Cushing’s after all


This summer I wrote about Yaretzi, a middle-aged golden retriever who was drinking and urinating excessively. We diagnosed protein-losing nephropathy, a kidney condition usually resulting from some other primary disease. We did extensive testing, ruling out problems such as diabetes and hyperadrenocorticism (HAC.) Unable to find an underlying cause, we focused on treating symptoms. Hormones to concentrate his urine, thereby reducing thirst. Blood pressure pills for hypertension. Aspirin to prevent blood clots.

Where other owners might have given up, Yaretzi’s mom steadfastly pursued an explanation, consulting specialists at Tufts University Cummings School of Veterinary Medicine Foster Hospital for Small Animals. A kidney biopsy in August diagnosed “focal segmental glomerulosclerosis.” That’s a mouthful, but really just describes the kidney lesions without identifying the cause. The pathologist explained it could be from a genetic mutation or from damage to specific kidney cells called podocytes. But what damaged the podocytes? No one really knew.

Yaretzi came home. We continued symptomatic treatment. The specialist and I emailed back and forth, tweaking medications, repeating tests, brainstorming. Yaretzi’s mom had many questions,  but I had few answers. “Ask the specialist at his three-month recheck,” was the best I could offer.

Recently Yaretzi returned to Tufts for follow-up. “His liver enzymes are going up and he’s starting to look more like a Cushing’s case,” the doc e-mailed me. “I would recommend you run an LDDS test.”  Cushing’s? Hadn’t we ruled that out months ago? Well, not exactly.

Hyperadrenocorticism, a.k.a. Cushing’s disease, is a disorder caused by the ill effects of long-term excessive cortisol. The most common reason for the increased cortisol is a pituitary tumor, which, although usually not malignant, does secrete adrenocorticotropic hormone (ACTH).

The concept is simple. The pituitary gland in the brain makes ACTH which talks to the adrenal glands, located in the abdomen near the kidneys, telling them to produce cortisol. In normal dogs, when cortisol reaches proper levels, the pituitary is happy and stops producing ACTH. The adrenals then stop making cortisol. In HAC, that pituitary tumor doesn’t have an “off” switch. It just keeps pumping out ACTH, telling the adrenals to keep pumping out cortisol. This scenario accounts for about 85 percent of cases. The remaining 15 percent are caused by adrenal gland tumors.

Cortisol overload affects many different systems, the severity and specific signs varying greatly case to case. Most dogs drink and urinate excessively, like Yaretzi. They are often inordinately hungry, have poor muscle tone and altered fat distribution, with a pot-bellied appearance. Other signs can include enlarged liver, hair loss, lethargy, muscle weakness, obesity, muscle atrophy, pimples, panting, incontinence, facial nerve paralysis, thin, wrinkled skin, and poor healing. HAC is fairly common, with poodles, dachshunds, Boston terriers, boxers, schnauzers, and beagles being particularly prone. Most are middle-aged or older, though it occasionally occurs in younger animals.

Although not a classic case, Yaretzi had fit the picture sufficiently that early on we tested for HAC. Definitive diagnosis usually depends on either of two possible tests. Neither is completely accurate. Each has pros and cons. For low dose dexamethasone suppression test (LDDST), we draw a baseline cortisol, then give a tiny intravenous injection of corticosteroid, then measure blood cortisol levels four and eight hours later. In normal dogs, the injected corticosteroid tells the pituitary to stop secreting ACTH. The adrenals then stop secreting cortisol. Thus we find relatively low cortisol levels at our four and eight hour checks.

The ACTH stimulation test also starts with a baseline blood cortisol. We then inject a dose of artificial ACTH, wait an hour, then recheck cortisol levels. A dog with HAC will have an unusually high second cortisol, as the hyperactive adrenals overreact to the stimulation.

Sounds simple, but it’s not that straightforward. LDDST is a highly sensitive test, effectively diagnosing 95 out of 100 dogs with HAC. Sounds great. But on the other hand, it is not very “specific.” Out of every hundred positive tests, as many as half may be false positives. In other words, despite the fact that the LDDST was positive, those dogs don’t really have HAC.

The ACTH stimulation test has better specificity, with only 15 percent false positives, but it is not as sensitive, missing the diagnosis on 15 percent of dogs with HAC. Which test we use to screen for hyperadrenocorticism varies, depending on the case. We opted for an ACTH stim test for Yaretzi in July. The test was negative so we assumed he did not have Cushing’s disease. But three months later, ultrasound showed enlarged adrenal glands, repeated blood tests showed changes in his liver, and he was clinically declining. We decided to check again for HAC, this time with an LDDST.

“So if you wait long enough, they eventually express themselves,” the specialist said when she saw the results. Yaretzi did indeed have HAC. LDDST can also help distinguish pituitary versus adrenal tumor, though often imaging techniques like ultrasound or MRI are indicated to differentiate these two possibilities. Yaretzi’s LDDST and ultrasound confirmed he had the pituitary form.

The main medications used to treat pituitary-dependent HAC are Lysodren and Trilostane. Lysodren selectively kills off part of the adrenals, thus lowering cortisol production. Trilostane inhibits an enzyme involved in cortisol synthesis. Both drugs are given orally but require close supervision and frequent monitoring, because they can occasionally create the opposite situation, a disorder called hypoadrenocorticism or Addison’s disease, which can be rapidly fatal. Since neither drug eliminates the pituitary tumor, lifelong therapy is required. Treatment for the adrenal form may be surgical, or medical, depending on whether the tumor is benign or malignant, and if it has spread. The prognosis for adrenal tumor is worse than for the pituitary form.

We sometimes opt not to treat HAC unless symptoms are severe enough to cause obvious distress for either dog or owner. Yaretzi meets those criteria. His HAC may not be at the root of all his troubles, but we hope treatment to lower his cortisol levels will improve his quality of life.