### Hepatic Insufficiency: Impact on the Autonomic Nervous System, Neurotransmitters, and

IBS Therapies

**Hepatic insufficiency**, also known as liver insufficiency or liver failure, refers to the liver's
impaired ability to perform its essential functions, such as detoxification, protein synthesis,
and metabolism of drugs and hormones. It can be acute (e.g., acute liver failure) or chronic
(e.g., cirrhosis) and significantly affects multiple systems, including the autonomic nervous
system (ANS), neurotransmitter regulation, and the management of conditions like **irritable
bowel syndrome (IBS)**. Below, we explore hepatic insufficiency in the context of the
sympathetic nervous system (SNS), parasympathetic nervous system (PNS), their
neurotransmitters (norepinephrine, epinephrine, acetylcholine), and its implications for IBS
therapies, including anticholinergics and emerging treatments like those in the GALAXI trials.

#### Hepatic Insufficiency and the Autonomic Nervous System

Hepatic insufficiency disrupts the balance between the SNS and PNS due to altered
metabolism, toxin accumulation, and systemic inflammation, leading to autonomic
dysfunction. This can exacerbate IBS symptoms and complicate its management.

1. **Sympathetic Nervous System (SNS) Dysfunctions**:

- **Mechanism**: The liver metabolizes catecholamines (norepinephrine, epinephrine) via

enzymes like monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). In
hepatic insufficiency, reduced enzyme activity leads to elevated catecholamine levels, causing
SNS overactivity.

- **Effects**:

- **Increased Heart Rate and Blood Pressure**: Overactive adrenergic receptors (α1, β1)
due to excess norepinephrine/epinephrine can cause tachycardia and hypertension,
mimicking anxiety or stress responses.

- **Mental Health Impact**: SNS overactivity amplifies anxiety and hypervigilance,

common in IBS patients, via heightened amygdala activity. This worsens gut-brain axis
dysregulation, increasing visceral hypersensitivity.
 - **IBS Aggravation**: SNS dominance can reduce gut motility, exacerbating **IBS-C**
(constipation-predominant) symptoms, or trigger diarrhea in **IBS-D** via stress-induced
motility changes.

- **Example**: In cirrhosis, portal hypertension and systemic vasodilation paradoxically

increase SNS activity to compensate, worsening IBS symptoms like abdominal pain.

2. **Parasympathetic Nervous System (PNS) Dysfunctions**:

- **Mechanism**: Hepatic insufficiency impairs acetylcholine metabolism indirectly through

systemic inflammation and altered vagal nerve signaling. Ammonia accumulation in hepatic
encephalopathy (HE) disrupts CNS cholinergic pathways, reducing PNS tone.

- **Effects**:

- **Reduced Heart Rate Variability (HRV)**: Decreased muscarinic receptor (M2) activity
impairs vagal control, lowering HRV, a marker of poor emotional resilience linked to anxiety
and depression in IBS.

- **Gastrointestinal Dysmotility**: Diminished M3 receptor signaling in the gut reduces

peristalsis and secretions, contributing to constipation or bloating, particularly in **IBS-C**.

- **Mental Health Impact**: Reduced PNS activity hinders relaxation, exacerbating stress-
related IBS flares and worsening mood disorders.

- **Example**: In HE, elevated ammonia levels impair vagal signaling, reducing PNS-
mediated gut motility, which can mimic or worsen IBS symptoms.

3. **Neurotransmitter Dysregulation**:

- **Norepinephrine/Epinephrine (SNS)**: Impaired hepatic clearance increases circulating

catecholamines, overstimulating adrenergic receptors and amplifying SNS-driven symptoms
(e.g., tachycardia, anxiety).

- **Acetylcholine (PNS)**: While acetylcholine metabolism is less directly affected, systemic

inflammation and HE disrupt muscarinic and nicotinic receptor signaling, reducing PNS
efficacy.

- **CNS Impact**: Ammonia and inflammatory cytokines in HE alter CNS neurotransmitter

balance (e.g., glutamate, GABA), further disrupting autonomic control and exacerbating
mental health issues like confusion or depression, which overlap with IBS comorbidities.
#### Impact on IBS and Its Therapies

Hepatic insufficiency complicates IBS management by altering drug metabolism, worsening

autonomic dysfunction, and increasing psychological comorbidities. Below, we examine its
effects on key IBS therapies, including anticholinergics and emerging treatments like those in
the GALAXI trials.

