Introduction

Gout is a common, complex, systemic and well-studied form of chronic inflammatory arthritis in adults for which treatment options are now available. It is due to deposition of sodium monourate crystals in peripheral joints and periarticular tissues driven by hyperuricemia at or above 6.8 mg/dL. Hyperuricemia itself results from genetic, environmental factors as well as from urate transporter dysfunction in the gut and in the kidneys.

Hyperuricemia may be due to either renal overload (overproduction or extrarenal underexcretion due to dysfunctional variants of transporters in the gut and intestine), or to renal underexcretion, or a combination of renal overload and renal underexcretion [1–4]. Renal overload may be due to overproduction by dietary purines, endogenous purine synthesis, purine breakdown and purine salvage (Hypoxanthine-guanine phosphoribosyltransferase deficiency and 5-phosphoribosyl-1-pyrophosphate deficiency).  Crystal deposition activates the NOD-like receptor protein 3 (NLRP3) inflammasome causing—via caspase-1 —release of the cytokine IL-1β and activates proteinase 3 and elastase. The kidney may cause hyperuricemia, but is also the target of hyperuricemia (calculi, renal disease, and its progression) [1–7].

At onset, gout affects one joint, frequently the metatarsophalangeal joint of the great toe, which is usually self-limited and heals in two weeks. Flare-ups subsequently affect two or more joints, becoming a chronic disease when tophi and erosions of the joint appear. Risk factors are diseases with high cell turnover and high intake of purine rich foods (meat, crustaceans, alcohol, and syrup containing fructose). It increases with age and women become hyperuricemic after menopause. It affects patients with hypertension, diabetes mellitus, and chronic kidney disease.  The diagnosis is made by demonstrating sodium monourate crystals in a joint by polarization microscopy or fine needle aspiration of tophi. The prevalence is 1% in Italy and in France, 2.5% in United Kingdom, Spain, Netherland, 3.9% in the USA and 1% in China. It is rare in Portugal, Czech Republic Former Soviet Union, Turkey, Malaysia, Japan, Korea, African countries. The prevalence increases with age up to 70-80 years of age.

Its name derives from the Latin word gutta (drop) to indicate the drop of a humour in excess precipitating in the joint. Garrod made seminal experiments on the role of uric acid (1848). Having found a cure for the disease — allopurinol, still the most used ― Gertrud B. Elion (1918-1999) and George H. Hitchings (1905-1998) received the Nobel Prize for Medicine in 1988 [8, 9].

 

Galen of Pergamum (129-c216 CE)

The first of doctors and unique among philosophers.
EMPEROR MARCUS AURELIUS

The Prince of Medicine.
VESALIUS, Defabrica corporis humani, 1555

Until the twentieth century he was the most influencial figure
in western medicine and perhaps in western culture.
SUSAN P. MATTERN, 2013 [10]

 A Thinking Doctor in Imperial Rome.
VIVIAN NUTTON, 2020 [11]

 

Biography

Galen (129-c.216 CE), the Greek-Roman physician, was born in Pergamum, Mysia, Anatolia (modern-day Bergama, Turkey), situated on the river Caicus, 16 kilometers from the Aegean Sea. He was the son of Nicon, a wealthy architect and Roman citizen, who owned a house in the city and a large estate. His grandfather had been an engineer. “The city of Attalus and Asclepius, the city that had turned on its Roman inhabitants and slaughtered them by thousands on a dark day in 88 BCE and then became the light of Roman Asia, beloved by Hadrian, adorned with every architecture glory – was Galen’s city” [10].

Between 143 and 144 CE, Galen received his primary education from his father, Aelius Nicon, at home. Initially, the education focused on meticulous skills in both oral and written Greek, as well as providing a foundation in literature, mathematics, geometry, and astronomy. In addition to this foundation, Galen also had tutors in philosophy. One of his teachers was the philosopher Eudemus. His father’s intention was to mold Galen into a rich gentleman and possibly a philosopher. His father, who carefully selected his later teachers and often accompanied him to school, guided his early education. During these formative years, Galen studied Plato, Aristotle, the Stoics, and the Epicureans with great enthusiasm.

At the age of 17 (in 145/146 CE), however, his studies shifted to medicine after his father was told in a dream by Asclepius that his son was destined for a medical career.

