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ORIGINAL ARTICLE
Mercury poisoning in two patients with tertiary
syphilis from the Ca’Granda hospital
(17th-century Milan)
Lucie Biehler-Gomez
1
| Mirko Mattia
1
| Carlotta Sala
1
|
Gaia Giordano
2
| Domenico Di Candia
2
| Carmelo Messina
3,4
|
Luca Maria Sconfienza
3,4
| Antonia Francesca Franchini
5
|
Alessandro Porro
5
| Paolo Maria Galimberti
6
| Fabrizio Slavazzi
7
|
Cristina Cattaneo
1
1
LABANOF, Laboratorio di Antropologia e Odontologia Forense, Sezione di Medicina Legale, Dipartimento di Scienze Biomediche
per la Salute, Università degli Studi di Milano, Milan, Italy
2
Sezione di Medicina Legale, Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy
3
Unità Operativa di Radiologia Diagnostica ed Interventistica, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
4
Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milan, Italy
5
Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy
6
Servizio Beni Culturali, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Milan, Italy
7
Dipartimento di Beni Culturali e Ambientali, Università degli Studi di Milano, Milan, Italy
Correspondence
Mirko Mattia, LABANOF, Laboratorio di
Antropologia e Odontologia Forense, Sezione
di Medicina Legale, Dipartimento di Scienze
Biomediche per la Salute, Università degli
Studi di Milano, Via Mangiagalli, 37, I-20133.
Milan, Italy.
Email: mirko.mattia@unimi.it
Funding information
L’Oreal - UNESCO for Women in Science -
Fellowship awarded to LBG; Lombardy
Region, Grant/Award Number: Bando Anno
2018 per la promozione di interventi di
valorizzazione di aree archeologiche, siti iscritti
o candidati alla lista Unesco e itinerari culturali
in Lombardia –Artt. 17, 18 E 20 L.R. 25/2016;
WOA Institution: Universita degli Studi di
Milano; Blended DEAL: CARE
Abstract
Syphilis was a widespread infectious disease in 17th-
century Italy, commonly treated with mercury-based
ointments and fumigations. Few reports exist on the
analysis of abnormally high Hg levels in bone as a
result of exposure to mercury-containing anti-syphilitic
medicine. In this research, two crania recovered among
the 2.9 million commingled bones resting under the
crypt of the former hospital of the poor of Milan were
submitted to pathological, radiological and toxicologi-
cal analysis. The crania showed gummatous lesions
characteristic of tertiary syphilis and inductively
coupled plasma mass spectrometry (ICP-MS) analysis
revealed over the double values of Hg in bone relative
to that of the control sample. Archival documentation
Received: 21 June 2021 Accepted: 21 September 2021
DOI: 10.1111/arcm.12721
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited.
© 2021 The Authors. Archaeometry published by John Wiley & Sons Ltd on behalf of University of Oxford.
Archaeometry. 2021;1–11. wileyonlinelibrary.com/journal/arcm 1
confirms the presence and use of mercury-based treat-
ments in the pharmacy of the hospitals of Milan. Con-
sequently, the individuals probably came into contact
with mercury as a treatment for syphilis, confirming its
medical use in 17th-century Milan and strengthening
our knowledge of the history of medicine.
KEYWORDS
ancient hospital, ICP-MS, infectious disease, mercury, syphilis,
syphilis treatment, venereal disease
INTRODUCTION
Syphilis (from the Latin for syphilis, idis) is a term coined in 1521 by the medical poet Girolamo
Fracastoro (1476 or 1478–1533), which became known after the publication of his didactic
poem Syphilis sive de Morbo Gallico libri tres in 1530. The protagonist of the poem, the
shepherd Siphilus, grew unfaithful to the Sun god, and as punishment unclean ulcers appeared
on his body. With this work, Fracastoro provided the first complete description of syphilis
(Marcovecchio, 1992). The term syphilis also refers to the Greek σιφλός(or shameful)
(Blancardus, 1683), because syphilis was called the ‘disease of shame’.
