The diagnostic work-up can be divided into 3 steps and prioritizes localizing the source of decreased albumin levels.
Albumin is an essential protein. It plays multiple roles including acting as a carrier molecule for drugs, hormones, and other substances in the body: a free radical scavenger; the main contributor to oncotic pressure; and contributes to wound healing. Low albumin levels can lead to a myriad of changes in the body, but there is a finite list of differential diagnoses for hypoalbuminemia. Lawren Durocher-Babek, DVM, MS, DACVIM, CHPV of Zodiac Pet and Exotic Hospital in Fortress Hill, Hong Kong, presented a stepwise approach to diagnosing and treating hypoalbuminemia in companion animals, during a session at the 2023 American Veterinary Medical Association Convention in Denver, Colorado.1
Clinical signs of a chronic, slow decrease in albumin levels are often nonspecific until the albumin is <2 g/dL. Once the albumin drops below this level, peripheral edema and a distended abdomen–caused by ascites–may be noticed suddenly.
Other clinical signs may include vomiting, diarrhea, inappetence, lethargy, polyuria, and polydipsia. In cases of liver disease, patients may also present with icterus. Durocher-Babek shared that "one of the biggest mistakes you can make with hypoalbuminemia is assuming you know the location [of the loss] based on clinical signs." Most of these clinical signs can be seen with all 3 sites of albumin loss, so clinicians should avoid jumping to conclusions about the site of albumin loss.
Localization is essential
"Even if you can't do anything else [diagnostically], localize it," said Durocher-Babek. "There is a well-defined list of possible causes that [you] can follow." Chronic hypoalbuminemia occurs due to loss from the kidneys, loss from the intestines, or decreased production from the liver. Although there are many underlying causes for the problem at each location, determining the location helps to narrow the differential diagnosis list and guide treatment.
The diagnostic workup starts with bloodwork, including a complete blood count (CBC), chemistry panel with electrolytes, and urinalysis. Durocher-Babek noted that microcytosis without anemia on the CBC should move a liver shunt high on the differential list. Other CBC changes may include anemia, leukocytosis, and thrombocytopenia. Chemistry panel changes will show the degree of hypoalbuminemia. Additionally, veterinarians may note azotemia, hypoglycemia, elevated liver values, hyperbilirubinemia, hyperkalemia, and hyponatremia. Durocher-Babek shared that elevated liver values do not always point to the liver as the cause, but hyperbilirubinemia is more exclusively seen with liver disease than the other causes.
The urinalysis is the starting place of localization. Veterinarians should pay specific attention to the urine specific gravity, presence of bilirubin, and presence of protein. "If there is protein on the dipstick, do a UPC to the lab to get a number," said Durocher-Babek.
Quantifying the protein in the urine is essential. If the UPC is greater than 1.5, the kidneys are likely the source of the hypoalbuminemia and additional diagnostics and treatment should focus on protein-losing nephropathy (PLN). If no protein is found on the dipstick or the UPC is less than 1.5, the workup should continue to determine if the intestines or liver are the cause.
"Bile acids are something you should do no matter what if you're thinking of any type of biopsies," said Durocher-Babek. Bile acids over 50 indicate the liver as the cause. If the liver is ruled out based on bile acids testing, then the intestines may be the cause.
Determining the underlying cause
Once a location is determined, additional diagnostics can be performed to help determine the underlying cause and guide treatment.
When the kidney is implicated as the site of albumin loss, additional diagnostics should include:
Kidney biopsies may also be considered, but Durocher-Babek noted that the risks of the procedure often outweigh the benefits. Additionally, in most cases, biopsy results do not change the treatment plan.
Protein losing enteropathy
Abdominal ultrasound, fecal testing (especially in young puppies), and a GI panel are recommended in cases of suspected PLE. Ultimately, the diagnosis requires biopsy and histopathology to distinguish between the 3 most common causes: inflammatory bowel disease, lymphoma, and lymphangiectasia. Biopsies can be obtained endoscopically, laparoscopically, or surgically.
For dogs, Durocher-Babek prefers endoscopic biopsies. She noted that although biopsies are not full thickness, they are often diagnostic. Endoscopy allows for visualization of dilated lacteals if present, and there is less concern for delayed healing and dehiscence at biopsy sites compared to surgical biopsies.
