Invited critical review
Diagnosing and monitoring hepatocellular carcinoma with alpha-fetoprotein: New aspects and applications

https://doi.org/10.1016/j.cca.2008.05.010Get rights and content

Abstract

Hepatocellular carcinoma is the 5th most common cancer in the world. Prognosis for this disease is poor since hepatocellular carcinoma is mostly diagnosed at an advanced stage. Serum alpha-fetoprotein (AFP) is one of the most common diagnostic markers for hepatocellular carcinoma. However, its diagnostic value is more and more questioned. Therefore, research has focussed on AFP related parameters (AFP mRNA and AFP glycoforms). The aim of this paper is to review the present knowledge on AFP and its related parameters in diagnosing and monitoring HCC. AFP related parameters can be arranged in two types: AFP mRNA and AFP glycoforms. AFP mRNA is a potentially prognostic marker and AFP mRNA assays are based on PCR techniques. The AFP glycoforms have diagnostic potential and assays are based on isoelectric focussing and lectin affinity electrophoretic methods. Up to now the diagnostic use of the AFP related parameters is limited. Although some of them are recommended as a complementary test, they cannot (yet) replace serum AFP as the golden standard of diagnostic markers for hepatocellular carcinoma.

Introduction

Worldwide, hepatocellular carcinoma (HCC) is the 5th most common cancer and the 3rd most important cause of cancer mortality, with a 5-year survival rate of merely 7% [1], [2]. HCC develops on a background of a chronically diseased liver, called a cirrhotic liver. Since HCC is a disease with a very poor prognosis due to resistance to conventional chemotherapy, and mostly diagnosed at an advanced stage when most potentially curative therapies are of limited efficacy; close follow-up of patients with cirrhosis is important in order to detect HCC at an early stage. Early detection enables us to provide the patient with the most optimal therapy [3], [4]. Current conventional methods for diagnosis and screening include physical examination, ultrasound imaging and serum alpha-fetoprotein (AFP) concentration measurements in high-risk patients. Despite the fact that serum AFP is still the golden standard amongst diagnostic markers for HCC, its diagnostic value is more and more questioned, due to poor sensitivity and specificity of the assay. As a result, research has focussed on AFP related parameters, like AFP mRNA and AFP glycoforms. For the last two decades, these related parameters have been extensively studied for use as potential new markers for diagnosis and monitoring of HCC. This review summarizes the present knowledge on AFP and its related parameters in diagnosing and monitoring HCC.

Section snippets

Synthesis and genetics

Alpha-fetoprotein was discovered in 1956 by Bergstrand and Czar using paper electrophoresis of human foetus serum proteins [5]. However, it was only in 1963 that AFP gained interest after discovery of AFP in adults during carcinogenesis [6]. The human alpha-fetoprotein gene is mapped on chromosome 4 (4q11–q13) and is part of the albuminoid gene superfamily which encodes, besides AFP, for several other proteins, including albumin and vitamin D-binding protein [7], [8]. AFP is synthesized by the

Immunoassays

Since Tatarinov detected AFP in serum of patients with hepatoma [41], serum AFP has developed to the most common diagnostic marker for HCC. The first conditionally quantitative serum assays for AFP were introduced in 1971 [10]. The association between serum AFP and HCC has been extensively described [6], [10], [42], [43], [44], [45], [46]. However, despite this clear association, sensitivity and specificity for this assay are poor [47] and vary according to study design, patient population and

Clinical aspects

In adult life, AFP synthesis is repressed. Elevated AFP serum levels are only seen in maternal serum during pregnancy, in certain tumours (e.g. HCC, gastric carcinoma, lung cancer, pancreatic cancer and testicular carcinoma) [78], [79], [80], [81], [82] and non-tumoral conditions (e.g. chronic hepatitis and liver cirrhosis) [83], [84], [85].

Summary and conclusions

Although sometimes called ‘obsolete’, measuring AFP concentration in the blood remains the easiest and preferred serum tumour marker for screening and diagnosing HCC in a clinical setting. AFP glycoforms show promising results as clinically useful HCC markers. AFP-L3, alone or in combination with AFP-P4 + P5, is an interesting parameter in this respect. Due to its high specificity it can be used complementary to the total serum AFP assay for early tumour recognition, diagnosis, follow-up after

Acknowledgement

EDB received a scholarship GOA BOFF07/GOA/017 from the University Ghent Research Fund (BOF).

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