20000.00024910-190603†Causes of death in the liver group: liver failure awaiting liver transplant, multiorgan failure secondary to hemophagocytic syndrome post-HSCT, and severe cryptosporidiosis.40.750.00009520-290300000.00024530-390000100.00042840-490100200.00093050-590100100.002037Crude death rate0.06250.3750.003983SMR15.794.1GvHD, Graft versus host disease; SMR, standardized mortality ratio.∗ Cause of death in the group without liver disease: severe GvHD post-HSCT.† Causes of death in the liver group: liver failure awaiting liver transplant, multiorgan failure secondary to hemophagocytic syndrome post-HSCT, and severe cryptosporidiosis. Open table in a new tab CNS, Central nervous system; DN, de novo (diagnosis of XHIM); ECU, extracellular unique domain; FH, family history (of XHIM); FTT, failure to thrive; GI, gastrointestinal; GU, genitourinary; NA, not applicable/available; TM, transmembrane domain; TNFH, tumor necrosis factor homology domain. CBD, Common bile duct; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancretography; US, ultrasound. GvHD, Graft versus host disease; SMR, standardized mortality ratio.
Referência(s)