Oncological-Therapy-Associated Liver Injuries

Abstract

Drug-induced liver injury (DILI) represents a large group of hepatic disease caused by various treatments, including oncological agents. The liver is an important organ with a role in drug metabolization and excretion and may be affected when oncologic treatment is initiated. The most common liver disease patterns induced by oncologic therapy are steatosis and steatohepatitis, focal nodular hyperplasia, pseudocirrhosis, acute hepatitis, hepatic necrosis, immune-mediated hepatitis, cholestasis, fibrosis and cirrhosis, sinusal obstructive syndrome. In rare cases, chemotherapy treatment is associated with a high-risk hepatic adenoma or hepatocellular carcinoma development. It was demonstrated that the majority of chemotherapy classes can induce these effects on the liver, for example, alkylating agents, antimetabolites, and antitumor antibiotics, but also immunotherapy agents can be involved. The majority of patients that receive oncological treatment who developed liver injury as adverse reactions are identified by symptoms and/or blood test abnormalities. Imaging techniques may be helpful in the diagnosis of oncological-therapy-associated liver injuries, for example, focal nodular hyperplasia, pseudocirrhosis, and sinusal obstructive syndrome. If liver disease occurs as an adverse effect of these agents, the recommendation to stop or continue the administration of oncologic treatment with close monitoring relies upon the risk and benefits of this medication.

1. Introduction

Drug-induced liver injury (DILI) represents a large group of hepatic diseases caused by various therapeutical agents.

There are two types of DILI, with differences in pharmacologic mechanism and clinical onset patterns. The first type, the predictable one, named intrinsic or direct, is typically dose-related and affects a large proportion of exposed individuals if the safe amount is exceeded. It produces distinctive liver lesions, and the onset of clinical and laboratory abnormalities is usually after a short time after drug consumption, hours to days. The effects can be also reproduced using routine animal testing [1].

The second type of DILI, the unpredictable one, named idiosyncratic, affects only a small proportion of susceptible individuals exposed to various doses (not dose-related). It produces variable liver injuries, and the onset of clinical and laboratory abnormalities may begin from days to weeks after drug consumption. Usually, the effects cannot be reproduced using routine animal testing [2].

Even the acetaminophen consumption is the cause of the majority of DILI in the USA, in this chapter, our focus will be on injuries induced by oncologic treatment [3]. Despite the chemotherapy possibility of decreasing tumor size and stage, fighting against micrometastatic disease, and prolonging overall survival, it is associated with side effects. The liver is an important organ with a role in drug metabolization and excretion and may be affected when oncologic treatment is initiated.

Several risk factors are associated with a higher incidence of adverse drug reactions, including DILI induced by chemotherapy. Host-related risk factors such as the old age, female sex, HLA class I allele A*33:01, chronic liver disease, and drug-related risk factors such as dose, site of metabolization, and lipophilicity, appear to influence the frequency of occurrence of oncologic treatment hepatic adverse effects. Identifying the risk factors for the development of liver injury after chemotherapy initiation can influence the treatment decision and also improve the patient outcome.

The majority of patients that receive oncological treatment who developed liver injury as adverse reactions are identified by symptoms and/or blood test abnormalities. Elevation of alanine transaminase (ALT), aspartate transaminase (AST), conjugated and total bilirubin (TB), and international normalized ratio (INR) with low values of albumin is frequently revealed in these patients. Symptoms may be absent or nonspecific, or patients can present jaundice, encephalopathy, or coagulopathy manifestation.

DILI, which includes the liver injuries produced by oncological agents, is defined if one of the following criteria is present: (a) more than 5× upper limit of normal ALT value, (b) more than 2× upper limit of normal ALP value (often with the elevation of gamma-glutamyltransferase (GGT)), or (c) more than 3× upper limit of normal ALT value accompanied by more than 2× upper limit of normal TB level value. In practice, there are situations when patients presented with elevated values of the aforementioned blood tests before starting the potential liver harmful treatment, and in this case, the mean of these values replaces the upper limit of normal.

The most recent guidelines of EASL (European Association For The Study Of The Liver) classified DILI in “hepatocellular,” “cholestatic,” or “mixed” types due to the pattern of changes in liver enzymes (Table 1) [2].

