key: cord-0010074-y0svo5ka
authors: Schwedes, C. S.
title: Mitotane (o, p‘‐DDD) treatment in a cat with hyperadrenocorticism
date: 2008-06-28
journal: J Small Anim Pract
DOI: 10.1111/j.1748-5827.1997.tb03310.x
sha: 31571e225249cdb8c189076cdad9f3ec9d5c3530
doc_id: 10074
cord_uid: y0svo5ka

An 11‐year‐old male castrated Persian cat with spontaneous hyperadrenocorticism was presented. Both adrenals were grossly enlarged and calcified. A diagnosis of pituitary‐dependent hyperadrenocorticism was made. Signs of hyperadrenocorticism resolved with long‐term mitotane treatment. Concurrent diabetes mellitus resolved after 220 days of therapy. No severe adverse drug reactions were noted.

Hyperadrenocorticism is a rare endocrine disorder in cats. Approximately 60 cases of spontaneous feline hyperadrenocorticism have been described or mentioned in the veterinary literature (Swift and Brown 1976. Meijer and others 1978, Peterson and Steele 1986, Helton-Rhodes and others 1993, Myers and Rruyette 1994a , Peterson and others 1994 , Duesberg and Peterson 1997 ). The treatment regimens described include unilateral or bilateral adrenalectomy, medical therapy with mitotane (o,p'-DDD), ketoconazole and metapyrone, and 6oCo irradiation. Currently, the recommended treatment is unilateral or bilateral adrenalectomy (Zerbe 1989, Peterson and others 1994) .

Although mitotane treatment in cats has been described, there are no detailed reports of long-term treatment.

An 1 I-year-old male castrated Persian cat with newly diagnosed diabetes mellitus was referred after a hypoglycaemic crisis to establish glycaemic control and to evaluate possible hyperadrenocorticism. T h e cat had received a first dose of regular insulin (H Insulin; Hoechst), of unknown quantity, the same morning.

O n initial presentation, the cat was depressed, slightly dehydrated and the mucous membranes were pale. Body temperature was 37.9"C. A potbellied appearance, hair loss on the ventral abdomen, very thin skin wirh prominent vein5 a i d some degree of muscle ;itrophy were noicd ( Fig I ) . Palpation of the ahdomeii rcvc.iIc'iI an enlarged liver.

Emergency blood ;iiialysis showcd . i n elevation of urea (25.0 mniolllitre) wiih normal creatininc. Ulood glucosr w.15 4. I mmolllitre. An intr.ivenoiis infiisioii o t lactated Ringer's solution was ~o i~i n i c i i i t~l and blood glticose Ievcls moriitor~~A. Insulin was withheld until fiirrher re\[\ could be performed.

Laboratory evaluation several h o u r \ after initial treatiiieiit revcalecl nioc1cr:iic leucocytosis with an increase in iii;itiirc neutrophils and lymphopenia ('1';ihlc I ).

T h e packed cell volume was iiorni;il, bur anisocytosis, polychroniasia and ii ucIc;itcii red blood cells were noted. l'he IhoJ chemistry profile showed a niarketlly clcvated blood glucose level a n d mild . i / ( itaemia. Liver enzymes were raised csccpi for alkaline phospharasc and gai1irii.i gliitamyl transferaae. l.ipids were iiicrcxwil. Total proteiri was markedly cIcv.itcC1 1wr electrophoresis showed a nornid disti-ilw tion pattern. Electrolyte values wcrc wi[hiii the reference ranges. Negative test rewlt\ were obtained for feline li.uk;ieini;i .md feline iininunode~cicncy virtrscs .inil i l l < , feline infectious peritonitis titrc WA'I I :LI(IO.

Radiography ( K g 2) \Iiowcd .I l l i \~ tended abdoinen with good c'oiitr.15t Aiic to fat accumularion. The livci-was ciilxgcJ and there were some gas-tilled bowel I ( i o p . Both kidneys were well drlinc.ircd .irill normal in size. Cranial t o the kidney5 .iii oval opaciticarion with calcit;c;ition w.i\ noted. T h e calcification was visiblc OII both sides ofrhc spinal coluiiiii (111 rhc veiitrodorsal view.

