Hepatic veno-occlusive disease (VOD) is a clinical syndrome that results from endothelial injury in both sinusoids and small hepatic venules. The endothelial damage is followed by progressive sinusoidal occlusion and venular obliteration, which in turn leads to hepatocellular necrosis, fibrosis, and ultimately liver failure. VOD classically presents with a triad of findings: weight gain (secondary to ascites), tender hepatomegaly, and jaundice. It was first described in the 1950s in Jamaican children who were known to consume herbal infusions referred to as “bush teas” containing pyrrolizidine alkaloids (1,2) and has since been confirmed to result from ingestion of these toxins (3). Now, however, VOD is most commonly seen to be a complication in hematopoietic stem cell transplant (HSCT) patients (4,5), with an incidence of 10% to 60% (6). There are also published cases of VOD that occur outside the setting of HSCT. Specifically, a syndrome of hepatic VOD with immunodeficiency (VODI) has been described (7,8).
We report a child who presented with end-stage liver disease because of VOD and required orthotopic liver transplantation (OLT). She had multiple infections and persistent hypogammaglobulinemia during the course of her illness. She then developed aggressive and refractory acute myelocytic leukemia (AML), ultimately leading to death. Interestingly, she is only the second OLT recipient reported who has been diagnosed as having an extramedullary AML and the first pediatric OLT recipient to develop AML of any type. We review the literature that supports a link among VOD, immunodeficiency, and AML.
A 3-month-old girl presented with hepatic failure and was transferred to our institution for assessment for liver transplantation. She was born at full term via normal spontaneous vaginal delivery after an uncomplicated pregnancy. Her parents were a nonconsanguineous couple of Hispanic descent. She had 1 older brother who was healthy. At 2 months of age she developed chickenpox after a known exposure to Varicella zoster virus. Two weeks later she developed decreased oral intake, nausea, vomiting, and diarrhea. Her symptoms were initially attributed to viral acute gastroenteritis. She then developed abdominal distention caused by ascites, which prompted reevaluation.
On examination she had multiple crusted lesions on her extremities and trunk consistent with recent V zoster infection. Her abdomen was distended and her liver was palpable 4 cm below the right costal margin. Laboratory workup (Table 1 ) revealed hypoalbuminemia, elevated transaminases, and coagulopathy. Immune testing showed a low immunoglobulin (Ig) G level as well as IgM and IgA deficiencies. B- and T-cell subsets were normal. Phytohemagglutinin (PHA) stimulation testing showed normal T-cell function. Infectious studies showed cytomegalovirus (CMV) and adenovirus infections. Bone marrow biopsy showed maturing hematopoiesis and no evidence of hemophagocytosis or tumor formation. Abdominal computed tomography (CT) scan showed a liver with heterogeneous enhancement and central hypodensity consistent with necrosis, but a normal portal vein. CT-guided liver biopsy showed sinusoidal dilation and hemorrhage with massive congestion and necrosis surrounding the central veins, consistent with VOD.
The patient was treated with supportive measures including intravenous 25% albumin, diuresis, gancyclovir, and weekly intravenous immunoglobulin (IVIG) infusions. Therapeutic anticoagulation was not administered because of the patient's late diagnosis and tenuous clinical status. Although her transaminase levels and coagulopathy did not worsen, the patient clinically decompensated 6 weeks after presentation when she developed respiratory distress from worsening pulmonary edema and ascites and was admitted to the pediatric intensive care unit. She underwent OLT at 5 months of age. Histopathological examination of the explanted liver (Fig. 1) showed that virtually all of the central vein lumens were obliterated by fibrosis. No features of viral infection were seen. She was discharged home on postoperative day 64 on tacrolimus and prednisone for immunosuppression, and intravenous gancyclovir for Epstein-Barr virus (EBV) and CMV prophylaxis.
As an outpatient, she was studied by the immunology service for hypogammaglobulinemia and received regular IVIG infusions. With this treatment, the patient's IgG level was maintained above a minimum goal of 500 mg/dL, and often exceeded 1000 mg/dL. Even so, her posttransplant course was complicated by 1 to 2 infectious complications each year, including CMV enteritis, systemic adenoviral infection, and Streptococcus viridans bacteremia, which required hospital admission. She also was treated with antibiotics for several ear and sinus infections, multiple urinary tract infections (pathogens included Enterococcus, Escherichia coli, and Klebsiella pneumoniae), and 2 episodes of fever and neutropenia.
At 7 years of age the patient was admitted with a 1-week history of a rapidly growing, 2 × 2 cm lymph node in the right inguinal region. The lymph node was firm, mobile, and tender with warm, erythematous overlying skin. A clinical diagnosis of infectious lymphadenitis was made, and treatment was commenced with trimethoprim/sulfamethoxazole and vancomycin. When the swelling persisted, a lymph node biopsy was carried out for histopathological examination (Fig. 2), which was consistent with myelomonocytic M4 AML. Immunohistochemistry for EBV was negative. Serologies were positive for EBV nuclear antigen IgG antibodies but negative for EBV viral capsid antigen IgM antibodies. Bone marrow and cerebrospinal fluid studies were negative for leukemic involvement.
The patient was started on induction chemotherapy with high-dose cytarabine, etoposide, and daunomycin. Despite chemotherapy, she developed a new left inguinal mass and significant hepatosplenomegaly. Abdominal and pelvic CT demonstrated increased bilateral inguinal node enlargement, extensive retroperitoneal adenopathy, and new radiolucencies in the liver and spleen. A left inguinal node biopsy was performed to differentiate tumour from an infectious process. Pathology confirmed progressive M4 AML. The patient failed extubation after the biopsy and less than 24 hours later died from cardiac failure.
