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Cappellini MD, Farmakis D, Porter J, et al., editors. 2021 Guidelines: For the Management of Transfusion Dependent Thalassaemia (TDT) [Internet]. 4th edition. Nicosia (Cyprus): Thalassaemia International Federation; 2023.

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2021 Guidelines: For the Management of Transfusion Dependent Thalassaemia (TDT) [Internet]. 4th edition.

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CHAPTER 6Liver disease

Authors: , , Geoffrey Dusheiko, and John Porter.

Introduction

Iron overload and viral hepatitis are the two main causes of liver disease in patients with thalassaemia leading to chronic inflammation, fibrosis and ultimately cirrhosis.

The approach to liver disease includes clinical parameters, biochemical/serological/molecular tests and imaging techniques in order to identify the aetiological factor(s) and assess the severity of the injury.

Clinical examination may reveal signs of systemic iron excess such as skin pigmentation and hepatomegaly while in later stages stigmata of chronic liver disease (i.e. palmar erythema, spider naevi), ascites and encephalopathy may follow.

Laboratory tests may show moderate elevations (2-3 times higher than the upper limit of normal) of the aminotransferases, aspartate transaminase (AST) and alanine transaminase (ALT) and a mild increase of alkaline phosphatase and gamma glutamyl transferase (γGT). In the presence of severe hepatic impairment, prolonged prothrombin time, low albumin and high serum bilirubin are found.

With regard to imaging techniques, ultrasonography (US) remains the gold standard to evaluate hepatic morphology and to recognise signs of fibrosis and cirrhosis. Portal hypertension can be also assessed by duplex ultrasonography or spectral Doppler imaging and colour Doppler imaging (Procopet & Berzigotti, 2017). Hepatic transient elastography (TE), a pulse-echo ultrasound technique, has replaced biopsy as a non-invasive diagnostic method for staging liver fibrosis. Liver stiffness, measured by TE, has also been shown to correlate with stages of fibrosis in patients with thalassaemia (Ferraioli et al., 2016; Paparo et al., 2013; Di Marco et al., 2010a), although specific cut-off values for the stage of fibrosis need to be defined. Moreover, it is believed that iron overload may affect the accuracy of TE in assesing liver fibrosis (Fraquelli et al., 2010). As compared to liver biopsy which is the gold standard examination for the evaluation of liver fibrosis but consists an invasive techniq with potential complications, TE is an easy-to-perform diagnostic tool with moderate to high accuracy, especially in thalassaemic patients with chronic HCV infection (Poustchi et al., 2013).

A) Hepatic Iron Overload

1. Pathophysiology

Hepatocytes are the main site of iron storage and also the principal site of synthesis of hepcidin, a hormone responsible for the regulation of iron transport to the extracellular space through activation of the cellular iron exporter, ferroportin. In cases of thalassaemia, the excess iron due to frequent transfusions initially accumulates in macrophages and later in hepatocytes, while hypoxia caused by dyserythropoiesis intensifies erythropoietin production leading to further suppression of hepcidin production and increased transferrin bound iron (TBI) and non-transferrin bound iron (NTBI) plasma levels. (Chaston et al., 2011).

Excessive levels of iron in the blood stream exceed the capacity of plasma transferrin to bind iron and lead to the appearance of NTBI in the plasma which consists a highly toxic iron species. The liver rapidly clears NTBI from the serum through divalent metal transporter 1 (DMT1) and incorporates it into ferritin. However, once the protective storage efficiency of ferritin is exceeded, unbound iron accumulates in the hepatocytes and leads to severe oxidative stress and overproduction of toxic reactive oxygen species (ROS), which cause lipid peroxidation and protein damage (Figure 1). The subsequent hepatic inflammation and necrosis lead to fibrosis and cirrhosis (Sikorska, Bernat & Wroblewska, 2016).Development of fibrosis in the absence of inflammation has also been found to be associated with iron accumulation in the liver and relates to direct activation of stellate cells (Philippe, Ruddell & Ramm, 2007).

Figure 1. Causes of liver disease in thalassaemia.

Figure 1

Causes of liver disease in thalassaemia. [DMT1, divalent metal transporter 1; FPN, ferroportin; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ROS,reactive oxygen species, NTBI, non-tranferrin bound iron; TBI, transferrin bound iron; TFR1 transferrin (more...)

2. Iron overload monitoring

Magnetic resonance imaging (MRI) R2 or R2* using liver iron content (LIC) (mg of iron/g dry weight) is considered the method of choice for iron load monitoring in thalassaemic patients. A yearly LIC assessment should be performed in all patients in order to monitor chelation therapy effectiveness (Brittenham, 2011). LIC values greater than 7mg Fe/g dry weight and 15mg/g dry weight are associated with moderate and severe iron overload respectively (Allali et al., 2017) while LIC>16mg/g dry weight is associated with an increased risk of hepatic fibrosis. MRI iron assessment of the liver is also mandatory as a pre- and post-transplant evaluation in cases of haematopoietic stem cell transplantation (HSCT) (Mavrogeni et al., 2018).

