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Spur Cell Anaemia in Cirrhosis: A Narrative Review

  • Akash Roy
    Affiliations
    Institute of Gastrosciences and Liver Transplantation, Apollo Multispeciality Hospitals, Kolkata, West Bengal, India
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  • Gajanan Rodge
    Affiliations
    Institute of Gastrosciences and Liver Transplantation, Apollo Multispeciality Hospitals, Kolkata, West Bengal, India
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  • Mahesh K. Goenka
    Correspondence
    Address for correspondence: Mahesh K. Goenka, Department of Gastroenterology, Institute of Gastrosciences and Liver Transplantation, Apollo Multispeciality Hospitals, Kolkata, 700054, India. Tel.: +91-9830040599.
    Affiliations
    Institute of Gastrosciences and Liver Transplantation, Apollo Multispeciality Hospitals, Kolkata, West Bengal, India
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Published:October 10, 2022DOI:https://doi.org/10.1016/j.jceh.2022.10.005
      The presence of anaemia has been linked to increased complications and a worse prognosis in cirrhosis. Spur cell anaemia (SCA) is a specific form of haemolytic anaemia reported in patients with advanced cirrhosis. The literature on the entity has not been systematically reviewed, despite the classical association and frequent association with worse outcomes. We undertook a narrative review of available literature on SCA which yielded only 4 were original studies, one case series and the rest of the literature as case reports and clinical images. SCA is usually defined by the presence of spur cell rate of ≥5%, although there remains a lack of consensus in the definition. SCA has been classically associated with alcohol-related cirrhosis but can be seen across the spectrum of cirrhosis and acute to chronic liver failure. Patients with SCA tend to have evidence of higher grades of liver dysfunction, abnormal lipid profiles, worse prognostic scores and a high mortality. Experimental therapies including corticosteroids, pentoxifylline, flunarizine and plasmapheresis has been tried with variable effect, but liver transplantation remains the management of choice. We propose a stepwise approach to diagnosis and re-enforce the need for further prospective research, especially in subgroups of advanced cirrhosis like acute to chronic liver failure.

      Keywords

      Abbreviations:

      ACLF (Acute on chronic liver failure), CTP (Child Turcotte Pugh), HCV (Hepatitis C Virus), HDL (High density lipoprotein), HEV (Hepatitis E Virus), INR (International Normalisation Ratio), LDH (Lactate Dehydrogenase), LDL (Low density lipoprotein), MELD (Model for end stage liver disease), NASH (Non-alcoholic steatohepatitis), OLT (Orthotopic liver transplantation), SCA (Spur cell anaemia), SMT (Standard medical Therapy), TC (Total Cholesterol), TG (Triglycerides), VLDL (Vey low density lipoprotein)
      Anaemia is a commonly encountered complication in patients with chronic liver disease and cirrhosis and is seen in 53–66% of the patients.
      • Paternostro R.
      • Kapzan L.
      • Mandorfer M.
      • et al.
      Anemia and iron deficiency in compensated and decompensated cirrhosis: prevalence and impact on clinical outcomes.
      ,
      • Scheiner B.
      • Semmler G.
      • Maurer F.
      • et al.
      Prevalence of and risk factors for anaemia in patients with advanced chronic liver disease.
      There are diverse aetiologies for anaemia in cirrhosis and frequently multiple causes co-exist.
      • Scheiner B.
      • Semmler G.
      • Maurer F.
      • et al.
      Prevalence of and risk factors for anaemia in patients with advanced chronic liver disease.
      The presence of anaemia has been linked to increased complications and a worse prognosis in cirrhosis.
      • Scheiner B.
      • Semmler G.
      • Maurer F.
      • et al.
      Prevalence of and risk factors for anaemia in patients with advanced chronic liver disease.
      ,
      • Bothou C.
      • Rüschenbaum S.
      • Kubesch A.
      • et al.
      Anemia and systemic inflammation rather than arterial circulatory dysfunction predict decompensation of liver cirrhosis.
      Spur cell anaemia (SCA) is a specific form of haemolytic anaemia reported in patients with advanced cirrhosis and has been associated with grave outcomes.
      • Keyserling K.
      • Koprowski S.
      Spur-cell anemia.
      The entity was initially reported in a seminal paper by Smith et al., noting bizarre erythrocytes with “curious projections” on their surfaces in a young male with alcohol-related cirrhosis and haemolytic anaemia.
      • Smith J.A.
      • Lonergan E.T.
      • Sterling K.
      Spur-cell anemia: hemolytic anemia with red cells resembling acanthocytes in alcoholic cirrhosis.
      However, the literature on the entity has not been systematically reviewed, despite the classical association and frequent association with worse outcomes. We undertook a narrative review of available literature on SCA in cirrhosis in this background.

      Methods

      We conducted this narrative review according to guidelines and checklist provided by Green et al.
      • Green B.N.
      • Johnson C.D.
      • Adams A.
      Writing narrative literature reviews for peer-reviewed journals: secrets of the trade.
      (Supplementary Table 1). Literature for this review was identified using specific search terms as Boolean combinations in MEDLINE and EMBASE (Supplementary Table 2). All studies from the inception of the particular database to 26th January 2022 were searched. We reviewed all designs of articles (cohort studies, case–control studies, case series, case reports). Articles published only as conference abstracts were excluded and language was restricted to English.

