Comparative Medicine 
Copyright 2004 
by the American Association for Laboratory Animal Science 303059 
Vol 54, No 1 
February 2004 
Use of Desferoxamine and S-Adenosylmethionine to 
Treat Hemochromatosis in a Red Ruffed Lemur 
(Varecia variegata ruber) 
Carlos R. Sanchez, DVM,* Suzan Murray, DVM, and Richard J. Montai!, DVM 
Hemochromatosis Avas diagnosed in a 14-year-old, male, red ruffed lemur (Varecia variegata ruber) on the basis 
of abnormal results of serum biochemical analysis, including high serum ferritin and transferrin saturation val- 
ues, and of liver biopsy. Therapy included chelation, using desferoxamine to remove excess iron and S- 
adenosylmethionine to improve liver function, and monthly peripheral blood removal by phlebotomy to reduce 
total body iron content. Response to treatment ?was assessed by changes in the lemur's attitude and appetite, as 
well as variations in serum biochemical and iron panel values. Initial improvement was associated with the onset 
of therapy. After 56 days of treatment, results of serum biochemical analysis indicated a decrease in iron panel 
values Treatment ?was temporarily discontinued from days 56 to 65, and the lemur's condition Avorsened, so therapy 
was re-instituted. HoAvever, the lemur died of hepatocellular carcinoma on day 110 of treatment. 
Hemochromatosis, the deposition of excess amounts of iron in 
parenchymal organs, with eventual tissue damage and impaired 
function of organs, was first recognized more than a century ago 
in humans (28). It was first described in lemurs in the late 1960s, 
and is suspected to be, in part, the result of dietary derangements 
(15, 16, 34). Although adjustments in diets have reduced the 
prevalence of hemochromatosis in lemurs in the last decade, the 
disease is still diagnosed in captive animals. 
The goal in treating hemochromatosis is to normalize the total 
body load of iron. In human patients, treatment is best accom- 
plished by reducing blood volume, using weekly phlebotomy to 
lessen the iron load (1, 12, 29). In cases where hemochromatosis 
coexists with chronic anemia or other blood disorders that prevent 
use of phlebotomy, iron chelation may be the best available 
therapy (18,29). Although it is less effective than phlebotomy, che- 
lation therapy is less invasive and can be routinely performed in 
animals that require anesthesia and/or sedation to undergo phle- 
botomy. Desferoxamine mesylate (DFO; Desferal, Novartis, E. 
Hanover, N.J.), a naturally occurring trihydroxamic acid produced 
by Streptomyces pilosas, is a chelating agent routinely used to re- 
move excess iron from the body. (3, 10, 13). Administration of S- 
adenosylmethionine (SAMe; Denosyl, Nutraceutics Corporation, 
St. Louis, Mo.) has reportedly improved hepatocellular function in 
various species (2,4). We describe intramusciilar administration of 
DFO and oral administration of SAMe as viable therapy for hemo- 
chromatosis in a red ruffed lemur (Varecia variegata. ruber). 
Case Report 
In December of 2001, a 14-year-old, male-red ruffed lemur that 
was housed with a 13-year-old, healthy, female red ruffed lemur in 
an indoor/outdoor enclosure and was fed a low-iron, low-vitamin C 
Received: 7/01/03. Revision requested: 8/18/03 Accepted: 10/10/03. 
Smithsonian National Zoological Park, 3001 Connecticut Avenue, North West, 
Washington, D.C. 20008-2598. 
'Corresponding author. 
diet, presented with history of weight loss and decreased appetite. 
