Composition, therapeutic properties and scientific evidence
The Chianciano waters belong to the sulphate-bicarbonate-calcic class, with sulphate concentrations among the highest documented in the Tuscan thermal panorama (up to ~1800 mg/L in Acqua Santa). The thermal compendium includes four distinct springs - Acqua Santa, Acqua Fucoli, Acqua Silene and Acqua Santissima - belonging to the same geochemical facies but differentiated by temperature, degree of mineralisation and gaseous content, with specific and complementary therapeutic indications.
Scientific research published in peer-reviewed journals has documented measurable effects on hepatobiliary function, with evidence of reduction of fasting cholecystic volume, modulation of the bile acid pool and improvement of symptoms of functional biliary disorders. Preclinical studies have also shown a possible role in modulating the gut-liver axis, with reduction of inflammatory markers and fibrosis in experimental models of hepatic steatosis.
In parallel, mud-balneotherapy with Acqua Silene is the subject of randomised controlled clinical trials that have documented its efficacy in the treatment of osteoarthritis of the knee, with improvement in pain, joint function and modulation of inflammatory and cartilage biomarkers, with persistent benefits over time.
Together, these data configure the Chianciano waters as a hydromineral system characterised by a stable chemical-physical base and documented clinical evidence, with hepatobiliary, gastrointestinal and osteoarticular therapeutic applications, within the framework of integrated thermal medicine recognised by the National Health Service.
A unique hydromineral system in terms of composition and depth
The Chianciano waters emerge from a deep hydrogeological system fed by aquifers hosted in the Triassic and Cretaceous limestones of the Apennine substratum. The high degree of fracturing and marked karstification of these formations allow the waters to rise through deep faults, resulting in prolonged contact with carbonate and evaporitic successions of the Upper Triassic.
The decades of underground permanence and the geochemical interaction with the rocks through which it passes give the water its characteristic sulphate-bicarbonate-calcic facies, with an anionic component dominated by sulphate (SO₄²-) and bicarbonate (HCO₃-), and a cationic component that is predominantly calcic (Ca²⁺) and magnesic (Mg²⁺). Sodium and potassium contents are relatively low, confirming the absence of significant contributions from clastic evaporitic formations.
Systematic analyses carried out by ARPAT, supplemented by internal monitoring from 2002-2011 and the most recent analytical determinations carried out in 2025 by the Department of Chemical Sciences of the University of Naples Federico II, document a remarkable compositional stability over time, with limited variations in individual ions but maintenance of the geochemical facies.
A particularly important fact concerns the sulphate concentration in Acqua Santa, which reaches values close to 1800 mg/L. This level is among the highest in the panorama of Tuscan thermal waters for therapeutic use and is the main chemical substrate of the hepatobiliary indications documented in the literature. The SO₄²-/HCO₃- ratio, greater than 2, highlights the clear predominance of the sulphate component over the bicarbonate component.
From a chemical-physical point of view, the four sources present:
- Temperatures between 15°C and 37.8°C
- Fixed residue at 180°C between ~2500 and ~3450 mg/L
- pH weakly acid-subneutral (6.1-6.9)
- High calcium and magnesium content
- Variable presence of free CO₂, particularly significant in Sillene Water
The combination of hydrogeological circuit depth, multi-year stability and high sulphate concentrations configures the Chianciano hydromineral system as unique in the regional context. It is the chemical-physical basis on which the biological mechanisms described in the following sections are based.
