LIVER DISEASE IN α-THALASSAEMIA

Luke KL Chan

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Amid A, Lal A, Coates TD, et al., editors. Guidelines for the Management of α-Thalassaemia [Internet]. Nicosia (Cyprus): Thalassaemia International Federation; 2023.

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Guidelines for the Management of α-Thalassaemia [Internet].

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Chapter 8LIVER DISEASE IN α-THALASSAEMIA

Luke KL Chan.

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Introduction

The liver plays an important role in iron homeostasis and is the major storage site of excess iron in the body. Similar to β-thalassaemia, excessive liver iron deposition secondary to ineffective erythropoiesis in haemoglobin H (HbH) disease could lead to chronic inflammation of hepatocytes, fibrosis, and ultimately cirrhosis. Furthermore, some patients with more severe forms of non-deletional HbH disease may require frequent on-demand transfusions or even become transfusion-dependent. This will eventually lead to transfusional iron overload. Concomitant liver diseases especially viral hepatitis would further aggravate liver damage. Cirrhosis is an important risk factor for hepatocellular carcinoma (HCC), which is a sinister complication with high mortality risk. HCC has been reported in patients with β-thalassaemia even in the absence of cirrhosis.

Prevalence and burden of liver disease in HbH disease

Box

HbH disease was once considered a relatively benign disorder with only few patients who were thought to develop clinically significant iron overload. However, in the early 1990s, Hsu et al. reported that iron overload occurred in 74% of a series of Chinese (more...)

Transfusion-transmitted viral infections are major complications in patients with thalassaemia, especially those on chronic transfusions. The prevalence of viral infections in patients with β-thalassaemia has been reported to range from 0.3–5.7% for HBV and up to 85% for HCV in different populations. The seroprevalence of HBV surface antigen and anti-HCV in patients with HbH disease has not been reported in detail, likely due to the fact that only a small portion of patients with HbH disease require frequent or regular transfusions. The risk of acquiring HBV and HCV from transfusion of blood products has been largely mitigated nowadays by regular donor screening and nucleic acid testing.

Similarly, there is a paucity of data in regards to the prevalence of HCC in patients with HbH disease. Macuso et al. identified two cases of HCC out of 105 evaluated patients with β-thalassaemia in a study performed in 2003 [5]. Since then, a significant increase in the incidence of HCC in adults with β-thalassaemia has been reported in both transfusion-dependent and non-transfusion dependent patients. However, data on the risk of HCC in patients with HbH disease are quite scarce [6–8]. It is important to note that HCC occurs more frequently in non-transfusion dependent β-thalassaemia (NTDT) than in transfusion-dependent β-thalassaemia (TDT) [6, 9].

Despite improvements in the screening of blood products for viral pathogens, liver disease has emerged as a significant cause of morbidity and mortality in thalassaemia, mostly due to HCC followed by cirrhosis [10]. This is possibly related to the improved survival of patients so that they live long enough to develop complications that usually occur later in life [6].

Pathophysiology of liver disease in HbH disease

Liver iron overload in HbH disease

Iron overload is the most important cause of liver damage in HbH disease. Unlike in TDT where excess iron is mostly contributed by blood transfusions, the major mechanism of iron accumulation in NTDT, including HbH disease, is increased intestinal iron absorption resulted from hepcidin suppression by ineffective erythropoiesis [11]. More importantly, absorbed iron directly deposits in hepatocytes, whereas iron from transfused blood would first saturate the reticuloendothelial system [6, 10]. Though both conditions are categorized as NTDT, ineffective erythropoiesis is less marked in HbH disease than in β-thalassaemia intermedia while chronic haemolysis plays a more significant role in the pathogenesis of the former [12]. A recent study proposed that this phenomenon makes iron loading less pronounced in HbH disease, as evidenced by a higher hepcidin and lower serum ferritin level than that in β-thalassaemia intermedia. However, further study is required to compare the burden of liver disease in these two distinct types of NTDT [13]. HbH disease with non-deletional types of mutation (e.g., HbH Constant Spring or HbH Quong Sze) usually has a more severe phenotype including a lower baseline haemoglobin, higher transfusion requirement, and more prominent hepatosplenomegaly [14]. A higher liver iron concentration (LIC) was also observed in non-deletional than in deletional forms of HbH disease [3, 15]. Patients with more severe disease phenotype including those with lower baseline haemoglobin level, higher transfusion requirement, and history of splenectomy are at higher risk of developing liver iron overload [3, 4, 15]. The spleen may act as a reservoir of excess iron, accounting for the higher LIC in splenectomised patients [16].

