Quarterly Reviews
 
Hematological problems and liver disease
 
Parijat Gupte, Aabha Nagral
Depart couponrxsms.com discountment of Gastroenterology
Jaslok Hospital and Research Centre
Mumbai - 400026, India.


Corresponding Author
: Dr. Aabha Nagral
Email: aabhanagral@gmail.com


Abstract

There has been significant progress in the understanding of the pathophysiologic basis of common haematological problems like cytopenias, coagulopathies and thrombophilic disorders in the background of liver disease. Diagnosis has improved with newer tests like detection of JAK2 mutation and better radiological imaging. Additionally, therapeutic options have expanded with availability of drugs like activated factor VII and eltrombopeg and improved expertise in procedures like TIPSS for treatment of the Budd-Chiari syndrome. Thus, there is increasing need for coordinated management of these problems by the hematologist and gastroenterologist. This article overviews the interface between hepatology and hematology and elaborates on some of the common problems encountered.

The liver is involved in or is responsible for various hematological abnormalities due to its unique portal circulation and its synthetic (clotting factors, thrombopoietin) and immune functions. Primary liver problems like cirrhosis can lead to hematological abnormalities and primary hematological diseases can in turn affect the liver and its functioning.
 
These disorders may be divided into:
 
1.     Red blood cell disorders
a.     Anaemia in liver disease
b.     Sickle cell hepatopathy
c.     Multiple transfusion-related diseases: transfusiontransmitted viral infections.
 
2.     White blood cell disorders
a.     Liver dysfunction in lymphoid malignancies
b.     Neutropenia related to drug therapy
3.     Platelet disorders
a.     Hypersplenism in chronic liver disease
b.     Autoimmune thrombocytopenia
c.     Drug-induced thrombocytopenia
d.     Thrombocytopenia following liver transplantation.
4.     Coagulation disorders
a.     Thrombophilia – i) Budd-Chiari syndrome, ii) Portal vein thrombosis
b.     Coagulopathy of cirrhosis
This article elaborates on some of the common problems encountered in clinical practice.
 
1. Red Blood Cell Disorders
A. Anaemia in liver disease
 
Anaemia in liver disease may be secondary to a variety of factors including
a)     Nutritional deficiency of iron, folate, Vitamin B12 and B6
b)     Blood loss secondary to variceal bleeding (always overt bleeding), portal hypertensive vasculopathy (may be overt or occult bleeding) and duodenal ulcer (more common in patients with cirrhosis)
c)     Anaemia of chronic disease
d)     Hemolysis
                      I.        Spur cell anaemia – seen in advanced chronic liver disease especially in alcoholics and has a poor prognosis. It is related to abnormal cholesterol loading of the red cell membrane and reduced deformability of the red cells. In the presence of hyperlipidemia, it is referred to as Zieve’s syndrome.[1]
                     II.        Wilson’s disease may be associated with a hemolytic anaemia in 1-12%.2 Hepatic necrosis leads to release of copper, which in turn has an oxidative action on RBC cell membrane phospholipids leading to their breakdown. These patients typically present as fulminant hepatic failure with hemolysis.[2]
                    III.        Ribavirin-induced hemolytic anaemia Ribavirin is used for treatment of hepatitis C along with interferon or pegylated interferon. It can cause significant dose-dependent hemolytic anaemia in about 10% of patients on interferon and ribavirin therapy.[3] There are clear recommendations on dose reduction depending on the fall in haemoglobin. Alternatively, erythropoietin growth factor up to a dose of 40,000 units s.c. weekly can be given. Newer growth factors with longer half-lives such as darbopoietin and pegylated erythropoietin are convenient for the lesser number of doses required. CERA (continuous erythropoietin receptor activator), a pegylated erythropoietin is one such agent with once monthly dosing.[4]
                    IV.        Autoimmune hemolytic anaemia seen in association with autoimmune hepatitis
e)     Hypersplenism
f)      Direct toxic effect of alcohol on the bone marrow - reversible suppression of hematopoiesis causing anaemia and impaired platelet production and function
g)     Rarely aplastic anaemia and pure red cell aplasia (PRCA) have been described with hepatitis viruses, but their association is not definite.[5]
h)     Other drugs related anemia
Along with the copper chelation caused by d-penicillamine, iron also gets chelated causing iron deficiency anaemia. Further, sideroblastic anaemia can be caused by trientene used for the treatment of Wilson’s disease.
 