A unique hydromineral system in terms of composition and depth
| Parameter | Holy Water 1 | Holy Water 2 | Holy Water 3 | Holy Water 4 |
|---|---|---|---|---|
| Temperature (°C) | 33,3 | 15-18 | 37,8 | 24,4 |
| pH | 6,1-6,5 | 6,8-6,9 | 6,4 | 6,3 |
| Fixed residue at 180°C (mg/L) | 3235-3451 | 2540-2721 | 2867 | 3095 |
| Conductivity at 25°C (μS/cm) | 3110-3520 | 2660-2810 | 2810 | 3010 |
| Hardness (°F) | 250 | 194 | N.A. | N.A. |
| Free CO₂ (mg/L) | 657-866 | 62-137 | Very high | N.A. |
Sources: ARPAT 2014; Terme di Chianciano (2020-2011); SEA Municipality of Chianciano Terme 2017
| Ion | Holy Water 1 | Holy Water 2 | Holy Water 3 | Holy Water 4 |
|---|---|---|---|---|
| Sulphate (SO₄²-) | ~1800 | 1250-1580 | 1642 | 1728 |
| Bicarbonate (HCO₃-) | 852 | 421-758 | 720 | 842 |
| Calcium (Ca²⁺) | 780 | 614-656 | 642 | 708 |
| Magnesium (Mg²⁺) | 169 | 69-89 | 166 | 173 |
| Sodium (Na⁺) | 23,7 | N.A. | 20,3 | 26,2 |
| Potassium (K⁺) | 6,06 | N.A. | N.A. | N.A. |
| Chloride (Cl-) | 21,2 | 22,7-24,0 | 16,7 | 22,5 |
| Fluoride (F-) | 2,5 | 1,4-1,9 | 2,8 | 3,1 |
| Silica (SiO₂) | 25,8 | 11,2-18,0 | N.A. | N.A. |
| Strontium (Sr) | 12,45 | 10,4-11,5 | N.A. | N.A. |
Sources: University of Naples Federico II - Department of Chemical Sciences (sampling 19.11.2025).
Four sources, one integrated therapy system
The Chianciano waters emerge from a deep hydrogeological system fed by aquifers hosted in the Triassic and Cretaceous limestones of the Apennine substratum. The high degree of fracturing and marked karstification of these formations allow the waters to rise through deep faults, resulting in prolonged contact with carbonate and evaporitic successions of the Upper Triassic.
The decades of subterranean permanence and geochemical interaction with the rocks through which it passes give the water its characteristic sulphate-bicarbonate-calcic facies, with an anionic component dominated by the sulphate ion (SO₄²-) and bicarbonate (HCO₃-), and a cationic component that is predominantly calcic (Ca²⁺) and magnesic (Mg²⁺). Sodium and potassium contents are relatively low, confirming the absence of significant contributions from chlorinated evaporitic formations.
Systematic analyses carried out by ARPAT, supplemented by internal monitoring from 2002-2011 and the most recent analytical determinations carried out in 2025 by the Department of Chemical Sciences of the University of Naples Federico II, document a remarkable compositional stability over time, with limited variations in individual ions but constant maintenance of the geochemical facies.
A particularly important fact concerns the sulphate concentration in Acqua Santa, which reaches values close to 1800 mg/L. This level is among the highest in the panorama of Tuscan thermal waters for therapeutic use and is the main chemical substrate of the hepatobiliary indications documented in the literature. The SO₄²-/HCO₃- ratio, stably above 2, highlights the clear predominance of the sulphate component over the bicarbonate component.
From a chemical-physical point of view, the four sources present:
- Temperatures between 15°C and 37.8°C
- Fixed residue at 180°C between ~2500 and ~3450 mg/L
- pH weakly acid-subneutral (6.1-6.9)
- High calcium and magnesium content
- Variable presence of free CO₂, particularly significant in Silene Water
The combination of hydrogeological circuit depth, multi-year analytical stability and high sulphate concentrations configures the Chianciano hydromineral system as unique in the regional context, providing the chemical-physical basis on which the biological mechanisms described in the following sections are based.
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Holy water. Principal indication: hepatobiliary function and hydropinotherapy
The Chianciano waters emerge from a deep hydrogeological system fed by aquifers hosted in the Triassic and Cretaceous limestones of the Apennine substratum. The high degree of fracturing and marked karstification of these formations allow the waters to rise through deep faults, resulting in prolonged contact with carbonate and evaporitic successions of the Upper Triassic.
The decades of subterranean permanence and geochemical interaction with the rocks through which it passes give the water its characteristic sulphate-bicarbonate-calcic facies, with an anionic component dominated by the sulphate ion (SO₄²-) and bicarbonate (HCO₃-), and a cationic component that is predominantly calcic (Ca²⁺) and magnesic (Mg²⁺). Sodium and potassium contents are relatively low, confirming the absence of significant contributions from chlorinated evaporitic formations.
Systematic analyses carried out by ARPAT, supplemented by internal monitoring from 2002-2011 and the most recent analytical determinations carried out in 2025 by the Department of Chemical Sciences of the University of Naples Federico II, document a remarkable compositional stability over time, with limited variations in individual ions but constant maintenance of the geochemical facies.
