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Toxic Effects of Nucleoside Reverse Transcriptase Inhibitors on the Liver

Value of Electron Microscopy Analysis for the Diagnosis of Mitochondrial

Cytopathy

from American Journal of Clinical Pathology

Posted 05/13/2003

Jean- Duong Van Huyen, MD, Alain Landau, MD, Christophe Piketty, MD,

Marie-France Bélair, Dominique Batisse, MD, Gustavo -Canali, MD,

ce Weiss, MD, PhD, Jian, MD, Michel D. Kazatchkine, MD, PhD,

Bruneval, MD

Abstract and Introduction

Abstract

Nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial

toxic effects resulting in multiple organ disorders. Liver involvement has

been associated mainly with severe lactic acidosis and massive steatosis.

However, patients with HIV infection who are receiving antiretroviral

treatment frequently have mildly abnormal liver test results that, to date,

have not been linked unambiguously to the toxic effects of NRTIs.

Thirteen patients with HIV infection treated with NRTI-based regimens had

low-grade abnormal liver test results associated with digestive and

nonspecific general symptoms. Histologic examination of liver samples showed

diffuse steatosis in only 6 cases and mild steatosis in the remaining cases,

associated with megamitochondria, mild lobular inflammation and necrosis,

Mallory bodies, and perisinusoidal fibrosis. In all cases, ultrastructural

study disclosed mitochondrial abnormalities.

Our work demonstrates that NRTI-induced toxic effects in the liver may occur

as indolent nonspecific disease with variable histologic features and

emphasizes the diagnostic value of electron microscopy, particularly when

diffuse steatosis is absent.

Introduction

The nucleoside reverse transcriptase inhibitor (NRTI) class of drugs,

including zidovudine (AZT), didanosine (ddI), lamivudine (also known as

3TC), zalcitabine (also known as ddC, or 2',3'-dideoxycytidine), and

stavudine (also known as d4T), is used widely in combination therapy with

nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease

inhibitors (PIs) in HIV-infected patients.[1] Thus, the benefits of

so-called highly active antiretroviral therapy (HAART) have been well

established.[2] However, the major limitation of HAART is a broad range of

side and toxic effects that are the main reason for discontinuing or

modifying antiretroviral therapy.[3-5] Among the different classes of

antiretroviral drugs, the toxic effects induced by NRTIs seem to be of

particular importance.

Long-term treatment with NRTIs gives rise to a broad spectrum of tissue

involvement, including hematologic disorders, myopathy, cardiotoxic effects,

peripheral neuropathies, and hepatotoxic effects.[6] These heterogeneous

adverse effects of NRTIs are related to defective mitochondrial DNA

replication secondary to the NRTI-induced deleterious inhibition of the

mitochondrial DNA polymerase gamma.[7] NRTIs also have been clearly

associated with peripheral lipodystrophy, which is characterized by

lipoatrophy of the face, legs, and arms. To date, reports of liver

involvement associated with NRTI-based therapy are rare compared with the

wide use of NRTIs.[8-14] In most of these cases, severe toxic effects on the

liver of AZT, ddI, or zalcitabine were associated with dramatic and

potentially lethal lactic acidosis. However, abnormalities of liver test

results frequently are observed during HAART. Thus, elevated

aminotransferase levels are present in 6% of patients undergoing an

NRTI-based regimen.[15] Fortgang et al[16] reported an incidence of 1.3

patients per 1,000 person-years for symptomatic NRTI-related hepatotoxic

effects. This progressive and indolent liver injury is certainly important

in the presence of a preexisting liver disease such as chronic viral

hepatitis or alcoholic liver disease.[3] Interestingly, in people receiving

NRTI-based regimens, these mild hepatic abnormalities have not been linked

clearly to mitochondrial toxic effects. Furthermore, little is known about

the diagnosis, outcome, and therapeutic implications of such low-grade toxic

effects on the liver.

We report the clinical, histologic, and ultrastructural evaluation of 13

HIV-infected patients treated with NRTIs. These patients were mildly

symptomatic and had only mildly abnormal liver test results. Our

observations highlight the limitations of standard liver histologic

examination and the value of electron microscopy (EM) in the diagnosis of

NRTI-induced hepatotoxic effects