Macrocytic anaemia, characterised by enlarged RBCs (macrocytes), is one of the most common findings of chronic alcohol consumption. Studies have shown that alcohol directly impairs the bone marrow’s ability to produce healthy RBCs, leading to the release of larger-than-normal red cells into circulation.^{7,9,11,12,13,14} This effect is often observed before any noticeable anaemia manifests and can persist even after alcohol intake is reduced or stopped.¹⁵

In a clinical context, elevated MCV values, or those significantly deviating from a patient’s baseline, may necessitate additional clinical and laboratory investigations to ascertain the aetiology of macrocytosis.^16,17

Instances of elevated MCV are also observed in patients with vitamin B12 or folate deficiency, commonly referred to as megaloblastic anaemia, as well as in individuals with chronic liver disease. To verify the diagnosis, a fully qualified biomedical scientist or technologist needs to analyse the peripheral blood smear (PBS) to detect the morphological characteristics that signify each disorder, along with other cellular components and features on the smear, which can offer vital insights into the cause of anaemia. The enlarged RBCs associated with chronic alcohol consumption are generally round, with target-appearing macrocytes¹⁷ (see Figure 2). This shape contrasts with the more oval macrocytes observed in megaloblastic anaemia¹⁷ (see Figure 3). Please note that each figure shows a small lymphocyte for comparing RBC sizes.

Numerous haematological abnormalities are present in individuals who abuse alcohol on a long-term basis.¹⁸

Megaloblastic anaemia resulting from folic acid deficiency and acquired sideroblastic anaemia are the most common causes of anaemia associated with this abuse. However, there are other reasons for this finding.¹⁹ A diagnostic conundrum may arise because coexisting nutritional deficiencies can obscure Sideroblastic anaemia, as observed in PBS.¹⁹ It is crucial to identify Sideroblastic anaemia in patients with anaemia who do not respond well to haematinics because it can be reversed by abstinence from alcohol.^20,21

Chronic alcohol consumption often leads to the development of Sideroblastic anaemia, a condition marked by a disruption in the mitochondrial haem synthesis process. The hallmark of this disorder is the presence of sideroblasts. The process of iron incorporation into haem is impaired, leading to the accumulation of iron within the mitochondria of RBC precursors. Ring sideroblasts are a form of erythroblast that have iron-loaded mitochondria with a ring-shaped arrangement of the iron granules surrounding the nucleus.²¹ Prussian blue staining reveals the presence of these iron-loaded mitochondria as blue granules surrounding the nucleus (see Figure 4).²² The underlying cause of Sideroblastic anaemia determines its pathophysiology. The number of mature erythrocytes decreases as a result of compromised haemoglobin production. The resulting anaemia is typically hypochromic and microcytic.²³

Sideroblastic anaemia is most likely caused by two mechanisms: direct antagonistic effects, e.g. chronic alcohol abuse on pyridoxal phosphate and/or related dietary deficiencies of this compound resulting from malnutrition.^24,25

In Sideroblastic anaemia, iron overload is a disorder related to the improper use of iron, where there is an increased delivery of iron to erythroblasts. The body absorbs more iron through the intestines when anaemia is detected. Subsequently, this leads to systemic iron accumulation and erythroblast mitochondria with higher iron content. Systemic iron overload occurs in certain types of Sideroblastic anaemia, typically when defects in iron metabolism affect the erythroid pathways at an earlier stage.^23,24 Congenital Sideroblastic anaemia, also known as autosomal recessive congenital Sideroblastic anaemia, is caused by mutations in various haem-synthesising genes. Mutations in SLC25A38 are the most prevalent among many genes.²³

Ringed sideroblasts were found in the bone marrow of approximately one-third of the patients with severe alcoholism.^7,21

Another complication associated with prolonged alcohol abuse is megaloblastic anaemia, primarily caused by folate deficiency. Other causes include a lack of vitamin B12 or the direct toxic effects of alcohol on the bone marrow. Diagnosing this condition requires evaluating folate and vitamin B12 levels, considering functional deficiencies and excluding related conditions, such as the previously mentioned Sideroblastic anaemia. The therapy aims to tackle alcohol use disorders while also addressing specific vitamin deficiencies.²⁶ In cases of folate deficiency, folate absorption and metabolism are disrupted by chronic alcohol consumption. Malabsorption can occur because of liver damage in chronic alcohol abusers, who often consume diets deficient in folate-rich foods. Consuming alcohol chronically can harm the stomach lining, leading to a decrease in the production of intrinsic factors, which are essential for the absorption of vitamin B12.¹⁹

