What is cryptogenic cirrhosis?

Cryptogenic Cirrhosis: Definition and Etiology

Cryptogenic cirrhosis is defined as cirrhosis of unknown etiology despite extensive clinical, laboratory, and pathologic work-up, constituting approximately 3-30% of all cirrhosis cases. 1

Definition and Diagnostic Criteria

• Cryptogenic cirrhosis is a diagnosis of exclusion made after ruling out all known causes of chronic liver disease 1
• The diagnosis requires thorough investigation to exclude viral hepatitis, alcoholic liver disease, autoimmune hepatitis, metabolic liver diseases, and other potential causes 1
• Histological examination can provide important clues and help identify potential etiologies, with most cases classified into four patterns: hepatitic, steatotic, biliary, and patternless (bland) 2

Common Underlying Causes

Non-alcoholic Steatohepatitis (NASH)

• NASH is considered one of the leading causes of cryptogenic cirrhosis in many Western countries 1
• This connection is supported by well-documented serial biopsy reports showing progression of NASH to cirrhosis without continuing definitive evidence of NASH ("burnt-out NASH") 1
• Patients with cryptogenic cirrhosis often have a disproportionately high prevalence of metabolic risk factors (type 2 diabetes, obesity, metabolic syndrome) resembling NAFLD patients 1
• In advanced cirrhosis, the pathological assessment seldom reports histological features of NASH or even steatosis, leading to the "burnt-out NAFLD" phenomenon 1

Autoimmune Causes

• Autoimmune disease appears to be a more common underlying cause in some parts of Europe 1
• Silent or "burnt out" autoimmune hepatitis (AIH) may be identified through residual histological findings such as foci of autoimmune-like inflammatory infiltrates 1, 3

Other Potential Causes

• Occult viral infection (non-A, non-B, non-C hepatitis) 1, 3
• Covert alcoholism that was not disclosed by the patient 1, 3
• Alpha-1-antitrypsin deficiency, particularly in heterozygotes, has been associated with cryptogenic cirrhosis 1

Clinical and Demographic Features

• Cryptogenic cirrhosis in children is often an aggressive disease that progresses to liver failure, necessitating liver transplantation 1
• Disease recurrence after transplantation is not uncommon, with some patients developing aggressive NASH or autoimmune disease 1
• Studies suggest cryptogenic cirrhosis may have distinct features compared to other etiologies:
  • Predominance in females 4
  • More advanced age at presentation 4
  • Less marked peripheral signs of chronic liver failure (jaundice, spider nevi, palmar erythema) 4
  • Milder alterations in laboratory liver function tests 4

Diagnostic Approach

• Liver biopsy remains an important diagnostic tool for evaluating cryptogenic cirrhosis, though it must be individualized based on risk-benefit assessment 1
• Classification schemes have been proposed based on clinical setting and residual histological findings 1
• Recent advances in genomic analysis and whole exome sequencing have helped unravel the underlying etiology in a subset of cases and identify new disorders 2

Clinical Implications

• Providing a specific diagnosis has important implications for treatment, genetic counseling, and transplant eligibility 2
• The diagnosis of cryptogenic cirrhosis has decreased over time with improved diagnostic techniques and recognition of conditions like NASH that can progress to cirrhosis 5
• NASH-related cryptogenic cirrhosis is associated with an increased risk of hepatocellular carcinoma, even in the absence of cirrhosis 1

Management Considerations

• After transplantation for cryptogenic cirrhosis, careful monitoring is essential as disease recurrence is not uncommon 1
• The degree of liver fibrosis is the strongest predictor of mortality in patients with NAFLD/NASH, which is often the underlying cause of cryptogenic cirrhosis 6
• Addressing metabolic risk factors is important in patients with suspected NASH-related cryptogenic cirrhosis 6