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History

A 4-year-old, male Halm's macaw (Diopsittaca nobilis nobilis) was presented to the Kansas State University Veterinary Health Center for progressive lethargy and falling from its perch. Three years before, the bird was presented to another veterinary referral center for lethargy, fluffed feathers, and a change in vocalizations. The owner had acquired the bird from a bird fair approximately 3 weeks before the onset of the abnormal clinical signs. At that time, the bird was diagnosed with a Chlamydia psittaci infection by a positive result of a polymerase chain reaction (PCR) DNA probe on a conjunctival swab sample and a C psittaci serologic titer of 1:50. Additionally, results of a plasma biochemical panel revealed increased activities of lactate dehydrogenase (LDH) (305 U/L; reference range, 40-250 U/L), aspartate transaminase (AST) (1483 U/L; reference range, 90-180 U/L), alkaline phosphatase (ALP) (855 U/L; reference range, 290-750 U/L), and creatine kinase (238 U/L; reference range, 280-500) and increased concentration of bile acids (524 [micro]mol/ L; reference range, 6-35 [micro]mol/L). (1)

Treatment at the previous referral center was initiated with doxycycline (25 mg/kg PO q24h; Vibramycin calcium, Pfizer Labs, New York, NY, USA) for 4 weeks. When the bird presented for reexamination 1 month after the initial diagnosis and treatment, liver values remained elevated (LDH, 397 U/L; AST, 4306 U/L; ALP, 916 U/L; bile acids, 680 [micro]mol/L), although the initial clinical signs had generally resolved. Milk thistle (unknown dose) was added to the bird's medication regimen, and doxycycline therapy was continued for an additional 2 months; however, liver enzyme activities and bile acid levels remained increased (LDH, 957 U/L; AST, 2471 U/L; ALP. 1058 U/L; bile acids, 450 [micro]mol/L) after 3 months of treatment. At that time, doxycycline therapy was discontinued and a liver biopsy was recommended, although not performed. The bird returned for re-examination 3 months after discontinuation of doxycycline and 6 months after the initial diagnosis with no external clinical signs of avian chlamydiosis or liver disease. Nonetheless, over the next 2 years, ALP and AST activities and bile acid levels continued to be elevated at each veterinary visit for this patient in which biochemical panels were submitted.

Thirty months after being diagnosed with C psittaci infection and initiation of doxycycline therapy, the bird was referred to the Kansas State University Veterinary Health Center. Physical examination revealed that the macaw weighed 176 g and was moderately depressed, with fluffed feathers and a palpable mass in the coelom. Although the owner reported a normal appetite, marked muscle wasting was present, and the bird had a body condition score of 2/5. To obtain radiographs and samples for diagnostic testing, the bird was anesthetized with 5% isoflurane in 2 L/ min of oxygen via a facemask and then maintained on 2.5% isoflurane for the duration of the procedures. A blood sample was obtained from the right jugular vein for a plasma hematologic evaluation, biochemical analysis, and testing for C psittaci antigen by polymerase chain reaction assay. Lateral and ventrodorsal radiographs were also obtained (Fig 1). Unfortunately, during recovery, the macaw went into cardiac arrest and could not be revived. A postmortem examination and histopathologic evaluation were then performed. Results of the plasma biochemical analysis completed after death showed similar elevations as those observed 3 years before, with increases in ALP (807 U/L) and AST (782 U/L) activities and bile acid levels (435 [micro]mol/L). Other biochemical findings were within reference intervals, and all hematologic findings were within normal range.

Diagnosis

Radiographs revealed a large soft tissue opacity extending throughout most of the ventral coelomic cavity consistent with a generalized expansion of the hepatic silhouette (Fig 2). This mass was consistent with a marked generalized enlargement of the liver. Generalized hepatomegaly is a nonspecific clinical sign that can indicate pathology from a variety of causes, including toxic insult, neoplasia, and bacterial infection, among others.