According to a recent study, alcohol directly affects erythrocyte membranes and decreases RBC survival.²⁷ High MCV is noted as a predictor of mortality in heavy drinkers, and erythrophagocytosis is a key process in alcohol-related anaemia. This reduced RBC survival may result from impaired liver function as a result of excessive alcohol consumption, which develops over time. These patients can also present with an under-recognised condition known as ‘Zieve’s syndrome’. This syndrome is characterised by a triad of haemolytic anaemia, hypertriglyceridaemia and jaundice²⁸ in patients with known liver diseases. It was first identified in 1958 in a cohort of 20 patients with haemolytic anaemia caused by alcohol abuse.²⁹

Some individuals who suffer from chronic alcohol abuse and liver disease (ALD) have been found to experience iron deficiency.³⁰ One cause is malnutrition,³⁰ which is common among alcohol abusers and may explain why some individual’s experience iron deficiency. However, there may be additional reasons for this finding. Consuming alcohol in large amounts over a prolonged period not only puts stress on the liver but also negatively affects the gastrointestinal tract. It can lead to inflammation in the intestines and cause erosions in the duodenum, compromising the intestinal mucosa’s integrity and resulting in duodenal bleeding (see Figure 5).^31,32,33 These conditions may facilitate the entry of bacterial endotoxins into the bloodstream (portal vein system) and disrupt iron absorption in the duodenum, potentially leading to iron deficiency. Therefore, it can be hypothesised that the iron status of individuals who consume alcohol, whether resulting in iron deficiency or overload (see later for a description of iron overload), might depend in part on their intestinal health, which can vary for multiple reasons (see Figure 5). This hypothesis warrants further investigation, and if confirmed, the mechanisms underlying iron deficiency in chronic alcohol abusers should be better understood.

The various causes of anaemia in individuals with ALD are shown in Figure 5. It is crucial to recognise that multiple mechanisms can occur concurrently, resulting in anaemia. Hospitalised chronic alcohol abusers can often present with either iron deficiency, an increased MCV, megaloblastic anaemia or, finally, Sideroblastic anaemia. However, a proper diet can be protective in cases of chronic alcohol consumption, indicating that alcohol itself does not necessarily cause iron deficiency or anaemia.³⁴

Hemochromatosis is a hereditary disorder characterised by abnormal iron accumulation. It results from a deficiency or dysfunction in hepcidin synthesis or activity caused by mutations in the genes responsible for regulating hepcidin production or function.

Hepcidin serves as the principal regulator of iron homeostasis, synthesised by the liver to inhibit iron absorption. The High Fe (HFE) gene plays a critical role in signalling the liver to produce hepcidin in response to elevated iron levels. Mutations in the HFE gene, such as C282Y, lead to hereditary hemochromatosis by impairing this signalling process, resulting in reduced hepcidin levels and subsequent iron overload. These genetic alterations result in enhanced absorption in the intestines and the release of iron from macrophages that store it. This leads to elevated systemic iron levels, resulting in iron deposits in multiple organs. Consequently, hemochromatosis is characterised by increased transferrin saturation (TSAT) and gradual iron accumulation in various tissues, mainly the liver, without anaemia or reticulocytosis.³⁵

Although hemochromatosis can result from mutations in non-HFE genes, the primary cause is inheritance of the C282Y mutation within the HFE gene. For individuals who are homozygous for this mutation, consuming excessive amounts of alcohol greatly exacerbates iron levels, including serum ferritin, iron and TSAT. In this population, high alcohol consumption leads to liver toxicity, which can elevate the risk of liver fibrosis and increase the likelihood of developing cirrhosis and hepatocellular carcinoma.³⁶ Therefore, chronic alcohol consumption can amplify the severity of the disease. Notably, hemochromatosis patients who consumed more than 60 g/day of alcohol had nearly nine times the risk of developing liver cirrhosis compared to those who drank less.³⁷ This accounts for the higher rates of liver fibrosis and cirrhosis observed in patients with both hemochromatosis and alcoholism compared to those with hemochromatosis who do not consume alcohol.³⁸

Granulocytes are a type of WBC distinguished by the granules found in their cytoplasm. They are categorised as neutrophils, eosinophils and basophils. Neutrophils are the most prevalent granulocytes in humans and serve as the primary defence in the innate immune system. Eosinophils and basophils constitute a smaller fraction of the total, the term ‘granulocytes’ and are frequently used informally to primarily denote neutrophilic granulocytes, also known as polymorphonuclear leukocytes (PMNs).³⁹