1. **Anticholinergics in IBS with Hepatic Insufficiency**:

- **Role in IBS**: Anticholinergics (e.g., dicyclomine, hyoscyamine) block muscarinic

receptors to reduce gut spasms and diarrhea in **IBS-D** or pain in all subtypes.

- **Challenges in Hepatic Insufficiency**:

- **Altered Metabolism**: The liver metabolizes many anticholinergics (e.g., dicyclomine

via cytochrome P450 enzymes). Hepatic insufficiency reduces clearance, increasing drug levels
and risk of toxicity (e.g., tachycardia, delirium).

- **Worsened PNS Suppression**: Anticholinergics further reduce already diminished PNS

tone, exacerbating constipation (worsening **IBS-C**), dry mouth, and cognitive impairment,
especially in HE.

- **Mental Health Risks**: Increased anticholinergic burden in hepatic insufficiency

heightens delirium risk, particularly in elderly patients, amplifying IBS-related anxiety or
depression.

- **Example**: Overuse of hyoscyamine in a cirrhotic patient may cause severe

constipation and confusion, worsening IBS symptoms and mental health.

- **Management**: Use low-dose, short-acting anticholinergics with close monitoring;

avoid in severe hepatic insufficiency (Child-Pugh C) due to toxicity risks.

2. **Dietary and Lifestyle Interventions**:

- **Role in IBS**: Low FODMAP diet, Mediterranean diet, and stress reduction (e.g.,
mindfulness) are first-line for all IBS subtypes, reducing bloating and motility issues.

- **Challenges in Hepatic Insufficiency**:

- **Nutritional Constraints**: Protein restriction in HE (to reduce ammonia) conflicts with

IBS dietary needs, potentially worsening malnutrition or gut dysbiosis.
 - **Fatigue and Compliance**: Hepatic insufficiency causes fatigue, reducing adherence to
complex diets or exercise regimens.

- **Mental Health**: Anxiety and depression, exacerbated by HE, hinder engagement with
stress-reduction therapies.

- **Management**: Simplify diets (e.g., low FODMAP with high-calorie, low-protein

options), use telehealth for dietary counseling, and integrate mindfulness to address
autonomic and psychological imbalances.

3. **Microbiome-Based Therapies**:

- **Role in IBS**: Probiotics (e.g., Bifidobacterium infantis) and antibiotics like rifaximin
improve gut dysbiosis and symptoms in **IBS-D** and **IBS-C**.

- **Challenges in Hepatic Insufficiency**:

- **Rifaximin Use**: Rifaximin, FDA-approved for IBS-D, is also used for HE to reduce
ammonia-producing gut bacteria. However, hepatic insufficiency alters gut microbiota,
potentially reducing probiotic efficacy.

- **Safety Concerns**: Emerging microbiome therapies (e.g., EBX-102-02) lack data in

hepatic insufficiency, and altered liver metabolism may affect drug delivery or efficacy.

- **Mental Health**: Microbiome dysbiosis in cirrhosis worsens gut-brain axis dysfunction,

amplifying IBS-related anxiety.

- **Management**: Rifaximin is safe in hepatic insufficiency and may benefit both HE and
IBS-D; probiotics should be strain-specific and monitored for efficacy.

4. **Brain-Gut Behavioral Therapies**:

- **Role in IBS**: Cognitive behavioral therapy (CBT, e.g., Regulora app), gut-directed
hypnotherapy, and mindfulness reduce stress-induced IBS flares.

- **Challenges in Hepatic Insufficiency**:

- **Cognitive Impairment**: HE causes confusion, reducing engagement with CBT or

hypnotherapy.

- **Autonomic Dysregulation**: Reduced PNS tone (low HRV) impairs relaxation

responses, limiting therapy efficacy.
 - **Mental Health**: HE-related depression and anxiety overlap with IBS comorbidities,
complicating psychological management.

- **Management**: Use digital CBT platforms for accessibility; tailor sessions to cognitive
capacity in HE patients.

