Cryptogenic Cirrhosis: An Approach To The Diagnosis In The Era Of Molecular and Genomic Medicine

Introduction and historical perspective: Cryptogenic cirrhosis(CC) is defined as cases of cirrhosis where the etiology remains uncertain after careful and extensive clinical, laboratory and histologic analysis. The incidence of CC has been steadily declining over the years. Prior to 1965 the CC constituted about 50% of all cases of cirrhosis. In 1965 Hepatitis B virus (HBV) was discovered which subsequently led to its recognition as a major cause of chronic hepatitis and cirrhosis worldwide. While autoimmune hepatitis (AIH) was first described as an important cause of chronic liver disease in 1950, its clinical diagnosis remained erratic. The first diagnostic criteria by an international working group were proposed in 1998 and subsequently modified in 2008, which led to improved diagnosis of AIH. Another landmark discovery in this field was discovery of hepatitis C virus (HCV) in 1989, which eventually led its recognition as one of the major causes of cirrhosis worldwide. Non-alcoholic steatohepatitis (NASH) was first described as a clinical entity by Ludwig in 1980, but it took few decades to understand its real impact on the burden of liver disease and contribution to cirrhosis. Now non-alcoholic fatty liver disease (NAFLD/NASH) has been recognized as the next big epidemic in chronic liver disorders. Over these years better understanding of many other metabolic disorders and their improved diagnosis [Wilson’s disease, A1AT deficiency, familial inherited cholestatic (PFIC) syndromes, iron overload syndromes] also contributed to the continued decline of CC. Currently CC seems to accounts for an estimated 5-30% of cases of cirrhosis in various studies. The wide difference in the reported incidence likely results from variations in clinical practice and resources available at different Institutions across the world. Some of it may also be contributed by ethnic and geographic differences. Overall, in developed countries and tertiary care medical centers, CC accounts for about 5-10% of all cases of cirrhosis. It accounts for about 10% of liver transplants and is present in 3-14% of adults awaiting liver transplantation. As the diagnosis of liver disorders continues to evolve, the proportion of CC cases continues to decline.