Consequently, Galen studied in Pergamum with private physicians personally selected by his father. Later, following Nicon’s death (148 CE), he studied in Smyrna (150 CE), Corinth and Alexandria (152-153 CE), as reported in Table 1.

PERGAMUM
Satyrus	Sophist
Aeschrion	Empiricist
Epicurus	Empiricist
Stratonicus	Empiricist
Aeficianus	Pneumatist
SMYRNA
Albinus	Platonist philosopher
Pelops	Stoic interpreter of Hippocrates

Table 1. Galen’s teachers in medicine [11].

In Alexandria, a city with a vibrant cultural life, Galen remained for 3-4 years. There, he learned anatomy through daily dissections [10]. In 157 CE, he returned to Pergamum and, at the young age of 28, was appointed as the doctor of the local gladiators. A man of independent ideas and means, Galen never belonged to a specific philosophical or medical sect, and he remained independent throughout his life.

 

From Pergamum to Rome

In 162 CE, he moved to Rome, the capital of the empire, where he cultivated a friendship with the influential senator Flavius Boethus and reunited with his former philosophy teacher, Eudemus. Both relationships opened many doors for him, particularly after Galen was able to restore Eudemus’ health, curing a disease that others had deemed fatal, and subsequently healed Boethus’ son and wife. Furthermore, his masterlful public dissections gained renown throughout the city and attracted important clients. However, this success also sparked the jealousy and resentment of local physicians, toward whom, like Pliny the Elder in the previous century, he openly expressed his disdain. His attacks were mainly directed against Methodists but also towards Erasistrateans.

For unknown reasons, in 166 CE he left Rome and returned to Pergamum, probably the fear of plague and/or the fear of the hatred generated by the envy of his Roman colleagues [10, 11].

He returned to Rome in 169 and was appointed physician of Marcus Aurelius, who valued his medical expertise as much as his philosophy. He was in charge of preparing theriac for the Emperor until the Emperor’s death (in 180 CE).

His subsequent life was not without difficulties, but he safely navigated the tumultuous years of Emperor Commodus. He served in office under Emperor Septimius Severus and likely died during the reign of Caracalla (197-217 CE). According to Arabic sources, Galen died in 216 or 217 CE.

 

Galen on health and disease

“Health is granted by a system based on the four elements (air, water, fire and earth), four qualities, two opposed pairs namely hot-cold and dry-wet, four humors (blood, phlegm, yellow bile and black bile (melancholy)), four seasons (spring, summer, autumn, winter) and temperaments that were nine (1 for each of the 4 qualities, 1 for each possible combination of the 4 qualities and 1 ideal temperament where all temperaments are in perfect balance [10]).

The temperaments (Figure 1) became 4 in Medieval Europe. Equilibrium between humors is associated with health, imbalance with disease. Galen attributes the humoral theory directly to Hippocrates, not to Polybus, Hippocrates’ son-in-law, as reported by Aristotle.

The liver is central to the body’s function. It generates blood from nutrients derived from food, which then circulates to the entire organism. The heart produces the innate heat that provides the energy for physical and mental health. It diminishes with age and disappears at death. The innate heat is maintained by the nutrients going from liver to the left ventricle and is cooled during respiration. Too much nutriment overheats, too little cools. Nutrients are relevant to acquired heat. Imbalance or excess of humours can be contrasted with drugs. Health is granted also by four faculties: attraction, expulsion, digestion (assimilation) and retention that allow appropriate handling of nutrients, and are present in every living organism, including plants.”

Between 169 and 180 CE, Galen prepared the theriac for Marcus Aurelius. It was based on that of Andronicus, made of 64 ingredients, including viper’s flesh, Cinnamomum and poppy-head juice (3.4%), equivalent to approximately 33 mg of opium per day.