      Results

      We identified 175 total articles in accordance to the pre-specified search strategy. Out of these, only 4 were original studies
      • Vassiliadis T.
      • Mpoumponaris A.
      • Vakalopoulou S.
      • et al.
      Spur cells and spur cell anemia in hospitalized patients with advanced liver disease: incidence and correlation with disease severity and survival.
      • Alexopoulou A.
      • Vasilieva L.
      • Kanellopoulou T.
      • Pouriki S.
      • Soultati A.
      • Dourakis S.P.
      Presence of spur cells as a highly predictive factor of mortality in patients with cirrhosis.
      • Pascoe A.
      • Kerlin P.
      • Steadman C.
      • et al.
      Spur cell anaemia and hepatic iron stores in patients with alcoholic liver disease undergoing orthotopic liver transplantation.
      • Virk Z.M.
      • Patel A.A.
      • Leaf R.K.
      • Al-Samkari H.
      Predictors of mortality and outcomes of liver transplant in spur cell hemolytic anemia.
      and one case series.
      • kumar Kedarisetty C.
      • Kumar R.
      Spur cells causing severe and transfusion-refractory anemia in patients with acute-on-chronic liver failure.
      The rest of the literature on SCA in cirrhosis was as case reports and clinical images. In the following sections, we comprehensively reviewed the available literature.

      Nomenclature and Definition of Spur Cells and Spur Cell Anaemia

      Spur cells, also known as acanthocytes (Greek acantha: thorn), are characteristic red blood cells that have spicules or spike-like projections on the surface, with the projections being irregular (in width and length) and unevenly distributed.
      • Privitera G.
      • Meli G.
      An unusual cause of anemia in cirrhosis: spur cell anemia, a case report with review of literature.
      These cells need to be differentiated from a similar type of cells known as burr cells (echinocytes) in whom the spike-like projections are regular and evenly distributed.
      • Foglia A.
      The acanthocyte-echinocyte differential.
      These cells have been described in multiple conditions like abetalipoproteinemia, hypothyroidism, neuroaconthocytosis, abnormalities of Kell blood group system (McLeod phenotype), myelodysplasia, anorexia nervosa, patients undergoing splenectomy and have also been reported with certain drugs like statins and misoprostol.
      • Isa H.M.
      • Mohamed A.M.
      Abetalipoproteinemia: three case reports, a novel microsomal triglyceride transfer protein gene mutation and a literature review.
      • De Franceschi L.
      • Bosman G.J.C.G.M.
      • Mohandas N.
      Abnormal red cell features associated with hereditary neurodegenerative disorders: the neuroacanthocytosis syndromes.
      • Filippini A.
      • Villa G.
      • Corrocher R.
      • De Franceschi L.
      Acute hemolytic anemia with acanthocytosis associated with high-dose misoprostol for medical abortion.
      Although the terms spur cells and acanthocytes are usually used interchangeably, some authors prefer to reserve the term acanthocytes specifically for abetalipoproteinemia.
      • Duhamel G.
      • Forgez P.
      • Nalpas B.
      • Berthelot P.
      • Chapman M.J.
      Spur cells in patients with alcoholic liver cirrhosis are associated with reduced plasma levels of apoA-II, HDL3, and LDL.
      Additionally, erythrocytes simulating spur cells with a spiculated appearance can also be seen due to an ethylene diamine tetra-acetic acid artefact after a delay of more than 6 h between storage and smear preparation.
      • Tyrrell L.
      • Rose G.
      • Shukri A.
      • Kahwash S.B.
      Morphologic changes in red blood cells: an illustrated review of clinically important light microscopic findings.
      In the context of liver disease, spur cells have been classically described in haemolytic anaemias seen in cirrhosis, especially with alcohol-related cirrhosis.
      • Keyserling K.
      • Koprowski S.
      Spur-cell anemia.
      Traditionally, SCA has been defined as those having a spur cell rate of ≥5% in the presence of associated features of haemolysis.
      • Vassiliadis T.
      • Mpoumponaris A.
      • Vakalopoulou S.
      • et al.
      Spur cells and spur cell anemia in hospitalized patients with advanced liver disease: incidence and correlation with disease severity and survival.
      ,
      • Alexopoulou A.
      • Vasilieva L.
      • Kanellopoulou T.
      • Pouriki S.
      • Soultati A.
      • Dourakis S.P.
      Presence of spur cells as a highly predictive factor of mortality in patients with cirrhosis.
      However, there remains a lack of consensus on the exact definition of SCA.
      • Virk Z.M.
      • Patel A.A.
      • Leaf R.K.
      • Al-Samkari H.
      Predictors of mortality and outcomes of liver transplant in spur cell hemolytic anemia.

