When Liver Disease Misleads the Diagnosis: Two Cases of TAFRO Syndrome With Porto‐Sinusoidal Vascular Disease

ABSTRACT

Background

TAFRO syndrome is a rare inflammatory disorder whose hepatic manifestations may mimic decompensated cirrhosis.

Cases:

We report two women with TAFRO syndrome associated with portal‐sinusoidal vascular disorder (PSVD), a rare cause of non‐cirrhotic portal hypertension. In both cases, liver biopsy excluded cirrhosis and confirmed PSVD.

Results

Clinical outcomes were markedly different. One patient achieved sustained disease control with anti‐IL‐6 therapy and remained stable for more than 6 years, whereas the other developed rapidly progressive and fatal disease.

Conclusion

PSVD may represent an underrecognized hepatic manifestation of TAFRO syndrome. Recognizing this association may facilitate earlier diagnosis, avoid misclassification as cirrhosis, and support timely therapeutic management.

Trial Registration

The authors have confirmed clinical trial registration is not needed for this submission.

1. Introduction

TAFRO syndrome, an acronym for Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis/Renal insufficiency, and Organomegaly, is a rare inflammatory phenotype within the spectrum of idiopathic multicentric Castleman disease (iMCD). Initially described as a distinct clinicopathological entity separate from iMCD, TAFRO syndrome is now recognized as a specific clinical subtype of iMCD (iMCD‐TAFRO). It is a rare entity with an incidence of less than 1 per 1,000,000 inhabitants. First described by Takai et al. in 2010, this condition is characterized by acute or subacute onset, marked systemic inflammation, and potentially life‐threatening multi‐organ involvement [1]. Compared with iMCD‐not otherwise specified, TAFRO syndrome usually follows a more aggressive course and diagnosis relies on clinicopathological integration [2].

Hepatic involvement is increasingly recognized in TAFRO syndrome and may present as porto‐sinusoidal vascular disease (PSVD), a group of non‐cirrhotic vascular liver disorders associated with portal hypertension. Histological findings include nodular regenerative hyperplasia, peliosis hepatis, and sinusoidal dilatation [3, 4].

2. Case Reports

2.1. Case 1

A 57‐year‐old woman was initially evaluated in 2012 for abdominal lymphadenopathy and inflammatory syndrome with mild liver abnormalities. Over subsequent years, she developed anemia, splenomegaly, ascites, and portal hypertension. Liver biopsy revealed peliosis hepatis (Figure 1). She later required placement of a Transjugular Intrahepatic Portosystemic Shunt because of refractory ascites and esophageal varices.

FIGURE 1.

Histopathological features of liver biopsy (2016) of the Case 1. Liver biopsy shows irregular and sometimes large parenchymal dilatation forming spaces lacking an endothelial lining (asterisk) and dissecting hepatocyte plates, suggestive of peliotic change. No histological evidence of cirrhosis is identified (H&E, scale bar 50 µm).

In 2018, she was admitted to intensive care for encephalopathy, generalized anasarca, and pericardial effusion. Hematological evaluation revealed recurrent pancytopenia marked by leukopenia (0.87 × 10³/mm³) with profound neutropenia (0.07 × 10³/mm³), thrombocytopenia (27 × 10³/mm³), anemia (9.1 g/dL), and circulating blasts (0.8%). Liver tests showed mild cholestasis with hyperbilirubinemia (total bilirubin 2.15 mg/dL). PET/CT showed diffuse lymphadenopathy. Lymph node biopsy demonstrated florid follicular hyperplasia with interfollicular plasmacytosis, while bone marrow examination showed megakaryocytic hyperplasia without fibrosis (Figure 2).

FIGURE 2.