The lemur was anesthetized by intramuscular administration of 
ketamine (15.3 mg/kg of body weight; Ketaset, Fort Dodge Animal 
Health, Overland Park, Kans.) and midazolam (0.5 mg/kg; Versed, 
Baxter Pharmaceutical Products Inc., New Providence, N.J.). An- 
esthesia was maintained with 2% isofluorane (Forane, Baxter 
Pharmaceutical Products Inc.). Physical examination revealed a 
thin animal, but was otherwise unremarkable. There was no evi- 
dence of hepatomegaly, splenomegaly, joint disease, or excess skin 
pigmentation. Complete blood cell count values were within nor- 
mal range. In contrast, serum biochemical analysis revealed hy- 
perbilirubinemia and high bile acids concentration. Serum iron 
concentration, total iron-binding capacity (TIBC), and transferrin 
saturation percentage were markedly high (Table 1). Moderate 
increase of alkaline phosphatase and creatine kinase activities 
also was observed (data not shown). 
A liver biopsy was performed one month later. To perform the 
procedure, medetomidine (40 |J.g/kg; Domitor, Pfizer, Exton, Pa.), 
butorphanol (0.40 mg/kg; Torbugesic Inj., Fort Dodge Animal 
Health), and midazolam (0.5 mg/kg) were given intramuscularly 
to the lemiir. Physical examination once again revealed a thin ani- 
mal, while laboratory results jdelded no appreciable change in h?- 
matologie and serum biochemical analysis results other than a 
markedly high serum ferritin concentration (Table 1). Four liver 
biopsy specimens were obtained using a Wolfe biopsy forceps. His- 
tologie examination of the liver revealed disrupted architecture, 
with regenerating nodules and thick bands of fibrosis and bile 
duct hyperplasia in the portal areas (Fig. 1). Using a Prussian blue 
stain, large amounts of iron were observed in macrophages in the 
periportal areas, with lesser amoimts of iron in hepatocytes (Fig. 2). 
CHnical and pathologic findings were indicative of hemochromato- 
sis associated with early stages of liver cirrhosis. 
A multi-component plan combining serial phlebotomy, chelation 
therapy, and treatment for hepatic insiifficiency was initiated. The 
iron chelator DFO was administered intramusciilarly at a dosage of 
108 
Table 1. Summary of h?matologie and iron panel values obtained from a red ruffed lemur (Varecia variegata ruher) under treatment for hemochr ornato sis 
Day 
Blood parameter Reference range 12/01 1 33 56 110 
8-171" NA 237 92 144 198 
29-91' 100 NA 83 88.5 91.5 
208-379- 409 NA 355 341 309 
90-318- 409 NA 297 302 283 
NA 40.6 NA NA 22.7 NA 
0.0-3.4" 4.3 2.1 2.7 2.3 16.0 
Serum ferritin (ng/ml) 
Transferrin saturation (%) 
TIBC (|ig/dl) 
Serum iron (|J.g/dl) 
Bile acids (|j.mol/L) 
Total bilirubin (mg/dl) 
^Values for Black and White ruffed lemurs (Varecia variegata variegata) > 10 years-old, provided by Graham Crawford DVM, San Francisco Zoo. 
''International Species Information System. Ruffed lemur {Varecia variegata) males > 2 year-old. 
TIBC - total iron-binding capacity; NA - not available. 
R 
C 
200x 
Figure 1. Photomicrograph of a section of liver from a biopsy speci- 
men obtained from a lemur with hemochromatosis. Notice regenera- 
tive nodules (A) with portal fibrosis (B) and bile duct hyperplasia (C). 
H&E stain; magnification, 200x. 
10 m^kg every other day for four weeks. Phlebotomy (10 ml/kg) was 
scheduled at monthly intervals, and SAMe at a dosage of 30 mg/kg 
given orally once a day was added to the treatment regimen to 
improve liver function. Metronidazole (15 mg/kg; Flagyl, G.D. 
Searle & Co., Chicago, 111.) was given orally for 14 days as therapy 
for possible bacterial involvement. 
