Late-onset combined immunodeficiency and bone marrow failure in severe autoimmune hepatitis: a case report

Abstract

Background

Late-onset combined immunodeficiency ( is a rare primary immunodeficiency characterized by hypogammaglobulinemia, T-cell lymphopenia, and susceptibility to opportunistic infections. While autoimmune liver involvement has been well documented in common variable immunodeficiency, no association with late-onset combined immunodeficiency has previously been reported. This case represents, to our knowledge, the first pediatric description of autoimmune hepatitis as the initial manifestation of late-onset combined immunodeficiency.

Case presentation

We present the case report of a 15-year old North African Arabic Tunisian boy.

A 15-year-old boy presented with severe hepatitis, clinically and histologically consistent with seronegative autoimmune hepatitis. Corticosteroid therapy led to clinical improvement and enabled a liver biopsy, which confirmed autoimmune hepatitis. Persistent hypogammaglobulinemia and lymphopenia involving T, B, and NK cells prompted further immunologic evaluation, confirming the diagnosis of late-onset combined immunodeficiency. The disease course was complicated by hepatitis-associated aplastic anemia and hemorrhagic events. Despite hematopoietic stem cell transplantation, the patient died from septic complications.

Conclusions

This case highlights the importance of screening for underlying immunodeficiency in adolescents presenting with atypical or seronegative autoimmune hepatitis. Early recognition of late-onset combined immunodeficiency and related complications, such as hepatitis-associated aplastic anemia, is crucial for timely multidisciplinary management and may significantly impact patient outcomes.

Introduction

Late-onset combined immunodeficiency (LOCID) is an adult-onset form of combined immunodeficiency that can be viewed as an attenuated variant of severe combined immunodeficiency (SCID) [1]. It is defined by the occurrence of opportunistic infections and/or a CD4+ T-cell count below 200/µL in the setting of hypogammaglobulinemia. In LOCID, patients often exhibit more severe clinical features than classic common variable immunodeficiency (CVID): lower overall lymphocyte counts, especially CD4+ T cells, and a higher incidence of splenomegaly, granulomas, gastrointestinal disease, and lymphomas. Systematic T-cell phenotyping by flow cytometry is essential for diagnosis [2]. Autoimmune manifestations are recognized in primary immunodeficiencies, but autoimmune hepatitis (AIH) has primarily been reported in classic CVID rather than LOCID variants [1, 3]. AIH is a chronic inflammatory liver disease of presumed autoimmune origin, classically occurring in females and characterized by elevated aminotransferases, hypergammaglobulinemia, and specific autoantibodies. It can present with acute or chronic liver injury [3, 4]. Cases in male adolescents are rare [3]. Approximately 10–15% of AIH cases in patients present as seronegative variants lacking characteristic autoantibodies or hypergammaglobulinemia, particularly in immunodeficiency contexts [3, 4]. While liver involvement occurs in 10–35% of patients with primary antibody deficiency [1, 5], its association with LOCID has not been previously reported. Here, we report, to our knowledge, the first known case of LOCID revealed by severe AIH in a male teenager.