B. Sickle cell hepatopathy
 
Sickle cell hemoglobinopathy is prevalent all over India and is more common in the central and southern parts of India. Sickle cell disease (SCD), a homozygous state presents with complications like sequestration crisis, vaso-occlusive crisis etc. Recently the varied presentations of liver disease in SCD were characterised.6 Patients may present with:
 
a)     Acute hepatocellular necrosis presenting with pain and fulminant liver failure, characterised by the high level of transaminases.
b)     Acute sequestration and cholestasis characterised by high bilirubin levels and mild to moderate transaminitis. It is usually associated with sepsis.
c)     Cirrhosis – Patients may present with cirrhosis and portal hypertension and can develop decompensation.
d)     Chronic sickle hepatopathy – Patient presents with asymmetric lobar hypertrophy and firm liver, chronic state of sequestration and mild to moderate abnormalities of liver tests.
e)     Gallstones are common in SCD and these individuals may present with jaundice due to extrahepatic biliary obstruction.
f)      Cholangiopathy - Imaging similar to primary sclerosing cholangitis, suggestive of diffuse biliary disease can be seen in some patients with high bilirubin levels and moderate transaminitis
g)     Venous outflow obstruction.
Biopsy in these patients with sickle cell hepatopathy is associated with increased risk of bleeding, hence should be done with care and only if very essential. Treatment with hydroxyurea has shown benefit in patients with chronic sequestration.[7]
 
C. Multiple transfusion-related diseases
 
In our country, thalassemia, aplastic anaemia and myelodysplastic syndrome constitute about 80-90% of chronically transfused patients. Hemophilia constitutes about 5% of chronically transfused patients. Repeated requirement of blood and blood products in these disorders predisposes these individuals to transfusion-transmitted infections e.g. hepatitis B virus (HBV), hepatitis C virus (HCV), human immune deficiency virus (HIV) and iron overload states. These are responsible for long-term morbidity because of development of chronic liver disease.
 
In the general population in India, prevalence of HBV and HCV is 2-4% and 1-2%, respectively. Recent studies from Western India have shown a prevalence of HBV and HCV in thalaessemia and hemophilia patients of 2.3% and 57%, and 6% and 23%, respectively.[8,9] Delayed introduction of universal vaccination of hepatitis B and delay in mandatory testing of blood for HCV by blood banks before transfusion has resulted in large numbers of these individuals becoming infected with HBV and HCV. Approximately more than 20% of HBV and HCV infected individuals progress to cirrhosis in 15-20 years depending on the risk factors. In these patients, progression to chronic liver disease is contributed by added risk factors like co-infection with HIV and iron overload.
 
Treatment of these infections also poses problems because of poor tolerance due to treatment-related side effects (e.g. interferon-induced cytopenias and ribavirin-associated anaemia), chances of recurrent infections, and cost involved in the treatment. Early vaccination of patients and safe blood banking can reduce the risk in these patients. Newer development of effective nucleos(t)ide analogues like entecavir, tenofovir with less risk of resistance will improve outcome in patients with chronic hepatitis B. The data on therapeutic intervention in these groups is limited and so there are no clear guidelines because long-term benefit of such treatment is yet unclear. Moreover, even after treatment, reinfection remains a possibility.
 
2. White Blood Cell Disorders
A. Lymphoid malignancies and liver disease
 
Lymphoid malignancies (lymphoma, leukemias) can present with jaundice and liver dysfuction, which can compromise treatment.[10,11] Liver dysfunction in lymphoreticular disorders can occur following:
 
a)     Obstructive jaundice due to enlarged lymph nodes in extrahepatic billiary obstruction in cases of lymphoma.
b)     Infiltration of liver can present as acute liver failure in cases of leukemia and lymphoma.
c)     Intrahepatic cholestasis and vanishing bile duct syndrome can present as a paraneoplastic syndrome in cases of Hodgkin’s lymphoma, even in the absence of infiltration of liver by lymphoma cells.
 
B. Neutropenia in liver disease
 
a)     Hypersplenism related – rarely symptomatic and needing treatment
b)     Treatment related – interferon/pegylated interferon, d-penicillamine
 
Clinical use of myeloid growth factors[12] – Treatment is warranted only if absolute neutrophil count is <1000 cells/mm3. It is given till ANC >1000/mm3.
 
