Modified diagnostic criteria, grading classification and newly elucidated pathophysiology of hepatic SOS/VOD after haematopoietic cell transplantation

Abstract

Sinusoidal obstruction syndrome (SOS), previously known as hepatic veno-occlusive disease (VOD), remains a multi-organ system complication following haematopoietic cell transplantation (HCT). When SOS/VOD is accompanied by multi-organ dysfunction, overall mortality rates remain >80%. However, the definitions related to the diagnosis and grading of SOS/VOD after HCT are almost 25 years old and require new and contemporary modifications. Importantly, the pathophysiology of SOS/VOD, including the contribution of dysregulated inflammatory and coagulation cascades as well as the critical importance of liver and vascular derived endothelial dysfunction, have been elucidated. Here we summarise new information on pathogenesis of SOS/VOD; identify modifiable and unmodifiable risk factors for disease development; propose novel, contemporary and panel opinion-based diagnostic criteria and an innovative organ-based method of SOS/VOD grading classification; and review current approaches for prophylaxis and treatment of SOS/VOD. This review will hopefully illuminate pathways responsible for drug-induced liver injury and manifestations of disease, sharpen awareness of risk for disease development and enhance the timely and correct diagnosis of SOS/VOD post-HCT.

Keywords: definitions; grading; haematopoietic cell transplantation; sinusoidal obstruction syndrome; veno-occlusive disease.

Fig 1.

Pathophysiology of SOS/VOD following HCT. Inflammation engendered by toxic metabolites from BMT conditioning and cytokine release results in activation of and damage to the endothelial cell lining of the hepatic sinusoids (A). Activated ECs upregulate surface adhesion molecules and release of heparinase, which contributes to the breakdown of EC scaffolding. Damage ECs round up resulting in gap formation, leakage and sinusoidal narrowing (B). Inflammation is accompanied by alterations of coagulation pathways. Increased expression of vWF along with the release of tissue factor and PAI-1 leads to platelet aggregation and a pro-thrombotic, hypo-fibrinolytic state. Ultimately, dissection of and embolisation of ECs along with Fibrin depo and clot formation culminate in sinusoidal blockage (1C).

Fig 2:

The complex and multifactorial pathophysiology of SOS/VOD following HCT. The initial damage to hepatocytes and sinusoidal endothelium during the development of SOS/VOD results in an inflammatory cascade involving EC damage, sinusoidal narrowing, and micro-vessel occlusion / sinusoidal blockage. These events culminate in the development of symptoms that characterise SOS/VOD, and in fact, occur well before clinical and laboratory findings of SOS/VOD are present. SOS/VOD may rapidly progress to reversal of portal venous outflow and hepatorenal syndrome culminating in SOS/VOD with renal or pulmonary dysfunction and multi-organ failure and in the worst case scenario, death of the patient. MOD, multi-organ dysfunction; MODS, multiple organ dysfunction syndrome.

Fig 3.

Current CTCAE v5.0 SOS grading severity.