 

The author

Galen was a prolific writer. He started as a student, authoring 3 texts respectively on the anatomy of the womb, the diagnosis of diseases of the eyes and a report on a debate between the Empiricist Philippus and the Hippocratic Pelops on the best method to meet patients’ needs.  In total, he left more than 300 books, which were revised repeatedly during his life. These works cover a wide range of subjects, including anatomy, ethics, lexicography, logic, and pharmacology. He wrote in Greek, but his thought has been preserved through translations into Arabic, Hebrew, Syriac, Armenian, and Latin.  We can say that Arabic translations played a crucial role in preserving his methods. A notable example is the Canon (Al-Quanun fi al-Tibb) of Avicenna (Abu al-Hussayn ibn Abdullah ibn Sina, 980-1037 CE). According to Vivian Nutton it can be considered an outstanding treatise of Galenic medicine [11].

 

Galen’s success

Galen achieved success in Rome. His prestige was immense, allowing him to care for the most important families. This enabled him to assemble an outstanding personal library in the Palatinum and to purchase a villa in Castellammare di Stabia.  Unfortunately, the library, which housed the most important copies of medical books from antiquity and his own works, was located near the Temple of Apollo on the Palatine Hill and in 192 CE caught fire and was irretrievably lost. He lost not only books in the fire but also gold, silver, and other valuables. Luckily, some of his books were housed in the Villa of Castellammare.

Galen provided medical care free of charge, but we know that he accepted gifts – such as the 400 aurei (gold coins) from Senator Flavius Boethus following the recovery of his son and wife. The great anatomist and pharmacologist “never lost the idea that medicine is about treating patients” [8]. Until the twentieth century he was the “most influential figure in western medicine and perhaps in western culture” [10].

 

Galen’s Text: Regarding sciatica, gout and arthritis

“Arthritis encompasses conditions such as sciatica and gout [12]. Sciatica refers to arthritis affecting the joints connected to the hip, while gout describes arthritis near the foot. Hence, gout typically begins in a single joint and progressively spreads to others, eventually becoming chronic. These three conditions share a common feature of an excessive buildup of fluid in the affected joint. This excess fluid overflows and infects the surrounding nerves, resulting in pain. The fluid that erupts can be sanguine or more commonly phlegmatic, or even a combination of phlegm, bile, and blood. More precisely, it can be said that in arthritis the prevailing humor is not typically phlegmatic but rather the one known as raw. This thick, mucus-like humor, when it remains in the joints for long periods, not only becomes denser but also more viscous. This is the origin of what is known as concretions, and once these develop, there is no hope of restoring the joint to its original condition.

It is evident that the differences in humor affliction can be discerned through color, symptoms, and the effects of administered drugs. Therefore, the description and diagnosis of humor color are widely known and understood. Although not everyone experiences the symptoms firsthand, they are not difficult to learn. For instance, bilious blood produces a sensation of intense heat in the patient, which worsens with the application of heat and is alleviated by cold.

To identify the humor involved, one should consider factors such as diet, physical activities, bathing routines, quantity and quality of exercises and foods, season, climate, age, and overall physical condition. These factors, along with the body’s various faculties, can assist in the diagnosis.

To treat the illness by removing the specific humor causing it, bloodletting is employed for plethoric bodies, followed by purgation. Subsequently, appropriate medications are administered in a specific order and timing to repel the excessive flow of humor. However, special caution is needed when treating the hip joint, as it is deep and forcing the blood out can affect nearby vessels and muscles. Initially, soothing drugs for hip pain are necessary, which neither excessively cool nor heat, as these may exacerbate the secretions.

While the focus here is not on poultices or baths but on the preparation of medicines, it is important to mention the treatment of the hip joint. In cases of sciatica, treatment often involves lancing the veins around the calf or ankles to alleviate the condition. However, in cases where strong drugs were used without evacuating the whole body, the accumulated humor may become thick and viscous due to the heat and dryness of acidic drugs, causing increased pain. Thus, beginning with the evacuation of the entire body, starting with a blood sample from the elbow, is crucial. Vomiting is particularly helpful in treating sciatica, and moderate emetics can be used in the initial stages.

For those who have suffered from improper obstruction of fluids caused by acidic drugs that are difficult to dissolve, enemas and potent infusions, such as coloquintid, can be more  effective.With these considerations in mind, medicines are prescribed following the methods passed down by ancient doctors. Andromachus’ writings on external medicines, specifically emollient poultices (malagma), serve as an excellent starting point, providing relief for chronic conditions including sciatica.” [12].