      Proposed Mechanisms for SCA

      Since the earliest descriptions of SCA in cirrhosis in the 1960s, observations and hypotheses were made that a protein or protein-bound substance was responsible for inducing the morphological changes in erythrocytes in SCA. These observations primarily stemmed from the fact that when normal erythrocytes were mixed and incubated with serum of patients suspected of SCA, similar changes were induced in the normal erythrocytes.
      • Smith J.A.
      • Lonergan E.T.
      • Sterling K.
      Spur-cell anemia: hemolytic anemia with red cells resembling acanthocytes in alcoholic cirrhosis.
      In a seminal report, Martinez-Maldonado demonstrated the role of low density lipoproteins in the alteration of erythrocytes' shape (spur-formation), thereby making them susceptible to accelerated haemolysis.
      • Martinez-Maldonado M.
      Role of lipoproteins in the formation of spur cell anaemia.
      In further works directed at identifying the mechanism, Cooper et al. demonstrated the alteration in cholesterol to phospholipid ratio in red cell membranes with free cholesterol being the predominant component.
      • Cooper R.A.
      • Diloy Puray M.
      • Lando P.
      • Greenverg M.S.
      An analysis of lipoproteins, bile acids, and red cell membranes associated with target cells and spur cells in patients with liver disease.
      While looking at specific lipoprotein abnormalities in alcohol-related cirrhosis, Duhamel et al. demonstrated significantly lower Apo-AII, high density lipoprotein 3 and low density lipoprotein levels and proposed the central role of Apo-AII deficiency in altering membrane morphology and susceptibility to haemolysis.
      • Duhamel G.
      • Forgez P.
      • Nalpas B.
      • Berthelot P.
      • Chapman M.J.
      Spur cells in patients with alcoholic liver cirrhosis are associated with reduced plasma levels of apoA-II, HDL3, and LDL.
      To further deliberate on the mechanistic aspects, the authors suggested decreased synthetic capacities of nascent lipoproteins and lipolytic enzymes (Lecithin Cholesterol Acyl-Transferase (LCAT), lipase) in cirrhosis compounded by deficient secretory capacities due to dietary deficiencies in alcoholics.
      • Duhamel G.
      • Forgez P.
      • Nalpas B.
      • Berthelot P.
      • Chapman M.J.
      Spur cells in patients with alcoholic liver cirrhosis are associated with reduced plasma levels of apoA-II, HDL3, and LDL.
      Overall, the abnormal red cell morphology with alterations in the red cell membrane eventually lead to markedly reduced survival and combined with hypersplenism in advanced cirrhosis proposed forms the mechanistic basis of excessive haemolysis observed in SCA.

      Prevalence of SCA in Cirrhosis

      The prevalence of SCA in patients with cirrhosis has been variably reported. Alexopoulou et al. in a study from Greece including 116 patients with cirrhosis, 36 patients (31.01%) had a spur cell rate of ≥5%.
      • Alexopoulou A.
      • Vasilieva L.
      • Kanellopoulou T.
      • Pouriki S.
      • Soultati A.
      • Dourakis S.P.
      Presence of spur cells as a highly predictive factor of mortality in patients with cirrhosis.
      Although SCA is commonly believed to be associated with alcohol-related cirrhosis, in this study, there was no difference based on alcohol versus other aetiologies (44% vs. 55%, P = 0.2).
      • Alexopoulou A.
      • Vasilieva L.
      • Kanellopoulou T.
      • Pouriki S.
      • Soultati A.
      • Dourakis S.P.
      Presence of spur cells as a highly predictive factor of mortality in patients with cirrhosis.
      Vassiliadis et al. in a study including 54 patients with advanced liver disease (Child Turcotte Pugh [CTP] ≥ 7), showed that spur cells were present at a rate of 1–4% in 17 (31.4%) and >5% in 9 (16.6%) patients.
      • Vassiliadis T.
      • Mpoumponaris A.
      • Vakalopoulou S.
      • et al.
      Spur cells and spur cell anemia in hospitalized patients with advanced liver disease: incidence and correlation with disease severity and survival.
      The most common aetiology of cirrhosis in patients with a spur cell rate of ≥5% was alcohol combined with viruses.
      • Vassiliadis T.
      • Mpoumponaris A.
      • Vakalopoulou S.
      • et al.
      Spur cells and spur cell anemia in hospitalized patients with advanced liver disease: incidence and correlation with disease severity and survival.
      Pascoe et al. reported spur cell anaemia in 7 (19.4%) of 36 patients with alcohol-related cirrhosis. However, the study did not explicitly clarify the definition of SCA and included any patient with haemoglobin <10 g/dl and significant acanthocytes on peripheral smear examination.
      • Pascoe A.
      • Kerlin P.
      • Steadman C.
      • et al.
      Spur cell anaemia and hepatic iron stores in patients with alcoholic liver disease undergoing orthotopic liver transplantation.

      Biochemical Characteristics and Prognostic Scores in Patients with SCA

      Overall, SCA has been reported in patients with advanced liver disease in patients having decompensated cirrhosis or acute on chronic liver failure.
      • Alexopoulou A.
      • Vasilieva L.
      • Kanellopoulou T.
      • Pouriki S.
      • Soultati A.
      • Dourakis S.P.
      Presence of spur cells as a highly predictive factor of mortality in patients with cirrhosis.
      ,
      • kumar Kedarisetty C.
      • Kumar R.
      Spur cells causing severe and transfusion-refractory anemia in patients with acute-on-chronic liver failure.
      Patients with SCA tend to have evidence of higher grades of liver dysfunction, abnormal lipid profiles and worse prognostic scores (model for end stage liver disease [MELD], CTP). Key biochemical findings from major studies reporting SCA in cirrhosis is summarised in Table 1.
      Table 1Summary of Studies Describing Spur Cell Anaemia.
      Authors/Year/CountryDesign/DirectionNumber of patientsStudy population and selection criteriaDemographic characteristicsHaematological parametersLiver function parametersLipid profilePrognostic scoresKey findingsMortality in SCA
      Alexopoulou et al./2014/GreeceCohort/ProspectiveTotal: 116

      With SCA: 36

      Without SCA: 80
      Decompensated cirrhosis

      Exclusion: Renal failure, sepsis, acute alcoholic hepatitis, bleeding, other haemolytic anaemia
      Age: 55 (49–65.5)

      Males: 89%
      Haemoglobin (g/dl) 8.9 (8.5–10.3)

      Reticulocyte (%): 4 (2.5–6)
      Bilirubin (mg/dl): 9.5 (5.2–14.2)

      Albumin: 3.2 (2.8–3.5)

      INR: 1.8 (1.6–2.3)
      TC (mg/dl): 99 (82–126)

      TG (mg/dl): 81 (50–110)

      LDL (mg/dl): 75 (64–92)

      HDL (mg/dl): 11 (7–23)

      VLDL (mg/dl): 16 (10–23)
      MELD: 21.5 (15–25.5)Advanced disease (Higher MELD) and worse survival.