DILI pattern	Hepatocellular injury	Cholestatic injury	Mixed injury
Liver biochemical blood tests abnormalities	≥5× ULN elevation in ALT; OR; Serum activity ALT to ALP is 5 or more.	≥2× ULN; elevation in ALP; OR; Serum activity ALT to ALP is 2 or less.	serum activity of ALT to ALP is between 2 and 5.
Histological abnormalities	Inflammation, necrosis, and apoptosis; severe necrosis involved zone 3.	Canalicular and hepatocelular cholestasis in zone 3.	more similar changes to that of cholestatic than hepatocellular type.

Table 1.

DILI pattern with his associated biochemical blood tests and histological abnormalities, adapted after EASL clinical practice guidelines, 2019: drug-induced liver injury [2].

2. Patterns of oncological-therapy-related liver injury

The most common liver disease patterns induced by oncologic therapy are discussed below, and the agents frequently involved are listed in Tables 2 and 3.

Class	Drug name	Patterns of drug-associated liver adverse effects
Alkylating agents	Cyclophosphamide	sinusoidal obstructive syndrome; cholestasis; acute hepatitis; hepatic necrosis;
	Chlorambucil	cholestasis; sinusoidal obstructive syndrome;
	Oxaliplatin	sinusoidal obstructive syndrome; pseudocirrhosis; steatosis; focal nodular hyperplasia;
	Ifosfamide	acute hepatitis;
	Melphalan	sinusoidal obstructive syndrome; acute hepatitis;
	Busulfan	sinusoidal obstructive syndrome; acute hepatitis; cholestasis;
Anti-metabolites	5-Fluorouracil	pseudocirrhosis; steatosis; acute hepatitis; sinusoidal obstructive syndrome; cholestasis;
	Methotrexate	hepatic necrosis; steatosis; steatohepatitis; focal nodular hyperplasia; acute hepatitis; fibrosis and cirrhosis;
	6-mercaptopurine	sinusoidal obstructive syndrome; cholestasis; focal nodular hyperplasia; acute hepatitis;
	6-thioguanine	sinusoidal obstructive syndrome; focal nodular hyperplasia; peliosis hepatitis; fibrosis;
	Capecitabine	acute hepatitis;
	Gemcitabine	pseudocirrhosis; acute hepatitis; cholestasis;
	Cytarabine	cholestasis; sinusoidal obstructive syndrome;
	Floxuridine	acute hepatitis; cholestasis; steatosis;
	Azathioprine	cholestasis; sinusoidal obstructive syndrome;
Antitumor antibiotics	Doxorubicin	acute hepatitis; cholestasis; sinusoidal obstructive syndrome;
	Dacarbazine	sinusoidal obstructive syndrome; hepatic necrosis;
	Dactinomycin	sinusoidal obstructive syndrome; steatosis;
	Mitomycin C	sinusoidal obstructive syndrome; acute hepatitis; steatosis;
	Actinomycin	acute hepatitis; sinusoidal obstructive syndrome;
	Bleomycin	acute hepatitis; steatosis;
	Mithramycin	hepatic necrosis;
Isomerase inhibitors	Etoposide	hepatic necrosis; acute hepatitis; cholestasis;
	Irinotecan	steatosis; steatohepatitis; sinusoidal obstructive syndrome;
	Topotecan	cholestasis;
Taxanes	Paclitaxel	cholestasis; sinusoidal obstructive syndrome;
	Docetaxel	cholestasis;
Hormone therapy	Tamoxifen	steatosis; steatohepatitis; cholestasis;
	Anastrozole	steatosis; acute hepatitis;
	Estrogens	cholestasis; hepatic adenoma and hepatocellular carcinoma; peliosis hepatis; sinusoidal obstructive syndrome;
Vinca alkaloids	Vincristine	sinusoidal obstructive syndrome; acute hepatitis;
	Vinorelbine	cholestasis;
	Vinblastine	acute hepatitis;
Platinum agents	Cisplatine	acute hepatitis; steatosis; sinusoidal obstructive syndrome; cholestasis;
	Carboplatin	sinusoidal obstructive syndrome;
Nitrosoureas	Carmustine	acute hepatitis; sinusoidal obstructive syndrome;
	Lomustine	acute hepatitis;

Table 2.

Commonly used agents in chemotherapy and their associated liver-related side effects.