Venereal syphilis is one of the four treponemal diseases, a group of bacterial infections
caused by the spirochetes Treponema pallidum, along with bejel, pinta and yaws. Syphilis, also
referred to as ‘the great mimicker’because of its large array of clinical manifestations,
progresses in three main clinical stages. Primary syphilis subsists for a few weeks and is
classically marked by the formation of a painless chancre at the site of inoculation that heals
swiftly, clearing locally the presence of the spirochetes. In secondary syphilis, the systemic
dissemination of spirochetes induces after a few months an extensive skin rash as well as other
possible symptoms, including malaise, weight loss, muscle aches, lymphadenopathy, meningitis,
hepatitis and ocular inflammation (among others), which resolve spontaneously. The bacteria
then enter an asymptomatic latent stage of variable duration and, if left untreated, their
reactivation causes tertiary syphilis with multiple organ involvement, years to decades after the
onset of infection (Ho & Lukehart, 2011; LaFond & Lukehart, 2006; Peeling & Hook, 2006).
At this point, the damage is primarily neurological (with symptoms including vertigo, insomnia,
emotional instability, memory impairment, hallucinations, personality changes, paresis and
tabes dorsalis, and may progress to meningovascular syphilis), cardiovascular or gummatous
(i.e., benign necrotic nodular lesions) (LaFond & Lukehart, 2006). Osteitis and periostitis may
be seen in secondary syphilis (Ortner, 2003), but characteristic bone changes are found in
tertiary syphilis and consist of gummatous bone lesions in the cranium and long bones as well
as extensive periosteal reactions on long bones (Hackett, 1975).
The first recorded outbreak of syphilis occurred among the French troops of King Charles
VIII in 1495 when entering Naples, leading the French to refer to the disease commonly as ‘le
mal de Naples’and the Italians as ‘il mal franzese’or ‘morbo gallico’(or Gallic disease). By
the 17th century, syphilis was a widespread and common condition in Italy, treated with various
chemical and natural methods: ointments, potions and fumigation (Tognotti, 2006). Ointments
were composed of mercury, pork fat, sulfur, frankincense and myrrh (among other substances),
and smeared on the joints several times a day (Micozzi & Santini, 1993). There is mention from
1552 of the use of resin, bark and wood from a tall plant called Guaiacum sanctum, commonly
known lignum vitae or lignum sanctum. Guaiacum treatments were administered externally in
ointments by friction, and internally in potions. The plant was imported from the
2BIEHLER-GOMEZ ET AL.
Dominican Republic, and as the disease was thought to originate from that region, following
the principle ubi morbus, ibi remedius, the cure must be sought in the place where the disease
emerged. However, given its high costs, regulations from 1578 aimed to limit its usage
(Cosmacini, 1999; Eppenberger et al., 2017). Another tropical plant exported from the New
World and adopted as an anti-syphilitic treatment is Sarsaparilla: roots of the plant of the genus
Smilax L. were crushed to make a decoction (Branda Castiglioni, 1668). Lastly, fumigation was
a painful treatment used to stimulate the release of ‘corrupt moods’through salivation, sweat
and diarrhoea: the patient was enclosed in a wooden barrel suffused with smoke of cinnabar
(i.e., red mercury sulphide), from which only the head came out (Micozzi & Santini, 1993).
The present case report will discuss the finding of two crania in the sepulchral chamber O of
the Ca’Granda crypt in Milan with pathological bone signs of tertiary syphilis, and the results
of inductively coupled plasma mass spectrometry (ICP-MS) to measure the levels of Hg
remaining in the bones.
