Paternally Inherited Phenotypes in Cholestasis (PIP-C)

Investigation of the Effect of Raised Serum Bile Acids on the Epigenome of Sperm and the Association With the Metabolic Health of the Children of Men With Cholestasis: a Case-control Study.

For some years investigators have known that the health of fathers at the time their baby is conceived has an influence on the health of their child in the future. Many studies looking at this effect have investigated fathers with obesity and other metabolic disorders. These disorders can alter the risk of obesity and diabetes in the children of these men. More recently, studies have been undertaken to establish the mechanism by which this risk is inherited by the children. Studies of sperm have identified that changes in the structure and function of the sperm play a role.

Primary Sclerosing Cholangitis (PSC) and Primary Biliary Cholangitis (PBC) are included in a group of cholestatic liver disorders that are associated with elevated levels of bile acids in the blood (cholestasis). A previous study has established that children born to women who have cholestasis during pregnancy are at an increased risk of obesity later in life. Our study will investigate whether there is a similar effect on the health of children if their father has cholestasis.

The study has 2 arms, the Sperm Epigenome arm and the Outcomes arm.

In the Sperm Epigenome arm of the study, the structure and function of sperm from men with PSC, PBC and other cholestatic liver disorders will be investigated and compared to the structure and function of sperm from healthy men.

In the Outcomes arm of the study, basic health parameters of fathers who had PSC, PBC or another cholestatic liver disease either before or after their child was conceived will be studied. Basic health parameters will also be studied in their child when the child is between 16 and 25 years of age.

Study Overview

• Status: Unknown
• Conditions: Primary Sclerosing Cholangitis; Cholestasis; Primary Biliary Cirrhosis
• Intervention / Treatment: Other: Questionnaire, semen sample, fasting blood sample; Other: Questionnaire; Other: Questionnaire, fasting blood sample

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SE5 9RS
    • Recruiting
    • King's College Hospital
    • Contact: Bernadette Solis; Phone Number: 02032991495; Email: bernadette.solis@nhs.net
  • London, United Kingdom, SE1 9RT
    • Recruiting
    • Assisted Conception Unit, Guy's Hospital
    • Contact: Jean Bvumbe; Email: Jean.Bvumbe@gstt.nhs.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Men with cholestatic liver conditions including but not restricted to Primary Sclerosing Cholangitis and Primary Biliary Cholangitis.

Fathers with cholestatic liver conditions including but not restricted to Primary Sclerosing Cholangitis and Primary Biliary Cholangitis and their children aged 16 - 25 yeas of age.

Description

Sperm Epigenome Arm:

Cholestatic men

Inclusion Criteria:

• Men who have a diagnosis of a cholestatic liver condition including but not restricted to Primary Sclerosing Cholangitis and Primary Biliary Cholangitis.
• Me who are able and willing to give informed consent.

Exclusion Criteria:

• Men who have a history of diabetes or obesity.
• Men who have gallstones, cancer or other acute cholestatic pathology.
• Men who have a history of alcohol excess or drug abuse.
• Men who smoke.
• Men who have blood-borne viruses e.g. HIV or hepatitis.
• Men unable or unwilling to give informed consent

Healthy men

Inclusion Criteria:

• Men who have no history of cholestasis, liver disease, diabetes or obesity.
• Me who are able and willing to give informed consent.

Exclusion Criteria:

• Men who have a history of cholestasis or liver disease.
• Men who have a history of diabetes or obesity.
• Men who have a history of alcohol excess or drug abuse.
• Men who smoke.
• Men who have blood-borne viruses e.g. HIV or hepatitis.
• Men undergoing fertility treatment due to male factor.
• Men unable or unwilling to give informed consent

Outcomes Arm:

Fathers

Inclusion Criteria:

• Fathers with a cholestatic liver condition including but not restricted to Primary Sclerosing Cholangitis and Primary Biliary Cholangitis.
• Fathers with cholestatic liver condition whose children are between 16 years - 25 years of age.
• Fathers with cholestatic liver condition who are able and willing to give informed consent.