Ultrasonographically, both ciArcii.il glands could be readily visualiscti. 'l'hc Icti adrenal measured 34 x 25 >: 30 i n i i i , r l i v right adrenal 38 x YJ x 27 inni (big . \ I .

They were heterogeneoub i n structure u iili focal acousric shadowing. T h c eiiIiiIgcJ liver was hyperechoic but hoiiiogeiicoii\, .I\ were the renal corticcs. No orhcr .iI)iioi malities were found.

A .icircnocorticnl function could be achieved hctween days 47 and 6 9 it was decided to try a niaintenance protocol with 50 mg/kg/week without corticoid or mi ncralocorticoid supplementation. 'livo weeks later the cat presented with extensive patches of thin corn necrotic skin t h a t rcquired extensive surgery (Fig 4) .

Wound healing was slow but uncomplicated. Sutures were removed 18 days after surgery.

Hair started to regrow and glycaemic control was maintained but the cat required increasing amounts of insulin (2 i 7 units). Three weeks after institution of iii:iintenance therapy the cat suffered an m i t e hypoglycaeniic crisis and insulin was decreased to 2 units twice daily.

The results ofan ACTH test performed on day 1 1 1 led to the reinstitution of miner.iIocorticoid and corticoid therapy.

h4itotanc W;IS discontinued on day 146.

Insulin dosage was further reduced and e\~entually stopped on day 220 after the initiation of mitotane treatment.

The cat was in good condition and clinic;d signs of hyperadrenocorticism had rcsolved. The abdomen had decreased in size and tension and the adrenal glands could now be palpated. This had not been possible on initial examination. A followup radiograph demonstrated no changes in adrcnal size and calcification.

On day 280 recurrence of polydipsia .ind thinning of the haircoat was noted.

'The blood glucose level was slightly above normill. ACTH testing showed considerable stimulation (Tible 2) and mitotane was administered again at 25 mg/kg/day for one week and then 37.5 mg/kg/day.

Due to inappetence, dosage was reduccd t o 12.5 mglkglweek after three lll0llt tl s. 

Although hyperadrenocorticism is an uncommon disease in cats there has been an increasing number of reports during the past few years (Swift and Brown 1976 , Meijer and others 1978 , Peterson and Steele 1986 , Helton-Rhodes and others 1993 , Myers and Bruyette 1994a , Peterson and others 1994 , Feldman 1995 , Duesberg and Peterson 1997 .

Clinical features resemble those observed wich canine hyperadrenocorticism in many respects. Affected cats mostly show increased appetite, polydipsia, polyuria, poor hair condition and a pendulous abdomen.

There are, however, some apparent differences. T h e vast majority of cats suffer from overt diabetes mellitus, a feature that is noted in only approximately 1 O per cent of canine patients with hyperadrenocorticism (Zerbe 1989, Myers and Bruyerte 1994a , Peterson and others 1994 , Feldnian 1995 . However, diabetic cats seem to do much better after successful therapy of hyperadrenocorticism than dogs: most cats could be stabilised on a much lower insulin dosage or insulin therapy could be stopped altogether (Feldman and others 1989, Zerbe 1989, Myers and Bruyette 19941) .

The cat presented in this report had overt diabetes mellitus that resolved after successful treatment.

Another typical condition i n feline hyperadrenocorticism is an extremely fragile skin chat tends to tear spontaneously, creating large wounds that are prone to infection in these already inimunosup- Another feature observed on t h e r d i ographs were the grossly cnl.irgcd .iricl calcified adrenals (Fig 2 ) . C:ilcitk.itioii o t the adrenals i n cats is noc t i n u~u ; i l (I'cwrson and others 1994), but tlicrc. .ire onI\ two repbrts of IiidogicnI cvicicncc ot'c..iIcified adrcnal glands in c;its with I i~p~. idrenocorticism (Swift and H i -o w n IO-0~ Imniink and others 1992).