Doses:
GM-CSF: 250 µg/m2/day
G-CSF: 5-10 µg/kg/day
Pegylated G-CSF: 6 mg, once in 2 weeks s.c.
 
3. Platelet Disorders
A. Thrombocytopenia in chronic liver disease
 
Above 70% of cirrhotic patients have some degree of thrombocytopenia and 1% develop severe thrombocytopenia (< 50,000/ cumm).13,14 Mild to moderate thrombocytopenia rarely cause serious clinical problems. Thrombocytopenia associated with chronic liver disease affects management in the following ways:
 
a)     Increases risk of bleeding during liver biopsy and other interventions in cirrhotic patients.
b)     Compromises treatment by interferon in HBV and HCV.
c)     Adds to the risk of bleeding in patients who are already coagulopathic.
 
Mechanisms of thrombocytopenia in chronic liver disease include:
 
a)     Splenic sequestration and destruction of platelets by an enlarged spleen. Hypersplenism is characterised by enlargement of the spleen, reduction in 1 or more cell line(s) in peripheral blood, normal or hyperplastic bone marrow, premature release of cells with reticulocytosis and/or large immature platelets. Hypersplenism rarely merits treatment unless symptomatic, e.g. there is serious bleeding (hypersplenic thrombocytopenia), severe symptomatic pancytopenia, left-sided portal hypertension with variceal bleeding (splenic vein thrombosis), mechanical encroachment affecting quality of life significantly.
b)     Decreased production of platelets in bone marrow.
c)     Autoantibodies to platelets - presenting like idiopathic thrombocytopenic purpura (ITP). It is frequently seen in HCV infection. HCV antibodies are positive in 10-30% of patients with chronic ITP[15] High affinity binding of HCV to platelet membrane with subsequent binding of anti-HCV antibody might lead to phagocytosis of platelets through an “innocent bystander” mechanism.
d)     Treatment with either intravenous immunoglobulin (IVIG) or anti-RhD Ig has proven to be effective in increasing platelet counts in HCV positive patients.[16] Responses to corticosteroids are significantly lower in HCV positive than in HCV negative patients. Approximately half the adult chronic ITP patients with HCV treated with INF-a therapy responded with a rise in platelet count.[17] Eltrombopag, an oral thrombopoietin receptor agonist, can increase platelet counts in a majority of patients with cirrhosis associated with HCV infection to >100 x 109/L and allow continuation of an for effective IFN-based therapy.[18]
e)     Decreased production of thrombopoietin (TPO) by the liver.
f)      Interferon-induced thrombocytopenia in patients who are on treatment for HCV. 6% of such patients require dose modification.[3],
g)     Thrombocytopathy – Decreased platelet function.
 
Mild to moderate thrombocytopenia rarely requires correction even for invasive procedures like liver biopsy. A platelet count of more than 80,000/mm3 is sufficient for performing a liver biopsy or other invasive procedures. For lower platelet counts, temporary platelet transfusion may be indicated if invasive procedures have to be performed or if the patient has significant overt bleeding or counts fall to <10,000/mm3. Repeated platelet transfusions may be associated with alloimmunisation and a platelet count which does reach the expected level.
 
Other methods like splenic artery embolisation and splenectomy have been performed to treat thrombocytopenia. Splenic artery embolisation is associated with complications such as splenic infarcts and abscess formation and splenectomy alone is not recommended (without a shunt procedure) in patients with generalised portal hypertension.
 
B. Thrombocytopenia associated with liver transplantation
 
Moderate to severe thrombocytopenia occurs in about half the patients in the 1st week following orthotopic liver transplantation, which occasionally may be severe (platelet count below 20,000/cumm).[20] It can complicate postoperative management by increasing the risk of intra-abdominal bleeding, bleeding following liver biopsy and bleeding at other sites like intracranial bleeding etc. During the normal course, platelet count improves by the second week. Causes for worsening or persistent thrombocytopenia are:
 
a)     Immediate sequestration and activation of platelets in graft sinusoids following reperfusion
b)     Decreased production of platelets where TPO synthesis by the liver has not normalised following transplantation.
c)     Persistent portal hypertension and hypersplenism, which takes a few weeks to a few months to resolve.
 