Leucopenia is often observed in individuals who regularly consume alcohol, frequently alongside other haematological abnormalities such as lymphopenia, anaemia and thrombocytopenia.^40,41,42 In cases where patients are referred for bone marrow tests because of unexplained abnormalities in their peripheral blood cells, 40% are identified as heavy alcohol consumers.⁴⁰ Research has further indicated that alcohol’s impact on leukocyte levels in peripheral blood can differ based on the quantity, duration and pattern of alcohol consumption.⁴¹ Some individuals who abuse alcohol may experience a temporary rise in granulocyte counts in their bloodstream. A study involving 45 healthy volunteers and 300 chronic drinkers, regardless of recent excessive drinking, found that alcoholics who had recently consumed large amounts of alcohol generally had higher neutrophil levels in circulation compared to healthy individuals or alcoholics who had not recently consumed alcohol.^41,43 Several factors affect granulocyte levels in the systemic circulation, such as the activity of haematopoietic precursor cells, the storage capacity of marrow pools for mature granulocytes, the immobilisation of granulocytes from the bone marrow into the bloodstream, and the removal of granulocytes by macrophages in the liver, bone marrow stroma and the spleen’s marginal zone under normal conditions. Furthermore, during an inflammatory response, granulocytes migrate from the bloodstream to tissue sites, and alcohol may affect each of these processes in various ways.^44,45

In the context of an infectious challenge, especially those caused by acute bacterial pathogens, bone marrow can rapidly mobilise a significant number of granulocytes from its reserve pool into the bloodstream. Simultaneously, the activation of haematopoietic stem and progenitor cells (HSPCs) supports the production of granulocytes, thereby strengthening the host’s immune response against invading microbes. Any disruption in this process can severely impair host immunity. Any interruption in this process can significantly compromise the host’s immune system. Alcohol misuse, especially in the form of acute intoxication or habitual binge drinking, greatly diminishes the granulopoietic response. Research has demonstrated that instances of excessive alcohol intake frequently occur before the development of severe infections in individuals.^7,46 Examination of bone marrow samples from alcoholic patients experiencing neutropenia reveals that almost all neutrophil precursors are stuck in an early stage of development.⁷ Furthermore, the depletion of neutrophil reserves in the bone marrow happens more swiftly in active chronic drinkers compared to healthy individuals.⁴⁷ The stimulation of HSPC proliferation and the transcriptional reprogramming of primitive haematopoietic precursor cells, which is crucial for enhancing their commitment to the granulocytic lineage, is vital for a robust granulopoietic response.^48,49,50 Consequently, chronic alcohol abuse disrupts several critical signalling pathways that control the activation of HSPCs during granulopoiesis.^48,49

In addition to affecting platelet size and causing thrombocytopenia (TP), alcohol generally impairs platelet function. This is particularly important in coagulation disorders. Decreased platelet (PLT) counts could impact their role in coagulation. Individuals with alcohol-related TP often experience longer bleeding times, which usually improve as PLT levels return to normal. The risk of major bleeding rises when other coagulation factors become dysfunctional, often as a result of repeated liver damage and hepatotoxic factors associated with alcohol dependence.⁵⁰

Thrombocytopenia is defined as a decrease in PLTs below 150 000 × 10⁹/L. The reference range is 150 000 – 400 000 × 10⁹/L. A significant reduction in platelet count (less than 50 000 × 10⁹/L) can lead to the development of petechiae.⁵⁰

The connection between TP and long-term alcohol use started gaining attention during the 1960s and 1970s. It has been experimentally demonstrated that TP has a distinct pathogenesis from other alcohol-related haematopoietic diseases (e.g. anaemia caused by vitamin deficiencies).^51,52

Although alcohol use is linked to a considerable disease burden, studies on TP are still scarce.^53,54,55,56 The origins of alcohol-related TP are intricate. Possible mechanisms include myelosuppression and the presence of platelets in the bloodstream, with platelet poisoning being a suspected factor.⁵⁷ The treatment approach for TP depends on its severity. In cases of bleeding, anticoagulants and antiplatelet drugs might be required. However, individuals with mild to moderate TP without bleeding may not need extensive evaluation beyond abstaining from alcohol.^7,58 Therefore, monitoring TP after alcohol cessation is advisable. Additionally, obtaining a history of alcohol use is crucial, as it might be hidden owing to stigma and fear of disclosure. Thrombocytopenia in chronic alcohol abuse can arise from factors other than direct alcohol toxicity, such as liver cirrhosis with portal hypertension, splenomegaly, folic acid deficiency, viral infections and alcohol-induced pancreatitis.⁵⁹