      SCA is an independent predictor for mortality (3.17 [95% CI 1.55–6.48]).
      1 month survival: 77%

      3-month survival: 33%
      Vassiliadis et al./2010/GreeceCohort/Prospective

      Median follow-up: 150 days
      Total: 54

      No spur cells: 28

      1–4% spur cells: 17

      ≥5% spur cells: 9
      Advanced cirrhosis (CTP ≥ 7)

      Exclusion: HCC, Chronic renal failure, haemoglobinopathies, Coombs positive anaemia, sepsis, active bleeding, cholestatic liver disease, anticoagulant therapy
      Age: 50 (44–76)

      Males: Males 88.9%
      Haemoglobin (g/dl) 8.1 (7.1–10.5)

      Reticulocyte (%): 4.5 (2.3–4.8)
      Bilirubin (mg/dl): 14.7 (2.5–30.1)

      Indirect: 3.8 (0.5–20.7)

      INR: 2.3 (2.0–4.7)
      TC (mg/dl): 84 (49–102)

      Triglycerides (mg/dl): 88 (58–102)

      LDL (mg/dl): 39 (14–60)

      HDL (mg/dl): 25 (18–30)

      VLDL (mg/dl): NA
      MELD: 30 (20–40)

      CTP score: 12 (10–13)
      Patients with SCA: Higher MELD

      Low TC, TG and LDL
      3-month survival: No spur cell: 92.3%

      1–4% Spur cells: 81.3%

      ≥5% spur cells: 22%

      1-year survival: Similar
      Pascoe et al./1999/AustraliaCross sectionalTotal: 36Patents with Alcoholic liver disease undergoing OLT

      Exclusion: Acute alcoholic hepatitis
      Age 39 (32–66)

      Males: 82%
      NANANANA7/36 (19.4%) had SCA
      Virk et al./2021/USAMulticentric cohort study69 patients with SCADecompensated cirrhosis

      Exclusion: Presence of alternative causes of haemolysis,
      Age: 53 (42.2–59.4)

      Males: 53.6%
      Haemoglobin (g/dl) 7 (6.5–7.7)

      Reticulocyte (%): 6 (4.1–7.9)
      Bilirubin (mg/dl): 13 (8.6–19.2)

      Indirect: 8 (5.1–11)

      INR: 2 (1.8–2.8)

      Albumin: 3 3 (2.5–3.3)
      NAMELD: 30 (25.8–34)

      CTP score: 11 (10–12)
      56.5% were transfusion dependent

      All patients (n = 11) who underwent LT has reversal of SCA with post LT 3 month survival of 81.8%
      57 patients who did not undergo LT had a 3 month mortality of 94.8%
      Kedarisetty et al./2020/IndiaCase series5 patients with SCAIncluded patients with Acute on chronic liver failureAge 38.6 (31–49)

      All males
      All patients had alcohol as the cause of chronicity while 2 patients had HEV as an acute insult and 3 were due alcoholic hepatitis.Outcomes were known in 4 patients of whom 3 (75%) died
      ACLF: Acute on chronic liver failure; CTP: Child Turcotte Pugh; MELD: Model for end stage liver disease; NASH: Non alcoholic steatohepatitis; HCV: Hepatitis C Virus; TC: Total Cholesterol; TG: Triglycerides; INR: International Normalisation Ratio; LDL: Low density lipoprotein; LDH: Lactate Dehydrogenase; HDL: High density lipoprotein; SMT: Standard medical Therapy; VLDL: Very low density lipoprotein; OLT: Orthotopic liver transplantation; HEV: Hepatitis E Virus; SCA: Spur cell anaemia; NA: Not available; LT: Liver Transplantation.

      Outcomes of Patients with SCA

      The presence of SCA in cirrhosis is associated with both advanced liver disease as well as an abysmal prognosis. The study by Alexopoulou et al. showed that in patients with spur cell rate ≥5%, the survival at 1-month and 3-month was 77% and 33%, respectively, with an overall median survival of 1.9 months.
      • Alexopoulou A.
      • Vasilieva L.
      • Kanellopoulou T.
      • Pouriki S.
      • Soultati A.
      • Dourakis S.P.
      Presence of spur cells as a highly predictive factor of mortality in patients with cirrhosis.
      SCA was shown to be an independent predictor of mortality in this group. Since at baseline, patients with SCA tend to have intrinsically more advanced liver disease, the authors adjusted the mortality for age, gender, MELD, sodium and liver function parameters and demonstrated those with spur cell rate of ≥5% had a three times higher risk for mortality than those with spur cells 0–4% (hazard ratio = 3.17 [95% confidence interval 1.55–6.48]).
      • Alexopoulou A.
      • Vasilieva L.
      • Kanellopoulou T.
      • Pouriki S.
      • Soultati A.
      • Dourakis S.P.
      Presence of spur cells as a highly predictive factor of mortality in patients with cirrhosis.
      Vassiliadis et al. reported a 3-month survival in patients without spur cells, with 1–4% spur cells and ≥5% spur cells as 92.3%, 81.3% and 22.2%, respectively, reinforcing the high mortality in patients with spur cells rate of ≥5%.
      • Vassiliadis T.
      • Mpoumponaris A.
      • Vakalopoulou S.
      • et al.
      Spur cells and spur cell anemia in hospitalized patients with advanced liver disease: incidence and correlation with disease severity and survival.
      In the most recently reported cohort of 69 patients with SCA, 58 patients who did not undergo a transplant had an adverse outcome, while 11 patients who underwent transplantation had an immediate and complete resolution of SCA.
      • Virk Z.M.
      • Patel A.A.
      • Leaf R.K.
      • Al-Samkari H.
      Predictors of mortality and outcomes of liver transplant in spur cell hemolytic anemia.
      The authors noted that both the corresponding MELD-Na and CTP scores consistently underestimated 90-day mortality in patients with SCA. Patients with SCA and a MELD-Na score between 20 and 29 had a 2.4 times higher likelihood of mortality than that expected based on the MELD-Na score alone.
      • Virk Z.M.
      • Patel A.A.
      • Leaf R.K.
      • Al-Samkari H.
      Predictors of mortality and outcomes of liver transplant in spur cell hemolytic anemia.
      Most of the studies on SCA have not specifically focused on patients with acute on chronic liver failure. In the only reported case series of five patients with acute to chronic liver failure, 75% of the patients with known outcomes died.
      • kumar Kedarisetty C.
      • Kumar R.
      Spur cells causing severe and transfusion-refractory anemia in patients with acute-on-chronic liver failure.

