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Approach to hypoalbuminemia (Proceedings)


Albumin is the major determinant of oncotic or colloidal osmotic pressure, the force that holds fluids within the vascular compartment. Most of the important osmotically-active particles in the bloodstream (such as sodium, urea and glucose) are relatively small, and pass freely between the vascular and interstitial compartments, the body's two major extracellular fluid compartments.

Albumin is the major determinant of oncotic or colloidal osmotic pressure, the force that holds fluids within the vascular compartment. Most of the important osmotically-active particles in the bloodstream (such as sodium, urea and glucose) are relatively small, and pass freely between the vascular and interstitial compartments, the body's two major extracellular fluid compartments. Albumin, in contrast, is too large to pass freely through the vascular endothelium, and remains within the bloodstream. The oncotic pressure within vessels due to the presence of albumin is the major force holding fluid within the vascular compartment, although other plasma proteins such as globulins also have some oncotic force. Hypoalbuminemia leads to a decrease in plasma oncotic pressure, which can eventually lead to a leakage of fluid out from the vascular compartment.

Clinical Signs of Hypoalbuminemia

The classic clinical manifestations of hypoalbuminemia include peripheral edema, ascites and pleural effusion. These clinical signs reflect the hypoalbuminemic patient's impaired ability to hold fluid within the vascular space, and usually only occur when plasma albumin levels drop to between 10 and 16 g/L. The fluid that typically leaks into extravascular spaces is a pure transudate:

Pure Transudate:

          Clear and colorless

          Protein < 25 g/L

          Specific Gravity < 1.018

          Few cells (if any) seen

Decreased oncotic pressure and loss of intravascular fluid can also lead to hypovolemia, which in turn can lead to problems such as poor peripheral perfusion and pre-renal azotemia.

Causes of Hypoalbuminemia

The potential causes of hypoalbuminemia are many, and include:

          Hepatic failure (failure of albumin synthesis)

          Gastrointestinal protein loss (protein-losing enteropathies)

          Renal protein loss (protein-losing nephropathies)

          Other external losses in exudate or hemorrhage

          Hyperglobulinemia (with a 'compensatory' decrease in albumin production)

          Starvation/protein malnutrition

          Chronic illness


          Laboratory error

Despite this multitude of potential etiologies, the diagnostic approach to hypoalbuminemia is usually very straightforward. Non-gastrointestinal and non-renal causes of external protein loss (such as third degree burns, open pyometra, and draining pyothorax or peritonitis) are usually obvious, while hyperglobulinemia, starvation, protein malnutrition and chronic illness rarely cause more than mild hypoalbuminemia. With the possible uncommon exception of hypoadrenocorticism, moderate to severe hypoalbuminemia can therefore usually be narrowed down to only three major potential causes:

1. Hepatic failure

2. Protein-losing enteropathy

3. Protein-losing nephropathy

Diagnostic Approach to Hypoalbuminemia

1. Initial diagnostic approach:

History                         Hematology

Physical examination     Biochemistry (including globulins)

                                    Urine analysis

Serum globulin levels can sometimes provide the clinician with a crude guide as to the potential cause of hypoalbuminemia. Serum globulins tend to be decreased with protein-losing enteropathies, normal with protein-losing nephropathies, and increased with hepatic failure.

2. Potential further diagnostic testing:

The above standard investigation will often suggest the likely cause of an animal's hypoalbuminemia. Further testing will be directed by the results of routine investigation, but usually entails specific investigation of urinary, gastrointestinal and hepatic function. Since definitive determination of gastrointestinal protein loss can be difficult and involve invasive testing, potential urinary protein loss and hepatic failure are usually investigated first.

(i) Protein-Losing Nephropathy (PLN)

Urinary protein levels are initially investigated by protein dipstick or laboratory measurement of protein concentrations. Normal animals have little or no protein in their urine, and such a finding in a hypoalbuminemic patient usually excludes PLN as a diagnosis. When proteinuria is detected in the absence of an active urine sediment (pyuria or hematuria), the magnitude of urinary protein loss can be more accurately quantified using a urine protein:creatinine ratio.