 

Preparations written by Andromachus for sciatic patients in his own words, from books on external drugs

Seeds of wild rue (Ruta graveolens L.), of silphium (the extinct plant), of laurel (Laurus nobilis L.), saltpeter, southernwood (Artemisia abrotanum L.), coloquintid (Citrullus colocynthis L.), cardamom (Elettaria cardamomum L.), ammi (Ammi visnaga L.), the eighth part of a mina (436.6 g) of green rue (Ruta graveolens L.). Some of these receive a pitch of terebenthine, resin, and the same quantity of wax and taurine fat, copper disulphate, fumes of ammonium salt, of rubber from the hogweed plant (Heracleum sphondylium L.), of native sulfur [12].

The effectiveness and warming properties of the mentioned medicines are well documented and do not require further recent verification. Wild rue seed, silphium, laurel berries, saltpeter foam, southernwood, coloquintide, cardamom, ammi, green rue, and natural sulfur all possess strong heating properties and can draw out the afflicting humors from deep within the hip joint. The poultice containing these ingredients is composed of pitch, turpentine, resin, wax, and fat. Ammonium fumes and galbanum not only contribute to the composition but also have emollient and softening properties. The gum of the hogweed plant is of a similar nature, but with faculties that are more potent.

 

Another remedy of Andromachus with the same effect

Andromachus provides another preparation for sciatica [12], which includes wax, turpentine, ammonium fumes, propolis, galbanum (Ferula galbaniflua, Boiss. and Buhse), bdellium (Commiphora mukul, Engl.), saffron (Crocus sativus L.), gum from the hogweed plant, sodium carbonate foam, and crushed iris oil (Iris florentina L.).

 

A remedy of Protas of Pelusium for hip and head pain and all chronic pain

It was made of wax (24 drachmae), seven drachmae of ammonium fumes, seven drachmae of trebentine, eight drachmae of  thapsia (Thapsia garganica L.) juice, and 1 cyathus (1 cup, 0,046 l) of oil [12].

 

Among emollient poultices a remedy for hip pain drawn by Andromachus from Heras of Cappadocia

“Three heminas of liquid pitch, or two and a half, wax, pine resin, wine sulfites, each a pound, six ounces of potassium nitrate, one quart of the green root parasite plant pedicularis (Pedicularis sylvatica L.), one quart of pyrethrum, two quarts of burnt wine dregs, two heminas of cardamom (Elettaria cardamomum L.), one quart of galbanum (Ferula gummosa L.). Liquids are added to the dry component. As Heras wrote near the end of his own book: they are added not in a pitch, or two and a half, but exactly three heminas” [12]. The title is verbatim that he gave.

 

Discussion

This study highlights Galen’s pivotal role in the historical understanding of gout, bridging the era of the Corpus Hippocraticum  and the Renaissance period. His treatise demonstrates a profound understanding of the disease pathogenesis, symptomatology, clinical course, differential diagnosis, therapeutic skills and prognostication. Gout starts in one joint and then, progressively, spreads to other joints becoming chronic.

In Galen’s view, gout is due to fluid overflow that infiltrates nerves and causes pain. The overflowing fluid may be blood, phlegm, or a mixture of bile blood and phlegm. The prevailing humor is crude, mucous and thick and by residing in the joint becomes thicker and thicker and causes concretions (tophi). When tophi appear, the disease cannot be cured.

The nature of infiltrating humor can be diagnosed through color of the joint, symptoms, effects of heat and cold, effects of drugs and specific information about age, diet, quantity and quality of exercise, and bathing habits.

Bloodletting, in Galen’s therapeutic framework, is essential for plethoric patients and should be implemented promptly. A proponent of the procedure, Galen would draw large quantities of blood, preferably overnight, until the patient fainted. To treat gout, an incision was made at the elbow. Venesection might be repeated.  Enemas and /or emetics may be needed to evacuate the humor. Poultices have not only a role in evacuating the humor(s) but may have emollient and softening properties.

Galen starts with two medical recipes by the pharmacologist Andromachus the Elder (and probably of his like-named son), physician of Nero in the century before, followed by another Andromachus’ recipe derived from Heras of Cappadocia, himself a pharmacologist of the previous century most valued by Galen, author of Narthex a book of medical remedies.