A particularly important fact concerns the sulphate concentration in Acqua Santa, which reaches values close to 1800 mg/L. This level is among the highest in the panorama of Tuscan thermal waters for therapeutic use and is the main chemical substrate of the hepatobiliary indications documented in the literature. The SO₄²-/HCO₃- ratio, stably above 2, highlights the clear predominance of the sulphate component over the bicarbonate component.
From a chemical-physical point of view, the four sources present:
- Temperatures between 15°C and 37.8°C
- Fixed residue at 180°C between ~2500 and ~3450 mg/L
- pH weakly acid-subneutral (6.1-6.9)
- High calcium and magnesium content
- Variable presence of free CO₂, particularly significant in Sillene Water
The combination of hydrogeological circuit depth, multi-year analytical stability and high sulphate concentrations configures the Chianciano hydromineral system as unique in the regional context, providing the chemical-physical basis on which the biological mechanisms described in the following sections are based.
Sillene water. Main indication: mud-balneotherapy and balneotherapy
Sillene water is the highest-temperature spring (approx. 37.8°C) and is characterised by a high free CO₂ content. It is not used for hydropinotherapy.
Its therapeutic use concerns:
- Thermal mud maturation for liver and joint applications
- Carbonated baths with hydromassage
- Balneotherapy in the Theia Thermal Pools
Randomised controlled clinical trials have documented:
- Significant reduction of pain in knee osteoarthritis
- Improved joint function (WOMAC, VAS)
- Modulation of inflammatory and cartilage biomarkers
- Persistence of benefit up to 9 months
Fango-balneotherapy with Sillene Water represents one of the best documented clinical applications of the thermal compendium.
Holy Water. Principal indication: inhalation cures
Acqua Santissima emerges at around 24°C, with an ionic composition similar to other springs but with specific characteristics that direct its use to inhalation therapies.
It is used for:
- Thermal aerosols
- Hot-humid inhalations
- Nasal showers
Indications include chronic and relapsing diseases of the upper respiratory tract: rhinitis, sinusitis, pharyngitis, laryngitis and chronic bronchitis.
It is not part of the hepatobiliary protocol but represents an autonomous therapeutic segment within the spa system.
Mechanisms of action of sulphate-bicarbonate-calcic waters
The therapeutic properties attributed to Chianciano waters are based on biological mechanisms consistent with hepatobiliary, intestinal and osteoarticular physiology. The combination of the high concentration of sulphate (SO₄²-), the presence of bicarbonate (HCO₃-), calcium (Ca²⁺) and magnesium (Mg²⁺) results in documented effects on biliary secretion, cholecystic motility, the intestinal-liver axis and inflammatory modulation.
The main mechanisms described in the literature fall into four functional axes.
1. Choleretic and cholagogue action
The sulphate ion represents the main pharmacological mediator of hepatobiliary activity.
The intake of sulphate-bicarbonate-calcium waters stimulates the release of cholecystokinin (CCK) in the duodenum, resulting in:
- Gallbladder contraction
- Release of the sphincter of Oddi
- Increased bile flow in the duodenum
This cholagogue effect was measured ultrasound in the controlled clinical study published in the World Journal of Gastroenterology (Corradini et al., 2012), which documented a significant reduction in fasting cholecyst volume after 12 days of hydropinotherapy.
In parallel, the increased hepatocyte secretion of bile (choleresis) contributes to the reduction of biliary stagnation, a predisposing condition for the formation of biliary sand and cholelithiasis.
2. Modulation of the bile acid pool and FXR receptor activation
The therapeutic properties attributed to Chianciano waters are based on biological mechanisms consistent with hepatobiliary, intestinal and osteoarticular physiology. The combination of the high concentration of sulphate (SO₄²-), the presence of bicarbonate (HCO₃-), calcium (Ca²⁺) and magnesium (Mg²⁺) results in documented effects on biliary secretion, cholecystic motility, the intestinal-liver axis and inflammatory modulation.
The main mechanisms described in the literature fall into four functional axes.