“Cats are a bit different and tricky,” said Durocher-Babek, noting that intestinal protein loss is much less common in cats than in dogs. “Because cats like to hide lymphoma, and cats like to pretend they have IBD when it is truly lymphoma, you usually need full thickness biopsies,” she stated. These can be obtained surgically or laparoscopically.
Hypoalbuminemia that occurs because of liver disease indicates at least a 75% loss of liver function. A thorough history to check for toxin exposure, including supplements, is essential. Portosystemic shunts should be ruled out by imaging. In the absence of a shunt or known toxin, biopsy samples are needed. Durocher-Babek recommended laparoscopic or surgical biopsies for small patients. Ultrasound-guided biopsy may be acceptable for larger patients. Biopsy samples should be submitted for both histopathology and culture. Durocher-Babek also recommended saving a sample in case copper quantification is needed.
Treatment of hypoalbuminemia
For sick patients, initial treatment should focus on improving oncotic pressure. This is often accomplished through the use of hetastarch or hypertonic saline. Fresh frozen plasma does not provide enough of an oncotic pull at typical doses but may be useful in patients with liver failure that need replacement of clotting factors.
Human albumin can be considered but has a high complication rate and induces a marked immune response. Additional treatments should include a focus on nutritional support, which may need to be provided by feeding tube. The diet selected should be a high-quality diet that meets the nutritional needs of the underlying disease process. Finally, a portion of the effusion may be drained if the patient is dyspneic or markedly uncomfortable.
Ultimately, “the best treatment for hypoalbuminemia is treatment of the underlying cause,” shared Durocher-Babek. For cases constrained by finances where a definitive underlying cause could not be identified, Durocher-Babek suggested treating for conditions that occur at the identified location. This may include antibiotic, steroid, and dietary therapy.
For patients with a UTI, Durocher-Babek recommended assuming pyelonephritis and treating based on sensitivity data for 6 to 8 weeks. IRIS recommendations suggest ARBs such as telmisartan over ACE-inhibitors for treatment of proteinuria, but Durocher-Babek noted that the expense of treatment can be much higher with ARBs. Additional supportive treatments include omega-3 fatty acids, low-protein diets, clopidogrel, and control of any concurrent hypertension. The goal of treatment is to decrease the UPC by at least 50% of the starting value.
Steroids are needed in some cases of glomerulonephritis. Durocher-Babek noted that UPC levels over 5 are often due to glomerulonephritis and steroids should be considered once infectious causes have been ruled out.
Protein losing enteropathy
Treatment of PLE will depend on the underlying histopathologic diagnosis but will generally include steroids or other immunosuppression and diet changes. Small cell lymphoma is treated with prednisone and chlorambucil while large cell lymphoma is treated with traditional CHOP protocols.
Patients with inflammatory bowel disease (IBD) or lymphangiectasia should receive steroids as a first-line treatment. Prednisone or prednisolone is often started first, but some patients can be transitioned to budesonide for maintenance. Chlorambucil may be needed in severe cases of IBD. Recommended diets for IBD include hypoallergenic and novel protein diets. For lymphangiectasia, low fat diets should be prioritized.
Treatment for liver failure is often supportive unless an underlying cause, such as a shunt, can be identified. Recommendations include antibiotics in cases of infection or suspected infection, liver protectants, and low protein diets. Treatment with copper chelation or surgical correction of a shunt are indicated if these underlying conditions are identified.
Take Home Points
When hypoalbuminemia is identified, veterinarians should focus on localizing the source. "If you can localize the problem, you're 80% of the way there," said Durocher-Babek.
Once the problem is localized, additional diagnostics to determine the specific cause can be pursued. Treatment should focus on improving oncotic pressure in the short term and treating the underlying disease to decrease ongoing loss.
Kate Boatright, VMD, a 2013 graduate of the University of Pennsylvania, is a practicing veterinarian, and freelance speaker and author in western Pennsylvania. She is passionate about mentorship, education, and addressing common sources of stress for veterinary teams and recent graduates. Outside of clinical practice, Boatright is actively involved in organized veterinary medicine at the local, state, and national levels.
1. Durocher-Babek L. Hypoalbuminemia: where has all the protein gone? Presented at AVMA Convention 2023: Denver, Colorado. July 15, 2023.