Case presentation

We present the case report of a 15-year old North African Arabic Tunisian boy

A 15-year-old previously healthy North African teenager was hospitalized after experiencing yellow discoloration of the eyes and skin and fatigue for over 10 days, which was clinically confirmed as jaundice. He had a family history of autoimmune polyendocrinopathy (AIRE mutation) and fatal AIH in a 14-year-old female cousin, but no personal history of recurrent infections. On exam, he had jaundice, hepatomegaly (liver edge 18 cm), and mild splenomegaly (2 cm below costal margin), without encephalopathy or bleeding. Laboratory tests revealed a severe hepatocellular injury pattern. Aminotransferases were markedly elevated, with aspartate aminotransferase (AST) at 98 times the upper limit of normal (ULN) and alanine aminotransferase (ALT) at 61 × ULN. Total bilirubin was significantly elevated at 681 µmol/L, predominantly in the conjugated form (645 µmol/L). Cholestatic enzymes were also increased: gamma-glutamyl transferase (GGT) at 11.4 × ULN and alkaline phosphatase (ALP) at 2.1 × ULN. Prothrombin time (PT) was reduced to 48%. Complete blood count revealed lymphopenia (750/µL), with normal hemoglobin (14.1 g/dL), platelet count (281,000/µL), and total white blood cell count (4720/µL). Abdominal ultrasound showed hepatosplenomegaly without biliary tract dilatation. No recent exposure to new medications or toxins was identified. Viral, metabolic, and genetic evaluations were negative, including tests for hepatitis A–E viruses, non-alphabetic viruses, hemochromatosis, Wilson’s disease, and alpha-1 antitrypsin deficiency. Human immunodeficiency virus (HIV) serology was also negative. Immunologic profiling showed homogeneousantinuclear antibody (ANA) 1:400, but anti-liver kidney microsomal type 1 antibody (anti-LKM1), anti-smooth muscle antibody (anti-SMA), and anti-mitochondrial antibodies were absent. Serum protein electrophoresis revealed a total protein level of 51 g/L, albumin at 35 g/L, and reduced gamma globulins (4.3 g/L). Quantitative immunoglobulin testing showed decreased IgG at 4.94 g/L (reference range: 6.58–18.37 g/L) and IgM at 0.24 g/L (reference range: 0.40–2.63 g/L), while IgA levels were within normal limits. A 24-hour urine collection showed no proteinuria.

Given the acute severe hepatitis and the family history of fulminant probable acute AIH, AIH was strongly suspected despite seronegative status. The revised International AIH Group pre-treatment score indicated probable AIH, and empirical corticosteroid therapy (prednisone 1 mg/kg/day) was initiated. A transjugular biopsy was not available locally, so treatment was started while arranging a percutaneous biopsy after partial stabilization. Liver function tests improved rapidly, with a marked decrease in aminotransferases and a progressive rise in PT (Table 1), allowing for a percutaneous liver biopsy to be performed within 1 month of presentation.

Table 1.

Bilirubin and liver enzyme trends under corticotherapy, from admission to liver biopsy (day 34)

	D0 (Admission)	D12 (steroids)	D17	D22	D27	D34 (LB)
AST (ULN)	98	77	39	—	—	—
ALT (ULN)	61	43	30	26	16.4	6.8
TB CB (µmol/L)	681 645	735 400	519 403	667 553	289 241	327 —
PT	48%	54%	59%	70%	75%	82%
GGT (ULN)	2.3	2.6	4.7	7.6	9.6	11
ALP (ULN)	2	1.7	1.3	1.5	2.2	1.9

An em-dash (—) signifies not measured. D day, LB liver biopsy, AST aspartate aminotransferase, ULN upper limit of normal, ALT alanine aminotransferase. TB total bilirubin, CB conjugated bilirubin, PT prothrombin time, GGT gamma-glutamyl transferase, ALP alkaline phosphatase

Histology revealed interface hepatitis with lymphoplasmacytic infiltration, hepatocyte injury (including ballooning and giant cells), and cholestasis, strongly suggesting AIH, supported by the absence of biliary or infectious features (Fig. 1). A gastroscopy was also performed to evaluate for endoscopic signs of portal hypertension; it revealed mycotic esophagitis without any evidence of portal hypertension.

Fig. 1.

A Hematoxylin and wosin stain, 20×: Lobular activity characterized by a lymphocytic inflammatory infiltrate (arrows). B Hematoxylin and eosin stain, 40×: Ballooned hepatocytes with intrahepatocytic cholestasis (arrows)

Because of the isolated hypogammaglobulinemia, persistent lymphopenia, and opportunistic infection, an underlying immunodeficiency was considered. Flow cytometry on peripheral blood revealed global lymphopenia affecting all subsets (Table 2).

Table 2.

Lymphocyte subsets by flow cytometry (Trucount method)

Lymphocyte subset	Percentage (%)	Absolute value (cells/μL)
Total lymphocytes (CD45+)	—	1222
T cells (CD3+)	57, 18	698
Helper T cells (CD3+ CD4+)	10, 16	113
Cytotoxic T cells (CD3+ CD8+)	32, 37	364
B cells (CD19+)	36, 62	487
NK cells (CD16+/CD56+)	2, 42	32

NK natural killer

These findings were consistent with LOCID. The patient started on intravenous polyvalent immunoglobulins along with corticosteroids (0, 75 mg/kg/d) and put on caspofungin for fungal esophagitis. Azathioprine (50 mg/day) was subsequently introduced 3 months after corticotherapy initiation once bilirubin levels normalized. Prophylactic trimethoprim–sulfamethoxazole was added for infection prevention.