MATERIALS AND METHODS
The Ca’Granda crypt
The Ospedale Maggiore, called ‘Ca’Granda’by the Milanese, was founded in 1456 by
Francesco Sforza in the heart of the city. It became one of the main institutions in Milan in the
16th century and a model during the Renaissance for similar healthcare institutions across Italy
and Europe because of its innovative and avant-garde free medical assistance to the poor, care
of the ill and scientific activity. From 1637 to 1697, the crypt located below the church of the
Beata Vergine Annunciata within the hospital grounds became the place of burial of the
deceased patients of the hospital (Agosti & Stoppa, 2017, pp.67–71; Cosmacini, 1999, 2001;
Vaglienti & Cattaneo, 2013). As part of the Ca’Granda Project undertaken by the University
of Milan and the Hospital Foundation for Cultural Heritage of the Ospedale Maggiore, cam-
paigns of archaeological excavations of the sepulchral chambers of the crypt have revealed the
presence of an estimated 2.9 million commingled bones. Their archaeological excavation and
anthropological study of the remains are currently underway and organized by the University
of Milan and Laboratorio di Antropologia e Odontologia Forense (LABANOF—Laboratory
of Forensic Anthropology and Odontology).
Crania CG19O-706 and CG19O-1808
Both crania were found among the commingled remains of sepulchral chamber O, dated
through detailed historical records and archives of the hospital specifying its use from 1637
(the date of the creation of the sepulchral chambers) to 1697 (the date of the creation of a
cemetery dedicated to the deceased patients of the hospital outside of the city walls).
Anthropological analysis
The crania were assessed for age at death, sex and population affinity using standard methods
(Hefner, 2009; Hefner & Ousley, 2014; Mann et al., 1991; Ubelaker, 1978; Walker, 2008).
Pathological analysis was performed following standard methods and references
(Aufderheide & Rodríguez-Martín, 1998; Buikstra, 2019; Ortner, 2003; Waldron, 2008) and
paleopathological diagnosis of tertiary syphilis following Hackett (1975, 1976).
MERCURY POISONING WITH TERTIARY SYPHILIS 3
Radiological imaging
The two crania were imaged using computed tomography (CT). Both crania were placed on the
CT table by lying on the skull base to ensure greater stability during scanning. As a
consequence, the resulting scans were directly obtained on a coronal plane. CT scans were
performed using a 64-slice CT system (Somatom Definition As, Siemens Medical Imaging,
Erlangen, Germany). We used a standard protocol for brain CT acquisition, with the following
parameters: field of view (FOV) =200 mm, section thickness =1 mm with a reconstruction
interval of 0.625 mm, 120 kVp, 138 mA. CT images were post-processed with multiplanar
reconstructions by applying different types of filters using the Siemens Syngo-via console.
Toxicological analyses
Samples of about 0.5 g were cut with a handsaw from the occipital bone of both crania. In
addition, a sample collected from the diaphysis of a radius with an incompletely fused
proximal epiphysis (age at death < 17 years) from the same sepulchral chamber and without
signs of syphilis was chosen as a control specimen. The bone of a juvenile individual was
selected as a control sample based on the assumption that, given his age, the individual would
be less likely to have been treated with or exposed to mercury in his short lifetime (external
contamination), while representing the normal physiological concentration of mercury in
modern era Milan.
The samples were prepared and processed as conventional matrices following (Di Candia,
Biehler-Gomez, et al., 2020, Di Candia, Muccino, et al., 2020). Validation data, metal dosage
and instrumental conditions were performed as per previous studies (Di Candia,
Biehler-Gomez, et al., 2020, Di Candia, Muccino, et al., 2020).
RESULTS
Cranium CG19O-706
The cranium was complete; only a portion of the right zygomatic process was damaged
post-mortem and the mandible was absent. White staining of taphonomic origin remained on
the anterior portion of the frontal bone, even after careful washing. Anthropological
estimations of sex (Walker, 2008) and age at death (Mann et al., 1991) revealed a male aged
20–24 years.
The frontal, parietal and right zygomatic bones showed osseous lesions. In particular,
confluent clustered pits converging in focal points can be seen on the zygomatic and
parietal bones, whereas destructive changes on the frontal bone are more severe, showing
clustered pits, marked cavitation and bone erosions and in some discrete areas, nodular
formation (Figs 1 and 2). Cortical destruction of the outer table is more extensive than that of
the diploe, suggesting an inward progression of the lesions. The observed cranial lesions
correspond to stages 6–7 of caries sicca (Hackett, 1975).
