ETIOPATHOGENESIS OF ANEMIA IN CIRRHOSIS

The liver, owing to its unique portal circulation, synthetic and immunological functions can give rise to multiple hematological manifestations, and anemia in cirrhosis is often multifactorial (Table ​(Table11).

To understand the development of anemia, it is imperative to understand the critical role played by this oxygen-carrying micronutrient: Iron. 80% of the body’s total iron stores (02-04 g) are stored as Hb in red blood cells (RBC). Ferric iron (Fe3+) following its absorption in the duodenum is converted to ferrous iron (Fe2+) by the action of ferric reductase duodenal cytochrome b. This iron is transported into the cytoplasm of the enterocyte and is either stored or exported by the iron exporter enzyme ferroportin. The next step involves oxidization of Fe2+ to Fe3+ form to ferroxidase hephaestin and ceruloplasmin (Cp). Fe3+ in combination with enzyme transferrin (Tf) undergoes circulation in the body. Erythrocyte precursors, known as erythroblasts, utilize a principal portion of Tf bound iron (Figure ​(Figure2).2). A highly efficient recycling system in the spleen and hepatic macrophages ensures optimal utilization of iron stores. Thus, the human liver is an important component of this highly efficient iron homeostasis. The liver synthesizes proteins involved in iron homeostasis: Tf (80 kDa glycoprotein), Cp (copper linked serum ferroxidase), multi-subunit protein ferritin, and a 25 amino acid peptide, hepcidin.

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IDA may occur secondary to acute or chronic blood loss. The various causes are variceal hemorrhage which usually presents with an overt GI bleed, and portal hypertensive gastropathy (may present with either overt or obscure GI bleed). The incidence of duodenal ulcer and ulcer-related bleed is more common in patients with cirrhosis. Besides, nutritional deficiencies including those of iron, Vitamin (Vit) B12, B6, and folate are common in patients suffering from cirrhosis. In addition, hypersplenism secondary to portal hypertension may contribute to iron deficiency. Amongst the etiological agents leading to the development of cirrhosis, a few, in particular, have been found to have a predominant role in the pathogenesis of anemia: alcohol may cause blood loss because of alcohol-induced gastritis. It also has a direct toxic effect on erythroid precursors and may cause Vit B12, folic acid deficiency. Besides, alcohol-related malnutrition may lead to reduced iron absorption. Hepatitis B and C may cause bone marrow aplasia, Wilson’s disease may be associated with hemolytic anemia in around 1%-12% of cases as copper released following hepatocyte necrosis causes oxidative dysfunction of phospholipids lining the RBC membrane leading to hemolysis and worsening of liver dysfunction[9]. Another form of acquired hemolytic anemia: Spur cell anemia may occur in alcohol-related cirrhosis wherein abnormal lipid metabolism leads to altered RBC membrane causing reduced deformability of RBC. A triad consisting of cholestatic jaundice, transient hyperlipidemia and hemolytic anemia — Zieve’s syndrome has been rarely reported in alcohol-related cirrhosis[10].

Although now of historical interest, Ribavirin, a nucleoside anti-metabolite, used in the treatment of chronic hepatitis C (CHC), causes dose-related hemolytic anemia in around 10% of patients[11]. Autoimmune hemolytic anemia may also be seen in patients with autoimmune hepatitis. D-Penicillamine, a copper chelating agent, used in the treatment of Wilson’s disease, in turn, may cause iron chelation manifesting as IDA. Another drug used in Wilson’s disease, Trientine, may cause sideroblastic anemia[9]. However, the most common cause of anemia in cirrhosis is anemia of chronic disease, which develops secondary to an underlying chronic inflammatory state. Before we proceed further to understand the pathophysiology of anemia of chronic disease in cirrhosis, it is worthwhile to mention the proposed hypothesis of ‘Eryptosis’: Programmed cell death of erythrocytes which may contribute to anemia. This is akin to apoptosis of nucleated cells despite the absence of organelles involved in apoptosis. In a murine model, a high bilirubin level has been shown to increases Ca2+ influx, sphingomyelinase activation within erythrocytes, thereby triggering eryptosis[12].

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