The conundrum of cryptogenic cirrhosis: Adverse outcomes without treatment options
Author(s): ,
Zachary Goodman
Affiliations:
Inova Fairfax Hospital, Falls Church, VA, USA
,
Jaime Bosch
Affiliations:
IDIBAPS, University of Barcelona, Barcelona, Spain
,
Nezam H. Afdhal
Affiliations:
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
,
Andrew Muir
Affiliations:
Duke Clinical Research Institute, Durham, NC, USA
,
Robert P. Myers
Affiliations:
Gilead Sciences, Inc., Foster City, CA, USA
,
G. Mani Subramanian
Affiliations:
Gilead Sciences, Inc., Foster City, CA, USA
,
Bryan McColgan
Affiliations:
Gilead Sciences, Inc., Foster City, CA, USA
,
Raul Aguilar Schall
Affiliations:
Gilead Sciences, Inc., Foster City, CA, USA
,
Mitchell L. Shiffman
Affiliations:
Liver Institute of Virginia, Richmond, VA, USA
,
Stephen Caldwell
Affiliations:
University of Virginia, Charlottesville, VA, USA
,
Anna Mae Diehl
Affiliations:
Duke Clinical Research Institute, Durham, NC, USA
,
Manal F. Abdelmalek
Affiliations:
Duke Clinical Research Institute, Durham, NC, USA
,
Vlad Ratziu
Affiliations:
Hôpital Universitaire Pitié-Salpêtrière, Paris, France
,
Stephen A. Harrison
Affiliations:
Pinnacle Clinical Research, San Antonio, TX, USA
,
Arun J. Sanyal
Affiliations:
Virginia Commonwealth University, Richmond, VA, USA
,
Maria Stepanova
Affiliations:
Inova Fairfax Hospital, Falls Church, VA, USA
Zobair Younossi
Affiliations:
Inova Fairfax Hospital, Falls Church, VA, USA
Corresponding author. Address: Betty and Guy Beatty Center for Integrated Research, Claude Moore Health Education and Research Building, 3300 Gallows Road, Falls Church, VA 22042, USA; Tel.: +1 (703) 776 2540; fax: +1 (703) 776 4386.
EASL LiverTree™. Younossi Z. Dec 1, 2018; 256777
Dr. Zobair Younossi
Dr. Zobair Younossi

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Graphical abstract

Graphical abstract

Patients with cryptogenic cirrhosis or NASH cirrhosis had similar clinical and demographic profile. Cryptogenic cirrhosis was associated with advanced fibrosis and a higher risk of liver-related decompensation or death. Cryptogenic cirrhosis may be a more advanced type of liver disease associated with the NAFLD spectrum. New research is required to address the lack of treatment options for cryptogenic cirrhosis.

Background & Aims

Although patients with cryptogenic cirrhosis have historically been considered as having “burnt-out” non-alcoholic steatohepatitis (NASH), some controversy remains. The aim of this study was to compare outcomes of patients with cryptogenic cirrhosis and NASH-related cirrhosis from a cohort with longitudinal follow-up data.

Methods

Patients with cryptogenic cirrhosis or NASH cirrhosis were screened for a clinical trial. Patients with <5% hepatic steatosis regardless of other histologic features were considered to have cryptogenic cirrhosis. Clinico-laboratory data and adjudicated liver-related events (e.g. decompensation, qualification for transplantation, death) were available.

Results

A total of 247 patients with cirrhosis (55.3 ± 7.4 years, 37% male) were included; 144 had NASH cirrhosis and 103 had cryptogenic cirrhosis. During a median follow-up of 29 (IQR 21–33) months (max 45 months), 20.6% of patients had liver-related clinical events. Patients with NASH cirrhosis and cryptogenic cirrhosis were of a similar age and gender, as well as having a similar body mass index, PNPLA3 rs738409 genotype, and prevalence of diabetes (p >0.05). However, patients with cryptogenic cirrhosis had higher serum fibrosis markers and greater collagen content and α-smooth muscle actin expression on liver biopsy. Compared to cirrhotic patients with NASH, patients with cryptogenic cirrhosis experienced significantly shorter mean time to liver-related clinical events (12.0 vs. 19.4 months; p = 0.001) with a hazard ratio of 1.76 (95% CI 1.02–3.06).

Conclusions

Populations with NASH and cryptogenic cirrhosis have similar demographics, but patients with cryptogenic cirrhosis have evidence of more active fibrosis and a higher risk of liver-related clinical events. Thus, we believe these patients belong to the same spectrum of disease, with cryptogenic cirrhosis representing a more advanced stage of fibrosis.

Lay summary

Significant liver damage and cirrhosis of the liver may develop without a known cause – a liver disease referred to as cryptogenic cirrhosis. In this work we found that, in the presence of metabolic abnormalities, cryptogenic cirrhosis may actually be a part of the non-alcoholic fatty liver disease spectrum. Yet, it appears to be more progressive than typical non-alcoholic fatty liver disease, leading to advanced liver disease at a faster rate.

Keyword(s)
NAFLD, NASH, Outcomes, Fatty liver, Cryptogenic cirrhosis
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