(1) Pet scanner in 2018 of the Case 1: Multiple interaortocaval, left para‐aortic, and right ilio‐inguinal lymph nodes, with the largest and most intensely hypermetabolic one located in the right internal iliac region (red arrow). Relative hypermetabolism of the left hepatic lobe (blue arrow). Moderate, diffuse osseous‐medullary hypermetabolism. (2) Pet scanner in 2025 of the Case 1: Marked increase in non‐hypermetabolic ascites, now abdominopelvic in extent. Persistence of a non‐hypermetabolic mesenteric infiltrate and stability of the non‐hypermetabolic splenomegaly. Stability of the intensely hypermetabolic right external iliac lymphadenopathy and partial metabolic response of the other previously described right iliac lymph nodes (red arrow). Compared with the 2018 pet scan, there is regression of the previously hypermetabolic lymphadenopathy and left hepatic lobe hypermetabolism (blue arrow).

Despite corticosteroids, intravenous immunoglobulins, rituximab, platelet transfusions, and cyclosporine, cytopenias (severe thrombocytopenia at < 1 × 10³/mm³) and fluid overload persisted. Extensive infectious investigations (including tests for histoplasmosis, Q fever, Whipple's disease, and HHV‐8 infection) were negative. She subsequently developed thrombosis of the TIPS and portal‐mesenteric venous system.

A diagnosis of TAFRO syndrome was established based on thrombocytopenia, anasarca, systemic inflammation, organomegaly, Castleman‐like lymph node histology, and increased megakaryocytes in bone marrow (Figure 3). Tocilizumab rapidly improved platelet counts, inflammatory markers, and ascites. Siltuximab was not available through compassionate access at our institution. Therefore, IL‐6 receptor blockade was initiated with subcutaneous tocilizumab. Due to subsequent tocilizumab shortages, treatment was switched to sarilumab. Clinical remission was maintained for more than 3 years under sarilumab therapy. An attempt to extend the dosing interval was associated with a rise in C‐reactive protein levels, leading to re‐escalation of the treatment schedule (Figure 2).

FIGURE 3.

Histopathological features of lymph node and bone marrow biopsies in TAFRO syndrome of the Case 1. Excisional lymph node biopsy (A1–A3) shows preserved overall nodal architecture (A1; H&E, × 100), with prominent paracortical aggregates of plasma cells (A2; H&E, × 400) and moderately atretic follicles (arrow) (A3; H&E, × 300). Bone marrow trephine biopsy (B1–B3) demonstrates preserved architecture (B1; H&E, × 100) with hypercellular marrow and mildly increased megakaryocyte density (arrows) (B2; H&E, × 100), while reticulin staining reveals a mildly increased network of thin black reticulin fibers throughout the bone marrow (MF‐1) (B3; × 500). Core needle lymph node biopsy (C1–C4) shows partial nodal architecture (C1; H&E, × 200), including atretic follicles with germinal centers (arrow) depleted of lymphoid cells and replaced by hyalinized material (C2; H&E, × 200), associated with prominent vascular proliferation (C3; H&E, × 300), and interfollicular plasma cell aggregates (arrow) (C4; H&E, × 900).

2.2. Case 2

A 68‐year‐old woman was first seen in September 2024 with thrombocytopenia at 67 × 10³/mm³ and regenerative anemia of 11.2 g/dL. The initial workup led to a diagnosis of immune thrombocytopenic purpura. In 2025, she developed worsening cytopenias (thrombocytopenia at 26 × 10³/mm³, anemia with Hb at 11.2 g/dL, and neutropenia at 1.86 × 10³/mm³), lower‐limb edema, hepatosplenomegaly, and portal hypertension. Bone marrow examination showed megakaryocytic hyperplasia without dysplasia (Figure 4).

FIGURE 4.

Histopathological features of bone marrow biopsy of the Case 2. Bone marrow biopsy (A–D) shows increased cellularity with preserved trilineage hematopoiesis and maturation (A; H&E, × 100). Higher magnification highlights megakaryocytes of variable size and lobulation without marked hyperlobulation or dysplastic features (arrows) (B; H&E, × 200). CD61 immunohistochemistry confirms the presence and distribution of megakaryocytes, in keeping with the H&E findings (C; × 200). Reticulin staining demonstrates mild increased network of thin black reticulin fibers (MF‐1) (D; × 200).