      Review of Literature from Case Reports

      As highlighted before, most of the literature on SCA is confined to case reports and clinical images. A descriptive analysis of case reports published on SCA has been provided in Table 2.
      • Privitera G.
      • Meli G.
      An unusual cause of anemia in cirrhosis: spur cell anemia, a case report with review of literature.
      ,

      Martín M, De D, Heras L. Spur-cell anaemia in a patient with cirrhosis. Images in Hepatology. n.d. https://doi.org/10.1016/j.jhep.2004.01.025.

      • Haruta I.
      • Hashimoto E.
      • Kabutake A.
      • Taniai M.
      • Tokushige K.
      • Shiratori K.
      Spur cell anemia associated with a cirrhotic non-alcoholic steatohepatitis patient.
      • Goel A.
      • Kumar J.D.I.
      • Nair S.C.
      • Joseph A.J.
      • Viswabandya A.
      • Eapen C.E.
      Spur cell anemia associated with alcoholic cirrhosis.
      • Karam D.
      • Swiatkowski S.
      • Purohit P.
      • Agrawal B.
      Case Report: High-dose steroids as a therapeutic option in the management of spur cell haemolytic anaemia.
      • Miki K.
      • Maruki T.
      • Imashuku S.
      Plasmapheresis for spur cell anemia in a patient with alcoholic liver cirrhosis.
      • Miwa T.
      • Hatano Y.
      • Kochi T.
      • et al.
      Spur cell anemia related to alcoholic liver cirrhosis managed without liver transplantation: a case report and literature review.
      • Raffa G.A.
      • Byrnes D.M.
      • Byrnes J.J.
      The diagnosis is in the smear: a case and review of spur cell anemia in cirrhosis.
      • Shah R.
      • Patel A.
      • John S.
      Spur cell anemia in end-stage liver disease: a zebra.
      • Zimmer V.
      • Bittenbring J.
      • Fries P.
      • Lammert F.
      Severe mixed-type iron overload in alcoholic cirrhosis related to advanced spur cell anemia.
      • Sundaram V.
      • Al-Osaimi A.M.S.
      • Lewis J.J.
      • Lisman T.
      • Caldwell S.H.
      Severe prolongation of the INR in spur cell anemia of cirrhosis: true-true and related?.
      • Singh Sangha M.
      • Aggarwal A.
      • Sandhu J.
      Rare cause of non-immune hemolytic anemia in end-stage liver disease.
      • Aihara K.I.
      • Azuma H.
      • Ikeda Y.
      • et al.
      Successful combination therapy--flunarizine, pentoxifylline, and cholestyramine--for spur cell anemia.
      The key features that emanate out of the case reports include a preponderance of SCA in patients with advanced cirrhosis, with a majority having alcohol as an aetiology although other aetiologies also being reported. Outcomes without liver transplant tend to be poor, and few cases report favourable outcomes using corticosteroids, plasmapheresis, intravenous immunoglobulin, flunarizine and pentoxifylline.
      • Karam D.
      • Swiatkowski S.
      • Purohit P.
      • Agrawal B.
      Case Report: High-dose steroids as a therapeutic option in the management of spur cell haemolytic anaemia.
      ,
      • Miki K.
      • Maruki T.
      • Imashuku S.
      Plasmapheresis for spur cell anemia in a patient with alcoholic liver cirrhosis.
      ,
      • Aihara K.I.
      • Azuma H.
      • Ikeda Y.
      • et al.
      Successful combination therapy--flunarizine, pentoxifylline, and cholestyramine--for spur cell anemia.
      While the mechanisms by which each of these agents acts in SCA is uncertain, few hypotheses have been proposed. Corticosteroids have been postulated to have interactions with phospholipids in red blood cell membrane especially leading to dimyristoyl phosphatidylcholine hydration which has a protective role against haemolysis.
      • Karam D.
      • Swiatkowski S.
      • Purohit P.
      • Agrawal B.
      Case Report: High-dose steroids as a therapeutic option in the management of spur cell haemolytic anaemia.
      ,
      • Manrique-Moreno M.
      • Londoño-Londoño J.
      • Jemioła-Rzemińska M.
      • et al.
      Structural effects of the Solanum steroids solasodine, diosgenin and solanine on human erythrocytes and molecular models of eukaryotic membranes.
      For pentoxifylline, the possible mechanisms that have been proposed include an increase in cellular ATP and calcium chelation leading to overall membrane stability.
      • Singh Sangha M.
      • Aggarwal A.
      • Sandhu J.
      Rare cause of non-immune hemolytic anemia in end-stage liver disease.
      ,
      • Fossaluzza V.
      • Rossi P.
      Flunarizine treatment for spur cell anaemia.
      Flunarizine, a calcium channel blocker, has been proposed to improve the deformability of erythrocytes by lowering the intracellular Ca2+ concentration.
      • Aihara K.I.
      • Azuma H.
      • Ikeda Y.
      • et al.
      Successful combination therapy--flunarizine, pentoxifylline, and cholestyramine--for spur cell anemia.
      The first reports of two cases describing the use of flunarizine showed prompt improvement with the drug administration. The authors hypothesised that the cholesterol accumulation in the RBC membrane is not the cause of haemolysis per se but rather the alteration of the transmembrane Ca2+ gradient that precipitates the event.
      • Fossaluzza V.
      • Rossi P.
      Flunarizine treatment for spur cell anaemia.
      Although the use of plasmapheresis for SCA was initially reported from Japan with unfavourable outcomes, a recent report demonstrated a successful outcome with plasmapheresis and standard therapy and demonstration of lipid profile changes with plasmapheresis.
      • Miki K.
      • Maruki T.
      • Imashuku S.
      Plasmapheresis for spur cell anemia in a patient with alcoholic liver cirrhosis.
      Table 2Summary of Case Reports on SCA.
      Author, YearAge, SexAetiology of cirrhosisHaematological parametersLiver function testsLipid profilePrognostic scoresTherapyOutcome
      Martin et al. 2004