Some studies showed that advancing age had a direct correlation with serum ferritin level and LIC in NTDT including HbH disease, suggesting that patients could develop clinically significant liver iron overload over time [4, 16, 17]. Tantiworawit et al. demonstrated that age >20 years was a significant risk factor of liver iron overload in NTDT (OR 30.2, 95 % CI 4.5-203). Huang et al. reported similar findings in a more recent study. The odd ratio of liver iron overload in patients >30 years of age was 77.8 (95% CI: 8.8–690.5). The proportions of patients with HbH disease were 40.7% and 55.6% respectively in these two studies [4, 15]. On the other hand, some groups did not demonstrate a correlation between age and LIC in NTDT [3, 18]. This could be partly attributed to the prior use of iron chelation therapy in some patients. Further investigations are warranted to study whether age affects LIC in HbH disease.

Hepatic fibrosis and cirrhosis in HbH disease

Iron toxicity to the liver and other organs is largely dependent on non-transferrin bound iron (NTBI) especially labile plasma iron, which appears when the iron binding capacity of transferrin is exceeded [19]. NTBI is efficiently taken up by the liver and mainly targets hepatocytes. It exerts toxicity by its ability to catalyse reactions that generate free hydroxyl radicals responsible for lipid peroxidation of cellular organelles [20, 21]. Clearance of debris from iron-laden hepatocytes induces inflammatory and profibrogenic signals, resulting in fibrinogenesis and ultimately cirrhosis [10, 19, 22–24]. As previously discussed, iron overload in NTDT is mostly related to hepcidin suppression secondary to ineffective erythropoiesis. This mechanism results in saturation of transferrin and emergence of NTBI earlier in the course of disease than TDT, in which NTBI only appears in the presence of severe iron overload after multiple blood transfusions, exceeding the protective effect of storage protein ferritin [16, 25, 26]. Prolonged duration of hepatic iron exposure significantly increases the risk of advanced liver fibrosis and cirrhosis [27, 28]. A study in Hong Kong showed that age ≥65 years (OR 5.0, 95% CI 1.5–17.5) and moderate-to-severe liver iron overload (OR 3.5, 95% CI 1.01–12.1) were independently associated with advanced liver fibrosis in HbH disease [3].

Box

Concomitant HCV infection has a synergistic role in liver injury and fibrosis progression in thalassaemia patients [29]. One of the possibilities is the chronic HCV infection further suppressed hepcidin level and exacerbated hepatic iron overload [29]. (more...)

Hepatocellular carcinoma

Most HCC in NTDT patients occurred after 45 years of age [10]. Liver cirrhosis is the strongest risk factor for HCC irrespective of its etiology. Thus when one reaches the cirrhotic stage, HCC surveillance should be considered [34, 35]. Hepatic iron overload promotes hepatocarcinogenesis via several mechanisms. First, excess iron triggers the generation of reaction oxygen species, which disrupt DNA and impair protein synthesis, leading to inactivation of tumour suppressor genes (e.g. TP53) or their products. As previously mentioned, NTBI would accelerate fibrinogenesis and indirectly increase the risk of HCC. Finally, immune dysregulation in iron overloaded liver would attenuate anti-cancer immune surveillance [35–37]. Importantly, the occurrence of hepatocellular carcinoma in the absence of liver cirrhosis in thalassaemia patients has been recurrently reported. A common feature in these patients is the considerably high liver iron burden [5, 9, 38, 39]. This suggests the necessity of extending HCC surveillance to NTDT patients who have not yet reached cirrhotic stage.