3. Modulation of the gut-liver axis
The pathophysiology of metabolic liver steatosis (MASLD) is closely linked to alterations in the intestinal barrier and translocation of lipopolysaccharides (LPS) into the portal circulation. In a mouse model of steatohepatitis (Carpino et al., 2022), Chianciano sulphate-bicarbonate-calcic water showed:
- Significant reduction in hepatic localisation of LPS
- Reduction of TLR4/NF-kB pathway activation
- Reduction of lobular inflammation
- Reduced activation of hepatic stellate cells
- Improved intestinal mucosal integrity (increased occludin expression)
These data suggest a modulating effect on the gut-liver axis, with potential impact on progression from simple steatosis to fibrosis.
4. Anti-inflammatory action and modulation of cartilage turnover
In the osteoarticular context, fangobalneotherapy with Chianciano waters acts through multiple mechanisms:
- Modulation of pro-inflammatory adipokines (reduction of adiponectin and resistin)
- Reduction of pain symptoms (VAS)
- Improvement of functional indices (WOMAC)
- Stimulation of cartilage turnover (increase in CTX-II)
A 2021 meta-analysis of 21 randomised trials confirms the clinical efficacy of fangobalneotherapy in gonarthrosis, with persistent benefits for up to nine months. The totality of the data suggests a biologically active effect not limited to thermal stress, but attributable to immunomodulatory and metabolic mechanisms.
Scientific evidence on hepatobiliary function
The available literature on Chianciano waters includes controlled clinical studies, observational studies and experimental preclinical models. The body of evidence documents measurable effects on cholecystic dynamics, the bile acid pool and hepatic inflammatory markers.
Clinical trial - Fraioli et al., 2011
Rheumatology International
Study design
61 patients with osteoarthritis of the knee divided into:
- Treated group: 3 cycles of mud-balneotherapy with Acqua Silene over one year
- Control group: conventional drug therapy only
Endpoints evaluated
- Visual Analogue Scale (VAS) of pain
- Lequesne's Algofunctional Index
Results
- Significant reduction in pain in the treated group
- Superior functional improvement over controls
- No adverse events reported
Conclusion
Fango-balneotherapy with Acqua Silene improves pain symptoms and joint function, with a favourable safety profile.
Randomised controlled trial - Fioravanti et al., 2015
International Journal of Biometeorology
Drawing
Prospective randomised, single-blind study with follow-up up to 12 months.
Population
Patients with symptomatic primary bilateral gonarthrosis (ACR criteria).
Endpoint
- Global pain (VAS)
- WOMAC (pain, stiffness, function)
Results
- Significant improvement of VAS and WOMAC in the treated group
- Persistence of benefit up to 9 months
- Progressive attenuation at 12 months
Clinical implication
The clinical benefit of fangobalneotherapy extends beyond the immediate effect of heat and suggests a rationale for repeated annual cycles.
Biomarkers and biological mechanisms
Subsequent studies have explored the underlying molecular mechanisms.
Adipokines (Fioravanti et al., 2015)
- Significant reduction in adiponectin (p < 0.001)
- Significant reduction in resistin (p < 0.0001)
- No change in visfatin
These results suggest a modulation of the adipose-articular axis and a systemic anti-inflammatory effect.
Cartilage turnover (Pascarelli et al., 2016)
- Significant increase in serum CTX-II (p < 0.001)
- Interpreted as stimulation of cartilage remodelling in response to controlled thermal stress.
Meta-analysis - Mennuni et al., 2021
Overall sample
21 randomised controlled trials
1,816 patients
Results
- Significant improvement in WOMAC scores
- Significant reduction in pain (VAS)
- Benefit maintained for up to 9 months
Conclusion
Fango-balneotherapy is a non-invasive, well-tolerated treatment option with evidence of clinical efficacy in the management of knee osteoarthritis.
Cost-effectiveness analysis - Ciani et al., 2017
The addition of fangobalneotherapy to conventional therapy has proven to be cost-effective compared to drug therapy alone, with improved quality of life and rational health care sustainability.
Summary of osteoarticular evidence
Clinical evidence indicates that fangobalneotherapy with Sillene Water:
- Reduces joint pain
- Improves function
- Modulates inflammatory biomarkers
- Stimulates cartilage turnover
- Presents persistent benefits over time
- It is well tolerated and sustainable from a health point of view
The totality of the data places fangobalneotherapy among the best-documented complementary options in the non-surgical management of gonarthrosis.