The subsequent recipe comes from Protas of Seleucium in Egypt, a man who is mentioned in the “litany of names of some authors or providers of drugs listed by Galen” of Vivian Nutton [13] that includes 15 men and one woman (Aquilia Secundilla).

Of great interest are the gouty patients described by Galen. The treatise On the Mixtures and Powers of Simple Dugs reports on an old man with chronic arthritis and chalky stones (tophi) who knocked at his door for immediate help. Galen who, probably, was in the middle of a discussion with his household about the use of the rancid cheese that had accumulated in the kitchen, immediately took a piece of that rancid cheese and pounded it in a mortar along with a piece of pickled pork leg and prepared a plaster that was put on the affected part. The plaster opened the chalky stone rendering incision unnecessary [10]. Galen reported also about another patient with a milder form of gout in an ambulatory patient, who was offered a cure by a street huckster. Galen challenged the charlatan to heal the patient.  The cure was not effective, as we learn in Simp. Med 1.29 11.432-33K, as enlightened by Susan P. Mattern [10].

Although Galen considered Hippocrates an infallible physician and cited him 2500 times [10], Galen did not swear by the Hippocratic aphorism related to the absence of gout in eunuchs. He knew by experience that at the time of Hippocrates, nutrition was more appropriate, and wine was never consumed before or at breakfast; conditions that, in his view, protected eunuchs from developing the disease. By contrast, for the eunuchs of Galen’s time, gout became a possibility due to poor nutrition and use of strong wines drank even before breakfast. Galen also observed that many patients with gout had fathers or grandfathers affected by the same disease, suggesting a possible hereditary component.

A very recent paper has identified eight Galenic case reports on inflammatory diseases of the musculoskeletal system selected from the list of 358 cases [14], some of them identified as gouty.

Gout is probably the first known noncommunicable disease that can be discussed in terms of Omran’s “Theory of Epidemiologic Transition” [16, 17]. Omran analyzed the changing patterns of population age distribution in relation to changes in mortality, fertility, life expectancy, and causes of death. The theory has been updated frequently, by taking into consideration poverty along with incomes and education. This made the theory suitable to explain the differences between high prevalence of gout in popes and low but slightly increasing prevalence in the general population. Gout should be discussed in terms of lifestyles, income, and education. In general, rich and educated people, when made aware of the risk, agree to modify their lifestyles, whereas people who are poor and uneducated may not. Those who do not understand the risk factors are more likely to experience higher morbidity and mortality from the disease, while those with access to education are more likely to achieve protection [18].

The above concepts were recently applied to gout in Roman Pontiffs, and it was shown that popes reigning before 1914 had a high prevalence of gout due to lifestyles causing gout. These lifestyles were later corrected through education, and by 1914 gout had virtually disappeared among popes. In contrast, individuals with poor nutrition, mostly those with low incomes, were not prone to gout. Their diets, working conditions, and daily commute to and from work provided them with protection from gout [19–22].

In Rome at the time of Galen, life expectancy at birth ranged between 20 and 33 years [21], and in the poorer quarters it was around 20 years. As a result, gout was primarily a disease affecting elderly aristocrats. However, some cases of gout were probably linked to a high lead concentration in water due to the lead used for water pipelines, tanks and for utensils. Studies have shown that lead content in human skeletons increased significantly between 200 BCE and 200 CE [23].

 

Conclusion

Galen fixed practical guidelines for the management of gout at the bedside. The goal was possible since he was a “thinker”, “observer”, “good doctor”, “healer”, “dietitian”, and a “pharmacologist going beyond empirism”[11]. Gouty patients presented Galen with opportunities to fully exercise his diagnostic, therapeutic, and prognostic skills. He achieved this through patient communication and meticulous observation during frequent visits, which sometimes occurred multiple times a day. These interactions served as occasions for Galen to critique inferior physicians and charlatans and to show his superior expertise and ingenuity, as shown by the two cases illustrated before [10].

 

Acknowledgements

We thank Dr. Rosaria Di Martino, Head Centro Servizio del Sistema Bibliotecario di Ateneo Università degli Studi della Campania Luigi Vanvitelli and CoordinatorE Biblioteche di Ateneo, for her expert assistance in literature searches.

Thanks are also due to Professor Joseph Sepe for the editing of the English text.

 

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