Class	Drug name	Patterns of drug-associated liver adverse effects
Tyrosine kinase inhibitors	Imatinib	acute hepatitis;
	Erlotinib	cholestasis;
	Lapatinib	acute hepatitis;
	Gefitinib	acute hepatitis;
	Pazopanib	hepatic necrosis;
	Sorafenib	acute hepatitis; cholestasis;
	Regorafenib	hepatic necrosis;
	Sunitinib	hepatic necrosis;
	Bortezomib	acute hepatitis;
	Idelalisib	acute hepatitis;
Monoclonal antibodies	Trastuzumab	acute hepatitis; nodular regenerative hyperplasia;
	Ipilimumab	immune-mediated hepatitis;
	Durvalumab	immune-mediated hepatitis;
	Nivolumab	immune-mediated hepatitis;
	Cetuximab	steatosis;
	Pembrolizumab	immune-mediated hepatitis;
	Atezolizumab	immune-mediated hepatitis;
	Gemtuzumab	sinusoidal obstructive syndrome;
	Rituximab	acute hepatitis;
	Bretuximab vedotin	hepatic necrosis;
	Avelumab	immune-mediated hepatitis;
Immunomodulatory drugs	Lenalidomide	cholestasis;
	Pegylated interferon α	immune-mediated hepatitis;
	Interleukin2	cholestasis; acute hepatitis; sinusoidal obstructive syndrome;
Biological agents	L-Asparaginase	hepatic necrosis; steatosis;

Table 3.

Immunomodulatory agents in chemotherapy and their associated liver-related side effects.

2.1 Steatosis and steatohepatitis

NAFLD affects 10–39% of the global population, and only 2% of these patients are caused by drugs. A common effect of chemotherapy is to increase the amount of hepatocellular fat content. Two entities are described, steatosis and steatohepatitis, often known as chemotherapy-induced acute steatohepatitis, “CASH.” Steatosis is defined by the accumulation of lipids within hepatocytes without inflammatory foci. Steatohepatitis is the lipid accumulation with concurrent inflammation of liver parenchyma on hepatocytes that appear enlarged (ballooning phenomes) and can lead to degeneration [4, 5, 6].

Various therapeutic agents used in oncology can induce steatosis or steatohepatitis. Regimens that contain antitumoral molecules such as 5-fluorouracil, methotrexate, tamoxifen, irinotecan, L-asparaginase, oxaliplatin, mitomycin C, bleomycin sulfate, and dactinomycin were linked with fatty liver transformation [7, 8]. Usually, specific changes are detected after a period of 3–12 months of chemotherapy.

Treatments recommended for patients diagnosed with cancer contain not only antitumoral agents. Associated medication used in oncology can also induce nonalcoholic fatty liver disease. Glucocorticoids used for induction treatment of acute leukemia may cause macrovesicular steatosis [9].

A high number, up to 85%, of patients treated with regimens mentioned above develop CASH due to altered lipoprotein synthesis and therefore abnormal lipid metabolism. The development of steatohepatitis is based on an abnormal function of hepatocyte mitochondria and peroxisomes, inside which the process of oxidation of fatty acids (FAO) takes place. Several chemotherapy agents inhibit free fatty acids (FFA) β-oxidation, which promotes the accumulation of reactive oxygen species (ROS) and lipid peroxidation and increases oxidative stress in hepatocytes. All these processes lead to CASH. At the same time, lipid peroxidation stimulates stellate cell activation, fibrosis, and necrosis of hepatocytes. The intramitochondrial accumulation of tamoxifen leads to the inhibition of FFA β-oxidation, ATP synthesis, and cellular respiration. Another mechanism of steatosis and steatohepatitis is explained by the alteration of lysosomal phospholipid metabolism, which promotes the activation of the adenosine pathway and therefore increases FFA synthesis and also coenzyme A sequestration. This mechanism was observed in patients undergoing treatment with irinotecan and methotrexate. For methotrexate, the increased level of homocysteine due to impaired methylenetetrahydrofolate reductase leads to increased pro-inflammatory cytokines and hepatic stellate cell activation, which promote liver fibrosis. Increased expression of acyl-coenzyme A oxidase 1 (ACOX1) was observed for patients treated with 5-fluorouracil and irinotecan. Inhibition of mitochondrial FFA β -oxidation and reduced expression of carnitine palmitoyl-transferase and ACOX1 induction were observed for irinotecan [10].