Initially, the patient improved: bilirubin remained normal, AST/ALT fell to 2–3 × ULN, PT rose to 89%, and lymphocyte count increased to 1900/µL. However, 2 weeks after starting azathioprine, he suddenly developed severe pancytopenia (hemoglobin 6.5 g/dL, platelets 9000/µL, neutrophils 100/µL) accompanied by mucosal bleeding and fever. He also developed infections (aspergillus-colonized sinusitis and Escherichia coli prostatitis). Azathioprine was discontinued immediately, but cytopenia persisted and worsened despite cessation, suggesting an immune-mediated aplasia rather than drug toxicity alone. Indeed, azathioprine-induced toxicity was ruled out given the persistence of bone marrow aplasia after drug withdrawal, a conclusion further supported by the findings of the pharmacovigilance investigation. A bone marrow biopsy revealed marked hypocellularity with aplastic anemia. Granulocyte colony-stimulating factor (G-CSF) and corticosteroid pulses were administered without response. Microbiological cultures identified Aspergillus fumigatus colonization in the paranasal sinuses and Escherichia coli in urine cultures. Due to progressive pancytopenia and severe infections, hematopoietic stem cell transplantation (HSCT) was undertaken 5 weeks after the onset of cytopenia. The patient underwent haploidentical HSCT from his mother, following a reduced-intensity conditioning regimen (fludarabine, cyclophosphamide, and low-dose total body irradiation). The graft was T-cell-replete, and graft-versus-host disease (GVHD) prophylaxis included post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil. Engraftment failed to occur, and the post-transplant course was complicated by refractory septic shock, leading to death 3 weeks after HSCT, despite maximal supportive care (broad antibiotics/antifungals, transfusions). Table 3 provides a chronological overview of the patient’s clinical course, therapeutic interventions, and outcomes.

Table 3 .

Chronological summary of the patient’s clinical course, treatments, and outcomes

Time (weeks)	Clinical event	Key findings/actions
T = 0	Initial presentation with jaundice, fatigue	Acute severe hepatitis; AST 98 × ULN, ALT 61 × ULN, PT 48%
T = 0 → 1 month	Corticosteroid therapy initiated (prednisone 1 mg/kg/day)	Rapid biochemical improvement; bilirubin and PT normalization
T = 4 weeks	Liver biopsy performed	Interface hepatitis with lymphoplasmacytic infiltrate and cholestasis, consistent with AIH
T = 12 weeks	Azathioprine introduced (50 mg/day)	Stable liver function prior to introduction
T = 14 weeks	Onset of pancytopenia	Hb 6.5 g/dL, platelets 9000/µL, neutrophils 100/µL; mucosal bleeding, fever
T = 14 weeks	Azathioprine discontinued	No hematologic recovery; bone marrow biopsy → aplastic anemia
T = 15–20 weeks	Intensive supportive care	Broad-spectrum antibiotics, antifungals, G-CSF, transfusions
T = 20 weeks	Haploidentical HSCT from mother	Reduced-intensity conditioning (fludarabine, cyclophosphamide, low-dose TBI); GVHD prophylaxis with post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil
T = 23 weeks	Post-transplant complications	Persistent aplasia, refractory septic shock (E. coli, Aspergillus); patient deceased 3 weeks post-HSCT

Discussion

This case highlights a rare intersection between autoimmunity and immunodeficiency. To the best of our knowledge, AIH as an initial manifestation of LOCID has not been previously reported in the literature. Existing reports primarily associate AIH with CVID, in which liver involvement is observed in up to 10% of patients, with AIH accounting for only a small proportion of these cases [6]. LOCID has only recently been recognized (through the DEFI study) as a distinct subset of CVID characterized by severe T-cell defects. The DEFI study's report found that 8.9% of adult patients with CVID met criteria for LOCID (opportunistic infections and/or CD4 < 200), and these patients had marked lymphopenia and reduced immunoglobulins despite immunoglobulin therapy [2].

Studies indicate that a significant proportion of patients with autoimmune liver diseases (AILD), including AIH, may have underlying immunodeficiencies. For instance, a study of 82 patients with AILD found that 15 (18%) had immunodeficiency, with 3 (3.6%) specifically diagnosed with combined immunodeficiency [7]. This suggests that LOCID may contribute to the pathogenesis of AIH in a subset of patients.