      Martín M, De D, Heras L. Spur-cell anaemia in a patient with cirrhosis. Images in Hepatology. n.d. https://doi.org/10.1016/j.jhep.2004.01.025.

      48, MaleCryptogenicHaemoglobin (g/dl) 7.7

      Reticulocyte (%): 4 (2.5–6)

      LDH (mg/dl) 1291

      Haptoglobin (0.072 g/l) 0.072

      Coombs test: Negative
      Bilirubin (mg/dl): 23 (Indirect: 15 mg/dl)

      Albumin: 2.2

      INR: NA

      PTI: 25%
      Standard medical therapyDeath
      Haruta et al. 2007
      • Haruta I.
      • Hashimoto E.
      • Kabutake A.
      • Taniai M.
      • Tokushige K.
      • Shiratori K.
      Spur cell anemia associated with a cirrhotic non-alcoholic steatohepatitis patient.
      61, MaleNASHHaemoglobin (g/dl) 5.2

      Reticulocyte (%): 9.1

      LDH (mg/dl) 331

      Haptoglobin (mg/dl) < 12

      Iron (mg/dl) 155

      Ferritin (ng/ml) 590

      Coombs Test: Negative
      Bilirubin (mg/dl): 13.6

      (Indirect: 9.6 mg/dl)

      Albumin: 2.3

      INR: NA

      PTI: 25.4%
      TC (mg/dl): 135

      Triglycerides (mg/dl): 48

      LDL (mg/dl): NA

      HDL): 29

      VLDL (mg/dl): NA
      SMTDeath
      Goel et al. 2008
      • Goel A.
      • Kumar J.D.I.
      • Nair S.C.
      • Joseph A.J.
      • Viswabandya A.
      • Eapen C.E.
      Spur cell anemia associated with alcoholic cirrhosis.
      47, maleAlcoholHaemoglobin (g/dl) 7.3

      Reticulocyte (%): Na

      LDH (u/L): 588

      Coombs Test: Negative
      Bilirubin (mg/dl): 11

      Albumin: 3.1

      INR: NA

      PTI: 22.8%
      SMTTransplant waitlist
      Karam et al. 2018
      • Karam D.
      • Swiatkowski S.
      • Purohit P.
      • Agrawal B.
      Case Report: High-dose steroids as a therapeutic option in the management of spur cell haemolytic anaemia.
      66, maleNASHHaemoglobin (g/dl) 6.6

      Reticulocyte (%): 5.2

      LDH (u/L): 1104

      Haptoglobulin (mg/dl) < 7.75

      Coombs Test: Negative
      Bilirubin (mg/dl): 11.2

      (Indirect: 5.7 mg/dl)

      Albumin: NA

      INR: 1.5
      CTP: 10SMT plus steroids (methylprednisolone × 7 days)Improved
      Miki et al.
      • Miki K.
      • Maruki T.
      • Imashuku S.
      Plasmapheresis for spur cell anemia in a patient with alcoholic liver cirrhosis.
      52, maleAlcoholHaemoglobin (g/dl) 7.9

      Reticulocyte (%): 22.4

      LDH (u/L): 438

      Haptoglobulin (mg/dl) 3

      Coombs Test: Negative

      Spur cells: 25%
      Bilirubin (mg/dl): 15.6

      (Indirect: 7.6 mg/dl)

      Albumin: 2.3

      INR: 1.65
      TC (mg/dl): 121

      Triglycerides (mg/dl): 53

      LDL (mg/dl): 29

      HDL): 15

      VLDL (mg/dl): NA
      CTP: 12SMT plus plasmapharesisImproved
      Miwa et al. 2018
      • Miwa T.
      • Hatano Y.
      • Kochi T.
      • et al.
      Spur cell anemia related to alcoholic liver cirrhosis managed without liver transplantation: a case report and literature review.
      26AlcoholHaemoglobin (g/dl) 2.1

      Reticulocyte (%): 5

      LDH (u/L): 449

      Haptoglobulin (mg/dl) < 10
      Bilirubin (mg/dl): 12.7

      (Indirect: 7.36 mg/dl)