On day 42, DFO administration was decreased to twice a week, 
and on day 49, it was decreased to once a week. Desferoxamine ad- 
ministration was temporarily suspended between days 56 and 65 
due in part to poor patient compliance to injection and concern 
that the polyuria and polydypsia that had developed may have 
been caused by the medication. However, DFO administration 
was re-instituted on the basis of the initial improvement that 
had been observed in the lemur's condition and serum biochemical 
values (decreases in: serum ferritin concentration, from 237 ng'ml to 
144 ng/ml; transferrin saturation, from 100% to 88.5%; TIBC, from 
409 Hg/dl to 341 |ig/dl; serum iron concentration, from 409 |ig/dl to 
341 |ig/dl; total bilirubin concentration, from 4.3 mg/dl to 2.3 mg/dl; 
and bile acids concentration, from 40.6 |lmol/L to 22.7 |j,mol/L); 
polyuria and polydypsia were attributed to being a clinical sign of 
liver disease. Administration of SAMe was continuous throughout 
the treatment. 
On day 110 of treatment, the lemur was anesthetized for follow- 
up blood tests and physical examination. The lemur was de- 
pressed, and mucous membranes were yellow-green tinged. The 
serum biochemical profile indicated severe hyperbilirubinemia 
(Table 1), and the lemur died 12 h later. Pathologic findings were 
Figure 2. Lower-magnification photomicrograph of the section of liver 
from Figure 1. Noticed nodular pattern, with densely blue-staining, 
iron-laden macrophages in the portal areas. Prussian blue stain for 
iron; magnification, 75x. 
indicative of marked hepatic insufficiency and ascites associated 
with liver cirrhosis, isch?mie necrosis, and hepatocellular carci- 
noma. The carcinoma was extensive, but did not extend beyond 
the liver. There were no additional relevant pathologic changes. 
Discussion 
A number of bird and mammal species are known to accumu- 
late excess amounts of iron under captivity conditions (21, 23, 25, 
30). In humans, hemochromatosis is considered the most common 
type of primary iron overload disease (lOD) (27,29). Primary lOD, 
which is hereditary, stems from an inherent defect in iron regula- 
tion that results in continuous over-absorption of iron from the 
gsastrointestinal tract (12,27). Hemochromatosis has historically 
been considered a common problem in lemurs in captivity (15,17, 
31,34). Development of hemochromatosis in lemurs and birds is 
thought to be multifactorial, with dietary derangements (a combi- 
nation of excess dietary iron, excess ascorbic acid intake, and lack 
of tannins in the diet), genetics, and environmental factors as pos- 
sible contributing causes (9, 17, 31). In this case, the cause of 
hemochromatosis was unclear as the lemur had been fed a low- 
iron, low-vitamin C diet, and its long-term cage mate remained 
unaffected. 
Diagnosis of hemochromatosis in human patients is based on 
physical examination findings, genetic analysis, blood tests, and 
possible liver biopsy results (27, 29). Although a complete iron 
panel (serum iron concentration; TIBC; transferrin, serum fer- 
ritin, and serum transferrin receptor values; and transferrin iron 
109 
Vol 54, No 1 
Comparative Medicine 
February 2004 
saturation percentage) may be necessary to diagnose hemochro- 
matosis, two tests in particular, determination of serum ferritin 
concentration and transferrin saturation percentage are consid- 
ered the most reliable methods to detect high tissue iron content. 
(1, 27, 28). Increase of these values in the absence of other causes 
of iron overload (transfusion, oral iron supplementation) is 
strongly suggestive of hemochromatosis. 
Severe hemochromatosis was diagnosed in this lemur on the 
basis of high bile acids concentration, hyperbilirubinemia, and 
high serum ferritin and serum iron concentrations, and high per- 
centage of transferrin saturation, along with hepatic histologie 
changes and high iron deposition observed in the liver biopsy 
specimen. In humans, deposition of iron targets several systems 
(liver, heart, pancreas, skin, and skeletal) (1, 3, 29). In animals, 
clinical signs of the disease usually are related to hepatic dysfunc- 
tion (21). Specifically, lemurs have high prevalence of liver disease 
characterized most often by hepatocellular necrosis, distorted ar- 
chitecture, and bile duct hyperplasia (15, 17, 21, 31, 34). In this 
case, hepatic cirrhosis and carcinoma had developed, as noted at 
necropsy. 