Exclusion Criteria:

• Fathers with a history of diabetes or obesity at the time of conception of their child.
• Fathers with a history of alcohol excess or drug-abuse at the time of conception of their child.
• Fathers who smoked at the time of conception of their child.
• Fathers with blood-borne viruses e.g. HIV and hepatitis at the time of conception of their child.
• Fathers unable or unwilling to give informed consent.

Children of cholestatic fathers

Inclusion Criteria:

• Adolescents / young adults (between 16 - 25 years of age) whose fathers have a cholestatic liver condition including but not restricted to Primary Sclerosing Cholangitis or Primary Biliary Cholangitis.
• Adolescents /young adults born from an uncomplicated singleton pregnancy.
• Adolescents /young adults who are able and willing to give informed consent.

Exclusion Criteria:

• Adolescents / young adults who were born as a result of multi-fetal pregnancy.
• Adolescents / young adults with a history of alcohol excess or drug-abuse.
• Adolescents / young adults who are under 16 years of age, or over 25 years of age.
• Adolescents / young adults with blood-borne viruses e.g. HIV and hepatitis.
• Adolescents / young adults who are unable or unwilling to give informed consent.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Sperm Epigenome arm/healthy men; Men with no significant health problems.	Other: Questionnaire, semen sample, fasting blood sample; Participants are asked to complete a questionnaire and provide a semen sample and fasting blood sample.
Sperm Epigenome arm/cholestatic men; Men with a cholestatic liver condition including but not restricted to Primary Sclerosing Cholangitis and Primary Biliary Cholangitis.	Other: Questionnaire, semen sample, fasting blood sample; Participants are asked to complete a questionnaire and provide a semen sample and fasting blood sample.
Outcomes arm/Cholestatic fathers; Fathers who were diagnosed with a cholestatic liver condition including but not restricted to Primary Sclerosing Cholangitis and Primary Biliary Cholangitis either before or after the conception of their child who is now aged 16 - 25 years of age.	Other: Questionnaire; Participants are asked to complete a questionnaire.
Outcomes arm/Children of cholestatic fathers; 16 - 25 years-old children of fathers who were diagnosed with a cholestatic liver condition including but not restricted to Primary Sclerosing Cholangitis and Primary Biliary Cholangitis either before or after their conception.	Other: Questionnaire, fasting blood sample; Participants are asked to complete a questionnaire and provide a fasting blood sample.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of male cholestasis on DNA methylation patterns in sperm		01/04/2018
Impact of male cholestasis on small RNA content in sperm		01/04/2018
Impact of male cholestasis on sperm histone retention		01/04/2018
Impact of paternal cholestasis on the BMI, hip and waist girth of their adolescent / young adult children		01/04/2018
Impact of paternal cholestasis on the general health of their adolescent / young adult children	The prevalence of heart, lung, diabetes, thyroid, kidney or liver disease in children of fathers with cholestasis will be investigated	01/04/2018

Secondary Outcome Measures

Outcome Measure	Time Frame
Impact of male cholestasis on seminal fluid composition.	01/04/2018

Collaborators and Investigators

• Sponsor: Guy's and St Thomas' NHS Foundation Trust
• Collaborators: King's College Hospital NHS Trust

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2017
• Primary Completion (Anticipated): April 30, 2020
• Study Completion (Anticipated): April 30, 2020

Study Registration Dates

• First Submitted: November 1, 2017
• First Submitted That Met QC Criteria: November 6, 2017
• First Posted (Actual): November 8, 2017

Study Record Updates

• Last Update Posted (Actual): August 2, 2019
• Last Update Submitted That Met QC Criteria: August 1, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Liver Cirrhosis; Cholangitis; Cholangitis, Sclerosing; Cholestasis; Liver Cirrhosis, Biliary
• Other Study ID Numbers: 182833

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No