      Albumin: 3

      INR: 2.1

      PTI

      : 30%
      TC (mg/dl): 215

      Triglycerides (mg/dl): 83

      LDL (mg/dl): 56

      HDL): 39

      VLDL (mg/dl): NA
      CTP 11

      MELD 24
      SMT (Blood transfusion)Improved
      Privitera et al. 2016
      • Privitera G.
      • Meli G.
      An unusual cause of anemia in cirrhosis: spur cell anemia, a case report with review of literature.
      44, maleAlcoholHaemoglobin (g/dl) 7.4

      Reticulocyte (%): NA

      LDH (u/L): 581

      Haptoglobulin (mg/dl) 2

      Coombs Test: Negative
      Bilirubin (mg/dl): 18.2

      (Indirect: 11.26 mg/dl)

      Albumin: 2.8

      INR: 2.5
      TC (mg/dl): 124

      Triglycerides (mg/dl): 45

      LDL (mg/dl): 94

      HDL): 21

      HDL3 0.23
      CTP 11SMTTransplant waitlist
      Raffa et al. 2021
      • Raffa G.A.
      • Byrnes D.M.
      • Byrnes J.J.
      The diagnosis is in the smear: a case and review of spur cell anemia in cirrhosis.
      57, maleAlcoholHaemoglobin (g/dl) 7.4

      Reticulocyte (%): 16%

      LDH (u/L): 263

      Haptoglobulin (mg/dl) < 10

      Coombs Test: Negative
      Bilirubin (mg/dl): 15.4

      (Indirect: 9.26 mg/dl)

      Albumin: 2.3

      INR: 2.7
      TC (mg/dl): 132

      Triglycerides (mg/dl): 74

      LDL (mg/dl): 59

      HDL): 59
      MELD 30

      CTP C
      SMT plus corticosteroids plus IVIgDeath
      Shah et al. 2014
      • Shah R.
      • Patel A.
      • John S.
      Spur cell anemia in end-stage liver disease: a zebra.
      32, maleAlcohol + HCVHaemoglobin (g/dl) 6.2

      Reticulocyte (%): NA

      LDH (u/L): 390

      (mg/dl) Undetectable

      Coombs Test: NA
      Bilirubin (mg/dl): 27

      (Indirect: 14 mg/dl)

      Albumin: 2.3

      INR: 3.3
      TC (mg/dl): 97

      Triglycerides (mg/dl): 61

      LDL (mg/dl): 34

      HDL): 51

      VLDL (mg/dl): 12
      SMTTransplant waitlist
      Zimmer et al. 2014
      • Zimmer V.
      • Bittenbring J.
      • Fries P.
      • Lammert F.
      Severe mixed-type iron overload in alcoholic cirrhosis related to advanced spur cell anemia.
      60, maleAlcoholHaemoglobin (g/dl) 6.1

      Reticulocyte (%): 5.5%

      LDH (u/L): 836

      Haptoglobulin (mg/dl) Undetectable

      Coombs Test: Negative
      Bilirubin (mg/dl): 27 (Indirect: 17 mg/dl)

      Albumin: 2.3

      INR: 3.3
      CTP CSMTDeath
      Sangha et al. 2020
      • Singh Sangha M.
      • Aggarwal A.
      • Sandhu J.
      Rare cause of non-immune hemolytic anemia in end-stage liver disease.
      45, femaleAlcoholHaemoglobin (g/dl) 4.3

      Reticulocyte (%): 18.3%

      LDH (u/L): 851

      Haptoglobulin (mg/dl) Undetectable

      Coombs Test: Negative
      Bilirubin (mg/dl): 19.6

      (Indirect: 9.2 mg/dl)

      INR: 2.5
      CTP C

      MELD 30
      SMT plus pentoxifyllineDeath within 3 months
      Sundaram et al. 2006
      • Sundaram V.
      • Al-Osaimi A.M.S.
      • Lewis J.J.
      • Lisman T.
      • Caldwell S.H.
      Severe prolongation of the INR in spur cell anemia of cirrhosis: true-true and related?.
      43, femaleAlcoholHaemoglobin (g/dl) 11.2

      Reticulocyte: 2 × 105/L

      LDH (u/L): NA

      Haptoglobulin (mg/dl) Undetectable

      Coombs Test: NA
      Bilirubin (mg/dl): 30

      (Indirect: 15.7 mg/dl)

      INR: 4.1
      CTP C

      MELD 40
      SMTDeath within 2 months
      Aihara et al. 2001
      • Aihara K.I.
      • Azuma H.
      • Ikeda Y.
      • et al.
      Successful combination therapy--flunarizine, pentoxifylline, and cholestyramine--for spur cell anemia.
      30, maleAlcoholHaemoglobin (g/dl) 7.7

      Reticulocyte: 152 × 105/L

      LDH (u/L): 342

      Haptoglobulin (mg/dl) 60

      Coombs Test: Negative
      Bilirubin (mg/dl): 9.1

      Albumin: NA

      INR: NA
      TC (mg/dl): 386

      Phospholipids 322
      Flunarizine, pentoxifylline and cholestyramineImproved
      ACLF: Acute on chronic liver failure; CTP: Child Turcotte Pugh; MELD: Model for end stage liver disease; NASH: Non alcoholic steatohepatitis; HCV: Hepatitis C Virus; TC: Total Cholesterol; TG: Triglycerides; INR: International Normalisation Ratio; LDL: Low density lipoprotein; LDH: Lactate Dehydrogenase; HDL: High density lipoprotein; SMT: Standard medical Therapy; VLDL: Very low density lipoprotein; OLT: Orthotopic liver transplantation; HEV: Hepatitis E Virus; SCA: Spur cell anaemia; PTI: Prothrombin index; NA: Not available.