Cranium CG19O-1808
The cranium was complete, but the mandible was absent. Both zygomatic processes were
damaged post-mortem, and the left maxilla showed a break of continuity of the bone tissue,
corresponding to a post-mortem fracture. The left parietal and occipital bones evidenced
4BIEHLER-GOMEZ ET AL.
taphonomic bone cracking and flaking, comparable with stage 2 of weathering
(Behrensmeyer, 1978), as well as a large region of loss of substance in the posterior area of the
left parietal bone (about 43 mm in diameter) of post-mortem origin. Anthropological
estimations of sex (Walker, 2008) and age at death (Mann et al., 1991; Mincer et al., 1993;
Moorrees et al., 1963; Ubelaker, 1978) showed a female aged between 16 and 20 years.
Pathological lesions were present on the frontal and parietal bones and are comprised of fine
clusters of pits encircling large and deep osteolytic lesions varying from 5 to 36 mm in diameter,
breaching both the external table and the diploe (Figs 3 and 4). The greater extension of the
lesion on the outer table indicates an inward progression of the lesions. Two lesions in
particular, located at the glabella and on the right parietal bone, also perforated the internal
table. The cranial lesions correspond to a stage 6 of caries sicca (Hackett, 1975).
ICP-MS results
ICP-MS analyses revealed the following Hg values: cranium CG19O-706 =1.41 mg/kg,
cranium CG19O-1808 =0.64 mg/kg, and control sample =0.38 mg/kg.
FIGURE 1 Cranium CG19O-706: (a) Norma verticalis; (b) Norma lateralis; (c) Norma frontalis; and (d) details of
the osteolytic bone destruction and nodular formation on the frontal bone
MERCURY POISONING WITH TERTIARY SYPHILIS 5
DISCUSSION
The anthropological and paleopathological analyses of the two crania revealed two young
adults, a male and a female, with deformative osteolytic and osteoblastic lesions on the external
table of the frontal and parietal bones including bone destruction and nodular formation,
consistent with stages 6–7 caries sicca.
The major differential diagnosis for osteolytic cranial lesions includes taphonomic
alterations, Langerhans cell histiocytosis, leukaemia, multiple myeloma, metastatic carcinoma
and syphilitic caries sicca. Taphonomic degradation of bone, and in particular osteophageous
insects and roots, do not show a preference for specific areas of the skeleton and would not
show nodular cavitation (Ortner, 2003). Langerhans cell histiocytosis encompasses three clinical
syndromes predominantly affecting children (Dorfman & Czerniak, 1998). Bone lesions in
leukaemia present as diffuse superficial solitary pits (Rothschild et al., 1997). Multiple myeloma
and metastatic carcinoma predominantly affect individuals over 40 years of age, with bone
lesions emerging within the diploe and progressing toward the external and internal tables
(Biehler-Gomez et al., 2019a, 2019b; Biehler-Gomez & Cattaneo, 2021; Ortner, 2003;
Strouhal, 1991). In the present case, destructive bone changes showed an inward progression.
The abundant blood supply to the bone marrow and periosteum tends to make these structures
a good reservoir of infection. The causative organism is borne through the blood stream to all
parts of the body. The disease is thus propagated via the blood stream, and the invasion of the
periosteum or bone is to be expected. The lesions observed in this study correspond to caries
sicca, a pathognomonic marker of tertiary syphilis (Hackett, 1975). On the one hand, cranium
CG19O-706 showed destructive bone lesions as well as nodular bone lesions, observable both
macroscopically and on CT scans, suggesting a more advanced stage of progression of the
gummatous lesion. On the other hand, cranium CG19O-1808 exhibited more extensive and
severe osteolytic destruction, with a higher number of cortically erosive lesions and a more
widespread distribution, but no nodular formation was noted through gross macroscopic
observation or radiological examination.
