Cangrande della Scala :: La mummia di Cangrande della Scala, signore di Verona

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Laboratorio
Cangrande della Scala

INDICE DEI CONTENUTI:

- La mummia di Cangrande della Scala, signore di Verona

- Risultati della ricerca

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"Laboratorio"

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Gino Fornaciari*, Federica Bortolotti**, Giacomo Gortenuti***,
Gian Cesare Guido°, Marco Marchesini°°, Silvia Martinucci°°°, Franco Tagliaro**

*Divisione di Paleopatologia, Dipartimento di Oncologia, dei Trapianti
e delle Nuove Tecnologie in Medicina, Università di Pisa (Italy)
**Sezione di Medicina Legale, Dipartimento di Medicina e Sanità Pubblica, Università di Verona (Italy)
***Dipartimento di Radiologia, Ospedale Civile Maggiore di Verona (Italy)
°Dipartimento di Scienze Morfologico-biomediche, Università di Verona (Italy
°°Laboratorio di Palinologia ed Archeoambientale, Centro Agricoltura Ambiente,
San Giovanni in Persiceto, Bologna (Italy)
°°°Dipartimento di Farmacocinetica e Metabolismo, Centro ricerche GlaxoSmithKline, Verona (Italy)

KEY-WORDS: natural mummy, Digitalis, poisoning, Italy, late Middle Ages
PALABRAS CLAVE: momia natural, Digitalis, envenenamiento, Italia, tarda Etad Media

 Abstract
Cangrande della Scala (1291-1329), lord of Verona, suddenly died of acute diarrheic illness on 22 July 1329, after the conquest of the city of Treviso and of a large part of Northern Italy. Imaging (digital X-ray and CAT) and autopsy studies of the well-preserved natural mummy of Cangrande showed a good preservation of the internal organs and liver, as well as the feces in the rectum. Histology evidenced liver fibrosis and a severe irregular lung emphysema, with nodular fibrosis and massive anthracosis. Immunochemical analysis of extracts of feces and liver revealed the presence of toxic concentrations of digoxin and digitoxin, equivalent to several dozens of nanograms per gram, with presence of Digitalis pollen in the feces. Administration of a brew or foxglove decoction designed to cure or, more likely, to poison the prince, was almost certainly responsible for this acute and fatal intoxication.

Corresponding author: G. Fornaciari, Division of Paleopathology, Department of Oncology, Via Roma 57, 56126 Pisa – Italy.
E-mail: g.fornaciari@med.unipi.it
Web page: www.paleopatologia.it


Introduction
Cangrande (previously christened Can Francesco) della Scala (March 9, 1291July 22, 1329) was an Italian nobleman, the most celebrated of the Della Scala family which ruled Verona from 1277 to 1387. Well known as the leading patron of the poet Dante Alighieri, Cangrande was also one of the great military men of his age and important autocrat of that period. In 1311 he became sole ruler of Verona and was regarded as the leader of the Ghibelline faction in northern Italy, taking control of several cities such as Vicenza, Padua and Treviso until his death in 1329.
In the spring of 1329 Cangrande obtained the title of Imperial Vicar of Mantua from the Emperor, intending to move against the Gonzaga family that was ruling the city at that time. However, these  plans were postponed owing to a change of government at Treviso during which a number of powerful exiles offered to help him conquer the city in exchange for their reinstatement. On 2 July 1329 Cangrande left Verona and on 18 July he subdued and made his state entry to Treviso.
However, his triumph was ruined by the illness he contracted after having drunk, as reported by contemporary sources, from a polluted spring a few days before. Soon after arrival at his lodgings he settled his affairs and died on the morning of 22 July 1329. Rumors of poisoning immediately started to spread. At nightfall his body, escorted by the nobles, was taken from Treviso to Verona, where it was temporarily placed in the church of Santa Maria Antiqua. From there, it was moved twice, once to the churchyard, and then to a marble tomb over the church entrance, above which is an equestrian statue of Cangrande in tournament armour.

In February 2004 Cangrande’s tomb was opened, to allow the paleopathological study of the corpse. When the very heavy stone lid of the sarcophagus (Fig. 1A) was raised, what appeared was a well preserved body, wrapped in precious silk textiles and still wearing some clothes (Fig. 1B). He was lying on his back with his arms folded across the thorax and his lower limbs extended (Fig. 1C).