Calcifications here were pi-oniiiicnr enough to be detected I-.idiogr;ipliic.ill! Ultrasonographically, acoustic slixio\ ins was evident. Neither adrcnal dccrc.iw1 111 size during trc;itmcnt, as determined I)! follow-up radiography.

Polydipsia and polyuria iii h \ p r adrenocorticoid cats h a s hccn u t r r i l ) u t e d I I I an early development of diabetes mellitus and subsequent osmotic diuresis (Peterson and others 1994, Feldman 1995) . However, there are reports of cats with hyperadrenocor-ticism which show polydipsia and polyuri'i without having diabetes rnellitus (Feldman and Nelson 1987, lrnmink and other9 1992) . This cat, too, showed increased thirst along with hair coat deterioration when the relapse occurred. Blood glucose Icvr4 was 8.6 mmol/litre at that time. This was the same level as had been measured one month before when water intake and the serum fructosaniine value (Reusch and Hoyer-Ott 1995) had been normal ( 2 16 tiniol/litre, reference range <340). As 8.0 mmol/litre is well below the threshold t o r glucosuria in cats, osmotic diuresis secmix very unlikely to be the sole reason for t h e increased thirst. However, glucosuria cannot be entirely excluded from a spot hmiple.

The blood profile performed within hours of dmission (Table 1) revealed changes rathcr typical of hyperadrenocorticism and diahetes niellitus. Noteworthy is the marked rlevation in total protein. As the cat W;I\ clinically dehydrated some degree of hqxrproteinaemia is expected. Glucocorticoid administration can lead to hyperproteinarmia in human beings (Werner and others 1989) and in normal dogs (Moor-c a i d others 1992) and might be possible in cats as well. A coronavirus infection H'.IS, however, initially considered. When total protein was checked on frequent latcr-occasions it turned out consistently to he 'high normal'.

The presence of nucleated red blood cells in conjiinction with a normal red blood cell count leads to the diagnosis of a subclinic.il regenerative anaemia of unknown origin masked by dehydration.

Stimulation of the bone marrow is known to occur in bitches with hyperadrenocorticism but this usually leads to erythrocytosis (Feldman 1995).

Testing protocols for hyperadrenocorticism in cats .ire not as established as they are in dogs. Dexamethasone suppression tests have bren performed with dosages from 0.0 1 to 1 .0 mg/kg intravenously (IV) and orally (Johnston and Mather 1979 , Medleau and others 1987 , Smith and Feldman 1987 . Whereas dosages of 0.01 and 0.1 mg/kg (IV) d o not lead to complete adrenocortical suppression for eight hours in all healthy cats, dosages of 1.0 mg/kg (IV) reliably suppress cortisol levels for up to 32 hours Feldman 1987, Bruyette 1994) . Differentiation between P D H and functional adrenocortical tumour in clinical cases might be possible using very high-dose dexamethasone suppression tests (Bruyette 1994) .

In this case, the results of the dexamethasone suppression test and the symmetrical appearance of both adrenals led to a diagnosis of PDH.

ACTH levels, unfortunately, could not be determined due to the lack of validated assays for feline ACTH. A computed tomography scan was not performed.

ACTH stimulation testing is not a conclusive test for hyperadrenocorticism in cats. It is reliable, though, for the diagnosis of hypoadrenocorticism (Bruyette 1994, Myers and Bruyette 1994b) . Intramuscular injection of 0.125 mg tetracosactrin, an ACTH analogue in aqueous solution and determination of cortisol levels at baseline and 30 minutes were chosen from various reported protocols (Johnston and Mather 1979 , Kemppainen and others 1984 , Smith and Feldrnan 1987 , Bruyette 1994 . Cortisol determinations were performed using high-pressure liquid chromatography. As endogenous cortisol and prednisolone cannot be differentiated by this method it was necessary to omit the steroid administration on the preceding evening.

