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Underlying mechanisms and recommended therapy for cytopenias associated with chronic hepatitis C and cirrhosis

Splenomegaly is a frequent finding in chronic liver disease, and it also occurs in acute viral hepatitis, infectious mononucleosis, and other viral infections. Hypersplenism implies a decrease in one or more of the circulating blood cell lines, in association with splenomegaly and in the absence of inadequate bone marrow function. Although this pathology was previously thought to be related to a combination of
sequestration of blood elements within the enlarged spleen, increased destruction of circulating blood cells, and a dilutional effect resulting from an increased circulating blood volume, more recent interest has focused on additional underlying mechanisms -- most notably inadequate thrombopoietin (TPO) production. The role of this cytokine in physiological settings is to regulate megakaryocyte growth and development and platelet production.

A number of groups have studied TPO in patients with chronic liver disease, including chronic hepatitis C. There is some evidence that TPO levels are inappropriately low in cirrhotics for the degree of thrombocytopenia present, suggesting therefore that an impaired response contributes to the low platelet counts and that impaired hepatocyte TPO production may be responsible. However, not all investigators have been
able to demonstrate consistently low TPO levels in cirrhotics with thrombocytopenia. But studies in liver transplant recipients suggest that hepatic TPO production is restored after transplantation, with subsequent resolution of thrombocytopenia several days later.

Chronic hepatitis C virus (HCV) infection can be associated with thrombocytopenia in the absence of florid hypersplenism, with even an idiopathic thrombocytopenic purpura-like syndrome being described. TPO levels have been reported to be normal in noncirrhotic HCV patients, suggesting that its diminished production is not the cause of thrombocytopenia in these circumstances.

Correction of thrombocytopenia has been attempted by portal decompression with surgical shunts in the past and, more recently, by transjugular intrahepatic portosystemic shunt in patients with portal hypertension, without any consistent improvement in platelet counts.

Administration of TPO is currently under investigation for management of thrombocytopenia in patients with liver disease, including during interferon therapy to counteract the myelosuppressive effects of the drug. Granulocyte colony-stimulating factor has also been administered to patients with hypersplenism and has led to an increase in absolute neutrophil counts but without an improvement in thrombocytopenia.

Paul Martin, MD, 07/26/01

Suggested Reading
Espanol I, Gallego A, Enriquez J, et al. Thrombocytopenia associated with liver cirrhosis and hepatitis C viral infection: role of thrombopoietin.

Hepatogastroenterology. 2000:47;1404-1406.
Martin TG III, Somberg KA, Meng GY, et al. Thrombopoietin levels in patients with cirrhosis before and after orthotopic liver transplantation. Ann Intern Med. 1997:127;285-288.

Peck-Radosavljevic M. Thrombocytopenia in liver disease. Can J Gastroenterol. 2000:14(suppl D);60D-66D.

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