The prevalence of liver involvement in primary immunodeficiency syndromes further supports this association. Pediatric studies show 36% of unexplained childhood hepatitis cases have underlying immunodeficiencies [5, 8]. These findings highlight the need for immunodeficiency screening in patients with AIH, particularly those with atypical presentations or treatment-resistant disease.

In our patient, the first clue to LOCID was the combination of unexplained hypogammaglobulinemia and persistent lymphopenia. Flow cytometry confirmed pan-lymphopenia (low T, B, and NK cells), as reported in LOCID. LOCID is thought to be an attenuated SCID-like condition: unlike classic SCID in infancy, it presents later with somewhat indolent courses but can still be life-threatening. Diagnosis requires high suspicion and detailed immunophenotyping [2].

Interestingly, AIH was the presenting manifestation of immunodeficiency in this adolescent. The diagnosis of AIH was supported by histology and treatment response. AIH is classically defined by chronic hepatitis with lymphoplasmacytic inflammation, elevated IgG, and autoantibodies [9]. However, up to 10–15% of patients with AIH can lack typical autoantibodies or hyper-IgG, called “seronegative AIH,” and this is more common when immune function is impaired [6]. In this patient, hypergammaglobulinemia was absent by definition of LOCID, and the usual tissue autoantibodies (anti-LKM1, SMA) were negative. These atypical features might have obscured the AIH diagnosis. Nevertheless, clinical severity, positive ANA, family history, and absence of other causes led us to treat empirically. As in similar cases of CVID-associated AIH, response to immunosuppression and liver biopsy were crucial for diagnosis. After steroids, liver tests improved markedly, and biopsy confirmed interface hepatitis with plasmacytic infiltrates [6]. CVID-AIH cases have emphasized that, in patients with hypogammaglobulinemia, diagnosis often rests on excluding other causes and demonstrating typical histology and steroid response [6].

The subsequent development of bone marrow aplasia highlights a known complication of AILD. Hepatitis-associated aplastic anemia (HAAA) is a variant of aplastic anemia that usually follows acute, often seronegative, hepatitis. It is thought to be immune-mediated: activated cytotoxic T-lymphocytes, especially CD8+ cells, secrete interferon-gamma, suppressing hematopoiesis [10, 11]. Indeed, the literature notes that severe aplastic anemia can occur within weeks to months after acute hepatitis, viral or autoimmune, with poor prognosis [5, 12]. Our patient’s course paralleled these descriptions: pancytopenia and marrow aplasia developed about 14 weeks after AIH onset and were refractory to conventional therapies. Notably, standard AIH treatments (steroids, azathioprine) can control liver inflammation but do not prevent the development of aplastic anemia [12].

Management of HAAA typically involves supportive care (transfusions, antibiotics) and definitive therapy with immunosuppression or HSCT [12]. For acute HAAA, matched-sibling HSCT is considered first-line if available; immunosuppressive therapy is an alternative when no donor is present [12, 13]. Recent studies suggest HSCT provides more durable hematopoietic recovery than immunosuppressive therapy in HAAA [13]. In our patient, the severity of marrow failure in the setting of underlying immunodeficiency justified early transplant referral. Regrettably, the patient succumbed to infectious complications despite treatment with broad-spectrum antibiotics.

Conclusion

This case emphasizes that severe or atypical AIH in a young patient warrants evaluation for underlying immunodeficiency. The absence of autoantibodies or hypergammaglobulinemia should not rule out AIH, especially if lymphopenia is present. Conversely, new-onset cytopenias during AIH therapy should prompt investigation for immune-mediated aplasia. Multidisciplinary management, combining immunosuppressive therapy, immunoglobulin replacement, and consideration of HSCT, is critical. Early recognition of LOCID is important, as it impacts treatment strategy and prognosis in such complex cases.

Author contributions

Sahbani Feriel and Hajer Hassine were responsible for the conception of the work, data collection, analysis, and drafting of the manuscript. All authors read and approved the final manuscript.

Funding

The authors received no specific funding for this work.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Ethical approval was not required for this study as it describes a single case. Written informed consent was obtained from the patient’s parent for participation and publication of this case report.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.