Related evidence on waters of the same chemical class
Acque di Chianciano belongs to the class of sulphate-bicarbonate-calcic mineral waters, a category widely studied in spa medicine for its physiological effects on:
- biliary secretion and outflow
- digestive function and intestinal motility
- modulation of inflammation
- osteoarticular wellbeing (particularly in balneo-mud applications)
It is important to point out that each spring has a unique mineral signature (total mineralisation, sulphate/bicarbonate ratio, CO₂ content, emergence temperature, trace elements) and therefore results from studies of other waters are not transferable “by identity”. However, the literature on waters of the same hydrochemical family supports rationales and biological mechanisms consistent with those observed for Chianciano.
1. Hepatobiliary and digestive environment: why sulphates matter
In spa literature, sulphate-rich waters are associated with:
- increased biliary secretion (choleresis)
- improvement of cholecystic motility (cholagogue action)
- support in the management of functional dyspepsia and uncomplicated biliary disorders
- subjective benefit on bloating, slow digestion and regularity
This picture is consistent with the clinical results available on Chianciano (cholecystic dynamics and bile acid pool) and with traditional hydropinic use.
2. Gut-liver axis: shared rationale in functional mineral waters
Studies on mineral waters with similar profiles suggest that modulation of digestive function and bile may have effects on:
- composition of the microbiota
- intestinal barrier and permeability
- metabolic-inflammatory signals (particularly in the context of dysmetabolism)
In Chianciano, this rationale finds specific support in preclinical evidence on the MASLD model, which indicates a potential action along the gut-liver axis.
3. Osteoarticular area: balneo-mud as a “family” of evidence
For gonarthrosis and, more generally, for pain and stiffness in degenerative diseases, the international literature on balneotherapy and mud therapy (also on waters of different origin but with similar applications) shows good consistency:
- reduction of pain
- improved joint function
- persistence of benefit for several months
- generally favourable tolerability profile
The evidence on Chianciano (trials, biomarkers, meta-analysis and cost-effectiveness) fits into this body of findings, strengthening its clinical robustness.
4. In summary
- The “class” evidence does not replace the specific evidence on Chianciano.
- However, they serve to explain why, from a physiological and clinical point of view, the indications attributed to sulphate-bicarbonate-calcic waters are consistent and why Chianciano is historically placed in this therapeutic vein
Indications for use and therapeutic appropriateness
The use of the Chianciano waters is part of integrated thermal medicine. The modalities of use - hydropinotherapy, inhalation cures, mud-balneotherapy and balneotherapy - must be customised according to the patient's clinical picture and medical assessment.
The reported indications are derived from published clinical evidence, established hydrological tradition and National Health Service recognition for specific conditions.
Hydropinotherapy (Acqua Santa and, in association, Acqua Fucoli)
Main indications
- Functional disorders of the biliary tract
- Dyspepsia of hepatobiliary origin
- Biliary dyskinesias
- Post-cholecystectomy syndrome
- Functional constipation associated with slow transit
General mode of recruitment (typical protocol)
- 400-500 mL per day
- In the morning, on an empty stomach
- At emergency temperature
- Slow intake, in small sips
- Cycle of 12 consecutive days
- The duration and mode can be changed on the advice of the spa doctor.
Appropriateness
Hydropinotherapy does not replace prescribed drug therapies for complex organic diseases (symptomatic cholelithiasis, acute hepatitis, advanced cirrhosis, cholangitis).
It is indicated as a complementary treatment in functional conditions or in uncomplicated phases.
Mud and balneotherapy (Sillene Water)
Main indications
- Osteoarthritis of the knee
- Osteoarthrosis of other sites
- Chronic degenerative joint pain
- Post-traumatic joint outcomes
Typical mode
- Application of mud matured in thermal water
- Pack duration: approx. 15-20 minutes
- Followed by thermal bath
- Cycle of 12 sessions
- Annual or six-monthly repetition according to medical indication
Appropriateness
Not indicated in cases of:
- Acute joint inflammatory states
- Feverish phases
- Unstable heart failure
- Oncological pathologies in active phase without specialist evaluation
Inhalation cures (Holy Water)
Main indications
- Chronic and relapsing rhinitis
- Rhinosinusitis
- Pharyngitis and chronic laryngitis
- Chronic bronchitis
- Selected paediatric respiratory diseases
Mode
- Thermal aerosol
- Hot-humid inhalations
- Nasal showers
Cycle duration: generally 12 sessions.