ACOX1 is the first limiting enzyme of peroxisomal FAO and may be increased as a response to decreased mitochondrial FFA β-oxidation. A high level of ACOX1 leads to increased expression of pro-inflammatory genes and a high amount of ROS, processes associated with immune cell infiltration. A hepatic steatosis liver can progress to steatohepatitis if contained hepatocytes own altered mitochondrial FFA β-oxidation and high amounts of ROS and inflammation. Mitochondria can be a direct target of every chemotherapy agent via cytotoxicity effect, and every agent can also have multiple pathways to induce steatosis or steatohepatitis [11].

Histologically, there are no marked differences between metabolic steatohepatitis and CASH. Even actually is rare recommended, if liver biopsy is performed on this patient, microvesicular steatosis is usually described. Distribution can be focal, multifocal, or diffuse. Macroscopic, fatty liver has a yellowish appearance and may be enlarged.

Recognition of this liver disease is important for adequate management that improves the prognosis. Usually, clinical manifestations of patients with chemotherapy-induced steatosis and steatohepatitis are subtle. Transaminase levels show elevation of ALT/AST. Steatosis and steatohepatitis liver is characterized by hyperechogenicity with posterior beam attenuation on transabdominal ultrasound examination. On computed tomography, a reduction in liver parenchymal attenuation can be observed when compared with the spleen. With high accuracy, magnetic resonance imaging can quantify the number of lipids in the liver due to spectroscopy and elastography available modes. A reduction in liver signal intensity is described in out-of-phase imaging for patients with steatohepatitis [12, 13, 14]. Delayed regeneration and prolonged liver disfunction were observed in oncologic patients with steatosis and more obvious with steatohepatitis, which was associated with a higher risk of postoperative hepatic failure, infections, and longer period of the intensive-care-unit stay [4, 15]. Repeated chemotherapy cycles are responsible for more severe inflammation, fact that worsens hepatocellular damage and leads to the development of fibrosis, cirrhosis, and liver failure [16, 17]. A limited CASH risk with the best oncologic treatment effects was observed for chemotherapy regimens with a maximum duration of 4 months [18].

For patients diagnosed with cancer, blood lipid and transaminase levels should be performed before initiation and regularly during oncologic treatment. Steatosis and steatohepatitis are in most cases reversible even though they can persist for a few weeks or months after treatment completion [7, 19]. Once the diagnosis was confirmed, the recommendation to stop or continue the administration of oncologic agents with close monitoring relies upon the risk and benefits of this medication. Healthy eating habits and limited high-fat alimentation are recommended to prevent increased blood lipid levels and worsening steatosis or steatohepatitis. Hepatoprotective drug administration, to prevent the worsening damage to the liver, is indicated [20].

Risk factors for CASH occurrence can be patient-related (metabolic syndromes, obesity, diabetes, dyslipidemia, alcohol abuse, preexisting chronic liver disease or hepatic location of the tumor, genetic polymorphism, gut microbiota, and chemotherapy history) or drug-related (cumulative or maximum dose of treatment or combination of more agents) [4]. Special attention is required for women with breast cancer with the A2 allele of CYP17A1 due to the associated increased risk of developing steatosis when treated with tamoxifen [21, 22].

2.2 Focal nodular hyperplasia

Focal nodular hyperplasia is the second most common benign hepatic lesion with unclear pathogenesis. Some explanations for this lesion may include a similar mechanism to focal sinusoidal obstruction syndrome [23].

Some agents used in oncology such as 6-thioguanine and oxaliplatin have an increased risk of inducing nodular hyperplasia and early fibrosis [24, 25]. Focal nodular hyperplasia is characterized by solitary or multiple lesions in liver parenchyma, which usually appear on CT as homogeneous, isodense, or mildly hypodense images. Contrast-enhanced CT shows arterial hyperenhancement, and late enhancement can be seen when a central scar is visible. These lesions may be incorrectly labeled as hypervascular liver metastasis. Characteristic MRI features for focal nodular hyperplasia are nonspherical shape lesions with imprecise margins and particularly hyperenhanced zones in the hepatobiliary phase for specific contrast agents. Signal isointensity on T1- and T2-weighted images, the absence of halo enhancement, and the absence of restriction to water diffusion in the echo-planar sequence are other characteristics that support the diagnosis of focal nodular hyperplasia [23, 26].