Protein:creatinine ratio < 1:            Normal

Protein:creatinine ratio < 2:             Suspicious ('gray' zone)

Protein:creatinine ratio > 2:             Protein-losing nephropathy

(ii) Hepatic Failure

Hepatic failure may be suggested by the results of routine serum biochemistry and urinalysis:

Hypoalbuminemia             Low serum urea

Hyperglobulinemia             Hypoglycemia

Hyperbilirubinemia             Ammonium biurate crystalluria

Elevated SAP and ALT

Not all patients with hepatic failure, however, will exhibit the classic biochemical changes usually associated with liver dysfunction. Hypoalbuminemia can occasionally be the only real clue to hepatic failure. In such cases, although abdominal radiography and ultrasonography may assist in determining hepatic size and structure, liver function testing is the primary means of establishing the presence of liver failure:

Resting ammonia and rectal or oral ammonia tolerance testing

Resting and post-prandial serum bile acids

Since ammonia cannot be transported, ammonia can only be measured if an in house chemistry analyzer is available. Such analyzers can produce spuriously high ammonia results, particularly if samples are not tested as soon as collected. Immediate testing has the advantage of providing a rapid diagnosis. Bile acids have the advantage of being stable and easily transportable.

(iii) Protein-Losing Enteropathy (PLE)

GI signs in a hypoalbuminemic patient with normal renal and hepatic function strongly suggest PLE, particularly if hypoglobulinemia is also present. Some patients with PLE can however have profound hypoalbuminemia and ascites with no history of vomiting or diarrhea. In such patients, PLE is a diagnosis of exclusion that can often only be confirmed by intestinal biopsies. Since collection of biopsies is invasive, PLN and hepatic failure should be excluded first. Infrequently, non-invasive tests such as fecal parasitology and culture, serum TLI, folate and B12 and breathe hydrogen analysis may suggest a cause of PLE. Recently, a fecal test measuring levels of alpha1-protease inhibitor has been developed (Texas A&M GI Laboratory) that may be a useful indirect indicator of the magnitude of fecal protein losses.

Major Differential Diagnoses for Hypoalbuminemia

1. Protein-Losing Nephropathy

Renal amyloidosis                         Glomerulonephritis

(Endogenous/exogenous glucocorticoids)

The common causes of PLN, amyloidosis and glomerulonephritis, can only be distinguished by renal biopsy. Since renal biopsy is invasive, and since neither disease tends to respond well to therapy, it is arguable whether biopsies are always indicated. High levels of exposure to glucocorticoids, either endogenous (hyperadrenocorticism) or exogenous, can cause mild to moderate proteinuria, but not of sufficient enough magnitude to cause hypoalbuminemia.

2. Hepatic Failure

Potential causes of hepatic failure are many. Common causes include:

Chronic hepatitis             Hepatic lipidosis

Cholangiohepatitis         Hepatic neoplasia

Copper toxicity               Feline infectious peritonitis

Cirrhosis                       Portosystemic shunting

Since the causes of hepatic failure are multiple, and many of the underlying etiologies are specifically treatable, establishment of a definitive diagnosis by fine needle hepatic aspiration, ultrasound-guided hepatic needle biopsy, laparoscopy or exploratory laparotomy for excisional liver biopsies (or by imaging techniques in the case of portosystemic shunts) is almost always indicated.

3. Protein-Losing Enteropathy

Common causes of PLE include:

Inflammatory bowel disease (IBD)             Lymphangiectasia

Neoplasia (lymphosarcoma)                   Gastrointestinal parasitism

Histoplasmosis                                         Pythiosis

Since the causes of PLE are multiple and responsive to different treatment regimes, gastrointestinal biopsy via either endoscopy or laparotomy is usually indicated. Since dogs with hypoalbuminemia and severe GI disease are prone to poor wound healing (especially at gut full-thickness biopsy sites), it is usually advisable to attempt a diagnosis via endoscopy before resorting to exploratory laparotomy. Biopsies at laparotomy, however, are sometimes needed to establish a definitive diagnosis.

Treatment of Hypoalbuminemia

Unless a diagnosis can be established and specifically treated, options for the management of hypoalbuminemia are unfortunately somewhat limited. Major therapeutic options include:

1. Treatment of the Specific Disease Process

As a general rule of thumb, most causes of PLE can be effectively treated, and many of the causes of hepatic failure can also be managed or, in limited instances, cured. The causes of PLN, on the other hand, rarely respond to specific therapy. Examples of disease-specific therapy include:

Immunosuppressive therapy

Inflammatory bowel disease

Chronic hepatitis

Lymphocytic cholangiohepatitis

Glomerulonephritis (uncommonly responds to therapy)