Liver biopsy demonstrated nodular regenerative hyperplasia consistent with PSVD (Figure 5). Endoscopy confirmed portal hypertensive gastropathy and esophageal varices. Shortly after admission, she developed fever, anasarca, respiratory distress, and hepatic encephalopathy requiring intensive care.

FIGURE 5.

Histopathological features of liver biopsy of the Case 2. Liver biopsy (A–B) shows mild, minimally active chronic portal inflammation composed predominantly of lymphocytes with rare neutrophils, with well‐preserved portal triads. The lobular architecture is partially maintained, with areas of vague nodularity (curve) and dilated sinusoids containing mixed inflammatory cells (asterisk). No significant steatosis is identified. These features are consistent with degenerative nodular hyperplasia and mild fibrosis (F1). Hematoxylin and eosin staining highlights nodular parenchymal architecture (A; H&E, × 200), while reticulin staining demonstrates corresponding nodular alterations of the reticulin framework (curve) (B; × 200).

TAFRO syndrome was diagnosed based on thrombocytopenia, anasarca, systemic inflammation, hepatomegaly, and bone marrow abnormalities. High‐dose corticosteroids followed by weekly tocilizumab were initiated. The course was complicated by septic shock, candidemia, refractory thrombocytopenia, autoimmune hemolytic anemia, and disseminated intravascular coagulation. Despite escalation to rituximab, the patient died from uncontrolled gastrointestinal bleeding in the setting of sepsis and liver failure.

3. Discussion

TAFRO syndrome is a rare and severe subtype within the spectrum of iMCD. Its clinical presentation is heterogeneous and may overlap with several systemic disorders, making diagnosis particularly difficult. Among its manifestations, hepatic involvement is increasingly recognized but remains underdiagnosed.

The association of thrombocytopenia, ascites, and hepatosplenomegaly frequently leads clinicians to suspect advanced chronic liver disease. Complications related to portal hypertension, including varices, ascites, and hypersplenism, may therefore be interpreted as consequences of cirrhosis rather than manifestations of an underlying inflammatory disorder. The two cases presented here illustrate this diagnostic pitfall, as both patients were initially managed within a hepatology setting before recognition of an underlying systemic hematological disease. These observations emphasize the importance of considering TAFRO syndrome in patients presenting with unexplained cytopenias, portal hypertension, and inflammatory features.

Hepatic involvement in TAFRO syndrome has been increasingly described during recent years and includes a broad spectrum of clinical, biochemical, and histopathological abnormalities [3]. Reported manifestations include hepatomegaly, mild, or moderate elevation of liver enzymes, cholestasis, hyperbilirubinaemia, and, less commonly, acute liver dysfunction [3, 4, 5, 6, 7]. Histological lesions are heterogeneous and include peliosis hepatis, nodular regenerative hyperplasia, intrahepatic cholangitis, and non‐specific sinusoidal dilatation. These abnormalities are often identified in the context of PSVD, suggesting a link between systemic inflammation and vascular liver injury. Consequently, TAFRO syndrome should be recognized as a potential underlying cause of PSVD, particularly when inflammatory manifestations coexist [3, 4, 7, 8].

Hepatic involvement has also been reported in Castleman disease more broadly. Described lesions include focal hepatic abnormalities characterized by lymphoid follicular hyperplasia, hyalinized vessels, and vascular vitreous degeneration, together with vascular and parenchymal changes such as peliosis hepatis, perisinusoidal fibrosis associated with nodular regenerative hyperplasia, nodular cirrhosis, diffuse fibrosis, and portal tract fibrosis. Additional findings include cholestasis, bile duct hyperplasia, plasma cell infiltration, inflammatory infiltrates, and Budd–Chiari syndrome‐associated cirrhosis [8, 9, 10, 11, 12].