It is striking that on day 18 of treatment the basal cortisol concentration was high (232 nmol/litre) with only a moderate increase (to 309 nmol/litre) after ACTH administration, which is considerably less than would be expected in a dog with a comparable baseline value. Healthy cats tend to have lower post-ACTH cortisol values than d o dogs (Duesberg and Peterson 1997) . Another explanation would be slow or incomplete resorption of ACTH From the injection site leading to the cortisol peak being missed by the blood sampling. Inadvertent drug administration by the owner would lead to similar results. In cats, bilateral adrenalectomy has been recommended as the treatment of choice for P D H (Zerbe 1989, Peterson and others 1994) . When mitotane treatment was first introduced, information about this treatment regimen was sparse. Mitotane had been used in four healthy cats others 1987, Zerbe 1989) and in one cat with hyperadrenocorticism (Feldman and others 1988) with an inconsistent efficacy in suppressing adrenocortical function. It had been well tolerated, however. Since then, two reports have been published suggesting that mitotane might be effective in treating cats with P D H when given on a long-term basis (Myers and Bruyette 1994a, Feldman 1995) . In the present case, mitotane was given at moderate levels (25 mglkglday) for 10 weeks, then for 11 weeks at 50 rng/kg/week. After a pause of 19 weeks, daily mitotane therapy was resumed for 13 weeks and then decreased to 12.5 mg/kg/week as continuous therapy.

The treatment regimen followed in this case was derived from the protocol for dogs described by Rijnberk and Belshaw (1995) , aiming at the complete destruction of all three zones of the adrenal cortex leading to both glucocorticoid and mineralocorticoid deficiency. In contrast, mineralocorticoid deficiency develops with conventional mitotane therapy in only about 5 per cent of dogs (Feldman 1995, Peterson and Kintzer 1997) . As mineralocorticoid deficiency is a potentially lifethreatening disease with the possibility of acute crises, fludrocortisone (a mineralocorticoid) was administered in conjunction with maintenance doses of prednisolone during the induction phase. No abnormalities in either the clinical appearance of the cat that were suggestive of hypoadrenocorticism or in the sodium or potassium concentrations were detected during this period. When adrenocortical tiinction seemed stable after day 69, cortiwid . i d miiieralocorticoid supplementat i o n was stopped and only reinstituted .ittcr an A(3.H stimulation rest gave evidcncc ofliyi'o~idreiiocorticism on day I I I .

Mitocane wxs well tolerated with only \light adverse reactions. Interestingly, progresh in destroying adrenocortical funct i o n w a s very slow initially. The same observation has been made by Nelson and others ( 1088) After inresrinal resorption, mitotane requires conversion into an intermediate meraholite (o,p'-DDA) to be active. The drug's rwo effects are mitochondria1 dcsrruction leading ro cell death and direct inhibition of steroid synthesis (Peterson .ind Kintzer 1997) . Species differences in resorption and activation of the drug and \..iriations i n tissue susceptibility could be ;in explanation for the reduced effectiveneu in cats. An increased metabolism of the drug, which is disposed of by hepatic microsonial enzymes, seems highly unlikely in the cat.

In this case. the daily dose of niitotane w a s 25 nigkg a t the beginning and 37.5 mglkg after day 18, which is lower than rhc induction dosages recommended for dog5 (Riinberk and Belshaw 1995). This, of course, could have contributed ro the delayed therapeutic response.

Why the cat responded abruptly after changing to 50 mglkg once weekly remains unclear. 3wo possible explanations include a cumulative effect of mitotane and a relatively high susceptibility of the adrenal cortex to a high dose pulsed therapy.

This case suggests that niitotane treatment in cats with PDH might be possible. In cats. much longer periods ofdrug administration seem to be necessary than for dogs. Whereas cats with bilateral ad renalectom y need to be monitored very closely in the perioperative and early postoperative periods, niitotane treatment requires frequent control examinations for the rest of the animal's life because of sudden changes in cort i coid product ion and insulin requiremenr. This involves much dedication on the part of the owner. However, more investigation is needed in this field before general recommendations for treatment can be made.

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