Part 1
An Endocrine Perspective On Detox, Metabolic Disease, and Imaging In The MASLD Era
From a 2025 interview with Angela Mazza, DO – Integrative Endocrinology & Metabolic Medicine
When liver pathways become overwhelmed—from environmental exposure, nutrient deficits, endocrine-disrupting chemicals, chronic inflammation, or metabolic overload—the result is a predictable cascade: impaired hormone clearance, disrupted thyroid activation, insulin resistance, and mitochondrial dysfunction. This relationship is gaining urgency in clinical medicine due to the sharp rise of metabolic dysfunction–associated steatotic liver disease (MASLD/MAFLD), now the world’s most common liver disorder and a hallmark of modern metabolic syndrome.
The Liver’s Endocrine Functions
Three endocrine pathways illustrate the liver’s pivotal role in hormonal homeostasis:
1. Estrogen Metabolism and Clearance
The liver performs Phase I and Phase II biotransformation to break down and neutralize estrogens before excretion. When these pathways are impaired, estrogen metabolites may accumulate, contributing to a clinical picture often described as estrogen dominance. Symptoms may include menstrual irregularity, fibrocystic breast changes, weight gain, mood fluctuations, or amplified vasomotor symptoms in menopause. Research confirms that impaired hepatic metabolism can meaningfully influence circulating estrogen levels and symptomatic expression (Liu et al., 2021).
Approximately 60% of the body’s active thyroid hormone (T3) is generated through hepatic conversion of thyroxine (T4) (Senese et al., 2018). When the liver is inflamed, infiltrated with fat, or burdened by oxidative stress, conversion efficiency declines. Patients may present with fatigue, constipation, cold intolerance, hair changes, or metabolic slowdown—despite normal thyroid bloodwork. This disconnect illustrates that hormone activation and utilization are just as essential as hormone production.
The liver stores glycogen, releases glucose, and is a primary site of insulin signaling. Hepatic insulin resistance is often the first measurable sign of future metabolic disease. Studies show that liver fat independently predicts insulin resistance and cardiometabolic risk, even before overt diabetes emerges (Bril & Cusi, 2017). This makes the liver central—not peripheral—to endocrine-metabolic dysfunction.
Together, these pathways demonstrate why hormonal symptoms frequently reflect underlying hepatic stress.
MASLD, Metabolic Overload, and Endocrine Disruption
MASLD/MAFLD has reached epidemic prevalence, affecting an estimated one-third of adults globally (Eslam, Newsome, & Sarin, 2020). It is strongly linked to insulin resistance, visceral adiposity, and mitochondrial stress—suggesting that it is as much a hormonal and metabolic disease as a hepatic one.
The pathophysiology forms a self-reinforcing loop:
· Insulin resistance drives hepatic fat accumulation
· Hepatic fat worsens inflammation and oxidative stress
· Inflammation interferes with thyroid conversion
· Reduced T3 slows metabolism and mitochondrial output
· Slowed metabolism worsens insulin resistance and fat storage
· Impaired detoxification worsens estrogen imbalance
This cyclical model highlights why MASLD is not merely a liver condition—it is a systemic metabolic disorder with endocrine consequences.
Detoxification, Nutrient Pathways, and Hormonal Balance
Effective hepatic detoxification depends on enzymatic pathways that require amino acids, antioxidants, and micronutrients such as selenium, B vitamins, magnesium, and sulfur-based compounds. When these nutrients are deficient, hormonal disruption is often an early clinical sign. Evidence shows that even mild micronutrient deficiencies can alter detoxification efficiency, oxidative stress, and metabolic signaling (Schmidt & Dalhoff, 2002).
Dr. Mazza’s integrative model focuses on:
· Reducing toxin load
· Restoring nutrient cofactors
· Improving mitochondrial resilience
· Enhancing insulin sensitivity
· Supporting endocrine balance
· Measuring progress rather than guessing
This final point—measurement—has become the missing ingredient in many detox or metabolic restoration programs.
Elastography: A New Frontier in Endocrine and Detox Imaging
Ultrasound elastography provides a non-invasive method to quantify liver stiffness, allowing clinicians to identify fibrosis earlier and track changes over time. As a radiation-free modality, it aligns ideally with integrative and preventive care.
Emerging literature supports elastography as a reliable tool for staging fibrosis in steatotic liver disease (Castera, Friedrich-Rust, & Loomba, 2019). For endocrinologists, this offers transformative potential: instead of waiting years for MASLD to progress toward cirrhosis, practitioners can verify improvement or progression in real time, correlating fibrosis scores with metabolic or detox interventions.