PSVD represents a rare group of vascular liver disorders characterized by architectural distortion of the hepatic microvasculature in the absence of cirrhosis, with or without portal hypertension. Histological patterns include nodular regenerative hyperplasia, obliterative portal venopathy, and incomplete septal fibrosis [13]. Clinically, affected patients may present with splenomegaly, thrombocytopenia, or ascites despite the absence of advanced fibrosis [14]. PSVD is frequently associated with systemic conditions, particularly hematological disorders, autoimmune diseases, prothrombotic states, and exposure to drugs or toxins [15, 16, 17, 18].

The association between TAFRO syndrome and PSVD raises important pathophysiological considerations. The principal mechanism is likely cytokine‐driven endothelial dysfunction. TAFRO syndrome is characterized by a cytokine storm with marked elevation of interleukin‐6 and other inflammatory mediators [19]. These cytokines may induce endothelial activation, increased vascular permeability, and microvascular injury, leading to sinusoidal dilatation, peliosis, and altered hepatic perfusion. Overexpression of vascular endothelial growth factor may additionally promote abnormal angiogenesis and capillary leak, contributing to anasarca and hepatic congestion. Chronic exposure to this inflammatory environment may eventually produce structural remodeling of the hepatic microcirculation consistent with PSVD [5, 13, 14, 15, 19]. These observations support the hypothesis that dysregulated lymphoproliferation and cytokine‐mediated vascular injury may affect the liver in Castleman‐related disorders.

Autoimmune mechanisms may also contribute to liver injury. The frequent association with immune dysregulation and the presence of autoantibodies in some cases suggest that immune‐mediated injury affecting biliary epithelium or vascular endothelium may occur. Acquired genetic alterations involving signaling pathways such as JAK–STAT or MAPK may further contribute to pathogenesis, although their role in hepatic involvement remains uncertain [19, 20].

Histopathological findings in TAFRO syndrome remain non‐specific and overlap considerably with those observed in iMCD. Lymph node biopsy typically demonstrates regressed germinal centers, marked vascular proliferation, and interfollicular plasmacytosis. Bone marrow examination frequently reveals megakaryocytic hyperplasia and variable reticulin fibrosis [21, 22]. Consequently, diagnosis relies upon the integration of clinical, laboratory, and histological findings, as reflected in the criteria proposed by Masaki and colleagues (Table 1) [23, 24].

TABLE 1.

Masaki's criteria (2021).

Major criteria

Anasarca, including pleural effusion, ascites and general edema

Thrombocytopenia ≤ 100.000/mm3 without myelosuppressive treatment

Systemic inflammation, defined as fever of unknown etiology above 37.5°C and/or serum C‐reactive protein concentration ≥ 2 mg/dL

Minor criteria

Castleman's disease‐like features on lymph node biopsy

Reticulin myelofibrosis and/or increased number of megakaryocytes in bone marrow

Mild organomegaly, including hepatomegaly, splenomegaly, and lymphadenopathy

Progressive renal insufficiency

Diseases to be excluded

Malignancies, including lymphoma, myeloma, mesothelioma…

Autoimmune disorders, including systemic lupus erythematosus, ANCA‐associated vasculitis…

Infectious disorders, including acid‐fast bacterial infection, rickettsial disease, Lyme disease, severe fever with thrombocytopenia syndrome…

POEMS syndrome

Hepatic cirrhosis

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

Note: Table summarizing the major and minor diagnostic criteria updated for TAFRO syndrome, Masaki's criteria (2021). The main difference between the Iwaki's and Masaki's criteria is the histopathological confirmation of lymph nodes diagnosis. Adapted from Nishimura et al. Journal of Clinical and Experimental Hematology, 2022, sous license CC BY‐NC‐SA 4.0.

Liver biopsy is not mandatory for diagnosis but may provide important information in patients with prominent hepatic involvement by distinguishing cirrhosis from PSVD. However, the procedure is often difficult because of severe thrombocytopenia, coagulopathy, portal hypertension, and ascites. When feasible, the transjugular approach may represent a safer alternative.

