Anicteric Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation in Children

Introduction:

Hepatic veno-occlusive disease (VOD) is a potentially fatal complication after hematopoietic stem cell transplantation (HSCT). Two criteria have been used for its diagnosis, the Baltimore criteria comprising of hyperbilirubinemia >2mg/dl and two of the following: weight gain >5% from baseline, hepatomegaly or ascites [1]. According to the Seattle criteria VOD is diagnosed if any two of the following are present by day +30 after HSCT: hyperbilirubinemia >2mg/dl, weight gain >2.5% from baseline and hepatomegaly [2]. Some patients with VOD may not have hyperbilirubinemia, remain anicteric, and progress to have severe VOD. The intent of our study is to evaluate the clinical course and outcomes of patients with anicteric VOD compared to those with hyperbilirubinemia.

Methods:

A retrospective review of all patients diagnosed with VOD while undergoing HSCT at Nationwide Children’s Hospital from 1992 through June, 2014 was done. Both Seattle and Baltimore criteria were applied to each patient. Supportive care treatment with level of care (LOC) was defined as follows: Level 1: General floor level management (i.e. diuretics, pain control, fluid restriction, etc.), Level 2: ICU level support for < 2 body systems (i.e. mechanical ventilation (MV) for respiratory failure, vasopressors (VP) for heart failure etc.) and Level 3: ICU level support > 3 body systems (i.e. MV + VP + Dialysis, etc.). Standard statistical methods were used for analysis.

Results:

30 patients were diagnosed with VOD over the last 22 years, 9 (30%) were anicteric, 20 (67%) icteric and one with undocumented bilirubin level was excluded from all further analysis. Patient demographics and characteristics are presented in Table 1. Majority (n=26) of the patients received myeloablative conditioning for malignant (n=24) or non-malignant (n=5) diseases. There was no difference in the characteristics of the two groups in regards to percentage weight gain, hepatomegaly, abdominal pain, demonstration of portal venous flow reversal, or outcome. Ascites was seen in 5 of the 9 and 19 of 20 cases with anicteric and icteric VOD respectively. The total duration of treatment and level of supportive care given was significantly higher in patients with icterus than without (P = 0.224) and P= 0.0081) respectively. Seven cases were diagnosed with VOD by the Seattle criteria at a median of day +15 post HSCT, but treatment was delayed by 1-11 days for lack of hyperbilirubinemia, 2 of these never developed hyperbilirubinemia; 4 of 7 cases died. Overall 2 with anicteric and 12 cases with icteric VOD died.

BM= Bone Marrow, MA= Myeloablative, PBSC= Peripheral Blood Stem Cell, RIC= Reduced Intensity Conditioning, TBI= Total Body Irradiation, UCB= Umbilical Cord Blood

Discussion:

The Baltimore criteria appear to be more stringent and cases with anicteric VOD do not meet these diagnostic criteria. This retrospective study describes the features of anicteric VOD at a single center. Even if the patients met the Seattle criteria, treatment was delayed for lack of hyperbilirubinemia or flow reversal on hepatic ultrasound, neither of which are required criteria. Patients with anicteric VOD had a better outcome than those with hyperbilirubinemia, but our study shows that there can be significant morbidity and even mortality associated with anicteric VOD. There seems to be a poor understanding and awareness of anicteric VOD as a diagnosis. Earlier disease recognition could lead to more prompt and aggressive treatment leading to improved outcomes.