Extravascular Protein Loss

  • Nephrotic Syndrome: proteinuria (may be massive, 3.5g or more/24hrs)
    • Normally, albumin is filtered by the glomerulus and catabolized by the renal tubules into amino acids, which are recycled
    • However, in presence of glomerular and tubular renal disease, excessive protein filtration may overwhlem this capacity, resulting in albumin loss and increased degradation
    • Note: in this setting, albumin synthesis will only increase when albuminuria exceeeds 100 mg/kg/d with an adequate dietary protein intak
  • Protein-Losing Enteropathy (see Protein-Losing Enteropathy, [[Protein-Losing Enteropathy]])
    • Normally, <10% of the total albumin is lost through the intestine
    • In these cases, intestinal protein loss may be exacerbated by other factors which impair albumin synthesis (sepsis, inflammation, etc)
  • Burns
    • Skin is the major site for extravascular albumin storage (and is the major exchangeable albumin pool needed to maintain plasma levels)
    • Hypoalbuminemia results from direct albumin loss from tissue damage, compromised hepatic blood flow due to volume loss, and from inhibitory tissue factors (TNF, IL-1, IL-6) released at the burn sites


  • Ascites (of Any Etiology): increases volume of distribution, resulting in hypoalbuminemia
    • Note: therefore, in this setting, serum albumin level is not a good index of the residual synthetic capacity of the liver (actual radioisotopic measurements of production are required)
  • Large-Volume IV Fluid Resuscitation


  • Cirrhosis (see End-Stage Liver Disease, [[End-Stage Liver Disease]])
    • Physiology
      • Decreased Albumin Synthesis
        • Loss of Hepatic Cell Mass
        • Decreased and Poorly-Distributed Portal Blood Flow: resulting in maldistribution of nutrients and oxygen to hepatocytes
        • Impact of Ascites on Albumin Synthesis
        • In patients without ascites, decreased albumin synthesis occurs
        • In patients with ascites, increased albumin synthesis may occur (due to a change in hepatic interstitial colloid levels, which may stimulate albumin synthesis)
      • Ascites-Associated Increased Volume of Distribution with Hemodilution: resulting in decreased serum albumin concentration
  • Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
    • Physiology
      • Normal Albumin Synthesis
      • Increased Volume of Albumin Distribution
  • Hypergammaglobulinemia (see Hypergamaglobulinemia, [[Hypergamaglobulinemia]])
    • Physiology: increased serum oncotic pressure -> increased hepatic interstitial volume -> downregulation of albumin synthesis
  • Protein Malnutrition
    • Physiology
      • Deficient protein intake -> rapid loss of cellular ribonucleic acid and disaggregation of the endoplasmic reticulum–bound polysomes -> decreased albumin synthesis
      • Albumin synthesis can decrease by more than 33% during a 24-hour fast
      • Albumin synthesis may be stimulated by amino acids produced in the urea cycle (such as ornithine)
  • Acute/Chronic Inflammation
    • Epidemiology
      • Hypoalbuminemia is present in hospital admission in 20% of patients
    • Physiology: TNF and IL-6 released as part of the inflammatory response (to infection, surgery, trauma) decrease serum albumin by mulitple mechanisms
      • Increased Vascular Permeability: allows albumin to diffuse into the extravascular space
      • Increased Albumin Degradation
      • Decreased Albumin Synthesis: TNF-alpha, which decreases transcription of the albumin gene
  • Zinc Deficiency


  • Decreased Serum Oncotic Pressure: seen only when serum albumin is <1.5 g/dL)

Clinical Manifestations

Pulmonary Manifestations

  • Pleural Effusion (see Pleural Effusion-Transudate, [[Pleural Effusion-Transudate]])
    • May cause pleural effusion in hosiptalized AIDS and other chronic disease patients
    • Usually small-moderate and bilateral (without cardiomegaly)

Other Manifestations

  • Anasarca: always seen
  • xxx
  • xxx


  • Treatment of Underlying Etiology
    • Optimize Nutrition
    • Prevent Protein Loss

Time Course of Resolution of Hypoalbuminemia

  • Acute Inflammation-Related Hypoalbuminemia: hypoalbuminemia due to acute inflammation should normalize within weeks of resolution of the inflammation