Gross postmortem examination of the macaw revealed a nodular and firm liver (Fig 3) with an increased reticular pattern and numerous adhesions to the proventriculus and ventriculus. There were numerous well-demarcated, pale, tan areas effacing roughly 60% of the liver parenchyma, with the largest measuring 0.3 X 0.5 X 0.3 cm. The lungs were diffusely congested and dark red. No other significant abnormalities were identified. Samples of the liver and lungs were negative on a PCR DNA probe for C psittaci.

On histopathologic evaluation of the liver tissue, the tan nodules were made up of an unencapsulated, moderately cellular neoplasm comprised of irregular tubules, acini, and cords supported by a fibrovascular stroma (Fig 4). The tubules were lined by a single layer of cuboidal to columnar epithelial cells. Neoplastic cells displayed indistinct cell borders, multiple basophilic nucleoli, eosinophilic cytoplasm, finely stippled chromatin, mild to moderate anisocytosis, and infrequent mitotic figures. These neoplastic cells frequently infiltrated, separated, and surrounded the remaining areas of normal hepatocytes. The neoplasm affecting the liver in this macaw were characteristic of a bile duct carcinoma.

Discussion

The Hahn's macaw, previously classified as Ara nobilis nobilis, is the smallest of the macaw species and one of 3 subspecies of red-shouldered macaws. Found endemically in northeastern South America, these macaws are popular in the pet trade. Although a decline has been noted in the wild population, this species is classified on the IUCN Red List of Threatened Species in the Least Concern category. (2)

This case illustrates the difficulty in making an accurate antemortem diagnosis from preliminary diagnostic testing (eg, plasma biochemical analysis, hematologic evaluation, and radiographic imaging). It also underscores the value of performing more advanced diagnostic testing when selecting a therapeutic protocol. This bird had a history of being diagnosed with avian chlamydiosis, which can cause liver disease and enlargement and can establish a chronic infection if not adequately cleared from the body. (3) The organ systems commonly affected by avian chlamydiosis include the liver, spleen, respiratory system, and central nervous system, although any body system may be affected. The typical presentation of a bird infected with C psittaci can include conjunctivitis, nasal and ocular discharge, biliverdinuria, a leukocytosis with concurrent heterophilia and monocytosis, elevation of aspartate transaminase, lactate dehydrogenase, creatine phosphokinase, and bile acids. However, affected birds may present with very nonspecific signs, such as lethargy, depression, and increased respiratory effort. (3,4) A definitive diagnosis of an active infection of C psittaci is made by identifying chlamydial antigen in tissue samples, isolating the C psittaci organism from a specimen, or seeing a significant rise in serologic titers over the course of 4 weeks. (3) A probable diagnosis could be made by presence of a high single titer or identifying C psittaci antigen on a cloacal swab or from respiratory tract and ocular exudates. (3)

Neoplasia occurs with moderate frequency in avian species. In one study, neoplasia was identified in 9% of cases of birds presented for postmortem examination to a referral institution over a 5-year period. (5) The most commonly noted neoplasms of this group were multicentric lymphoma and adenocarcinomas of the gastrointestinal tract. (5) Whereas birds of the order Psittaciformes are often purported to be more predisposed to neoplasia than those in other avian orders, (6,8) Psittaciformes had only the fifth highest prevalence of neoplastic disease of the orders surveyed in one study. (9)

