Chapter 65 Hepatic steatosis, steatohepatitis, and chemotherapy-related liver injury

Carlo M. Contreras, Antoine Brouquet, Dipen M. Maru, Jean-Nicolas Vauthey

Overview

Hepatic parenchymal damage from chemotherapy can be divided into two main categories: nonalcoholic fatty liver disease (steatosis and steatohepatitis) and sinusoidal injury. Both types of injuries may be caused by chemotherapy or other factors; however, hepatic injuries become relevant in the context of preoperative chemotherapy and can be a concern for the hepatic surgeon. Steatosis is linked to an increased body mass index (BMI) and to the use of chemotherapy agents, such as 5-fluorouracil (5-FU) and irinotecan. Steatohepatitis is observed in 5% to 10% of patients undergoing irinotecan-based chemotherapy, and sinusoidal injury is related to the use of oxaliplatin-containing regimens.

In patients undergoing liver resection, severe steatosis and high-grade sinusoidal injury increase the overall postoperative complication rate, and steatohepatitis can increase the 90-day posthepatectomy mortality rate, including death from postoperative liver failure. In the context of preoperative chemotherapy, preventive measures—such as limiting the duration of chemotherapy to 2 to 3 months—reduce the risk of hepatic injuries and therefore reduce surgical complication rates.

With the expansion of the indications for liver surgery in patients with hepatic malignancies, liver surgeons have become concerned with steatosis, steatohepatitis, and other liver damage from chemotherapy. Preoperative chemotherapy is widely used before resection of colorectal cancer liver metastases (see Chapters 81A and 87), and can induce different types of hepatic parenchymal injuries. Although most of these changes can be observed outside the context of preoperative chemotherapy, they have become more relevant in patients receiving preoperative chemotherapy for colorectal cancer liver metastase because they can affect perioperative outcome after hepatic resection. This chapter focuses on risk factors and prevention of chemotherapy-related liver damage as it affects liver resection.

Types and Etiology of Liver Parenchymal Damage

Hepatic parenchymal damage from chemotherapy (see Chapter 87) can be divided into two main categories: nonalcoholic fatty liver disease (NAFLD) and sinusoidal injury. NAFLD describes a large spectrum of histologic liver changes unrelated to alcohol consumption. It is important to note that these lesions may also be observed in the context of alcohol abuse. Steatosis is defined by an intracellular hepatocyte lipid accumulation, and it is the hallmark of NAFLD. Histologic evidence of an inflammatory component associated with steatosis defines steatohepatitis. Upon operative exploration, a liver that has undergone steatotic changes is recognized by its yellow-tan color, often referred to as yellow liver. NAFLD is typically graded according to the scoring system of Kleiner and colleagues (2005), which considers the degree of steatosis (0 to 3 points), lobular inflammation (0 to 3 points), and hepatocellular ballooning (0 to 2 points; Fig. 65.1). A score of 5 or more indicates steatohepatitis.

FIGURE 65.1 Steatohepatitis. Moderate steatosis (40% to 50% of hepatocytes), hepatocyte-ballooning degeneration (arrow), lobular inflammation (asterisk), and portal inflammation (arrowhead) can be seen in this specimen, which has a Kleiner score of 6 for nonalcoholic fatty liver disease. CV, central vein. Stained with hematoxylin and eosin, magnification ×200.

(From Chun YS, et al, 2009: Management of chemotherapy-associated hepatotoxicity in colorectal liver metastases. Lancet Oncol 10:278-286.)

Increased BMI is the main risk factor of nonalcoholic steatosis (Brouquet et al, 2009; Kooby et al, 2003; Vauthey et al, 2006). The use of chemotherapy may increase the risk of steatosis (Kooby et al, 2003), which can be detected in 30% to 47% of patients who have received systemic chemotherapy (Peppercorn et al, 1998; Sorensen et al, 1995). Although no specific chemotherapy regimen has been definitively linked to the occurrence of steatosis, it is generally attributed to the use of 5-FU or irinotecan in patients with liver metastases (Moertel et al, 1993; Sorensen et al, 1995; Vauthey et al, 2006). However, in these patients, it is difficult to ascertain whether chemotherapy directly induces steatosis or more likely aggravates preexisting NAFLD.

Steatohepatitis has long been described as a “second hit” in patients with preexisting steatosis, but the continuum between these two different types of NAFLD is uncertain. Macroscopically, no specific features distinguish the steatohepatitis from other types of NAFLD. Chemotherapy-related steatohepatitis was initially believed to be related to the use of any chemo- therapy (Bilchik et al, 2005; Fong et al, 2006), but only irinotecan has been confirmed as a risk factor for steatohepatitis (Vauthey et al, 2006). The effect of an elevated BMI on the development of chemotherapy-associated steatohepatitis is additive to the risk imposed by the use of irinotecan (Vauthey et al, 2006), and this risk can rise to up to 25% in patients with a BMI of 25 kg/m² or more who received irinotecan-based chemotherapy (Attal et al, 1992).