The Ospedale Maggiore was dedicated to the treatment of patients with curable or acute
diseases and without financial means (Cosmacini, 1992, 2001). By opposition, the Ospedale del
Brolo was the Milanese hospital specialized in the care of syphilitic patients. However, as the
FIGURE 2 Coronal computed tomographic (CT) sections of cranium CG19O-706. Note the osteolytic destruction
of the external table (arrows) and the nodular formation around some osteolytic lesions (asterisks)
6BIEHLER-GOMEZ ET AL.
FIGURE 3 Cranium CG19O-1808. (a) Norma verticalis; (b) Norma lateralis; (c) Norma frontalis; and (d) details
of the osteolytic bone destruction on the frontal bone
FIGURE 4 Coronal computed tomographic (CT) sections of cranium CG19O-1808. Note the extensive bone
destruction of the external table and to a lesser extent, the diploë (arrows)
MERCURY POISONING WITH TERTIARY SYPHILIS 7
Ca’Granda grew in notoriety, the Brolo lost in importance. The closure of the hospital was
finally decided on 12 December 1631, and all the patients hospitalized at the Brolo were pro-
gressively transferred to the Ca’Granda (Belloni, 1958; Bevacqua, 2004; Canetta, 1887).
Therefore, it is not surprising to find two cases with tertiary and long-standing syphilis in the
crypt of the Ca’Granda as their presence could be the result of the closure of the Ospedale del
Brolo. Another hypothesis could be that they presented to the hospital with acute symptoms
(e.g., related to neurosyphilis or cardiovascular complications), which would explain the
presence of two chronic long-standing cases of syphilis in Ca’Granda. Moreover, these
individuals may have been admitted to the hospital based on their social condition of poverty.
Given the commingling situation in the sepulchral chambers, no other information could be
extrapolated to clarify the reason for the presence of these two individuals in Ca’Granda
hospital.
The most common anti-syphilitic therapies in modern era Italy were based on the use of
mercury compounds (in the form of ointments by friction or fumigation) or
phytopharmaceuticals derived from tropical plants imported from the New World, in particular
Guaiacum and Sarsaparilla (in the form of decoction for ointments or potions) (Porro
et al., 2009). In fact, discussions at the time divided physicians over the use of these two
categories of medicine (Bellini, 1934). The inventories of the hospital pharmacy of the main
medical institutions of Milan (including Ca’Granda and Ospedale del Brolo), preserved today
in the archives of the former hospital of Milan, show that at the end of 1617 and 1623 there
were still present sarsaparilla, lignum sanctum, mercury ointment, ointment for the morbo gal-
lico,‘argento vivo’(or quicksilver, the common name for mercury) and ‘argento vivo ex (tint)
o’(or extinct quicksilver, the name given to mercury that had been crushed until no metallic
globule was visible) (Galimberti, 2014). This finding shows that treatments based on mercury
were indeed present in the pharmacy of the Brolo and Ca’Granda hospitals and used to treat
syphilis in 17th-century Milan.
Background concentrations of Hg in trabecular and cortical tissues in long bones are set at
0.30 and 0.08 mg/kg, respectively (Rasmussen et al., 2015). Generally, Hg levels are higher in
trabecular bone tissues (Rasmussen et al., 2017). From the literature, it is not entirely clear what
is the expected level of Hg in cranial bones, which is why the cranial samples were collected by
sampling both cortical and trabecular tissue. The Hg concentrations found in the syphilitic
crania were over double the value found in the control sample (without bone signs of syphilis).
The toxicological results obtained are in line with previous studies on dry bone Hg levels in
syphilitic cases due to treatment (Kepa et al., 2012; Rasmussen et al., 2008; Tucker, 2007). The
bone tissue is composed of organic matrix, inorganic matrix and water. The interaction between
bone water and the blood stream is essential for the incorporation of metal ions. Thus, the ions
are incorporated through the process of bone remodelling during primary or secondary mineral-
ization. A fraction of Hg ions remains trapped inside the bone matrix and can be detected after
death (Giordano et al., 2021). The high concentrations of the metal in the crania can be
explained by its accumulation in the bone by contact absorption permeating from the mercury-
containing ointment through the skin and diffusing into the tissues via the bloodstream (Kepa
et al., 2012). The Hg levels detected in the control sample are consistent with normal Hg con-
centrations in humans and reflect the control values of previous research (Kepa et al., 2012).