5. **Pharmacological Agents (Non-Anticholinergic)**:

- **Role in IBS**: Low-dose amitriptyline (for pain), linaclotide (IBS-C), and eluxadoline (IBS-
D) target specific symptoms.

- **Challenges in Hepatic Insufficiency**:

- **Amitriptyline**: Metabolized by the liver (CYP2D6), requiring dose reduction in hepatic

insufficiency to avoid toxicity (e.g., sedation, arrhythmia).

- **Linaclotide/Plecanatide**: Minimal systemic absorption makes them safer for IBS-C in

hepatic insufficiency, but efficacy may be reduced due to altered gut motility.

- **Eluxadoline**: Contraindicated in severe hepatic insufficiency (Child-Pugh C) due to

increased opioid-related side effects (e.g., pancreatitis risk).

- **Management**: Prioritize linaclotide for IBS-C; use amitriptyline cautiously with liver
function monitoring; avoid eluxadoline in severe cases.

6. **GALAXI Trials and IL-23 Inhibitors**:

- **Role in IBS Context**: The GALAXI trials (NCT03466411) evaluated guselkumab, an IL-
23p19 inhibitor, for Crohn’s disease (CD), achieving FDA approval in March 2025 for
moderately to severely active CD. While not directly approved for IBS, IL-23 inhibitors are
being explored for IBS-IBD overlaps due to low-grade inflammation in some IBS cases.

- **Challenges in Hepatic Insufficiency**:

- **Metabolism**: Guselkumab, a monoclonal antibody, has minimal hepatic metabolism,

making it safer in liver insufficiency compared to small-molecule drugs. However, systemic
inflammation in cirrhosis may alter immune responses, potentially affecting efficacy.

- **IBS-IBD Overlap**: IBS patients with suspected inflammatory overlap (e.g., post-
infectious IBS-D) may benefit from IL-23 inhibitors, but no GALAXI data directly address IBS.
Hepatic insufficiency complicates differential diagnosis, as IBS symptoms mimic CD flares.
 - **Mental Health**: IL-23 inhibitors may reduce gut-brain inflammation, potentially
alleviating IBS-related anxiety, but data are preliminary.

- **Management**: Consider guselkumab in IBS-CD overlap cases with confirmed

inflammation (e.g., elevated calprotectin); monitor liver function and avoid in active HE due
to infection risks.

#### Key Considerations for IBS Management in Hepatic Insufficiency

- **Autonomic Dysregulation**: Hepatic insufficiency amplifies SNS dominance and reduces

PNS tone, worsening IBS symptoms (e.g., pain, motility issues) and mental health (anxiety,
depression). Therapies must address this imbalance.

- **Drug Safety**: Most IBS drugs (e.g., anticholinergics, amitriptyline) require hepatic
metabolism, necessitating dose adjustments or alternatives like linaclotide.

- **Mental Health**: HE and IBS share psychological comorbidities, requiring integrated

approaches (e.g., CBT, low-dose antidepressants).

- **Microbiome Focus**: Rifaximin and probiotics are promising for dual management of HE
and IBS, leveraging gut microbiota modulation.

- **Emerging Therapies**: While GALAXI trials target CD, IL-23 inhibitors like guselkumab may
hold future promise for inflammatory IBS subtypes, especially in patients with hepatic
insufficiency due to low metabolic burden.

#### Conclusion

Hepatic insufficiency complicates IBS management by disrupting SNS and PNS balance,
elevating catecholamines, and impairing acetylcholine signaling, which exacerbates
gastrointestinal and psychological symptoms. Anticholinergics, while useful for IBS-D, pose
risks of toxicity and worsened autonomic dysfunction in liver failure. Dietary, microbiome,
and behavioral therapies are safer but face compliance challenges. Emerging treatments like
IL-23 inhibitors (e.g., guselkumab from GALAXI) are not yet IBS-approved but may benefit
overlap cases. Tailored, multidisciplinary care with careful drug selection and monitoring is
essential for managing IBS in hepatic insufficiency, addressing both autonomic and mental
health impacts. Consult a gastroenterologist and hepatologist for personalized treatment
plans.