Page 2515 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 153

HEMATOLOGIC MANIFESTATIONS OF LIVER DISEASE

Christopher Hillis and Wendy Lim

The liver plays key roles in the synthesis and clearance of proteins mass but a subnormal hematocrit from hemodilution. Hypersplenism
involved in hematopoiesis and hemostasis. The liver produces hema- results in sequestration of erythrocytes. Erythropoiesis is reduced by
topoietic growth factors such as thrombopoietin, contributes to heme nutritional deficiencies in folate or vitamin B 12 resulting from poor
biosynthesis and is a site of extramedullary hematopoiesis. Cytopenias intake or malabsorption, iron deficiency, bone marrow suppression
are detected in approximately 75% of patients with liver disease. The from alcohol or viral hepatitis, hepatitis-associated aplastic anemia,
liver plays a major role in hemostasis through synthesis of coagulation treatment-related toxicities for viral hepatitis (e.g., interferon, telapre-
factors, coagulation inhibitors, and fibrinolytic proteins. The liver is vir, boceprevir), and anemia of chronic disease. Patients with chronic
also involved in the clearance of plasma proteins, including activated liver disease or cirrhosis can also experience nonimmune hemolysis
coagulation factors, proteolytic enzyme–inhibitor complexes, fibrin, because of acquired alterations in the RBC membrane (e.g., spur cell
and fibrinogen degradation products. Lipid metabolism involves the anemia), Zieve syndrome (hemolytic anemia, hypertriglyceridemia,
liver, which in turn can affect the structure of the red blood cell and jaundice), or treatment-related toxicities (e.g., ribavirin).
(RBC) membrane. As a consequence, chronic liver disease is fre- The therapeutic approach to anemia in liver disease includes
quently associated with multiple hematologic abnormalities. transfusional support for symptomatic disease, identification and
Liver cirrhosis is often associated with the development of portal treatment of GI bleeding, supplementation for documented iron,
hypertension, which leads to the formation of portal gastropathy and vitamin B 12 , or folate deficiencies, discontinuation of bone marrow
gastric, esophageal, or rectal varices, which can result in gastro- suppressive medications or alcohol, and appropriate treatment for the
intestinal (GI) bleeding. Portal hypertension also causes hypersplen- primary cause of liver disease.
ism increasing the fraction of circulating platelets, leukocytes and Small studies have suggested that inadequate production or
erythrocytes sequestrated in the spleen which can manifest with response to erythropoietin (EPO) also contributes to chronic anemia
varying degrees of cytopenias. in hepatic disease, although the association is controversial. Nonethe-
This chapter discusses several common hematologic abnormalities less, EPO supplementation has demonstrated clinical efficacy, cost-
encountered in liver disease including RBC, leukocyte, and platelet effectiveness, and increased quality of life in patients with hemoglobin
abnormalities, coagulopathy and thrombosis. levels less than 12 g/dL undergoing antiviral therapy for hepatitis C.
The use of EPO to maintain a hemoglobin greater than 10 g/dL may
obviate the need for dose reduction or discontinuation of ribavirin,
RED BLOOD CELL ABNORMALITIES either of which reduce rates of sustained viral response. It may take
up to 6 weeks to observe a significant rise in hemoglobin in response
Morphologic Abnormalities to EPO.

The size and shape of the RBC membrane can be affected by abnor-
mal lipid metabolism caused by liver disease. Excess cholesterol in the WHITE BLOOD CELL ABNORMALITIES
outer RBC membrane bilayer is thought to be responsible for mor-
phologic abnormalities, including macrocytosis and target cells (Fig. Leukopenia
153.1), and for impaired migration of integral membrane proteins
causing a loss of RBC membrane fluidity and deformability. RBCs Leukopenia, particularly neutropenia, has been observed in up to
with excess membrane cholesterol are also rendered less deformable 55% of patients with cirrhosis. Splenic sequestration is considered to
from oxidative damage caused by an inability to repair peroxidized be the main culprit; however, reduced production of leukocytes may
membrane lipids. When these less deformable RBCs traverse through also be a consequence of altered granulocyte colony-stimulating factor
the splenic microcirculation, cytoskeletal damage and permanent (G-CSF) and granulocyte macrophage colony-stimulating factor
deformation can occur, resulting in the formation of acanthocytes (GM-CSF) levels, bone marrow suppression mediated by primary
(spur cells) and increased clearance in the reticuloendothelial system. infections or toxins (e.g., hepatitis B or C, alcohol), or medications
Spur cell anemia is a hemolytic anemia most commonly caused (e.g., interferon). Immune-mediated neutropenia can occur in the
by chronic or severe liver disease. Life-threatening hemolysis can context of hepatitis C or autoimmune hepatitis, and increased
ensue, as well as disseminated intravascular coagulation (DIC), GI apoptosis may also be responsible for a shortened neutrophil life span.
bleeding or liver failure depending on the primary cause. Spur cell Furthermore, impairment in neutrophil recruitment and phagocytic
anemia associated with hereditary diseases such as neuroacanthocy- function may contribute to an increased susceptibility for severe and
tosis syndromes or lipoprotein disorders tends to be milder (see recurrent infections in patients with cirrhosis. G-CSF and GM-CSF
Chapter 45). Treatment options for spur cell anemia associated with have been safely used in patients with cirrhosis and neutropenia in
liver disease are limited. The most effective therapy is liver transplan- the setting of hypersplenism or treatment of viral hepatitis, resulting
tation. Clinical improvement using flunarizine, pentoxifylline, and in improvements in leukocyte counts. The impact of these treatments
cholestyramine has been documented in case reports. on risk of infection or response to antiviral therapy is unclear.

Anemia PLATELET ABNORMALITIES

The etiology of anemia is multifactorial, although acute and chronic Thrombocytopenia
GI hemorrhage are primary contributors. Fluid retention increases
whole blood volume in patients with cirrhosis causing an apparent Thrombocytopenia is the most common cytopenia associated with
anemia, as 60% to 70% of these patients will have a normal red cell liver disease, occurring in up to 77% of patients with cirrhosis.

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