Scoring systems for liver histology to predict the outcome of primary sclerosing cholangitis

By studying the microscopic structure of liver tissue (liver histology), it is possible to assess the various abnormalities commonly found in primary sclerosing cholangitis (PSC). This can help to determine the severity and progression of PSC. Liver histology istypically scored in terms of grade and stage. Grading represents severity of the underlying disease process, which is measured by the degree of inflammation and necrosis (death of the liver cells). Staging represents the disease progression, which is measured by the degree of scarring (fibrosis) and cirrhosis found in the liver.

The low prevalence of PSC, and its chronic disease course, hinders the evaluation of solid clinical endpointssuch as liver transplantation or death. Therefore, substitute, or ‘surrogate’ endpoints, such as the Mayo risk score and other biochemical and clinical markers,are currently used in clinical trials for PSC. Unfortunately these surrogate endpoints are not yet validated for PSC.

There are no specific histologic scoring systems available to score disease grade and stage for PSC. This study was designed to determine if scoring systems developed for other liver diseases could be used to assess grading and/or staging of PSC.  Specifically, the aim was to assess if these other scoring systems were of prognostic value in predicting outcome of PSC. In such a case, liver histology could become important in the evaluation of the efficacy of treatment in therapeutic clinical trials, and may be used as a surrogate endpoint.

The systems used were the Ishak system (originally developed for chronic hepatitis), the Ludwig system (originally designed for primary biliary cholangitis  (PBC)), and a more recent system proposed by Nakanuma, again designed for PBC. The advantage of the Nakanuma scoring system is that it takes into account histologic features shared with PSC. Three endpoints were defined to measure outcome of PSC: 1. Transplant-free survival (a combination of PSC related death, liver transplantation and development of cholangiocarcinoma) 2. Liver transplantation alone 3. Development of cirrhosis related symptoms.

Sixty-four Dutch PSC patients from the Dutch ‘Epi PSC PBC project’ cohort were included (10 patients were diagnosed with small duct PSC). All patients underwent a liver biopsy to establish PSC diagnosis. There were 40 males and 24 females, 43 patients were also diagnosed with inflammatory bowel disease, ulcerative colitis being the most common. Eleven patients reached an endpointduring the study period; three were diagnosed with cholangiocarcinoma (two died) and eight patients underwent liver transplantation.

With this study the researchers demonstrated that the three staging systems are predictive indicators of both endpoint 1: transplant-free survival and endpoint 2. livertransplantation. The Nakanuma staging system appeared to have the strongest predictive value. Explanation for this may be that this system includes features specific for PSC. All three staging systems implicated that the degree of fibrosis is an important parameter to predict the likely course of the disease.

To assess if liver biochemistry could reflect the degree of liver injury as measured by liver biopsy, the researchers performed exploratory analyses to determine correlations between liver biochemistry and histologic grade and stage. No strong correlations were found. According to the researchers, this suggests that liver biochemistry does not adequately reflect the degree of histologic injury. They cite a recent study by Queen et al. who also demonstrated that PSC patients could have severely progressed liver disease in the setting of normal liver biochemistry.

A number of studies, including the current study, indicate that progression, and even improvement of histologic grade/stage can be assessed by liver biopsy. This study demonstrates that scoring liver histology is of prognostic value to determine disease outcome. Liver histology may therefore be considered to be a useful marker to assess disease progression in PSC.

Whilst noting and discussing limitations within the study, the researchers argue that applying the Nakanuma, Ishak and Ludwig staging systems in PSC is both feasible and clinically relevant. Histology may be useful to serve as surrogate endpoint in clinical trials in PSC, but further research in larger multi-centred cohorts is warranted to validate these present results.



Liver Biochemistry: A group of blood tests that detect stasis of bile and damage to the liver cells

Correlation: Astatistical measure that indicates the extent to which two or more variables fluctuate together

Efficacy: The ability to produce an intended or desired outcome

Fibrosis: The thickening and scarring of connective tissue (staging)

Grading: Histologic measurement of the severity of the underlying disease process, as measured by degree of necro-inflammatory activity (measured with a categorical scale)

Histology: The scientific study of the fine detail of biological cells and tissues using microscopes to look at specimens of tissues that have been carefully prepared using special processes called “histological techniques”

Histopathological: Microscopic examination of tissue in order to study the manifestations of disease.

Necro-inflammatory activity: Reflects the degree of necrosis and inflammation

Necrosis: Death of cells

Prognostic: Relating to or serving to predict the likely course of a medical condition

Staging: Histologic measurement of disease progression, as measured by the degree of scarring (fibrosis) and cirrhosis in the liver

Validation: A process by which the accuracy or soundness of a data collection system or instrument (such as staging, questionnaires and so forth) is assessed for dependability


The author of this lay version of the article is Dr Valmae Ypinazar (PhD), Senior Research Fellow, Griffith University, Southport, Queensland, Australia.

The original (English) version of the above article has been cheked and approved by Dr. E.M.G de Vries. 

This version is based on the full article:

Applicability and prognostic value of histologic scoring systems in primary sclerosing cholangitis.

 Elisabeth M.G. de Vries1, Joanne Verheij2, Stefan G. Hubscher3, Mariska M.G. Leeflang4, Kirsten Boonstra1, Ulrich Beuers1, Cyriel Y. Ponsioen1,

1 Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; 2 Department of Pathology,

Academic Medical Center, Amsterdam, The Netherlands; 3 School of Cancer Sciences, University of Birmingham and Department of Cellular

Pathology, Queen Elizabeth Hospital, Birmingham, United Kingdom; 4 Department of Clinical Epidemiology, Biostatistics and Bioinformatics,

Academic Medical Center, Amsterdam, The Netherlands