2.3 Pseudocirrhosis

Pseudocirrhosis is an imagistic term characterized by hepatic nodularity due to diffuse regenerative nodular hyperplasia but with insignificant fibrosis, different from the classic histopathological attributes of cirrhosis, features that appear after oncologic treatment initiation [27]. Pseudocirrhosis is associated with antineoplastic drugs used for the treatment of metastatic breast, colon, and pancreatic cancers. These agents are oxaliplatin, 5-fluorouracil, gemcitabine, capecitabine, irinotecan, methotrexate, and tamoxifen [28]. It can also appear in patients with carcinoid tumors and Hodgkin lymphoma.

Pseudocirrhosis can represent a cause of portal hypertension and even liver failure, but it lacks the typical clinical and paraclinical features of cirrhosis. The synthetic function of the liver is usually preserved.

On CT examination, pseudocirrhosis looks like macronodular cirrhosis with capsular retraction, diffuse nodularity, lower liver volume, and hypertrophy of the caudate lobe. For up to 9% of cases, signs of portal hypertension, including portosystemic shunts, can appear on imaging evaluation. The severe capsular retraction has been described in some cases of liver metastasis from breast cancer, and those must be excluded due to different treatments and prognoses that are associated with this stage [6, 23].

2.4 Acute hepatitis

Multiple oncological agents are involved in acute hepatitis occurrence, with high-frequency vinblastine, rituximab, etoposide, anastrozole, 6-mercaptopurine, 5-fluorouracil, lapatinib [6, 29, 30]. Even though not routinely indicated, if liver biopsy is performed on patients that underwent treatment with anastrozole, the histopathology report revealed necrosis of hepatocytes limited in acinar zone 3. This zone is related to P450 isoenzymes that are involved in drug metabolism. Histopathological report of liver biopsy of patients treated with lapatinib revealed portal-to-portal and portal-to-central bridging necrosis and hepatocellular necrosis in acinar zone 1 [31, 32]. Etoposide-induced acute hepatitis is described as a viral hepatitis pattern [29].

Clinical manifestation of acute hepatitis can range from mild symptoms to ill-appearing patients. Usually, AST and ALT are markedly increased. Imaging findings are nonspecific and may include hepatomegaly with decreased attenuation, splenomegaly, wall thickening of gallbladder, ascites, and periportal edema. Severe forms of acute hepatitis appear in patients with prior chronic hepatitis B or C due to reactivation when treated with rituximab. Patients with MHC class II alleles HLA-DQA1∗02:01, DQB1∗02:02, or DRB1∗07:01 are at high risk of liver injury if receiving regimens with lapatinib [6, 33].

Acute hepatitis induced by anticancer treatment rapidly improved after drug withdrawal. Liver enzymes and bilirubin return to normal values after a few months of treatment discontinuation [5].

2.5 Hepatic necrosis

Acute liver failure due to hepatic necrosis is a major and worrisome complication of chemotherapy-induced liver injury. Oncologic agents that produce acute hepatitis are more likely to cause hepatic necrosis. Mithramycin, etoposide, and dacarbazine are some of these offending drugs. Mithramycin also known as plicamycin is an antineoplastic antibiotic that has been reported as the most hepatotoxic chemotherapeutic drug capable of causing liver necrosis. Histopathologic reports of the hepatic biopsy reveal centrilobular necrosis.

Clinically, patients with hepatic necrosis develop acute encephalopathy with deterioration of liver synthetic function. Almost all patients receiving plicamycin have increased levels of LDH, aminotransferases, and alkaline phosphatase with normal values of bilirubin. These modifications occur on the first day of treatment, reach the maximum level the next day, and then decrease to normal 3 weeks after treatment cessation. When severe necrosis develops, a computer tomography scan reveals a substantial decrease in the enhancement of liver parenchyma and cystic appearance [6, 34, 35].

2.6 Immune-mediated hepatitis

Metastatic melanoma, non-small-cell lung cancer hepatocellular carcinoma, and urothelial carcinoma are types of cancer that benefit from immunotherapy agents’ efficacy. Side effects are not rare for this class of treatment and are named immune-related adverse effects, including the liver with immune-mediated hepatitis [36].

Immune checkpoints are cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1). Monoclonal antibodies against these targets are ipilimumab against CTLA-4, pembrolizumab, nivolumab against PD-1 and atezolizumab, avelumab, and durvalumab against PD-L1. From this list, the higher hepatotoxicity was found for CTLA-4 inhibitors, ipilimumab. Patients diagnosed with metastatic melanoma develop immune-mediated hepatitis in 2–9% of cases if they are treated with ipilimumab, and if dacarbazine is associated, the percentage rises up to 31.6% [37, 38].