Bile duct carcinomas have been reported in young psittacine birds of the genus Amazona. (10-13) Carcinomas of the liver in parrots have been linked to infection with psittacid herpesvirus 1 (HV-1), specifically genotype 3. (14) Psittacine HV-1 is well known for being the causative agent of Pacheco's disease, which can cause sudden death in various psittacine species. Psittacine HV-1 has also been reported to be associated with the occurrence of mucosal papillomatosis and bile or pancreatic duct carcinomas. (14) Some believe the presence of mucosal papillomatosis is correlated with the ensuing development of bile duct carcinomas. (13) The presence of an infectious disease that predisposes the bird to the development of this type of neoplasia may explain why this neoplasia is diagnosed in younger birds. In the case we describe, paraffin-embedded, formalin-fixed liver tissue was submitted and found to be negative on PCR for psittacid herpesvirus strains 1, 2, 3, and 4. The negative result obtained suggests that the previously identified psittacid herpesvirus may not play a role in the pathogenesis of this bird's bile duct carcinoma. However, the sensitivity of PCR tests on formalin-fixed tissue is slightly reduced because of the deterioration of DNA cause by formalin. (15) The potential remains that a viral agent plays a role in the development of bile duct carcinomas in young psittacine birds.

Diagnosis of intracoelomic neoplasms in avian species often occurs late in the disease process when treatment is either unrealistic or impossible. (7,16) Bile duct carcinomas are often associated with increased gamma-glutamyl transferase and bile acid levels; however, these tests are not specific for bile duct carcinomas. (14) With the diagnosis of hepatomegaly, an endoscopic liver biopsy would have been the diagnostic method of choice. Coelioscopy would have allowed visualization of the gross pathology affecting the liver, as well as collection of biopsy samples for histopathologic examination and PCR testing for C psittaci. However, as occurred in this case, severely compromised patients are associated with increased anesthetic risk, thereby making it difficult to obtain diagnostic samples through more invasive techniques. Other diagnostic tests that would have been beneficial include coelomic ultrasound with fine needle aspirate and computed tomography scanning. Cytologic evaluation of the liver aspirates likely would have yielded an antemortem diagnosis.

Even when bile duct carcinomas are diagnosed antemortem, there is little available information on appropriate or effective treatment of this type of neoplasm in avian species. A single report exists regarding the treatment of a bile duct carcinoma in a bird. A 25-year-old yellow-naped Amazon parrot (Amazona auropalliata) was diagnosed with a bile duct carcinoma. After treatment with carboplatin, administered twice at doses of 100 mg/[m.sup.2] and 125 mg/[m.sup.2], hepatomegaly showed a marked reduction, and associated clinical signs resolved for 30 days after treatment. (17) However, no long-term follow-up or final outcome was reported, making it difficult to evaluate the degree of success achieved by this protocol. More research is required before appropriate recommendations for therapy may be made regarding the treatment of bile duct carcinomas in avian species.

Acknowledgments: We thank the Avian and Zoological Medicine Service, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA, for its contributions to the management of this case.

This case was submitted by Louden Wright, DVM, James W. Carpenter, MS, DVM, Dipl ACZM, and Pankaj Kumar, DVM, from the Departments of Clinical Sciences (Wright, Carpenter) and Diagnostic Medicine/ Pathobiology (Kumar), College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.

References

(1.) Hawkins MG, Barron HW, Speer BL, et al. Birds. In: Carpenter JW, ed. Exotic Animal Formulary. 4th ed. St Louis, MO: Elsevier Saunders; 2013:183437.

(2.) Hilton-Taylor C, ed. 2000 IUCN Red List of Threatened Species. Cambridge, UK: International Union for Conservation of Nature and Natural Resources; 2000.

(3.) Crosta L, Melillo A, Schnitzer P. Chlamydiosis (psittacosis). In: Speer BL. ed. Current Therapy in Avian Medicine and Surgery. St Louis, MO: Elsevier Saunders; 2016:82-93.

(4.) Vanrompay D, Ducatelle D, Haesbrouck R. Chlamydia psittaci infections: a review with emphasis on avian chlamydiosis. Vet Microbiol. 1995;45(2-3):93119.

(5.) Nemeth NM, Gonzalez-Astudillo V, Oesterle PT, Howerth EW. A 5-year retrospective review of avian diseases diagnosed at the Department of Pathology, University of Georgia. J Comp Pathol. 2016; 155(23): 105-120.