  • Hypoalbuminemia in the first 24h of admission is associated with organ dysfunction in burned patients. Burns. Jun 7 2012
  • Risk factors for reintubation in the post-anaesthetic care unit: a case-control study. Br J Anaesth. Jul 9 2012
  • Relevance of albumin in modern critical care medicine. Best Pract Res Clin Anaesthesiol. Jun 2009;23(2):183-91
  • Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ. Nov 18 2006;333(7577):1044
  • Albumin administration improves organ function in critically ill hypoalbuminemic patients: A prospective, randomized, controlled, pilot study. Crit Care Med. Oct 2006;34(10):2536-40
  • Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev. Nov 9 2011;CD001208
  • Inhibition of albumin synthesis in chronic diseases: molecular mechanisms. J Clin Gastroenterol. Apr 2005;39(4 Suppl 2):S143-6
  • Cochrane Injuries Group Albumin Reviewers. Human albumin administration in critically ill patients: systematic review of randomised controlled trials. Cochrane Injuries Group Albumin Reviewers. ALYSIS. Jul 25 1998;317(7153):235-40
  • Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med. Jan 2008;34(1):17-60
  • Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. Jan 2008;36(1):296-327
  • Serum albumin: relationship to inflammation and nutrition. Semin Dial. Nov-Dec 2004;17(6):432-7
  • A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. May 27 2004;350(22):2247-56
  • Preoperative serum albumin level as a predictor of operative mortality and morbidity: results from the National VA Surgical Risk Study. Arch Surg. Jan 1999;134(1):36-42
  • Hypoalbuminemia in renal failure: pathogenesis and therapeutic considerations. Kidney Blood Press Res. 2005;28(5-6):307-10
  • Albumin administration–what is the evidence of clinical benefit? A systematic review of randomized controlled trials. Eur J Anaesthesiol. Oct 2003;20(10):771-93
  • Serum albumin level on admission as a predictor of death, length of stay, and readmission. Arch Intern Med. Jan 1992;152(1):125-30
  • Low levels of plasma proteins: malnutrition or inflammation?. Clin Chem Lab Med. Feb 1999;37(2):91-6
  • Appetite and inflammation, nutrition, anemia, and clinical outcome in hemodialysis patients. Am J Clin Nutr. Aug 2004;80(2):299-307
  • Revisiting mortality predictability of serum albumin in the dialysis population: time dependency, longitudinal changes and population-attributable fraction. Nephrol Dial Transplant. Sep 2005;20(9):1880-8
  • Comparing outcome predictability of markers of malnutrition-inflammation complex syndrome in haemodialysis patients. Nephrol Dial Transplant. Jun 2004;19(6):1507-19
  • Inflammation and dietary protein intake exert competing effects on serum albumin and creatinine in hemodialysis patients. Kidney Int. Jul 2001;60(1):333-40
  • Relationships among inflammation nutrition and physiologic mechanisms establishing albumin levels in hemodialysis patients. Kidney Int. Jun 2002;61(6):2240-9
  • Inflammation and reduced albumin synthesis associated with stable decline in serum albumin in hemodialysis patients. Kidney Int. Apr 2004;65(4):1408-15
  • Use of 125-I- and 51-Cr-labeled albumin for the measurement of gastrointestinal and total albumin catabolism. J Clin Invest. Dec 1967;46(12):2064-82
  • Resuscitating patients with early severe sepsis: a Canadian multicentre observational study. Can J Anaesth. Oct 2007;54(10):790-8
  • A survey of Canadian intensivists’ resuscitation practices in early septic shock. Crit Care. 2007;11(4):R74
  • Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med. Aug 30 2007;357(9):874-84
  • Excess mortality after human albumin administration in critically ill patients. Clinical and pathophysiological evidence suggests albumin is harmful. BMJ. Jul 25 1998;317(7153):223-4
  • Debate: Albumin administration should be avoided in the critically ill. Crit Care. 2000;4(3):151-5
  • The change in serum protein concentration in response to the stress of total joint surgery: a comparison of older versus younger patients. J Am Geriatr Soc. May 1996;44(5):555-8
  • Quality indicators for the care of undernutrition in vulnerable elders. J Am Geriatr Soc. Oct 2007;55 Suppl 2:S438-42
  • Albumin synthesis (second of two parts). N Engl J Med. Apr 13 1972;286(15):816-21
  • Albumin synthesis. 1. N Engl J Med. Apr 6 1972;286(14):748-57
  • Alcohol, amino acids, and albumin synthesis. Gastroenterology. Dec 1974;67(6):1200-13
  • Serum albumin. Hepatology. Mar-Apr 1988;8(2):385-401
  • Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomised trials. BMJ. Mar 28 1998;316(7136):961-4
  • Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet. Mar 24 2001;357(9260):911-6
  • Hypoalbuminemia 3 months after hospital discharge: significance for long-term survival. J Am Geriatr Soc. Jul 2005;53(7):1222-6
  • Admission serum albumin is predicitve of outcome in critically ill trauma patients. Am Surg. Dec 2004;70(12):1099-102
  • A paradigm for consensus. The University Hospital Consortium guidelines for the use of albumin, nonprotein colloid, and crystalloid solutions. Arch Intern Med. Feb 27 1995;155(4):373-9
  • Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann Surg. Mar 2003;237(3):319-34
  • Morbidity in hospitalized patients receiving human albumin: a meta-analysis of randomized, controlled trials. Crit Care Med. Oct 2004;32(10):2029-38
  • Patient survival after human albumin administration. A meta-analysis of randomized, controlled trials. Ann Intern Med. Aug 7 2001;135(3):149-64