Management of TAFRO syndrome remains challenging and is largely based on expert opinion and retrospective studies. Corticosteroids are commonly used as first‐line treatment but often induce only transient improvement. Therapies targeting interleukin‐6, particularly tocilizumab and siltuximab, have become central because of the pivotal role of this cytokine in disease pathogenesis. In cases of inadequate response, additional immunosuppressive agents such as rituximab or ciclosporin may be required. Although sarilumab is not currently recommended for the treatment of iMCD‐TAFRO because of the lack of supporting clinical evidence, our observation suggests that IL‐6 receptor blockade with sarilumab may represent a pragmatic alternative when both siltuximab and tocilizumab are unavailable. Nevertheless, no conclusions regarding its efficacy can be drawn from a single case.

Supportive care is equally essential and includes management of fluid overload, infections, and complications related to portal hypertension. Prognosis remains variable, with substantial early mortality in severe forms [25, 26]. Poor prognostic factors include advanced age, severe thrombocytopenia, renal dysfunction, and marked inflammatory activation (Table 2). The cases presented here highlight the importance of recognizing TAFRO syndrome in patients with unexplained portal hypertension associated with systemic inflammatory manifestations.

TABLE 2.

Disease severity classification according to total score.

Anasarca
Pleural effusion on imaging	1 point
Ascites on imaging	1 point
Pitting edema on physical examination	1 point
Thrombocytopenia
< 100 × 103/mm3	1 point
< 50 × 103/mm3	2 points
< 10 × 103/mm3	3 points
Fever and/or inflammation
≥ 37.5°C but < 38.0°C or for CRP ≥ 2 mg/dL but < 10 mg/dL	1 point
Fever ≥ 38.0°C but < 39.0°C or for CRP ≥ 10 mg/dL but < 20 mg/dL	2 points
Fever ≥ 39.0°C or for CRP ≥ 20 mg/dL	3 points
Renal insufficiency
GFR < 60 mL/min/1.73 m2	1 point
GFR < 30 mL/min/1.73 m2	2 points
GFR < 15 mL/min/1.73 m2 or need for hemodialysis	3 points

Note: Table summarizing the relationship between score and disease severity. 0–2 points: Insufficient for diagnosis. 3–4 points: Mild. 5–6 points: moderate. 7–8 points: Slightly severe. 9–10 points: Severe. 11–12 points: Very severe. Adapted from Masaki et al. International Journal of Hematology103 (2016): 686–692.

4. Conclusion

The two cases reported here illustrate the wide spectrum of TAFRO syndrome, ranging from a chronic, treatment‐responsive course to a fulminant and fatal presentation. In both patients, hepatic involvement in the form of vascular liver disease played a central role in the initial clinical picture and contributed to diagnostic delay by suggesting primary liver pathology with secondary thrombocytopenia.

These observations highlight the association between TAFRO syndrome and PSVD. Radiological and clinical features may closely mimic decompensated cirrhosis, particularly in the presence of thrombocytopenia, splenomegaly, and signs of portal hypertension. Awareness of this diagnostic pitfall is essential, especially for hematologists evaluating patients with unexplained cytopenias and systemic inflammation.

Early recognition of TAFRO syndrome and prompt initiation of appropriate treatment remain crucial to improving outcomes. Further collection of cases and systematic characterization of hepatic involvement are needed to better define its prevalence, pathophysiology, and prognostic significance within the TAFRO spectrum.

Author Contributions

All authors contributed to the conception and design of the case report, critical revision of the manuscript, and approved the final version for publication.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Consent

The first reported patient provided written informed consent for the publication of this report and any accompanying images, in accordance with institutional and international ethical standards (including the Declaration of Helsinki). For the second patient, written informed consent could not be obtained because the short interval between diagnosis and death, together with her impaired cognitive status, precluded obtaining consent. All identifying information has been removed to protect patient confidentiality.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data supporting the findings of this case report are available from the corresponding author upon request.