Serum ferritin (SF) is the most widely used marker of total body iron load. SF values higher than 2000 ng/ml are associated with liver iron overload (Krittayaphong et al., 2018). However, SF measurement has low specificity and should be interpreted with caution since it can be elevated also in the case of concomitant inflammation, malignancy or oxidative stress (Chirico et al., 2015; Puliyel et al., 2014).

Transient elastography has been used for the assessment of liver fibrosis in thalassaemic patients with initially promising results. Its value as a means of estimation of iron overload has been examined in recent studies. TE values were found to be strongly correlated to MRI T2* results (Pipaliya et al., 2017). LIC values, SF levels and TE stiffness measurements in patients with sickle cell anaemia were also correlated and found to improve after successful chelation therapy (Delicou et al., 2018), although this correlation was not confirmed by other studies (Ou et al., 2017). Further studies focusing on the effectiveness of TE in assessing liver iron overload need to be conducted in order to draw robust conclusions.

3. Treatment

Three chelators are currently available for the treatment of iron overload in thalassaemic patients: deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX). They are all proven to effectively reduce LIC (Maggio et al., 2011, 2002; Taher et al., 2009), while specifically DFX may have a positive effect on liver fibrosis as well (Deugnier et al., 2011; Maira et al., 2017; Sousos et al., 2018).

B) Viral Hepatitis

Hepatitis C virus infection

Chronic infection with hepatitis C virus (HCV) in combination with iron load hepatotoxicity remains a major risk factor for acceleration of liver fibrosis in thalassaemic patients. Antiviral treatment used to be quite challenging, mainly due to the haemolytic effect of ribavirin and interferon (IFN)-induced cytopenias (Kowdley, 2005). Recent advances in HCV therapies have improved treatment success rates and minimised adverse events significantly.

1. Hepatitis C virus epidemiology

The prevalence of HCV infection among thalassaemic patients shows great variation in published data (Di Marco et al., 2010b), ranging between 19 and 75% and depending on the region where it was studied(Behzadifar, Gorji & Bragazzi, 2018; Jang et al., 2017; Kountouras et al., 2013; Triantos et al., 2013).The most frequent HCV genotype (GT) in thalassaemic patients is GT 1b, reflecting the distribution of genotypes in the general population per geographical area (Di Marco et al., 2010b; Dodd, Notari & Stramer, 2002). More recent epidemiological studies in specific eastern Mediterranean countries describe the increase of GT3 prevalence (Ahmadi-Ghezeldasht et al., 2018) as well. The implementation of systematic blood donor screening with molecular methods in the last two decades has dramatically decreased HCV transmission through transfusions in Western countries (Dodd et al.2002), although such methods may not yet be extensively applied in developing countries.

2. Hepatitis C virus infection, diagnosis and treatment

All thalassaemic patients who were transfused before 1991 should be screened for HCV infection. HCV diagnosis requires two steps: a) blood testing for anti-HCV antibodies, b) HCV-RNA by polymerase chain reaction (PCR) testing in the case of positive anti-HCV result (Figure 2). The diagnosis of chronic HCV infection must be followed by fibrosis stage evaluation with TE, hepatic function assessment and genotype determination when a pangenotypic regimen is not available in order to select the best treatment option (EASL HCV Guidelines, 2020).

Figure 2. Hepatitis C virus (HCV) diagnosis algorithm.

Figure 2

Hepatitis C virus (HCV) diagnosis algorithm.

The HCV treatment landscape has changed dramatically in recent years. Direct acting anti-viral agents (DAAs) have emerged (Table 1), yielding > 95% rates of sustained virological response (SVR) which is the equivalent of complete cure. DAAs have replaced interferon in the treatment of HCV infection and have combined efficacy with a very safe profile. Treatment duration varies between 8 and12 weeks, with ribavirin co-administration not being needed in many cases. Pangenotypic regimens that provide high SVR rates across genotypes are also available and have further simplified therapy (Table 1). As a result, the indication for HCV treatment in the thalassaemic population is similar to that of the general population (EASL HCV Guidelines, 2020). Specific phase 3 (Hézode et al., 2017), randomised (Mangia et al., 2017) and real-life studies (Sinakos et al., 2017) have confirmed DAAs effectiveness in thalassaemic patients, showing SVR rates comparable to those in the general population and more significantly without any additional safety concerns. It should be noted that before treatment initiation, drug-drug interactions between concomitant medications and DAAs should be checked. Liverpool University site for Hepatitis Drug interactions (https://hep-druginteractions.org/query) is a very useful tool for everyday clinical practice. In general, co-administration of anti-viral agents with chelation treatment is not contra-indicated, while specific caution should be taken with certain anti-arrhythmic drugs that share common metabolic paths with DAAs with the consequence that co-administration may affect drug levels (EASL HCV Guidelines, 2020).

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Table 1

Summary of approved Direct Anti-viral Agents(DAAs) per Hepatitis C Virus Genotype (EASL 2020).

Hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection was reported to be present in 5% of thalassaemic patients based on an Italian registry (Borgna-Pignatti et al., 2014). This rate could be higher in countries where blood donors are not adequately assessed. Diagnosis is made by the presence of detectable HBV surface antigen (HBsAg) in serum for more than 6 months. HBV DNA levels in serum detected by PCR, presence of HBV e antigen (HBeAg), fibrosis stage and transaminase levels guide the decision for treatment. Currently approved drugs for treatment of chronic HBV infection include pegylated interferons and oral nucleoside/nucleotide analogues (EASL HBV Guidelines, 2017), but interferons should be avoided due to their myelosuppressive effect (Kowdley, 2005). Prevention is mandatory and HBV vaccination is strongly recommended. Immunisation of thalassaemic children for HBV has been proven to be effective without any tolerance issues (Sharifi, Milani & Shooshtari, 2010).

Hepatitis E virus (HEV) infection

Hepatitis E virus (HEV) infection rates have been increasing lately, even in high-income countries (Capai, Charrel & Falchi, 2018). Despite the fact that the predominant route of HEV transmission is consumption of contaminated food, it is estimated that 1/5000 blood donations could be contaminated (Capai, Charrel & Falchi, 2018). Since acute HEV infection may have severe complications in patients with pre-existing liver disease, testing for IgM anti-HEV antibodies and HEV viral load assessment should be performed in cases of acute hepatitis or unexplained flares of chronic liver disease (EASL HEV Guidelines, 2018) in thalassaemic patients. A case of acute hepatitis E infection in a thalassaemic patient has been already reported (Politis et al., 2018). In severe cases, treatment guidelines include ribavirin and IFN, although further investigation is needed (EASL HEV Guidelines, 2018). Universal screening of blood donors is not a worldwide strategy due to cost and differences in the frequency of immunoglobulin (Ig) G anti-HEV antibodies in the general population.

C) Hepatocellular Carcinoma

1. Incidence and Pathophysiology

The incidence of hepatocellular carcinoma (HCC) in thalassaemic patients has increased lately due to the prolonged survival achieved by effective iron chelation therapies and decrease of heart-associated complications (Borgna-Pignatti et al., 2014). Co-existence of specific risk factors such as iron overload and HCV or HBV infection contribute to the development of HCC and provide an explanation for the reported younger age of HCC diagnosis (Mancuso et al., 2006) in this population. Furthermore, there are reported cases of HCC in non-cirrhotic thalassaemic patients (Deugnier & Turlin, 2001; Papadopoulos et al., 2020).HCV infection and iron overload are reported to work in a synergistic way towards HCC development. More specifically, it has been described that HCV induces reduction of serum hepcidin (Girelli et al., 2009) promoting further accumulation of total iron, while unbound iron has been connected to carcinogenesis through the production of ROS. Moreover, frequent blood transfusions cause continuous antigenic stimulation which could potentially have an immunomodulatory effect (Refaai & Blumberg, 2013).

2. Screening for HCC

Screening patients with thalassaemia for HCC has a pivotal role in their clinical management. Abdominal US should be performed every 6 months in cirrhotic patients (EASL HCC Guidelines, 2018), while alpha fetoprotein (AFP) is not considered a reliable marker in general and especially in thalassaemic patients (Fragatou, Tsourveloudis & Manesis, 2010). The early onset of HCC and the observation of HCC cases even in non-cirrhotic patients indicate that biannual screening should be extended not only to cirrhotic patients, but also to every patient with high risk factors such as HCV and/or HBV infection, non-transfusion-dependent thalassaemia (NTDT) with LIC≥ 5 mg Fe/g dry weight, transfusion-dependent thalassaemia (TDT) with LIC≥ 7 mg Fe/g dry weight or serum ferritin ≥1000 ng/ml (Moukhadder et al., 2017). Annual MRI R2 or R2* to evaluate LIC also contributes on early HCC prevention through strict iron overload monitoring and treatment (Taher et al., 2008).

3. Treatment

Few data exist on efficacy of HCC treatments in patients with thalassaemia. Treatment strategies according to stage of HCC and severity of liver disease used for the treatment of HCC in the general population (i.e. surgical resection, transarterial chemoembolisation (TACE), percutaneous radiofrequency ablation (RFA) and ethanol injection) have been used with success (Mancuso, 2010; Mancuso et al., 2006, 2005). However, the administration of sorafenib, a multi-kinase inhibitor indicated for advanced HCC did not yield adequate response in three thalassaemic patients with HCC in an Italian study (Restivo Pantalone et al., 2010). Further multi-centre prospective studies need to be conducted in order to clarify the effectiveness of the new immunomodulatory anti-cancer drugs in thalassaemic patients. Liver transplantation for the treatment of HCC in thalassaemic patients remains controversial. Two studies by Manusco et al. and Restivo Pantalone et al. have shown promising results, but larger studies are needed to clarify the role of liver transplantation in these patients (Mancuso, 2010; Restivo Pantalone et al., 2010).

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Summary.

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© Thalassaemia International Federation.
Bookshelf ID: NBK603097PMID: 38683910
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