Concomitant chronic HCV infection could induce necroinflammation and significantly increase the risk of HCC [5, 39]. Although chronic HBV infection is implicated in around half of HCC cases worldwide, its effect on HCC development in NTDT patients is not well characterized [35]. Alcohol and non-alcoholic liver disease are cofactors that possibly worsen liver damage and promote the development of HCC in iron loading disorders including thalassaemias [33].

Biliary tract disease

Hyperbilirubinaemia is a common feature found in more than half of the patients with HbH disease owing to chronic haemolysis [40]. Consequently, like other thalassaemia syndromes, cholelithiasis is also common in HbH disease. The reported prevalence of gallstones in HbH disease was 28–42%, which was 8-fold higher than the background population though lower than patients having β-thalassaemia [40, 41]. This risk increased with concomitant Gilbert’s genotype. The possible complications of gallstones include cholangitis and cholecystitis [14, 25, 40].

Diagnosis and treatment of liver disease in HbH disease

Evaluation and monitoring of liver iron overload

Monitoring of liver iron burden and early detection of complications are the cornerstones of managing liver disease in HbH disease. Serum ferritin is an easily available test, which has reasonable correlation to LIC in thalassaemia. However, it is very important that serum ferritin level is significantly lower in NTDT than in TDT despite similar LIC [42]. The lower serum ferritin to LIC ratio than TDT is also observed in HbH disease [43, 44]. This is likely the effect of preferential iron absorption by the liver in NTDT (please see Chapter 11). Another pitfall of serum ferritin is the lack of specificity as it also increases in response to inflammation [45]. MRI T2* has replaced liver biopsy as the gold standard of LIC quantification in thalassaemia because its non-invasive, rapid, accurate, and reproducible nature [46, 47]. It may however be less available in resource-limited settings. In non-transfusion dependent patients with HbH disease, LIC monitoring could be started at around 10 years of age [48] or when the ferritin exceeds >300 ng/dl. Some patients especially those with deletional type HbH disease have milder disease phenotype and slow kinetics in iron accumulation. In these patients, assessment of LIC could be commenced at 15 years of age, or at the start of adulthood [49, 50]. LIC should be measured after 8–10 transfusions for those who are on a regular transfusion programme. The frequency of liver iron quantification by MRI T2* should be individualized according to the baseline value and serum ferritin level (please see Chapter 11) [10, 51, 52].

Detection of hepatic complications in HbH disease

Since cirrhosis is a significant risk factor of HCC development, early detection of liver fibrosis would be useful to identify high risk patients warranting close monitoring and early intervention. Transient elastography, which measures the velocity of an elastic shear wave propagating through the liver parenchyma, is an extensively validated method to detect liver fibrosis and cirrhosis [53]. Liver stiffness measurement by transient elastography correlates with different stages of liver fibrosis in various liver diseases including thalassaemia [28, 54]. Being non-invasive, highly reliable and reproducible, and more easily available nowadays, the test should be considered especially when risk factors of liver fibrosis are present [55].

USG is able to detect early HCC amenable to curative treatment [56, 57]. Regular USG screening is therefore recommended every 6 months in patients with risk factors, including patients with concomitant viral HBV and/or HCV infection, established liver cirrhosis irrespective of the aetiology and moderate to severe liver iron overload [35, 56]. Alpha-fetoprotein is not sensitive enough to be used alone to screen for or diagnose HCC [6]. Table 1 summarizes the monitoring strategy of liver disease in HbH disease.

Table 1

Strategy of liver disease monitoring in HbH disease

Iron chelation therapy for hepatic iron overload

Evidence suggests that all the three available iron chelating agents, namely deferoxamine, deferiprone and deferasirox were able to improve hepatic iron overload in thalassaemia [10, 58, 59]. Reduction in body iron burden by chelation therapy was associated with improvement in liver enzymes, liver stiffness measurement, and stage of liver fibrosis in β-thalassaemia intermedia [60, 61]. Patients with β-thalassaemia intermedia treated with deferasirox for at least 3 three years had stabilization or improvement in fibrosis stage regardless of the change in LIC [62]. The use of chelation therapy could also potentially prevent carcinogenesis induced by iron toxicity but clinical data is required to confirm the hypothesis [63]. Although we are lacking in direct evidence showing the beneficial effects of iron chelators on liver outcomes in HbH disease, treatment of liver iron overload is still recommended based on the favourable findings in studies including other NTDT patients.

