Severe hepatic sinusoidal obstruction syndrome in a patient with Wilms tumor and hereditary spherocytosis

Abstract

A 7-year-old girl with a history of splenectomy for hereditary spherocytosis (HS) was diagnosed with renal hematoma after a blunt abdominal trauma while receiving aspirin. Multiple erythrocyte transfusions and transarterial embolization were performed without success. Eventual nephrectomy revealed severely necrotic and perforated Stage III Wilms tumor (WT). Radiochemotherapy was administered, but by the eighth week, she developed severe hepatic sinusoidal obstruction syndrome (HSOS). Her ferritin level at the time was 3406 ng/ml. Defibrotide and aggressive supportive measures provided full recovery. The patient was given deferasirox for iron chelation therapy and finished her treatment without incident. To our knowledge, just one patient with HS and WT has been described in the literature. The role of iron excess in HSOS pathogenesis in non-transplant patients has not been addressed before either. Transfusional hyperferritinemia, in addition to chemotherapeutics and radiation, may have contributed to the development of severe HSOS in our patient.

Introduction

Hepatic sinusoidal obstruction syndrome (HSOS), also known as hepatic veno-occlusive disease, is one of the potentially fatal oncological emergencies of pediatric cancer treatment. The clinical picture is characterized by an acute form of hepatic dysfunction, which necessitates early identification and intervention to enhance the chance of complete recovery [1]. The diagnostic criteria for HSOS continue to evolve and include the Baltimore criteria, the modified Seattle criteria, and finally, the European Society for Blood and Marrow Transplantation (EBMT) pediatric criteria, which were also improved and expanded in 2020 [2, 3]. The EBMT criteria require two or more of the following for HSOS diagnosis: Transfusion refractory thrombocytopenia, otherwise unexplained weight gain of more than 5% above baseline value within three days, hepatomegaly above baseline value, and ascites confirmed by imaging. HSOS is most commonly observed in hematopoietic stem cell transplantation (HSCT) patients, but, certain antineoplastics, such as dactinomycin, pre-existing liver disease, and radiation therapy can also cause HSOS in nonHSCT patients [4, 5]. Iron overload is an inevitable outcome of repeated red blood cell transfusions posing significant morbidity and potential mortality [6]. Additionally, it has been identified as an independent risk factor for HSOS among patients undergoing HSCT [7]. However, the role of hyperferritinemia in HSOS has not been investigated in nonHSCT patients. Hereditary spherocytosis and Wilms tumor co-occurrence is also a rare condition, with only one case report described in the currently available literature [8]. In this context, we present a patient with hereditary spherocytosis (HS) and transfusional iron overload who developed a severe form of HSOS during chemotherapy for Wilms’ Tumor (WT).

Case

A 7-year-old child with transfusion-dependent hereditary spherocytosis (HS) who had a splenectomy 9 months before had been referred to our clinic with an abdominal mass. The patient's history revealed a blunt trauma to the right flank while on low-dose aspirin therapy for post-splenectomy reactive thrombocytosis. In another center, an emergency ultrasound scan showed a large hematoma in the right kidney. Her vital signs and hemoglobin levels were stable, so a cautious approach of monitoring without immediate intervention was chosen, and the aspirin was stopped. During the follow-up, a computed tomography (CT) scan of the abdomen showed signs of active bleeding with contrast leakage and an enlarging hematoma that was compressing the renal parenchyma. To control the bleeding, a right renal transcatheter arterial embolization was performed. However, the patient's hemoglobin levels continued to decrease, and she needed six units of packed red blood cells, since the renal hematoma was first identified. Repeat CT scans showed further growth of the mass lesion. Based on the possibility of tumoral bleeding caused by a renal tumor, a decision was made to proceed with a nephrectomy, as other differential diagnoses were considered as well (Fig. 1). The eventual diagnosis was severely necrotic and ruptured Stage III WT without anaplasia. Chemotherapy (dactinomycin, doxorubicin, and vincristine) and whole abdominal RT were initiated. In the eighth week of therapy, the patient complained of fever, vomiting, and mild abdominal pain. The laboratory findings were as follows: Hemoglobin 8.2 g/dl, platelet: 6.10⁹/L, AST: 89 U/L, ALT: 58 U/L. The following day, the patient developed jaundice, abdominal distention, and painful hepatomegaly. She had a weight gain of 2 kg (11% of baseline weight). The platelet count was 4 × 10⁹/L despite appropriate platelet transfusion, and liver function tests rapidly deteriorated. Transfusion refractory thrombocytopenia, a bilirubin increase of 5 mg/dl in the last 48 h, severe painful hepatomegaly, and unexplained weight gain were consistent with the diagnosis of HSOS. The treatment involved defibrotide, N-acetyl cysteine, spironolactone, and ursodeoxycholic acid, and the patient was admitted to the pediatric intensive-care unit. AST, total bilirubin, direct bilirubin, and INR continued to increase, with values reaching 4378 U/L, 15 mg/dl, 7.5 mg/dl, and 2.96, respectively. The patient also exhibited increased ammonia and ferritin (3406 ng/ml) levels. Fresh-frozen plasma was administered to treat coagulopathy, whereas morphine was used for pain management. On the 6th day of treatment, ultrasonography revealed hepatomegaly, reversed portal blood flow, as well as severe ascites with pleural effusion. The patient needed oxygen support and serial paracentesis procedures to relieve the respiratory compromise due to ascites. A doubling of the bilirubin level within 48 h, liver enzymes elevated to above five times the normal range, the requirement of fresh frozen plasma to correct coagulopathy, the necessity for paracentesis to alleviate respiratory distress resulting from ascites, and a weight gain exceeding 10% categorized the patient as having a very severe (Grade IV) HSOS [2]. By the seventh day, liver function tests started to improve (Fig. 2), and the patient was discharged on the 25th day of her hospitalization. Iron chelation with deferasirox was given until the ferritin level decreased below 1000 ng/ml. She completed her chemotherapy according to the recommended dose adjustments of the protocol.