Radiology
At first, the mummy of Cangrande was studied by digital radiography and by volumetric computer tomography (Gortenuti, Montemezzi & Schenal, 2006). Some dense material appeared in the esophagus lumen (Fig. 2A, star), consisting in alimentary material, regurgitated immediately before death. Maxillary sinuses were partially occupied by dense, diversified material , as a possible result of chronic sinusitis. The cranial cavity revealed a good preservation of the menynx (Fig. 2A, riangle) and brain residuals in the posterior cerebral fossa (Fig. 2A, arrow).
The right thoracic cavity showed some residuals of the lung, formed by a number of irregular cavities surrounded by dense fibrous tissue (Figs. 2B-3, high arrows). These cavities can be interpreted as emphysematous bullae, delimited by fibrous septa.
Abdominal CT showed a good preservation of the liver, positioned in the right thoracic cavity, with its typical anatomic shape (Fig. 3 star), and presence of feces in the rectal ampulla (Fig. 3, low arrows) .
Mild arthritis of the column, elbows and hips, as well as meniscus calcification of the knees, could be related to the intense physical activity of the Prince, who was a knight and soldier. The rotulae appeared laterally dislocated owing to a typical taphonomic process of initial decomposition in an empty space.

Figura 1 Figura 2 Figura 3

Autopsy
At the moment of autopsy the abdomen appeared very expanded, probably due to putrified changes (Fig. 1D). The skin showed a dark brown color at the head and legs, and light brown under the clothes. The soft tissues of the face appeared preserved, with retracted lips revealing the upper anterior incisors and a flattened nose (Fig. 1D, insert a). The incisors showed some enamel hypoplasia lines. The hair was curly and brown. The stature was 1.73 m.
In order to avoid damage to the mummy, autopsy was performed by a circular opening of the abdomen, from the sternum to the pubis, which allowed us to reach the abdominal and thoracic cavities (Fornaciari, 2006).
The viscera appeared totally collapsed on the posterior wall, forming a homogeneous layer of about 5 cm. Samples  for histology were collected according to the topography of the different organs.
The liver was highly positioned in the right thoracic cavity under the hemidiaphragm, and showed a typical anatomic shape, with a transversal diameter of 30 cm, antero-posterior diameter of 15 cm, and weight of 220 g (Fig. 4A).

Histology
For rehydration we used Sandison’s  solution, specific for mummified tissues. This solution consisted of: 30cm3 of ethyl alcohol at 95%, 50 cm3 of aqueous formalin at 1%, 20 cm3 of sodium carbonate at 5% in aqueous solution. We employed a ratio between lesion-volume / rehydrating solution- volume of 1/10, embedded for seven days.
After rehydration and routine paraffin-embedding, some sections were submitted to standard haematoxylin-eosin and Van Gieson’s staining procedures.
Histology of the liver showed typical hepatic tissue with many collapsed fibrous portal zones close, but not confluent to each other, by liquefaction of the hepatic cells (Fig. 4B) and  portal areas with fibrosis surrounding dilated vessels (Fig. 4C).
These findings can “create the illusion of a pattern of interconnected, proliferative portal areas suggestive of cirrhosis” (Aufderheide, 2003).
Histology of the aorta revealed some small atheromatous plaques on the luminal surface. The aortic media was well preserved, with regular layered patterns of elastic tissue and lamellae, stained according to Weighert’s method.
Histology of the right lung showed areas of collapsed alveoli with fibrosis and fibro-hyaline nodular formations, surrounded by massive anthracosis (Figs. 5B-C). The pulmonary tissue surrounding two fibrous and anthracotic areas appeared to be still expanded, with dilated and confluent alveoli, destruction of the septal walls and presence of cell-rich exudate in the lumen (Fig. 5A). This is a classical picture of irregular emphysema (Fornaciari, 2006).
The severe anthracosis, very similar to a “coal workers’ pneumoconiosis”, is easy to explain because the palaces of the late Middle Ages had no fireplaces, but were heated with large braziers, resulting in very smoky environments. just like the temporary military quarters of Cangrande’s numerous  campaigns.
Finally, the nodular fibrosis of the lungs was the result of tuberculosis, a very common disease in the crowded and unhealthy medieval towns of those times.

Figura 4 Figura 5

Pollen analyses
The results of pollen analyses (Tab. 1) (Marchesini & Marvelli, 2006) are reported. The pollens on the external skin derive from external application of chenopodium - probably in the form of an ointment - and by pollinic rain at the moment of the prince’s death (late spring and summer plants). Internally there is a large amount of pollens of chamomile, black mulberry and, totally unexpected, of foxglove (Digitalis sp.  perhaps purpurea) in the feces.
In the Middle Ages chamomile was largely used by os as sedative and antispasmodic drug, and black mulberry was used as astringent; instead foxglove was considered only a poisonous plant.

Toxicology
In order to establish the presence of  digoxine and digitoxine in samples of the liver and feces, immunochemical methods with different antiserums were used, to minimize the risks of errors caused by cross-reactions (Tab. 2) (Guidi & Brocco, 2006).
After rehydration of the samples, the tests made it possible to identify compounds immuno-reactively similar to two glycosides of Digitalis in toxic concentrations, of the order of tens of ng/g in the two samples (Tab. 3).