Treatment involves close observation in case of moderate thrombocytopenia, and platelet transfusion in severe cases. Intravenous immunoglobulin (IVIG) has been shown to be of benefit in some cases, even in non-immune causes of low platelet count. In persistent cases, other causes like drugs, graft dysfunction, and sepsis should be actively looked for. Splenectomy may be considered in cases where hypersplenism seems to be the cause. Theoretically, drugs like eltrombopag appear to be an attractive option but its role in this situation is not yet clearly defined.
 
Budd-Chiari syndrome (BCS)
 
Primary BCS is characterised by a blocked hepatic venous outflow tract, occurring at various levels from the small hepatic veins to the inferior vena cava, resulting from thrombosis or its fibrous sequellae.[21] It is predominantly seen in middle-aged individuals and has equal sex distribution. Though initial reports from Asia suggested inferior vena cava (IVC) as the common site of obstruction,[22,23] recent reports suggest that hepatic vein is a more common site of obstruction as seen in the Western population.[24]
 
Aetiologically, genetic (protein C, protein S deficiency, antithrombin III deficiency, factor V Leiden mutation, prothrombin gene G20210 mutation) and acquired thrombophilic conditions (myeloproliferative disease, antiphospholipid syndrome, lupus anticoagulant) are recognised as important causes of BCS.
 
Thrombophilic conditions have been observed in up to 59% of patients in the Indian population.[24,25] Factor V Leiden and Prothrombin Gene G20210 mutations were less common compared to that seen in the Western patient population.[26] Myeloproliferative disease (MPD) is an important cause of BCS which may be silent at the time of presentation. Peripheral blood counts may be normal due to hypersplenism, hemodilution and iron deficiency. Somatic mutation, V617F in JAK2, in the peripheral granulocytes is identified as a marker of MPD and is detected in more than 50% of patients of MPD.[27] It can be detected at the occult stage. Patients with BCS should undergo testing for JAK2 mutation. In case of a negative result, a bone marrow biopsy should be performed. Paroxysmal nocturnal hemoglobinuria (PNH) is a possibility when a patient presents with BCS associated with pancytopenia.
 
Early recognition and initiation of anticoagulant therapy is recommended for all patients irrespective of aetiology. Patients with mild disease (10%) can be controlled with this treatment modality alone. Patients with short length stenosis, either of the hepatic veins or of the IVC, are candidates for percutaneous transluminal angioplasty or stent placement. Anticoagulation and angioplasty appear to succeed in controlling BCS in only 20–30% cases. Patients in whom the disease is not controlled with the above-mentioned interventions require transjugular intrahepatic portosystemic shunt (TIPSS) placement. Ten to twenty percent of patients who have poor hepatic function or in whom TIPSS fails, require liver transplantation, which has a 5-year survival rate of almost 80%.[28]
 
Portal vein thrombosis (PVT)
Hepatocellular carcinoma is the commonest cause of PVT but non-malignant PVT incidence is reported in 0.6 to 12 % of patients with cirrhosis.[29,30] PVT can be asymptomatic or it may present with worsening of liver disease. It complicates the procedure of liver transplantation. Dampened portal flow, previous abdominal surgery and sclerotherapy are identified as causes of PVT. The role of inherited coagulation disorders has been studied with mixed results. Amitrano et al[31] documented thrombophilic state (FVL, MHFTR and PTHR mutations) in 69% individuals with PVT, which was significantly higher than in the controls. In contradiction, Mangia et al observed no significant role of thrombophilic mutations in PVT. Identification of these predisposing factors can be crucial in patients undergoing liver transplantation as it can increase the risk of postoperative venous thrombosis.
 
Isolated portal vein (in the absence of cirrhosis) thrombosis in India is commonly seen at an early age, predominantly in children and adolescents, commonly referred to as extrahepatic portal venous obstruction (EHPVO). The portal vein is typically replaced by a leash of collateral vessels referred to as a portal cavernoma. It primarily presents as manifestations of portal hypertension such as variceal bleeding or splenomegaly with hypersplenism. Umbilical vein catheterisation and sepsis were considered as predisposing causes for PVT. Thrombophilia studies in patients with PVT have not shown presence of Factor V or prothrombin gene G20210A mutations, but 70% of children had either deficiency of protein C or abnormally elevated anti-cardiolipin antibodies.[33,34]
 
Coagulopathy of liver failure
 
Normal hemostasis results from an interplay between coagulation factors (pro and anticoagulants), fibrinolytics and platelets.
 
