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Cryptogenic Cirrhosis

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Clinical Epidemiology of Chronic Liver Diseases

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Abstract

Cryptogenic cirrhosis (CC) is defined as the development of cirrhosis in the absence of a clear etiology of liver dysfunction. Over time, definitions of various forms of liver disease have been refined and improved so that the incidence of CC is in decline. With the advent of hepatitis C testing and better definitions of alcohol related liver disease these etiologies of cirrhosis have decreased their impact on the diagnosis of CC. Autoimmune hepatitis and non-alcoholic fatty liver disease (NAFLD), both of which can lose their characteristic histologic features with advancement to cirrhosis, have taken over as the primary explanations for developing CC, but even now as definitions and recognition of NAFLD improve these numbers are waning. Since CC is a diagnosis of exclusion, prospective investigations are challenging and thus study methodology has a large impact on how relevant data are interpreted. Herein we focus on how the diagnosis of CC is made, the liver diseases that have contributed most to this diagnosis over time, and how study design affects the results and interpretation of prior investigations.

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Authors and Affiliations

  1. Division of GI/Hepatology, Department of Medicine, University of Virginia Medical Center, Charlottesville, VA, USA

    Zachary Henry, Curtis K. Argo & Stephen H. Caldwell

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  1. Zachary Henry
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  2. Curtis K. Argo
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  3. Stephen H. Caldwell
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Correspondence to Zachary Henry .

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Editors and Affiliations

  1. Division of Gastroenterology and Hepatology, Alameda Health System Highland Hospital, Oakland, CA, USA

    Robert J. Wong

  2. Robert G. Gish Consultants LLC, Hepatitis B Foundation, Stanford Health Care, San Diego, CA, USA

    Robert G. Gish

Summary Table of Landmark Literature

Summary Table of Landmark Literature

Study title and authors

Study design

Summary results

Main limitations

Powell EE, et al. Hepatology. 1990;11(1):74–80

Retrospective cohort study of NAFLD patients to associate clinical outcomes and histologic changes over time

• First study to associate NASH with progression to CC—loss of histologic features of NASH

• Weight loss may improve features of NASH

• Retrospective nature impedes ability to control for confounding factors

Caldwell SH, et al. Hepatology. 1999;29(3):664–669

Retrospective case-control study comparing patients with CC to patients with NASH, HCV cirrhosis, and PBC cirrhosis

• Metabolic features of NASH (obesity and T2DM) were significantly more prevalent in CC than HCV cirrhosis or PBC cirrhosis

• NASH and CC groups had much more overlap than in clinical feature than other causes of cirrhosis

• Retrospective nature impedes ability to control for confounding factors

• Absence of NASH cirrhosis or AIH cirrhosis control groups limit comparison

Poonawala A, et al. Hepatology. 2000;32(4):689–692

Retrospective case-control study of patients with CC at time of transplant listing compared to age-matched controls with other etiologies of cirrhosis

• Metabolic risk factors (obesity and type 2 diabetes mellitus) were significantly more common in CC and NASH than other causes of cirrhosis suggesting NASH as a major etiology of CC

• Retrospective in nature so could not control for all confounding factors

• Selection bias introduced by using only patients listed for liver transplantation

Caldwell SH, et al. Ann Hepatol. 2009;8(4):346–352

Retrospective case-control study comparing histology findings in patients with NASH that has progressed to CC to patients with HCV cirrhosis

• NASH patients lose steatosis histologically once progressed to cirrhosis, but other features remain

• Features of NASH are much less common in HCV cirrhosis biopsies

• Only a single comparison group of HCV cirrhosis patients—including other groups may have noted more overlap

• Small sample size—only 7 NASH/CC patients

Charlton MR, et al. Gastroenterology. 2011;141(4):1249–1253

Retrospective cohort study of the scientific registry of transplant patients (SRTR) data

• NASH increased rapidly from 2001 to 2009 as an indication for LT

• CC declined over the same period of time

• Selection bias from poor definitions of disease process in large, anonymous database

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Henry, Z., Argo, C.K., Caldwell, S.H. (2019). Cryptogenic Cirrhosis. In: Wong, R., Gish, R. (eds) Clinical Epidemiology of Chronic Liver Diseases. Springer, Cham. https://doi.org/10.1007/978-3-319-94355-8_18

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