HCV New Drug Research

From Journal of Viral Hepatitis

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P. Spagnolo; S. Zeuzem; L. Richeldi; R. M. du Bois
Authors and Disclosures
Posted: 12/20/2010; J Viral Hepat. 2010;17(6):381-390. © 2010 Blackwell Publishing


Abstract
Lung complications may occur as a result of hepatic disease from any cause and represent a highly heterogeneous group of conditions. Early recognition of such complications may be challenging but is crucial both in forming a meaningful differential diagnosis and in avoiding severe sequelae and irreversible damage. Although a number of different pathogenetic mechanisms are likely to be involved, chronic liver dysfunction may cause pulmonary manifestations because of alterations in the production or clearance of circulating cytokines and other mediators.

This is likely to be the case in hepatopulmonary syndrome, portopulmonary hypertension and primary biliary cirrhosis, although their pathogenesis remains largely speculative. Moreover, the severity of lung manifestations may or may not correspond to that of liver impairment, making disease outcome often unpredictable. Congenital and inflammatory disorders, however, may primarily affect both the liver and lung.

Apart from specific diseases, a number of medications can also result in pulmonary and hepatic toxic effects. This is particularly important with cytokine therapy – used to treat viral hepatitis, among other diseases – because treatment consists of drug discontinuation, which, in turn, may cause reactivation or progression of the underlying disease that the drug was used for.

This review summarizes salient diagnostic and therapeutic aspects of these often misdiagnosed conditions and highlights, based on the most recent literature, the need for early referral of such patients to centres with specific expertise in the field. In fact, a multidisciplinary approach involving pulmonologists, hepatologists and, in particularly severe cases, transplant surgeons has been already proven successful.

Introduction
The liver plays a key role in homoeostasis; a diseased liver leads to deleterious effects on multiple organs, including the lungs. Pulmonary complications may occur as a result of hepatic disease from any cause and embrace a wide and heterogeneous spectrum of conditions involving diverse pathogenetic mechanisms. Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH) are likely manifestations of decreased hepatic clearance or increased hepatic production of circulating mediators, including cytokines and growth factors, although the pathogenesis of these conditions remains largely speculative. In such patients, lung complications are often misdiagnosed because anaemia, ascites and muscle wasting are more common causes of respiratory symptoms. On the other hand, alpha1-antitrypsin deficiency and cystic fibrosis – two congenital diseases – as well as sarcoidosis, may primarily affect both the lungs and the liver (the so-called hepatopulmonary axis). Autoimmune liver disease may also be complicated by diffuse parenchymal lung disease. Furthermore, drugs such as amiodarone can cause pulmonary and hepatic toxicity. Table 1 illustrates two groups of lung/liver disorders: those disorders that are complications of chronic liver disease, and those in which simultaneous lung and liver involvement are seen as part of the same disease process. Table 2 summarizes diagnostic tests for specific conditions. Knowledge of these associations is essential to formulating a prompt diagnosis – thus influencing therapeutic strategies – and management of these conditions should equally involve pulmonologists, hepatologists and, in particularly severe cases, transplant surgeons in a multidisciplinary approach.

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Abstract and Introduction
Hepatopulmonary Syndrome
Portopulmonary Hypertension
Primary Biliary Cirrhosis
Primary Biliary Cirrhosis
Sarcoidosis
Hepatitis C Virus-associated Lung Disease
Lung Complications of Other Viruses
Alpha1-antitrypsin Deficiency
Cystic Fibrosis
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Conclusion
Pulmonary involvement is a common complication of chronic liver disease, mainly owing to decreased hepatic clearance of toxins or increased hepatic production of circulating inflammatory mediators – although mechanical and predisposing factors may also be involved. The severity of lung manifestations may or may not parallel that of liver impairment, thus rendering disease outcome predictability and patient management more challenging. Therefore, early referral of patients to centres that specialize in this medical field is strongly recommended – as well as a multidisciplinary management approach involving pulmonologists, hepatologists and, in particularly severe cases, transplant surgeons. The precise percentage of individuals who manifest lung complications of hepatitis because of viral causes is unclear, because many studies are confounded by patients not having been screened for lung disease at presentation of their liver disease. Further, the diagnosis of a lung problem is often made while patients are on antiviral therapy – which itself can cause lung problems in some patients. Prospective studies are needed to address this important issue.


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