The Role of Sodium Chloride and the Treg/Th17 Axis in Autoimmune Hepatitis

The purpose of this study is to determine whether a salt restriction diet improves immune parameters in patients with autoimmune hepatitis.

Study Overview

• Status: Completed
• Conditions: Autoimmune Hepatitis
• Intervention / Treatment: Other: Low Salt Diet; Other: Liberal salt diet

Detailed Description

The etiology of autoimmune hepatitis (AIH) is unknown although both genetic and environmental factors are thought to be involved. A defect in immune regulation affecting regulatory T cells (Tregs) has been demonstrated in AIH. Tregs function in the maintenance of immune homeostasis by controlling autoreactive immune responses to self-antigens.

Rationale: the western diet has been postulated as a potential environmental risk factor for the increasing incidence of autoimmune diseases in developed countries. Data from the investigators' laboratory also suggests that increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic Th17 cells. The dramatic in vitro effects of high salt on the induction of pathogenic Th17 cells from naïve human CD4 cells {Kleinewietfeld, Hafler. Nature. 2013 Apr 25;496(7446):518-22. doi: 10.1038/nature11868.}, and block of in vitro Treg suppression, in line with in vivo effects on worsening murine experimental autoimmune encephalomyelitis (EAE), have prompted the investigators to examine the effects of increased dietary sodium chloride in a human in vivo system.

The investigators hypothesize that excess dietary salt may function as an environmental trigger that favors induction and expansion of pathogenic Th17 cells and leads to functional impairment of Tregs, thereby favoring development of autoimmunity. The investigators aim to study their established in vitro model in humans by altering the salt intake in patients over a 20-day period.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Adults 18-50 years of age
• Children 1-17 years of age
• ALT and/or ALP/GGT level > 2X upper limit of normal
• ANA or SMA >/= 1:40
• ANA or SMA >/= 1:80
• or LKM >/= 1:40
• or SLA positive
• IgG > upper limit of normal

Exclusion Criteria:

• Chronic hepatitis C
• Decompensated Liver Disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low salt/ Liberal salt Diet; Cross-over trial of liberal salt and low salt diet.	Other: Low Salt Diet; On Day 0, patients will be randomized to one of the two crossover liberal/low or low/liberal salt diet groups. Each subject will complete two controlled dietary phases: 10-days of low salt diet, a washout period of 3-days, and 10-days of liberal salt diet.; Other: Liberal salt diet; On Day 0, patients will be randomized to one of the two crossover liberal/low or low/liberal salt diet groups. Each subject will complete two controlled dietary phases: 10-days of low salt diet, a washout period of 3-days, and 10-days of liberal salt diet.
Experimental: Liberal salt/Low salt diet; Cross-over trial of low salt and liberal salt diet	Other: Low Salt Diet; On Day 0, patients will be randomized to one of the two crossover liberal/low or low/liberal salt diet groups. Each subject will complete two controlled dietary phases: 10-days of low salt diet, a washout period of 3-days, and 10-days of liberal salt diet.; Other: Liberal salt diet; On Day 0, patients will be randomized to one of the two crossover liberal/low or low/liberal salt diet groups. Each subject will complete two controlled dietary phases: 10-days of low salt diet, a washout period of 3-days, and 10-days of liberal salt diet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in production of pathogenic TH17 cells.	Measuring TH17 cells by flow cytometry and qRT-PCR. There are no known normal ranges. The investigator will calculate the change by observing the difference from baseline values.	26 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in regulatory T cell function.	Measuring T cell function by flow cytometry. There are no known normal ranges. The investigator will calculate the change by observing the difference from baseline values.	26 days

Collaborators and Investigators

• Sponsor: Yale University

Study record dates

Study Major Dates

• Study Start (Actual): August 27, 2013
• Primary Completion (Actual): August 1, 2019
• Study Completion (Actual): June 1, 2021

Study Registration Dates

• First Submitted: November 4, 2013
• First Submitted That Met QC Criteria: January 28, 2014
• First Posted (Estimate): January 31, 2014

Study Record Updates

• Last Update Posted (Actual): July 28, 2021
• Last Update Submitted That Met QC Criteria: July 27, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Autoimmune hepatitis; Liver dysfunction; Elevated serum auto antibodies
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Immune System Diseases; Autoimmune Diseases; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis, Autoimmune
• Other Study ID Numbers: 1303011696; YSOM Pediatrics Department (Other Identifier: Yale University School of Medicine)