Suppurative cholangiohepatitis

Intensive nutritional support

Hepatic lipidosis

Copper chelating agents

Copper-associated hepatopathy of Bedlingtons and other dog breeds

Ursodeoxycholic acid (UDCA)

Chronic hepatitis and cholangiohepatitis

DMSO and/or colchicine

Renal amyloidosis (very rarely effective)

Given the myriad of potential different diagnoses, treatments and prognoses, it is obviously best to establish a definitive diagnosis before instituting specific therapy. However, in rare instances where a diagnosis is not obtainable, rather than euthanasia it may be worth a therapeutic trial with immunosuppressive doses of glucocorticoid. Glucocorticoids, however, can worsen edema and ascites by promoting volume retention, and will obviously obscure future attempts to obtain a diagnosis.

2. Drain Pleural and Peritoneal Cavities

Drainage of fluid from affected body cavities is indicated if the volume of fluid present is causing significant dyspnea (pleural effusion) or abdominal discomfort (ascites). However, unless effective specific therapy is also instituted, body cavity fluid tends to build up rapidly after drainage. Repeated body cavity drainage will predispose the patient to dehydration and hypovolemia due to excessive fluid loss, and also carries a significant risk of causing secondary bacterial pleuritis or peritonitis. Drainage should therefore not be performed merely because a mild to moderate amount of body cavity fluid is present, particularly if that fluid is causing the patient few problems.

3. Transfuse with Colloids

Crystalloids are sodium-based electrolyte solutions or solutions of glucose in water. Colloid solutions, in contrast, contain larger molecules that do not readily leave the vascular space. Colloid solutions therefore perform the same job as endogenous albumin, that is holding water within the vascular compartment, thereby expanding blood volume.

Plasma is the prototype colloidal solution. Synthetic colloid solutions such as dextrans and hydroxyethyl starch (Hetastarch) are now also available as plasma volume expanders. Human serum albumin, a concentrated and purified form of albumin, has also been used in dogs and cats with surprisingly few reports of adverse reactions. The most commonly used form of human serum albumin, the 25% solution, has an oncotic effect about five times that of plasma.

Colloid Solutions

Conceptually, plasma or human serum albumin would initially appear to be the colloidal solutions of choice in hypoalbuminemic patients, and probably are in patients with a failure of albumin production due to liver failure. In such patients, transfused albumin would be expected to effectively circulate for a number of weeks. However, in patients with PLN or PLE, transfused plasma or albumin are likely to be almost completely ineffective, since the donated albumin tends to very rapidly leak out of the vasculature by the same route as the animal's own albumin. In fact, in such patients often plasma albumin has not even measurably increased immediately after transfusion.

A second problem associated with the use of plasma is that blood donors and blood bank centrifuges are not always readily available. In many instances, the lack of a centrifuge means that in an emergency whole blood must be given instead of plasma, thereby subjecting the patient to a large volume of superfluous red blood cells. In less urgent situations, plasma can sometimes be extracted from red cells by sitting whole blood in the refrigerator for a day, and letting the erythrocytes settle. Problems with obtaining plasma promptly in an emergency can be prevented by pre-ordering and storing in the refrigerator plasma products purchased from an animal blood bank. Human serum albumin may be a little more convenient than plasma, since it is more stable than plasma, can be purchased in smaller volumes, and can be stored without freezing for use as needed at a later date.

Because of the problems associated with the use of plasma or albumin in patients with PLN or PLE, synthetic colloids are the probably fluid of choice in such animals. Most commercial synthetic colloids tend to contain molecules that are larger than albumin. These molecules therefore remain in the circulation rather than leak out via the same route as albumin, and are gradually eliminated over a day or two by metabolic degradation.

Recent studies in dogs with low oncotic pressure due to number of causes, however, have shown that even synthetic colloids are rarely effective for more than a day or so. Colloid transfusions should therefore be scheduled for a time at which they will be most effective (prior to and during anesthesia and surgery, for example), and given up to two or even three times daily in critically ill patients.

Crystalloid solutions such as normal saline expand blood volume and hydrostatic pressure without increasing oncotic pressure. In fact, such solutions often decrease oncotic pressure by diluting the concentration of the patient's remaining albumin. Indiscriminate use of crystalloids in patients with moderate to severe hypoalbuminemia (particularly if edema, ascites or pleural effusion are present) is therefore highly dangerous, and can cause acute pulmonary edema.

Crystalloid solutions are very dangerous in the patient with moderate to severe hypoalbuminemia

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