Cirrhosis is associated with increased risk of bleeding, an aftermath of multiple causes. In cirrhosis, all coagulation factors are reduced except factor VIII/ VWF, which is secreted by the endothelium. Though quantitatively, clotting factors are reduced, a balance is maintained between the pro and anticoagulant systems, resulting in hemostasis. In the fibrinolytic system too, all factors are reduced except the tissue plasminogen activator (tpA) and the platelet-activating factor (PAI-1), which are not synthesised in the liver. An important fibrinolysis-inhibiting factor called thrombin activatable fibrinolysis inhibitor factor (TAFI) is also reduced; this leads to accelerated fibrinolysis in patients of stable advanced cirrhosis. Cirrhosis is associated with decreased platelet function, which is partly compensated by increased factor VIII and Von Willebrand factor (VWF). Thus despite altered levels of pro and anticoagulant systems, a compensated state is maintained which prevents excessive bleeding in a stable cirrhotic patient.[35,36]
 
Infection or sepsis leads to activation of coagulation and fibrinolysis and impairment of platelet aggregation. There is also production of endogenous heparinoids from the endothelium and mast cells. This leads to instability of a critically balanced system leading to an increased bleeding tendency
 
Prevention and treatment of bleeding in cirrhosis
 
Our understanding of the coagulation cascade has undergone a change in recent times. The classic ‘Y’ cascade of intrinsic and extrinsic pathways has been replaced by the initiation, amplification and propagation type of model. Tissue factor and its activation of factor VII is the initial and important stage. Prothrombin time (PT) which represented the extrinsic pathway in an earlier model, is now taken to represent the initiation phase.[37]
 
Prothrombin time was originally designed to investigate obstructive jaundice and later adapted to monitor patients on vitamin K antagonists (VKA). To reduce inter laboratory variability, the International Normalised Ratio (INR) was introduced which used WHO standardised thromboplastin for calibration.[38] Prothrombin time and INR do not accurately predict the risk of bleeding in patients of chronic liver disease. This may be due to the following reasons:
 
a)     Current PT/INR was designed for VKA-related coagulation abnormalities. But coagulation defects associated with chronic liver disease are qualitatively and quantitatively different from those with VKA.
b)     PT reflects abnormality in coagulation but does not include abnormalities in anticoagulant factors, which occur simultaneously, and counterbalance the risk of bleeding caused by procoagulant deficiency. Hence it does not represent the global state of coagulation. As PT is a part of MELD, which is used for organ allocation, it is important to have a reproducible and representative assay. Alternative calibration methods using plasma from patients of chronic liver disease has been suggested in estimation of INR in these individuals and is called INR Liver.[39]
Ideal test or group of tests to assess the status of the entire coagulation system is still not available and hence assessment of blood product requirement and risk of bleeding before intervention or surgery is difficult. Thromboelastography, which graphically represents clotting factor and platelet function, is a good indicator to rationalise blood product requirement during surgery or intervention.[40]
 
Role of factor VIIa and antifibrinolytics
 
Factor VIIa is a new therapeutic tool available for prophylactic or therapeutic prevention of bleeding. It enhances thrombin generation and platelet function. Though it has shown significant improvement in prothrombin time in trials of acute liver failure, liver biopsy, liver transplantation or variceal haemorrhage, it failed to show significant decrease in blood product requirement or mortality related to bleeding.[41,42,43,44,45] In the future, improvement in diagnostic tests which better reflect the status of coagulation, would probably help in adjusting the dose and frequency of this agent to optimise coagulation.
 
Prevention of clot lysis by either serine protease inhibitors like aprotinin or lysine analogues which inhibit binding of plasminogen to fibrin like aminocaproic acid and tranexamic acids have not undergone significant scrutiny in clinical trials in liver disease patients. Hence definite regimens and dosing schedules are not available. Recently aprotinin has shown increased chances of renal dysfunction and adverse cardiovascular events.[46] There is also an increased risk of thrombosis with these agents. These agents are still used in dental procedures, mucosal bleeds or prophylactically in surgery to reduce blood loss.
 
In conclusion, recent developments in the field of haematology and hepatology have led to a better understanding of the aetiology, clinical presentation and management of these diseases. Early recognition and timely coordinated management by both sub-specialties will help in achieving better outcome in these potentially treatable conditions.

Tefferi A. Classification, diagnosis and management of myeloproliferative disorders in the JAK2V617F era. Hematology Am Soc Hematol Educ Program. 2006:240–5.

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