Immunotherapy contains agents that increase the host’s immune system to fight against tumors, but the subsequent uncontrolled T cell activation is responsible for hepatotoxicity and liver disease. Liver biopsy revealed diffuse T-cell infiltrate, eosinophil infiltration, portal, and periportal inflammation, and spotty or confluent necrosis [39, 40, 41]. Usually, patients are asymptomatic and, in rare cases, fevers, malaise, or symptoms related to fulminant liver failure can be present. Elevation in serum of ALT, AST, and bilirubin occurs especially after ipilimumab. Anti-nuclear, anti-smooth muscle, or other autoimmune hepatitis antibodies are negative. These clinical and paraclinical abnormalities occur from 6 to 14 weeks after immunotherapy initiation or after three doses of this regimen [42, 43]. Some risk factors contribute to a higher chance of liver injury development: a higher dose of treatment, multiple agents association, preexisting liver disease, or autoimmune diathesis [44].

Treatment with corticosteroids or mycophenolate mofetil is indicated for patients with important hepatotoxicity after immunotherapy for cancer [39]. HLA-DRB1*07:01 allele is associated with an increased risk for lapatinib liver injury. Infliximab should not be indicated due to the risk of hepatotoxicity [45, 46].

2.7 Cholestasis

Chemotherapeutic regimens include kinase inhibitors (e.g., erlotinib, sorafenib, nilotinib), thiopurines (6-mercaptopurine and azathioprine), estrogens, 5-fluorouracil, cytarabine, interleukin-2, alkylating agents (chlorambucil, cyclophosphamide, cisplatin), and mitomycin are associated with cholestatic liver injury [29, 35].

Thiopurines cause a variety of DILI phenotypes that can be intrinsic or idiosyncratic with a mixed or cholestatic form of hepatic injury [47]. Intrahepatic cholestasis is the most frequent type of injury in patients undergoing treatment with 6-mercaptopurine (frequently when the daily dose exceeds 2 mg/kg). Azathioprine may produce hepatic injury, but less frequently than 6-mercaptopurine, and this one has been related to a mild form of liver toxicity; however, long-term use can cause cholestatic liver disease [35].

Significant hepatotoxicity has been linked to fluorodeoxyuridine, a metabolite of fluorouracil that was previously administered through the hepatic artery to patients with hepatic metastases from colorectal cancer. In several cases, the treatment has been linked to irreversible intrahepatic and extrahepatic biliary strictures. Monitoring of aminotransferases helps with identifying the right time for drug discontinuation when the liver is suffering [29].

Interleukin-2 therapy is used in melanoma and renal cell cancers, and a lot of patients undergoing this treatment can develop a deep and reversible intrahepatic cholestasis with increased serum levels of biochemical markers of cholestasis. Some potential physiopathological mechanisms may include chemical hepatitis and biliary sclerosis. Allopurinol can block xanthine oxidase involved in drug metabolism, which rises hepatotoxicity. Histologically features of this hepatic injury appear as cholestasis with variable hepatocellular necrosis. Laboratory tests show elevated levels of bilirubin, alkaline phosphatase, and aminotransferases. Jaundice is the clinical feature that is associated with this type of hepatotoxicity [6]. In conclusion, cholestasis is induced by a multitude of antineoplastic drugs and withdrawal usually leads to recovery of the liver and jaundice disappearance [29].

2.8 Fibrosis and cirrhosis

Liver fibrosis and cirrhosis induced by chemotherapy are usually associated with alkylating agents, 6-thioguanine, and methotrexate.

Methotrexate is a folic acid antagonist that inhibits the proliferation of certain body cells, particularly those that are multiplying rapidly such as tumor cells, bone marrow cells, and skin cells. Long-term methotrexate treatment, commonly used to treat severe psoriasis or rheumatoid arthritis, can induce hepatic fibrosis, which leads to cirrhosis without producing significant symptoms [48]. The use of methotrexate as maintenance therapy in children with acute leukemia was related to fibrosis and cirrhosis development in multiple cases [49, 50]. Furthermore, cirrhosis induced by methotrexate has led to the transplantation of the liver in an important number of patients. Hepatic stellate cells have a central role in the physiopathological mechanism. The hepatic test may be normal or ALT can be temporarily increased. In rare cases, a liver biopsy may be necessary to confirm the diagnosis [29].

