Hepatobiliary complications of hematopoietic cell transplantation, 40 years on

Abstract

Liver problems caused by infection, cholestasis and sinusoidal liver injury in the months following HCT have become less frequent because of preventive and pre-emptive strategies. When patients develop jaundice after transplant, the time to search for treatable causes is early in the course of jaundice, as the risk of mortality rises steeply with small increments of serum bilirubin above normal. Chronic hepatitis C, persistent GVHD, cirrhosis and hepatocellular carcinoma are significant liver problems in the longest-lived survivors of HCT.

Figure 1. Histology of Sinusoidal Obstruction Syndrome (SOS) after myeloablative hematopoietic cell transplant (Figure 1 can be found in the on-line Supplementary Material)

A. Zone 3 of the liver acinus in an early phase of SOS, with disruption of sinusoidal anatomy, red blood cells extending through the space of Disse, hepatocyte necrosis, and subendothelial edema in a patent central vein (CV) (H&E). B. Extensive hepatocyte necrosis and dropout, disruption of sinusoids, extravasation of red blood cells throughout zone 3, and subendothelial fibrosis (Masson trichrome). C. Alpha actin-positive stellate cells within zones 2 and 3 that contain areas of extensive hepatocyte necrosis; periportal hepatocytes are intact (PV, portal vein) (alpha-smooth muscle actin immunohistology). D. A later phase of SOS, showing extensive collagenization of sinusoids adjacent to two central veins, with hepatocyte dropout and extinction of hepatocyte cords in between the veins (Masson trichrome). E. Central vein and zone 3 hepatocytes later after transplant, illustrating eccentric phlebosclerosis and collagen deposition in sinusoids (Masson trichrome). F. Lower power view of confluent fibrosis in and around adjacent central veins, with central to central bridges forming a picture of “reverse” cirrhosis two months after transplant (Masson trichrome). (Photomicrographs by Howard M. Shulman, M.D.)

Figure 2. Histology of graft-vs.-host disease (GVHD) involving the liver (Figure 2 can be found in the on-line Supplementary Material)

A. Portal area showing small bile ducts (arrows) with a distorted appearance, lymphocyte infiltration, and epithelial drop-out (H&E). B. Small bile ducts, showing dysmorphic features, cytoplasmic eosinophilia, apoptosis (arrow), atypical nuclei, and lymphocytic infiltration (H&E). C. Liver lobules from a patient with severe multisystem acute GVHD, showing fibrotic portal spaces and periportal bile thrombi (arrows) (Masson trichrome). D. Immunohistochemical stain for cytokeratin 19 in a patient with longstanding liver GVHD, illustrating ductular reaction at the periphery of a portal but without an identifiable interlobular bile duct. E. A portal space showing absence of recognizable bile duct epithelium in a patient with longstanding refractory chronic GVHD (H&E). F. Diffuse lobular inflammation, from a patient with a hepatitic onset of GVHD following discontinuation of immunosuppressive drug therapy (H&E). (Photomicrographs by Howard M. Shulman, M.D.)

Figure 3. Infections in the liver following hematopoietic cell transplant (Figure 3 can be found in the on-line Supplementary Material)

A. Fungal liver abscesses demonstrating the variability of findings in different samples. On the left, a sterile healing abscess with a necrotic center devoid of fungal elements, surrounded by inflammatory cells and a pseudo-capsule (asterisk) (H&E). On the right, an acute abscess with a small focus of red-staining fungal elements (arrow) in a field of degenerative neutrophils, surrounded by a pseudo-capsule (PAS). B. Immunohistochemistry for hepatitis B core antigen, in a patient with fulminant hepatitis B after transplant, showing extensive periportal hepatocyte cytoplasmic and some nuclear staining. C. Focal microabscess (arrow) in the liver lobule caused by cytomegalovirus, in which lymphocytes and neutrophils are seen adjacent to enlarged, brick-red cells containing CMV (H&E) D. Confluent hepatocyte necrosis caused by Adenovirus infection; in the rim of hepatocytes surrounding the necrotic area are darker “smudged nuclei” typical of Adenovirus (H&E). E. Confluent hepatcyte necrosis (upper right) caused by Varicella Zoster Virus infection, with absence of PAS staining of necrotic cells. F. Diffuse infiltration by plasmacytoid cells and immunoblasts with displacement of portal structures, caused by Epstein-Barr Virus lymphoproliferative disease (H&E). (Photomicrographs by Howard M. Shulman, M.D.)