First described in the 1970s, VODI is an autosomal recessive primary immunodeficiency associated with hepatic centrilobular vein occlusion, hepatocyte necrosis, and fibrosis (9,10). The clinical criteria used to diagnose VODI are shown in Table 2 and include clinical evidence of immunodeficiency such as infection with enterovirus, CMV, mucocutaneous candidiasis, or Pneumocystis jerovici; hepatomegaly, hepatic failure, or VOD not explained by iatrogenic factors; a pattern of disease consistent with autosomal recessive inheritance; and onset before 1 year of age (11). Liver biopsies from patients with VODI are indistinguishable from those of patients with VOD following HSCT (8). As of 2009, a total of 20 cases of VODI had been described, the majority of which were identified in Sydney, Australia, where the frequency amongst the Lebanese population is 1:2500 live births (8,10). Interestingly, all of the Australian patients determined to have VODI had hypogammaglobulinemia at presentation (11).
There have also been a handful of case reports outside Australia with clinical presentations resembling VODI. One case report describes 2 siblings, also of Lebanese descent, who were diagnosed as having humoral and cellular immune defects and VOD (12). A separate case series describes 1 infant with DiGeorge syndrome and 5 children with severe combined immunodeficiency who were diagnosed as having centrilobular fibrosis or VOD at autopsy (13). Two of these patients had transfusion-associated graft-versus-host disease and the other 4 had undergone HSCT. Interestingly, not all of them exposed to chemotherapeutic agents, which are known to be associated with VOD. This provides further support for a possible link between immunodeficiency and predisposition for VOD.
Based on her history and presentation, our patient fulfills the clinical criteria needed to diagnose VODI. She clearly had an immunodeficiency with hypogammaglobulinemia, and she was diagnosed as having varicella, adenovirus, and CMV during her pre-transplant workup. In addition, she had symptom onset before 12 months and a family structure consistent with autosomal recessive inheritance.
Molecular genetic studies have identified mutations in the SP110 gene on chromosome 2 in patients diagnosed as having VODI (8). SP110 is an immunoregulatory gene expressed within the promyelocytic leukemia nuclear body, which may play a role in viral response, apoptosis, and progression of malignancies (14–16). To date, there have been no other reported cases of malignancies in patients with VODI; however, 1 child with VODI developed hemophagocytic syndrome after hepatic transplantation (10).
Molecular testing for SP110 mutations should be considered in patients who present with features of immunodeficiency and VOD. Penetrance is complete and asymptomatic homozygous individuals have not been identified; therefore, testing of siblings of a proband who are healthy and older than age 12 months is not recommended (10). If the disease-causing mutations in the family are known, however, carrier testing for at-risk family members is possible and should be considered in accordance with a genetic counselor. Unfortunately the availability of molecular testing for VODI was not recognized until several years after our patient died, limiting our ability to identify an SP110 mutation in her case. It is likely that both of her parents and possibly her brother are heterozygotes for SP110 mutations. As such, genetic counseling has been offered to the family, and they are still deciding whether to pursue molecular testing.
Although varicella and other viral infections are a known cause of fulminant hepatitis, there are scarce data linking viral infections to VOD. One case report describes a boy with Bruton's agammaglobulinemia who developed vomiting and fevers, then progressed to intractable ascites and liver failure. Extensive infectious workup was positive only for human herpes virus 7. After transplantation, his explanted liver revealed advanced VOD (17). Neither this history nor that of our patient proves a causative relation between viral infection and VOD; it is possible that both are manifestations of underlying immunodeficiency. It is also conceivable that in patients with VODI, exposure to a pathogenic virus may elicit hepatic sinusoidal changes, which in turn trigger events leading to VOD.
If refractory to medical management, then VOD can lead to liver failure and require transplantation, as seen in our patient. OLT recipients, like all recipients of solid organs, are vulnerable to post-transplant complications including neoplasias, the most common of which are B-cell lymphoproliferative disorders related to EBV. Acute leukemia is an uncommon complication after solid organ transplantation, reported to affect only 0.2% to 2.5% of recipients (18). There has been speculation that OLT recipients have an increased risk of developing AML. The reason for this increased risk is unclear; however, it does not seem to be based on immunosuppression alone (18).
Of only 10 reported cases of AML after solid organ transplantation (18–23), all occurred in adult patients and only 1 of the malignancies was extramedullary (22). In 2 cases the blasts were determined to be donor derived based on chromosome analysis (19,22). Our patient's AML was entirely extramedullary, with no blasts or immature myelomonocytic precursors seen on her bone marrow biopsy. Karyotyping determined that her malignancy was not donor derived (donor was male). Therefore, our patient is only the second OLT recipient reported to develop an extramedullary AML, and the first pediatric OLT recipient to develop AML of any type.
Although OLT may be considered a part of the treatment for VODI, the cases reported in the literature to date have a high rate of complications (10). Our patient had a successful OLT, but her persistent hypogammaglobulinemia required regular IVIG infusions. In addition, she had repeated viral and bacterial infections both pre- and posttransplant and a rare and greatly treatment-refractory cancer. Her unusual clinical course was likely because of a combination of both her primary immune disorder, which alone may predispose toward malignancy, and her posttransplant immunosuppression. This suggests that increased vigilance to identify and treat neoplastic complications may be necessary in posttransplant patients with a diagnosis of VODI.
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