Patients who receive treatment with methotrexate need rigorous monitoring, especially those who have both obesity and diabetes [51]. It has been demonstrated that folic acid may reduce hepatic injury [29].

2.9 Sinusal obstructive syndrome

Previously named veno-occlusive disease, sinusoidal obstruction syndrome is the last step of hepatic sinusoidal injury evolution. The most exposed are patients who receive cytoreductive chemotherapy combined with radiotherapy or are in the setting of bone marrow transplantation [52].

Cyclophosphamide, oxaliplatin, irinotecan, 5-fluorouracil, 6-mercaptopurine, dacarbazine, vincristine, mitomycin-C, cytarabine, busulfan are chemotherapy agents involved in hepatic sinusoidal injury [53, 54, 55, 56, 57, 58]. Usually, sinusoidal obstruction syndrome occurs 5 weeks or later after administration of the aforementioned agents [23].

Direct injury of endothelial cells that lined the hepatic sinusoids is the mechanism of this type of disease. Endothelial injury promotes erythrocyte extravasation and aggregation into space of Disse, which impairs venous outflow. This leads to sinusoidal congestion. The next step is a fibrotic reaction due to hepatic stellate cell activation, which leads to presinusoidal collagen deposit and central venules obstruction with sinusoidal obstruction syndrome development and centrilobular necrosis. Increased activity of matrix metalloproteinase 2 and 9 may facilitate this process [59, 60].

No direct hepatocellular function alteration was observed for this entity [61, 62]. Histological findings vary from hepatic sinusoidal dilatation to subendothelial fibrin deposits associated with centrilobular necrosis of hepatocytes and low grades of nodular regenerative changes. The macroscopic liver had a bluish marbled appearance. Due to the area affected, sinusoidal obstruction syndrome can be classified into mild, moderate, or severe if less than 1/3, 1/3–2/3, or more than 2/3 of the lobule was affected [7, 63]. There are three phases of sinusoidal obstruction syndrome: acute, subacute, and chronic. Patients may present painful hepatomegaly, short periods of jaundice, weight gain, and encephalopathy. Some patients have splenomegaly and ascites due to portal hypertension. Transient elevation of transaminases and bilirubin can be revealed on blood tests [64, 65].

Transabdominal ultrasound revealed hepatosplenomegaly, decreased flow in portal vein on Doppler mode, ascites, and gallbladder wall thickening. In the hepatobiliary phase of gadoxetic-acid-enhanced MRI, sinusoidal obstruction syndrome can present a diffuse heterogenous reticular pattern. CT and MRI findings also include narrowing of main hepatic veins [66, 67].

Viral hepatitis, Budd-Chiari syndrome, or other forms of DILI must be excluded before sinusoidal obstruction syndrome diagnosis. The evolution of persistent sinusoidal obstruction syndrome is represented by progression to regenerative nodular hyperplasia followed by fibrosis and cirrhosis development. Also, sinusoidal obstruction syndrome can impair chemotherapy response and liver regeneration after resection, which worsens prognosis. Patients with hepatitis C infection, stem cell transplant recipients, and those treated for Hodgkin lymphoma are more susceptible to developing sinusoidal obstruction syndrome after specific chemotherapeutic regimens. In addition, patients with colorectal cancer with hepatic metastasis are more susceptible to sinusoidal obstruction syndrome development if the oxaliplatin or irinotecan treatment is combined with 5-fluorouracil [57, 58, 68].

Sinusoidal obstruction syndrome changes can be reversible after cessation of chemotherapy. Supportive therapy and administration of bevacizumab or defibrotide sodium can reduce liver injury and may improve the efficacy of systemic treatment. Delaying surgery for patients with suspected sinusoidal obstruction syndrome can be an option [69].

Except for the patterns discussed above, other chemotherapy-induced liver disease exists, with a low frequency. For example, estrogens, which are used for advanced prostate cancer, are associated with a high risk of peliosis hepatitis, hepatic adenoma, or hepatocellular carcinoma development [70].

Despite the pattern of liver disease induced by oncologic agents administration, a correct diagnosis and management may reduce the hepatic damage and improve the prognosis of these patients.

Acknowledgments

This work was supported by a grant of the Romanian Ministry of Education and Research, CNCS—UEFISCDI, project number PN-III-P1-1.1-TE-2019-1474, within PNCDI III.