Use of phlebotomy for the treatment of iron overload in hu- 
mans, domestic animals, and birds is well documented in litera- 
ture (1,12,24,25,29,35). However, in the case of this lemur, serial 
phlebotomy would have required multiple anesthesia events, and 
was, thus, considered impractical. Instead, therapy was based on 
iron chelation with DFO, liver support with SAMe, and monthly 
phlebotomy to reduce total body iron content and to monitor 
progress. Desferoxamine is the only iron chelator approved in 
North America and has been successfully used for years in hu- 
mans, birds, and domestic animals (3,7, 8,10,12,13,18,26). 
Although it is not as effective as phlebotomy to achieve rapid 
removal of excess iron from the body, long-term therapy with DFO 
slows accumulation of hepatic iron and retards or eliminates pro- 
gression of fibrosis. In contrast, hepatic cirrhosis due to iron over- 
load rarely resolves in response to therapeutic phlebotomy only 
(1). The dosage and route of administration of DFO in this lemur 
were extrapolated from those used to treat chronic iron toxicosis 
in children under three years of age. Instead of daily administra- 
tion, DFO was administered every other day because of its poten- 
tial adverse effects (cardiac, ocular, or auditory abnormalities or 
cerebral neurotoxicosis) and limited experience with it in non-hu- 
man primates (21). Adverse effects attributed to DFO administra- 
tion were not noticed during treatment of this lemur. 
S-Adenosylmethionine was administered to help maintain and 
protect liver function. This medication has been documented to 
support liver function in a variety of species, including humans, 
rodents, dogs, and other non-human primates, without inducing 
cytotoxic effects or relevant adverse effects (2, 4-6, 14, 19, 20, 32, 
33). The SAMe contributes to three major biochemical pathways? 
transmethylation, transsulfiiration, and aminopropylation?all of 
which are essential functions of hepatocytes (11, 19, 22). The 
SAMe is also a precursor of glutathione, which is a major compo- 
nent of the antioxidant defense system and, thus, may have anti- 
oxidant properties (4, 32). 
Transferrin saturation percentage, serum iron and serum fer- 
ritin concentrations, and TIBC were monitored during treatment. 
While this lemur was receiving DFO, ferritin, serum iron, and 
TIBC values initially decreased to near-normal limits after 30 
days of treatment. These laboratory findings correlated with im- 
provement in clinical signs of the disease. However, cessation of 
DFO therapy resulted in the return of an increase in the afore- 
mentioned values. On the basis of activity level, appetite, and in- 
teraction with keepers, subjectively the lemur's condition 
improved when SAMe therapy was instituted. 
Although this lemur initially improved in response to treat- 
ment, during the fifteenth week after treatment, its condition 
worsened, and on day 110, it died. On postmortem examination, 
hepatocellular carcinoma was diagnosed as the cause of death. 
Hepatocellular carcinoma is reported to be one of the principal 
causes of death in untreated humans patients with hemochroma- 
tosis, and thus, it was not an unexpected finding (1, 12, 29). Al- 
though this lemur did not survive, the authors believe that the 
treatment would have been more successful had it been initiated 
earlier in the course of disease. Furthermore, the improvement in 
the serum iron panel and liver function values, and clinical signs 
of disease warrant further investigation into this protocol as a po- 
tential treatment for lemurs with hemochromatosis. 
Acknowledgments 
We thank the Small Mammal House and Department of Animal 
Health staff at the Smithsonian National Zoological Park for provid- 
ing excellent care to this lemur. We thank Bonnie Coy for her assis- 
tance in preparing this manuscript. This work was supported in part 
by FONZ grant 02-351000. 
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