Dr. Mazza believes elastography will become a foundation of imaging-validated metabolic medicine.
 STRAIN vs SHEAR WAVE ELASTOGRAPHY Strain elastography evaluates tissue stiffness by measuring deformation when pressure is applied. The resulting color map is qualitative—blue tones represent softer, homogeneous tissue, while green indicates early fibrosis and red denotes firm, scarred regions. In one liver case, strain imaging showed homogenous blue echoes centrally with lateral areas of red scarring, prompting biopsy for confirmation. Shear wave elastography, however, quantifies stiffness in kilopascals. In a comparable case, homogeneous teal echoes with a mean value of 5 kPa confirmed normal tissue consistency—allowing the clinician to cancel a planned biopsy. This demonstrates shear wave’s precision and reliability in real-time liver evaluation. Source: www.barddiagnostics.com |
Supplemental Insights: Additional Dimensions of the Liver–Endocrine Connection
While the liver’s role in hormone metabolism, binding protein production, and endocrine cross-talk is well-established, emerging research highlights several additional mechanisms that deepen our understanding of the liver–endocrine axis:
1. Sex Hormone–Binding Globulin (SHBG) as a Metabolic Signal: The liver synthesizes SHBG, a critical binding protein that modulates the bioavailability of testosterone and estrogen. Low SHBG levels are strongly associated with insulin resistance, metabolic syndrome, and MASLD, making SHBG not only a transport molecule but also a biomarker for endocrine-metabolic stress.
2. Hepatokines as Endocrine Messengers: The liver produces its own hormone-like signaling molecules—such as FGF21, fetuin-A, and hepassocin—that influence thyroid pathways, adipose tissue behavior, glucose metabolism, and systemic inflammation. These hepatokines act as messengers that allow the liver to function as an endocrine organ influencing distant tissues.
3. Estrogen’s Protective Effects on Hepatic Metabolism: Estrogen supports mitochondrial efficiency and reduces hepatic fat accumulation. This explains why MASLD risk rises sharply after menopause and why estrogen balance is tightly linked to liver health. Impaired estrogen clearance or low estrogen states may accelerate hepatic steatosis.
4. Cortisol and Stress-Driven Fatty Liver Progression: Chronically elevated cortisol—whether from stress, Cushing physiology, or sleep disruption—promotes gluconeogenesis, insulin resistance, and visceral adiposity. This creates a hormonal environment that accelerates fatty liver progression, illustrating how HPA-axis imbalance directly burdens hepatic metabolism.
5. Deiodinase Activity and Hepatic T3 Activation: The liver is a major site of deiodinase (D1 and D2) activity, driving conversion of T4 into metabolically active T3. Fibrosis, steatosis, or hepatic inflammation can suppress this conversion, reinforcing the clinical observation that thyroid-related symptoms often parallel liver dysfunction.
Why These Concepts Matter
These additional mechanisms emphasize that liver health cannot be separated from endocrine health. SHBG, hepatokines, cortisol physiology, estrogen balance, and deiodinase activity all demonstrate a bi-directional, hormone-dependent feedback system. Recognizing these pathways gives clinicians more precise diagnostic insight and more therapeutic leverage—particularly in MASLD, metabolic syndrome, menopause, thyroid dysfunction, and stress-related disorders.
Conclusion: Repair the Liver, Reset the Hormones, Restore Metabolic Health
The liver and endocrine system operate as a unified axis. MASLD has made that reality undeniable. By adopting an integrative, imaging-supported approach—targeting detoxification, insulin resistance, mitochondrial resilience, and hormone balance—clinicians can intervene earlier and more effectively.
In Dr. Mazza’s view, the clinical path forward is clear:
Support the liver. Protect the hormones. Break the metabolic cycle.
References
Bril, F., & Cusi, K. (2017). Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: A call to action. Diabetes Care, 40(3), 419–430.
Castera, L., Friedrich-Rust, M., & Loomba, R. (2019). Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology, 156(5), 1264–1281.
Eslam, M., Newsome, P. N., & Sarin, S. K., et al. (2020). A new definition for metabolic dysfunction–associated fatty liver disease. Journal of Hepatology, 73(1), 202–209.
Liu, Y., Zeng, X., & Yan, Z. (2021). Estrogen metabolism and liver disease: From physiology to pathology. Frontiers in Endocrinology, 12, 1–12.
Senese, R., Cioffi, F., & de Lange, P. (2018). Thyroid hormone and metabolism. Thyroid Research, 11, 1–10.
Schmidt, L. E., & Dalhoff, K. (2002). Food–drug interactions and liver detoxification. Drug Safety, 25(9), 673–683.
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