Sinusoidal injury is a variant of the sinusoidal obstruction syndrome first described in association with bone marrow transplantation. In the operating room, a liver that has sustained sinusoidal injury is characterized by vascular ectasia, commonly referred as blue liver. The initial damage affects endothelial cells of the sinusoids, leading to a rupture of the continuity of the sinusoidal wall, which triggers a coagulation cascade and induces the deposition of coagulation factors, erythrocyte aggregates, and cytoplasmic fragments into the perisinusoidal space, ultimately leading to sinusoidal obstruction (Attal et al, 1992; Rubbia-Brandt et al, 2004).

Histologically, the severity of sinusoidal injury can be graded according to a scoring system developed by Rubbia-Brandt and colleagues (2004). This system evaluates the proportion of centrilobular involvement relative to the entire lobular surface (Fig. 65.2). A score of 0 indicates no sinusoidal dilation; 1 indicates mild sinusoidal dilation, characterized by centrilobular changes limited to one third of the lobular surface; 2 indicates moderate sinusoidal dilation, characterized by centrilobular changes extending to two thirds of the lobular surface; and 3 indicates severe sinusoidal dilation, characterized by evidence of complete lobular involvement. There is strong evidence that sinusoidal injury is caused by the use of platinum compounds, including oxaliplatin (Aloia et al, 2006; Brouquet et al, 2009; Nakano et al, 2008; Rubbia-Brandt et al, 2004; Vauthey et al, 2006), and the incidence of sinusoidal injury can range from 19% to 52% in patients who have received preoperative oxaliplatin-based chemotherapy (Aloia et al, 2006; Brouquet et al, 2009; Nakano et al, 2008; Rubbia-Brandt et al, 2004; Vauthey et al, 2006).

FIGURE 65.2 Severe sinusoidal injury with sinusoidal congestion and dilation (arrow) in hepatic metabolic zones 1 (arrowhead), 2, and 3. cv, central vein. Stained with hematoxylin and eosin, magnification ×200.

(From Chun YS, et al, 2009: Management of chemotherapy-associated hepatotoxicity in colorectal liver metastases. Lancet Oncol 10:278-286.)

Pathophysiology of Chemotherapy-Associated Liver Damage

Although histologically distinct, the NAFLD and sinusoidal injury pathways both involve chemical damage by reactive oxygen species (ROS) (Fig. 65.3). The initial event in the NAFLD sequence is likely drug-related damage to the mitochondrial membrane that interferes with oxidation of fatty acids and ultimately leads to the accumulation of ROS within hepatocytes (Laurent et al, 2004; Pessayre et al, 2001). Fluoro-β-alanine, a fluorouracil metabolite, is also believed to impair metabolism in hepatocytes, thus prolonging their exposure to toxic substances (Miyake et al, 2005).

FIGURE 65.3 Cytotoxic drugs impair mitochondrial oxidation, leading to reactive oxygen species production, Fas ligand death receptor expression, and cytokine induction. Lipid peroxidation results in cell death, stellate cell activation, and fibrosis. 5-FU, 5-fluoruracil; ROS, reactive oxygen species.

(From Chun YS, et al, 2009: Management of chemotherapy-associated hepatotoxicity in colorectal liver metastases. Lancet Oncol 10:278-286.)

The pathophysiology of sinusoidal injury also involves the accumulation of ROS. Wang and colleagues (2000) developed a rodent model of sinusoidal injury using exposure to pyrrolizidine alkaloids, which deplete the sinusoidal endothelial cells’ glutathione stores, leaving them susceptible to subsequent ROS injury. Pyrrolizidine alkaloids also decrease nitric oxide concentrations, resulting in the upregulation of matrix metalloproteinase activity, which can be prevented by pretreatment with a nitric oxide donor (DeLeve et al, 2003). Damage induced by exposure to pyrrolizidine compounds can also be abrogated in a dose-dependent manner by pretreating sinusoidal endothelial cells with exogenous glutathione or N-acetyl-L-cysteine in this model (Wang et al, 2000). However, these preventive pharmacologic strategies have not yet been tested in humans.

Preoperative Detection of Liver Injury

The definitive diagnosis of hepatic injury relies on the pathologic examination of non–tumor-bearing liver tissue after liver resection. The preoperative detection of liver injury is useful to devise the best surgical strategy in patients with severe hepatotoxicity (Fig. 65.4). Numerous modalities have been proposed to detect chemotherapy-related liver injuries preoperatively, but no consensus has been reached. Although abnormal liver function tests may suggest hepatic injury, assessment of the severity of hepatic injury is not possible based only on these laboratory values (Brouquet et al, 2009; Nakano et al, 2008). The combination of macroscopic and microscopic examinations of the liver provided by preoperative laparoscopy with intraoperative liver biopsies probably offers the best assessment of the effects of preoperative chemotherapy in patients at high risk for surgical complications (Vauthey et al, 2006). However, this is an invasive approach, which limits its routine use. Image-guided liver biopsy has also been proposed to assess liver injuries; however, the practicality of such an approach is questionable because of the heterogeneity of hepatic lesions and because of interobserver variations in the histologic identification of chemotherapy-related liver injuries.