Safety and medical assessment
Thermal cures are generally well tolerated. The available clinical studies on the Chianciano waters report no significant adverse events in the protocols analysed.
However, it is recommended:
- Preventive medical assessment
- Communication of ongoing drug therapies
- Special attention in patients with complex chronic diseases
Treatments covered by the National Health Service require a doctor's prescription according to current regulations.
Role in integrated medicine
The Chianciano Waters fit in as a complementary treatment, not a replacement, within:
- Pathways to hepatobiliary health
- Multidisciplinary management of gonarthrosis
- Strategies for functional prevention and metabolic well-being
Clinical appropriateness is determined by the integration of medical assessment, available scientific evidence and individual patient characteristics
Concluding Synthesis
The Chianciano waters represent a hydromineral system with defined chemical-physical characteristics, documented compositional stability and studied clinical applications in the hepatobiliary, osteoarticular and respiratory fields.
Available scientific evidence includes:
- randomised clinical trials
- preclinical studies on a liver metabolic model
- Meta-analysis on balneotherapy
- cost-effectiveness evaluations
- safety and tolerability data
Therapeutic applications must be framed in the context of integrated medicine, with preventive medical assessment and clinical appropriateness.
Chianciano's spa tradition is now part of a contemporary paradigm that integrates:
- digestive and biliary physiology
- intestine-liver axis
- inflammatory modulation
- neuroendocrine mechanisms
- osteoarticular rehabilitation
Thermal cures do not replace drug therapy when indicated, but can be a complementary support with a physiological rationale and documented basis
Bibliography
GEOCHEMISTRY AND HYDROGEOLOGY
ARPAT. Main thermal emergencies in Tuscany. Hydrogeology and water chemistry. Florence: ARPAT; March 2014.
Municipality of Chianciano Terme. Strategic Environmental Assessment - Environmental Report, Operational Plan. Approval February 2017.
Terme di Chianciano spa. Thermal water comparison - In-house analytical data (2002-2011 sampling).
HEPATOBILIARY FUNCTION
Corradini SG, Ferri F, Mordenti M, et al. Beneficial effect of sulphate-bicarbonate-calcium water on gallstone risk and weight control. World J Gastroenterol. 2012;18(9):930-937. PMID: 22408352.
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OSTEOARTICULAR PATHOLOGIES
Fraioli A, Serio A, Mennuni G, et al. A study on the efficacy of treatment with mud packs and baths with Sillene mineral water (Chianciano Spa Italy) in patients suffering from knee osteoarthritis. Rheumatol Int. 2011;31(10):1333-1340. PMID: 20390281.
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Chelsechsi S, Tenti S, Secciafico I, Gálvez I, Fioravanti A, Ortega E. Balneotherapy year in review 2021: focus on the mechanisms of action of balneotherapy in rheumatic diseases. Environ Sci Pollut Res Int. 2022 Feb;29(6):8054-8073. doi: 10.1007/s11356-021-17780-0. Epub 2021 Nov 29. PMID: 34845635.
RELATED EVIDENCE
Gravina AG, Romeo M, Pellegrino R, et al. Just Drink a Glass of Water? Effects of Bicarbonate-Sulphate-Calcium-Magnesium Water on the Gut-Liver Axis. Front Pharmacol. 2022;13:869446. PMID: 35837275.
Gravina AG, Pellegrino R, Romeo M, et al. The use of bicarbonate-sulphate-calcium-magnesium and sodium-low drinkable water improves functional gastrointestinal symptoms in patients with non-alcoholic fatty liver disease. Clin Nutr ESPEN. 2023;57:281-287. PMID: 37739669.
Arab JP, Karpen SJ, Dawson PA, et al. Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives. Hepatology. 2017;65(1):350-362.
GUIDELINES AND GENERAL REFERENCES
Rinella ME, Neuschwander-Tetri BA, et al. AASLD Practice Guidance on the Clinical Assessment and Management of Nonalcoholic Fatty Liver Disease. Hepatology. 2023;77(5):1797–1835.
Maraver F, Armijo F, Fernández-Torán MA, et al. Peloids as thermotherapeutic agents. Int J Environ Res Public Health. 2021;18(4):1866.