(6.) Castro PF, Fantoni DT, Miranda BC, Matera JM. Prevalence of neoplastic diseases in pet birds referred for surgical procedures. Vet Med Int. 2016:1-7.

(7.) Filippich LJ. Tumor control in birds. Semin Avian Exot Pet Med. 2004;13(l):25-43.

(8.) Leach MW. A survey of neoplasia in pet birds. Semin Avian Exot Pet Med. 1992;l(2):52-64.

(9.) Garner MM. Overview of tumors: a retrospective study of case submissions to a specialty diagnostic service. In: Harrison GJ, Lightfoot TL, eds. Clinical

Avian Medicine. Vol 2. Palm Beach, FL: Spix; 2006: 566-571.

(10.) Elangbam CS, Panciera RJ. Cholangiocarcinoma in a blue-fronted Amazon parrot (Amazona aestiva). Avian Dis. 1988;32(3):594-596.

(11.) Anderson WI, Dougherty EP, Steinberg H. Cholangiocarcinoma in a 4-month-old double yellowcheeked Amazon parrot (Amazona autumnalis). Avian Dis. 1989;33(3):594-599.

(12.) Potter K, Connor T, Gallina AM. Cholangiocarcinoma in a yellow-faced Amazon parrot (Amazona xanthops). Avian Dis. 1983;27(2):556-558.

(13.) Hillyer EV, Moroff S, Hoefer H, Quesenberry KE. Bile duct carcinoma in two out of ten Amazon parrots with cloacal papillomas. J Assoc Avian Vet. 1991 ;5(2):91--95.

(14.) Phalen D. Psittacid herpesviruses and associated diseases. In: Speer BL, ed. Current Therapy in Avian Medicine and Surgery. St Louis, MO: Elsevier Saunders; 2016:47-51.

(15.) Greer CE, Lund JK, Manos MM. PCR amplification from paraffin-embedded tissues: recommendations on fixatives for long-term storage and prospective studies. PCR Methods Appl. 1991;1(1): 46-50.

(16.) Zehnder A, Graham J, Reavill DR, McLaughlin A. Neoplastic diseases in avian species. In: Speer BL, ed. Current Therapy in Avian Medicine and Surgery. St Louis, MO: Elsevier Saunders; 2016:107-141.

(17.) Zantop DW. Treatment of bile duct carcinoma in birds with carboplatin. Exot DVM. 2000;2(3):76-78.

Caption: Figure 1. (A) Right lateral and (B) ventrodorsal radiographic views of a Hahn's macaw that presented for progressive lethargy and falling off its perch. Please evaluate the history, physical examination findings, test results, and Figure 1. Based on your case assessment, formulate a list of differential diagnoses before proceeding.

Caption: Figure 2. (A) Right lateral and (B) ventrodorsal radiographic views of the macaw described in Figure 1. Arrows in Figure 2A indicate an enlarged soft tissue opacity occupying most of the coelomic cavity and in Figure 2B indicate the extent of the enlarged hepatic silhouette.

Caption: Figure 3. Gross image of the liver and viscera from the postmortem examination of the macaw described in Figure 1. Arrows highlight the numerous tan nodules effacing the majority of the hepatic parenchyma.

Caption: Figure 4. Photomicrograph of the liver from the macaw described in Figure 1. (A) Neoplastic epithelial cells arranged in irregular tubules, acini, and cords that infiltrate the hepatic parenchyma and are characteristic of a cholangiocarcinoma. Multifocally, hepatocytes contain aggregates of golden brown granular pigment (hemosiderin). (B) Unaffected hepatic parenchyma is shown on the right of the image (hematoxylin and eosin; bar = 100 [micro]m).
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Publication:Journal of Avian Medicine and Surgery
Article Type:Report
Geographic Code:1USA
Date:Jun 1, 2017
Words:2425
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