      SCA and Liver Transplantation

      While the overall outcomes with SCA have been shown to be poor, liver transplantation has been advocated as the only definitive management. Multiple case reports and a recent multicentric study show favourable outcomes with LT in SCA.
      • Virk Z.M.
      • Patel A.A.
      • Leaf R.K.
      • Al-Samkari H.
      Predictors of mortality and outcomes of liver transplant in spur cell hemolytic anemia.
      ,
      • Kerlin P.
      • Thomson A.
      • Clouston A.
      • Cobcroft R.
      Spur cell anaemia resolves after orthotopic liver transplantation (OLT).
      ,
      • Alkhouri N.
      • Alamiry M.R.
      • Hupertz V.
      • et al.
      Spur cell anemia as a cause of unconjugated hyperbilirubinemia after liver transplantation and its resolution after retransplantation.
      According to the study by Virk et al., all eleven patients who underwent LT had an immediate and complete resolution of SCA, and with around 59.0 patient-years of post-transplant follow-up, no transplanted patient developed features of haemolysis.
      • Virk Z.M.
      • Patel A.A.
      • Leaf R.K.
      • Al-Samkari H.
      Predictors of mortality and outcomes of liver transplant in spur cell hemolytic anemia.
      Therefore, given the grave outcomes with SCA, liver transplant seems to be the definitive therapy for patients with SCA, while transplant-ineligible patients should be offered some form of an investigational therapy.

      Towards a Systematic Approach to SCA

      SCA is an important entity to consider in patients with cirrhosis presenting with anaemia. Although classically associated with alcohol-related cirrhosis, the entity has been described across the spectrum of cirrhosis and acute on chronic liver failure. While anaemia is multifactorial, the approach to it involves a stepwise approach. The approach centres around ruling out common causes like gastrointestinal bleed, nutritional deficiencies, haemoglobinopathies, bone marrow dysfunction and the entire spectrum of haemolysis including entities like auto-immune haemolytic anaemia which have an immune nature of haemolysis determined by direct anti-globulin test.
      • Gonzalez-Casas R.
      • Jones E.A.
      • Moreno-Otero R.
      Spectrum of anemia associated with chronic liver disease.
      ,
      • Acharya G.K.
      • Liao H.I.
      • Frunza-Stefan S.
      • Patel R.
      • Khaing M.
      Autoimmune hepatitis: diagnostic dilemma when it is disguised as iron overload syndrome.
      Additionally, alcohol-related cirrhosis is frequently associated with secondary iron overload by alterations in the homeostasis between hepcidin and transferrin receptor.
      • Premkumar M.
      • Aggarwal A.
      • Mehtani R.
      • et al.
      Role of hepcidin, altered iron metabolism and systemic inflammation in the pathogenesis of iron deficiency anemia, anemia of chronic disease, and iron refractory anemia in cirrhosis and ACLF.
      In similar lines, although there is no consensus guidelines on the diagnosis of SCA, the diagnosis entails a systematic approach of establishing the presence of haemolysis, ruling out other causes and documentation of spur cells >5% in peripheral smear by an pathologist or haematologist.
      • Virk Z.M.
      • Patel A.A.
      • Leaf R.K.
      • Al-Samkari H.
      Predictors of mortality and outcomes of liver transplant in spur cell hemolytic anemia.
      A rare but important entity that is often confused with SCA is Zieve syndrome. This condition is primarily seen in patients with alcoholic hepatitis and alcohol-related cirrhosis and is thought to occur as a result of alcohol-related toxicity to the red cell membrane.
      • Gremida A.
      • Paleti S.
      • Perez E.T.
      • McCarthy D.
      Hemolysis in alcoholic liver disease: Zieve's syndrome.
      It is marked by jaundice, haemolysis and transient hyperlipidemia but characteristically does not show the presence of any spur cells on the peripheral smear examination. Additionally, in contrast to the grave prognosis of SCA, Zieve syndrome has a better prognosis with resolution after alcohol cessation.
      • Vassiliadis T.
      • Mpoumponaris A.
      • Vakalopoulou S.
      • et al.
      Spur cells and spur cell anemia in hospitalized patients with advanced liver disease: incidence and correlation with disease severity and survival.
      ,
      • Raffa G.A.
      • Byrnes D.M.
      • Byrnes J.J.
      The diagnosis is in the smear: a case and review of spur cell anemia in cirrhosis.
      Interestingly, peripheral smear features simulating auto-immune haemolytic anaemia although with direct antiglobin test negativity has been reported in Zieve syndrome.
      • Cruz C.
      • Bassett J.
      • Torres D.
      Zieve's syndrome: autoimmune hemolytic anemia associated with alcoholic liver disease and hyperlipidemia: 643.
      SCA is a form of haemolytic anaemia seen in patients with cirrhosis characterised by a significant proportion of spur cells. The condition has been associated with a grave prognosis and is seen across the spectrum of advanced decompensated cirrhosis. Experimental therapies have been tried with variable results, but liver transplantation remains the definitive solution in the face of otherwise dismal outcomes. Further research on subgroups of advanced cirrhosis like acute to chronic liver failure is mandated. There remains a dearth of literature that needs to be addressed in the future with well-designed prospective studies.

      Credit authorship contribution statement

      Akash Roy: Conceptualisation, Writing - Original Draft, Writing - Review and Editing.
      Gajanan Rodge: Conceptualisation, Writing-review and editing, Visualisation.
      Mahesh K Goenka: Writing - Review and Editing.

      Conflicts of interest

      The authors have none to declare.

      Acknowledgements

      None.

      Funding

      No financial disclosures.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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