Management of concomitant liver diseases and cirrhosis

Consultation with a hepatologist is recommended in the management of viral hepatitis in patients with thalassaemia. The availability of direct-acting antiviral (DAA) drugs (e.g., combination therapy with sofosbuvir and velpatasvir, or ledipasvir and sofosbuvir) has remarkably improved the outcomes of thalassaemia patients with HCV infection. Studies confirmed the excellent tolerability of DAAs in patients with thalassaemia and the rate of achieving sustained virological response was 90–100% [64, 65]. HCV treatment should be sought to prevent the development of complications including HCC [66]. Management of chronic HBV infection in patients with HbH disease should follow the standard of care for the general population. HBV vaccination is recommended in patients who are seronegative for HBV and who are planned for transfusion therapy. When liver cirrhosis is diagnosed, evaluation by a hepatologist is recommended. Screening of variceal disease should be considered [67].

Management of hepatocellular carcinoma

Early diagnosis remains crucial to decrease mortality resulting from HCC. Once diagnosed, patients should be managed according to the severity of liver disease and the stage of HCC. Patients should be referred to appropriate oncology, surgery, or radiation oncology specialists, but the haematology team should be involved in optimizing the care of patients. Treatment modalities including surgical resection and thermoablation in early stage disease should follow the same indications applied to the general population with HCC [56]. Patients with thalassaemia without significant comorbidities should not be precluded from liver transplantation if indicated [35]. The use of chemoembolization in intermediate stage and systemic treatments in advanced stage HCC should also follow the same indications in non-thalassaemia patients [56].

Summary

Liver disease is one of the leading causes of morbidity and mortality in thalassaemia syndromes. Iron overload due to ineffective erythropoiesis, which promotes fibrinogenesis and carcinogenesis, is the major mechanism of disease manifestation. Iron often accumulates slowly in HbH disease and thus liver complications often occur in adulthood or even at advanced age. Concomitant liver disease, especially chronic HCV infection, further increases the risk of cirrhosis and hepatocellular carcinoma. Liver iron burden should be regularly monitored by serum ferritin and MRI T2*. Iron chelation is effective to remove excess hepatic iron and to reduce the risks of developing complications. Viral hepatitis should be managed according to the respective guidelines applied to the general population. USG liver in patients with risk factors enable early detection of HCC to decrease mortality.

Recommendations

Regular monitoring of liver iron burden by serum ferritin and MRI T2* should commence at 10 years of age or older for patients with milder disease phenotype.
Iron chelation therapy is recommended in patients with LIC ≥5mg/g dry weight or serum ferritin ≥500 ng/mL in non-transfusion dependent patients with HbH disease.
Vaccination against the hepatitis B virus in seronegative patients prior to blood transfusion therapyisrecommended.
Annual screening of HBV and HCV infection is recommended in patients receiving blood transfusions, and positive anti-HCV results should be followed by HCV-RNA to identify chronic infection.
Consultation with a hepatologist is recommended for management of concomitant HBV and/ or HCV infection, or when liver cirrhosis is established.
Evaluation for liver fibrosis and cirrhosis with transient elastography is recommended in patients with liver iron concentration ≥5mg/g dry weight or serum ferritin ≥500 ng/mL.
Biannual ultrasonography of liver for HCC surveillance is recommended in patients with HbH disease when risk factors (liver iron overload, cirrhosis, HBV and/ or HCV infection) are present.

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Chan LKL. LIVER DISEASE IN α-THALASSAEMIA. In: Amid A, Lal A, Coates TD, et al., editors. Guidelines for the Management of α-Thalassaemia [Internet]. Nicosia (Cyprus): Thalassaemia International Federation; 2023. Chapter 8.

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Introduction
Prevalence and burden of liver disease in HbH disease
Pathophysiology of liver disease in HbH disease
Diagnosis and treatment of liver disease in HbH disease
Summary
Recommendations
References

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