Inherited liver diseases are a group of metabolic and genetic defects that typically cause early chronic liver involvement. Most are due to a defect of an enzyme/transport protein that alters a metabolic pathway and exerts a pathogenic role mainly in the liver. The prevalence is variable, but most are rare pathologies. We review the pathophysiology of such diseases and the diagnostic contribution of laboratory tests, focusing on the role of molecular genetics. In fact, thanks to recent advances in genetics, molecular analysis permits early and specific diagnosis for most disorders and helps to reduce the invasive approach of liver biopsy. 1. Introduction An early chronic liver involvement may be observed in a number of genetic and metabolic diseases although with different penetrance, age at onset, and outcome. Clinical symptoms and laboratory data are frequently overlapping, thus rendering a differential diagnosis difficult. A great improvement both in imaging [1] and in molecular genetics [2] in the last years helped to discriminate between the different diseases thus reducing the need of pathology (Table 1). On the other hand, liver biopsy is often complex in children, mainly due to the smaller specimen size [3]. For some diseases, prenatal diagnosis is also available [4]. Table 1: Inherited liver diseases that predispose to early cirrhosis. Specific therapies are available for several genetic and metabolic diseases and their effectiveness is strongly related to the precocity of diagnosis. A growing number of children with such diseases now survive well into adulthood [5]. On the other hand, liver transplantation now offers a long-term survival [6]. We will review the genetic and metabolic entities responsible for early chronic liver diseases focusing on the contribution of laboratory and molecular diagnosis (Table 2). Table 2: Main characteristics of genetic liver disease that predispose to early cirrhosis. 2. Alpha-1 Antitrypsin Deficiency Alpha-1 antitrypsin (AAT) deficiency (OMIM 613490) is an autosomal recessive (codominant) disease due to mutations in the SERPINA1 gene that encodes the serine protease inhibitor AAT. The protein, mainly synthesized by liver cells, inhibits proinflammatory proteases such as neutrophil elastase, thus, protecting the lung from proteolytic damage. AAT deficiency has an incidence of 1？:？2,000–5,000 but the number of diagnosed patients is underestimated. AAT deficiency appears with chronic obstructive pulmonary disease, emphysema, and disseminated bronchiectasis usually between the 4th and the 5th decade [7]. The
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