Short summary

We aim to perform a register based cohort study of all liver stiffness measurements (LSM) performed on all registered Danish hepatitis B and C patients to explore the prognostic ability of LSM in this group. Outcomes will be liver cirrhosis, incompensated liver disease and death, both liver related and overall death.

Rationale

Formation of fibrosis is the main driver of disease in most chronic liver diseases (CLD).

Vibration-controlled transient elastografy (VCTE) is a new non-invasive ultrasound based technology with a high inter- and intra-observer agreement that provides clinicians with a liver stiffness measurement (LSM) that functions as a proxy for the degree of liver fibrosis.

More research on the role of VCTE in predicting outcomes for patients with chronic hepatitis B (CHB) and chronic hepatitis C (CHC) is needed.

Objectives 

1. To describe the current distribution of LSM among patients with CHB and CHC in Denmark and for both viruses to determine the development of LSM over time and correlation with liver related outcome (cirrhosis, decompensated cirrhosis) and liver related death/liver transplantation and overall death.
2. To evaluate the effect of time between repeated measurements and the applicability of the OUH definition of change (20/2/7) at a national level. 
3. To identify risk factors associated with presence or development of fibrosis, cirrhosis, LRO and death, and to validate the effect of treatment on LSM over time.

Hypotheses

1. In the Danish hepatitis population retained in care approximately 90 % will have at least one valid LSM that allows for inclusion in the study. More than half of the patients will have minimal or no signs of disease progression and approximately 15 % will have signs of cirrhosis. Patients with a normal LSM at inclusion will have no or minimal progression in LSM and a high LSM value at inclusion will be associated with progression on subsequent LSM.
2. Based on a previous study done by our group we have proposed a rule of 2/20/7 that will predict true disease progression. That is an increase of at least 2 kilo pascal (kPa), that also represents at least a 20 % increase from the value of the previous LSM and is above the upper limit of normal (7 kPa).
3. Risk factors associated with presence or development of fibrosis and cirrhosis, liver related outcomes and death will be a high LSM at inclusion, alcohol abuse, age at index LSM, ethnicity, treatment of viral hepatitis and male gender.

Description of the cohort

All patients with hepatitis B and/or C in the Danish hepatitis databases DANHEP and Infcare hepatitis who have at least one recorded LSM.

Data and biological material

This is a register based historical cohort study. The study will include patients with at least one reliable LSM in the DANHEP and Infcare hepatitis  databases. The LSM measurements will be extracted directly from the Fibroscan software at the individual clinics who reports to DANHEP and missing values will be sought after in the Infcare database and from the DANHEP database. The Personal Identification number PIN (CPR) will be used to merge measurements with clinical databases:

• • DANHEP and Infcare Hepatitis 
• The National Patient Registry 
• The National Pathology Data Bank 
• The Central Office of Civil registration
• The Cause of Death Register 
• The Registry of Drug Abusers Undergoing Treatment
• The Cancer Register
• The National Registry of Alcohol Treatment
• Data on sex, age, parent's country of birth and vital status will be derived directly from the Central Office of Civil registration. 
• Data on genotype and blood samples (ALAT, INR and thrombocytes) will be extracted from DANHEP
• Information of alcohol abuse will be taken from The National Patient Registry and National Registry of Alcohol Treatment  as the data on alcohol use in DANHEP are lagging. Data on Odense patients on alcohol abuse are adequate and will be used to validate the data from LPR. 
• Data on the cirrhosis status, liver related complications and liver related and overall death will be sought in DANHEP, infcare, The National Patient Registry, the National Pathology Data Bank, the Cause of Death Register and the Cancer Register
• Information on intravenous drug use will be taken from DANHEP and the Register of Drug Abusers Undergoing Treatment.
• Data that are missing after going through the mentioned databases and registers will be sought after in the individual patient files.