Conclusions
In conclusion we can affirm that:
 

  1. the concentrations of digoxine and digitoxine in the liver and in the feces of Cangrande are toxic;
  2. digoxine and digitoxine are the active principles of Digitalis (Digitalis purpurea and Digitalis lanata);
  3. the origins of intoxication are to be searched in the oral administration of an infusion or decoction of leaves and flowersof Digitalis;
  4. the gastrointestinal symptoms manifested by Cangrande, characterized by vomiting and gastroenteric irritation with diarrhea, as reported by the different sources in great clinical detail – corporei fluxus stomachique doloris acuti, fluxu obiit, fluxu ventris et febre ob laborem exercitus (Varanini, 2004) – are compatible with the early phase of Digitalis intoxication;
  5. deliberate poisoning under the guise of medical treatment is probable;
  6. one of Cangrande’s physicians was hanged by his successor Mastino II, emphasizing on this possibility.

It transpires that the actual cause of death was poisoning from lethal amounts of  digitalis, a drug which is extracted from one of the ‘foxglove’ families of plants. Evidence leans towards deliberate murder by poisoning. A physician of Cangrande’s was hanged by his successor Mastino II (Varanini, 2004), adding more weight to the possibility that foul play was at least suspected, although who was ultimately behind the killing is likely to remain a mystery.
One of the principal suspects at least in terms of motive seems to be Cangrande’s nephew, the ambitious Mastino II himself.

Tables

External
skin

Plant

%

Chenopodium sp.
(goosefoot)

51.0

Summer plants

21.2

Late spring plants

14.5

Others

13.3

 

 

 

Left
colon

Matricaria chamomilla
(chamomile)

83.3

Morus nigra
(black mulberry)

16.7

 

 

 

Rectum
feces

Matricaria chamomilla

88.9

Digitalis sp.
(foxglove)

11.1

Table 1. Results of pollen anlyses, with presence of Digitalis (foxglove) in the feces

 

 

Method

Sensitivity
ng/ml

Precision
C.V.%

 

Digoxin

Digoxin IMMULITE®
(immmuno-competition)

0.1

3.5-5.7

Digoxin Tina-quant ®
(immmuno-competition)

0.15

2.7-4.5

Digoxin Assay Emit ®2000
(immmuno-enzymatic)

0.2

2.0-4.4

Digitoxin

Digitoxin
IMMULITE/IMMULITE®1000
(immmuno-competition)

0.65

3.9-4.6

Table 2. The immunochemical methods adopted and their sensitivity.

 

 

Digoxin-DPC

Digoxin Roche

Digoxin Syva

Digitoxin-DPC

Liver (ng/g)

14.0

5.6

16.8

62.4

Rectal feces (ng/g)

15.6

7.2

11.2

41.6

(toxicity in ng/ml)

(2.1-1.7)

(>2.0)

(>2.0)

(>45)

Table 3. Toxic concentrations of  digoxin and digitoxin in the liver and rectal feces of Cangrande.

 


Bibliography
Aufderheide, A.C., 2003. The Scientific Study of Mummies. Cambridge: Cambridge University Press.
Bartolotti, F.  et al., 2006. Nuove ipotesi sulla causa di morte di Cangrande della Scala dai risultati delle analisi tossicologiche. In: E. Napione (ed.) Il corpo del Principe. Ricerche su Cangrande della Scala. Venezia: Marsilio Editori, 73-81.
Fornaciari, G., 2006. Primi risultati dello studio paleopatologico della mummia di Cangrande. In: E. Napione (ed.) Il corpo del Principe. Ricerche su Cangrande della Scala. Venezia: Marsilio Editori, 49-59.
Gortenuti, G., Montemezzi, S. and G. Schenal, 2006. Il corpo di Cangrande della Scala. Ricerche radiologiche. In: E. Napione (ed.) Il corpo del Principe. Ricerche su Cangrande della Scala. Venezia: Marsilio Editori, 61-65.
Guidi, G.C. and G. Brocco, 2006. Misura di digossina e digitossina su campioni biologici del secolo XV. In: E. Napione (ed.) Il corpo del Principe. Ricerche su Cangrande della Scala. Venezia: Marsilio Editori, 83-87.
Marchesini M. and S. Martelli, 2006. Il corpo di Cangrande della Scala. Risultati delle indagini palinologiche. In: E. Napione (ed.) Il corpo del Principe. Ricerche su Cangrande della Scala. Venezia: Marsilio Editori, 93-1003.
Napione, E., 2006. Significato e prospettive di una ricerca pluridisciplinare. In: E. Napione (ed.) Il corpo del Principe. Ricerche su Cangrande della Scala. Venezia: Marsilio Editori, 27-35.
A.T. Sandison, 1955. The histological examination of mummified material. Stain Technology, 30, 277-283.
Varanini, G.M., 2004. La morte di Cangrande della Scala. Strategie di comunicazione intorno al cadavere. In: P. Marini, E. Napione and G.M. Varanini (ed.s) Cangrande della Scala. La morte e il corredo di un principe nel medioevo europeo. Venezia: Marsilio Editori, 11-21.

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