Cranium CG19O-706 showed over twice the concentration of Hg found in cranium CG19O-
1808. Although a definitive explanation for this difference cannot be drawn, factors that may
have had an influence on the bone concentrations of Hg include time, duration and quantity of
metal exposure.
The treatment of mercury may not be associated with a specific hospital (i.e., Ospedale
del Brolo or Ospedale Maggiore) as the pharmacy was shared within the district.
Theoretically, and despite the knowledge that mercury-based remedies were present in the
pharmacy of the hospitals at the time of hospitalization of both CG19O-706 and CG19O-
8BIEHLER-GOMEZ ET AL.
1808, it is possible that these individuals may have been treated with mercury even before
their admission to the hospital and then had required treatment at Ca’Granda for other
causes.
These findings suggest that a remedy with a mercury basis was applied in the two discussed
cases, and archival documents show that the pharmacy of the Ca’Granda and Brolo hospitals
possessed large quantities of mercury-based treatments in the 17th century. Whether the institu-
tion administering the heavy metal as a medical treatment for syphilis was the Ospedale del
Brolo, Ca’Granda hospital or both, cannot be confirmed, given that the patients of Brolo
hospital were transferred to Ca’Granda after its closure. Even if the individuals had been
patients at Brolo hospital and were later admitted to Ca’Granda, the finding of Hg ions can be
associated with previous medical treatment for syphilis that remained entrapped within the
bone matrix. Regardless of the impossibility to confirm where the mercury-based remedy
occurred, these results attest of the use of mercury as a syphilitic treatment in the 17th-century
Milan, corroborating historical accounts (Micozzi & Santini, 1993) and strengthening our
knowledge of the history of medicine.
CONCLUSIONS
During archaeological excavations, two crania with extensive bone lesions were found in the
sepulchral chambers of the crypt of the Ca’Granda hospital in Milan and submitted to
anthropological, pathological, radiological and toxicological analyses. Results revealed two
young individuals, a male and a female, with benign gummatous lesions typical of tertiary
syphilis. Mercury levels showed very high concentrations of the metal in the crania with respect
to the control sample. These results are consistent with the use of mercury as an anti-syphilitic
remedy. Moreover, examination of the archives at the former hospital of the poor of Milan
evidenced that mercury-based ointments and decoctions were present at the time of
hospitalization of the two individuals of the present research, strengthening the possibility of
mercury poisoning as part of an anti-syphilitic therapy. Very few studies investigating Hg levels
in bones exist to test the possible use of the metal as a treatment against syphilis (or even
leprosy). In this research, our results suggest that the individuals may have received
mercury-based treatments for syphilis at the hospital, confirming that mercury was used as a
treatment for syphilis in 17th-century Milan and strengthening our knowledge of the history of
medicine.
FUNDING
L.B.G. was awarded a L’Oréal–UNESCO grant ‘For Women in Science’Italian edition. The
Ca’Granda project was funded by the Lombardy Region for three years (Bando anno 2018 per
la promozione di interventi di valorizzazione di aree archeologiche, siti iscritti o candidati alla lista
UNESCO e itinerari culturali in Lombardia—artt. 17, 18 e 20 L.r. 25/2016). Open Access
Funding provided by Universita degli Studi di Milano within the CRUI-CARE Agreement.
PEER REVIEW
The peer review history for this article is available at https://publons.com/publon/10.1111/arcm.
12721.
ORCID
Lucie Biehler-Gomez https://orcid.org/0000-0001-6674-7850
Mirko Mattia https://orcid.org/0000-0002-5445-9453
MERCURY POISONING WITH TERTIARY SYPHILIS 9
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How to cite this article: Biehler-Gomez, L., Mattia, M., Sala, C., Giordano, G., Di
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