Fig. 1.

Axial CT images showing the progress of renal mass lesion: a day of admission, b 26th day of admission, c 54th day of admission

Fig. 2.

The evolution of laboratory parameters and the course of HSOS

Currently, she has been in remission for WT for 38 months, and her liver function tests are within normal limits except for mild indirect hyperbilirubinemia due to spherocytosis.

The patient’s parents provided informed consent for the case report.

Discussion

Hepatic sinusoidal obstruction syndrome (HSOS) is an uncommon yet life-threatening complication of childhood cancer treatment. HSOS has an incidence of 3–14% in different WT case series, reaching an incidence of 45.1% in liver biopsy samples obtained during nephrectomy for WT [9–12]. Dactinomycin treatment, having a right-sided WT, past abdominal radiation, being younger, and having a lower body weight have all been recognized as potential risk factors [5]. The first three of the aforementioned characteristics were present in our patient.

WT with abundant necrosis might mimic renal hematoma or abscess [13, 14]. Our patient had a diagnostic delay due to a history of trauma, aspirin use, and a necrotic tumor resembling a hemorrhage radiologically. Stage III WT patients with evident rupture, such as our patient, are recommended to receive whole abdomen irradiation in addition to flank radiotherapy [15]. It is widely recognized that right-sided renal tumors, such as in our patient’s case, are more susceptible to developing liver endothelial damage due to prior treatment involving irradiation and chemotherapy [16].

Iron-induced liver damage is multifactorial and still poorly understood [17]. The oxidative stress mediated by iron-generated oxyradicals and lipid membrane damage might cause liver injury, and contribute to HSOS development. In hematopoietic stem cell recipients, the role of iron overload in HSOS has been well documented, and a serum ferritin level above 1000 ng/ml before the transplant period is found to be an independent risk factor for HSOS as well as for mortality [7]. Despite the absence of other known risk factors for HSOS development of a transplant patient, our patient experienced a notably severe course when compared to HSOS patients without a history of transplantation described in the literature [4]. The most likely causes of HSOS in our patient are dactinomycin and radiation therapy, but high ferritin levels in our patient raised the question of whether iron overload contributed to HSOS. We could not demonstrate other findings suggestive of iron overload, such as liver iron concentration in biopsy samples or magnetic resonance imaging, at that time due to the patient’s poor health condition. However, it is well known that pediatric cancer survivors are prone to iron overload, and late cardiac, hepatic, and endocrine effects [18]. Iron plays an essential role in anthracyclin-dependent cardiotoxicity and causes significant organ dysfunction when accumulated in the body [6, 19]. However, the impact of hyperferritinemia on toxic events during cancer chemotherapy is still unclear and needs further investigation. Given that serum ferritin testing is cheap and easily accessible, it may be reasonable to monitor iron overload, especially in multi-transfused patients with cancer.

Wilms tumor has been linked to various cancer predisposition syndromes and overgrowth disorders [20]. Our patient was the offspring of third-degree consanguineous marriage, and neither of her parents exhibited clinical manifestations of HS. Her family history was insignificant for any type of malignancy. She did not have any signs or symptoms suggestive of Wilms’ tumor predisposition syndromes, such as aniridia, hemihypertrophy, or overgrowth. Notably, within the existing literature, a sole case report of an association between WT and HS has been documented [8]. HS is the most frequent form of inherited hemolytic anemia with an estimated incidence of ranging from 1:1000 to 1:2500 [21]. Given the lack of documented evidence of a genetic link or shared pathogenesis between HS and WT, as well as the relatively high prevalence of hereditary spherocytosis in the general population, the current association between these two conditions appears to be coincidental.

Conclusion

HSOS disease is a life-threatening oncological emergency. Chemotherapy, radiotherapy, and a right-sided tumor are the probable causes of HSOS in our patient. Hyperferritinemia may be a facilitating factor as well, which requires further support and investigation.

Abbreviations

WT

Wilms tumor

HS

Hereditary spherocytosis

HSOS

Hepatic Sinusoidal Obstruction Syndrome

RT

Radiation therapy

CT

Computed tomograpy

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

INR

International normalized ratio

NWTSG

National Wilms Tumor Study Group

Author contributions

All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the report.

Funding

The author has no financial relationship relevant to this article to disclose.

Declarations

Conflict of interest

The author has no conflicts of interest relevant to this article to disclose.

Research involving human participants and/or animals

Not applicale.

Informed consent

The patient’s parents provided informed consent for the case report.