Background
Cirrhosis is an end-stage disease that invariably leads to death. It is the 14th most common cause of death in adults worldwide and results in 1.03 million deaths per year [
1]. Chronic infection with hepatitis B virus (HBV) is one of the major causes of cirrhosis and 30% of deaths are attributable to HBV [
2,
3]. China is a highly endemic area of HBV, where 78% of patients with cirrhosis are HBsAg positive [
4]. In patients with cirrhosis, the 5-year probability of decompensation is 15–20%, while the 5-year survival rate decreases from 84 to 14–35% once clinical decompensating events occur [
5‐
7].
Anemia is a common comorbidity in cirrhosis that is associated with poor prognosis [
8]. Erythrocyte abnormalities were clinically important and frequent findings in patients with chronic disease. Mean corpuscular volume (MCV), a measurement of the average volume of red blood cells (RBCs), has been documented to be associated with an increase in many clinical conditions [
9‐
12]. Typically, anemia can be classified into macrocytic anemia (> 100 fL), normocytic anemia (80–100 fL), and microcytic anemia (< 80 fL) based on the patient’s MCV level. A recent study has reported that the elevated MCV level was associated with increased liver cancer mortality, especially in men who are hepatitis B surface antigen (HBsAg) positive [
13]. Therefore, in this study, we hypothesized that a common association might exist between macrocytic anemia and the severity of liver impairment in patients with HBV-related decompensated cirrhosis.
We used the Model for End Stage Liver Disease (MELD) score for evaluating the severity of liver impairment of HBV-related decompensated cirrhosis. The MELD score was developed to predict the short-term mortality of end-stage liver disease because of the shortage of donated livers. It had been validated subsequently as an accurate predictor of survival among different populations of patients with advanced liver disease and was adopted for organ allocation for liver transplantation instead of the older Child-Pugh score in the USA since 2002 [
14‐
16]. Liver transplantation is generally recommended for patients with MELD score of > 15, if possible [
17].
The goal of the present study is to investigate whether the MELD score is higher in the macrocytic anemia group in patients with HBV-related decompensated cirrhosis.
Discussion
In this retrospective study, we demonstrated that macrocytic anemia, defined as anemia in which the RBCs are larger than their normal volume (100 fL), is associated with the severity of liver impairment in patients with HBV-related decompensated cirrhosis. This finding remains substantial even after adjusting for demographics and laboratory parameters, such as age, gender, smoking, drinking and total cholesterol.
An MCV level greater than 100 fL, which is also known as macrocytosis, may not always be associated with anemia. Moreover, it presents independently from anemia in most cases [
10]. Nevertheless, we chose anemia as one of our inclusion criteria because 84.2% of the 1445 pre-screened patients have anemia. This result was consistent with the finding of another study, which reported that about 75% of patients with chronic liver disease have a diverse aetiology of anemia [
25]. Furthermore, patients with cirrhosis may have anemia due to a lack of haematopoietic factors, shortened erythrocyte survival, reduced bone marrow function, or gastrointestinal bleeding. All these conditions indicate impaired liver function and a high risk of mortality. Therefore, patients without anemia were excluded from the data analysis to avoid potential bias in our present study.
The importance of macrocytic anemia or macrocytosis seems to be underestimated in the past. Only a few studies focused on its risk of adverse events or death [
9‐
13]. Among these studies, Yoon et al. documented that the elevated MCV level was associated with increased liver cancer mortality in men [
13]; this finding was consistent with the result of our study. A small-sample study also found a markedly higher MCV in patients with chronic liver failure than in healthy subjects [
26]. These observations, though not directly, provided evidence for our conclusion that patients with HBV-related decompensated cirrhosis who have macrocytic anemia were more likely to present worse liver condition.
There are several potential pathological mechanisms that explain why macrocytic anemia is associated with the severity of liver impairment. First, patients with advanced liver damage are more likely to have vitamin B
12 or folate deficiencies [
27], which directly result in macrocytic anemia. Vitamin B
12 and folate coenzymes are required for thymidylate and purine synthesis, thus, their deficiencies result in retarded DNA synthesis and eventually will develop into macrocytic anemia [
28‐
30]. Second, macrocytic anemia in liver disease may be due to an increased deposition of cholesterol on the membranes of circulating RBCs [
31,
32]. This deposition effectively increases the surface area of the erythrocyte. Third, hemolytic anemias are common in advanced liver failure. In this case, excessive destruction of RBCs and increased reticulocyte count can be observed. The immature erythrocytes are approximately 20% larger compared to the mature erythrocytes, which result in macrocytic anemia [
25]. Moreover, erythrocyte morphology is affected by various factors in liver disease, such as causes, degree of liver damage, and drugs used. Complicated mechanisms, which allow the synchronized performance of their independent or collaborative functions, determine the shape of RBCs. Nevertheless, we firmly believe that there is a positive correlation between macrocytic anemia and the severity of liver impairment in patients with HBV-related decompensated cirrhosis.
In addition, we used the MELD score, which is a formula comprising creatinine, bilirubin, and INR values, to evaluate the severity of liver impairment and risk of death. In our study, patients with macrocytic anemia had higher levels of bilirubin and INR, but no significant difference was observed in creatinine levels and eGFR. Thus, macrocytic anemia might be unrelated to kidney damage in patients with HBV-related decompensated cirrhosis.
There were a few limitations in this study. First, we used the MELD score for evaluating the severity of liver impairment in patients with HBV-related decompensated cirrhosis. Although the MELD score could provide an accurate prediction of short-term mortality of patients with cirrhosis, a follow-up data might be better and more credible. Second, the analysis did not include data on serum vitamin B12, folate, reticulocyte count, drugs, and measures of haemolysis, which could contribute to better understand the mechanisms of macrocytic anemia in patients with cirrhosis.