Hypoalbuminemia

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Hypoalbuminemia
Other namesHypalbuminosis
PDB 1bm0 EBI.jpg
Structure of albumin
Specialty Internal Medicine, Pediatrics
Symptoms Peripheral edema; ascites; effusions; fatigue; generalized weakness
Complications Hypovolemia, Circulatory collapse, Zinc deficiency, Hyperlipidemia
CausesMalabsorption (Protein Losing Enteropathy)
Diagnostic method Level below 3.5 grams per deciliter
TreatmentAlbumin infusion in hepatic resection (>40%), nephrotic syndrome (with diuretics and corticosteroids), spontaneous bacterial peritonitis (with antibiotics), and hepatorenal syndrome (with terlipressin)
Frequency70% (elderly inpatients)

Hypoalbuminemia (or hypoalbuminaemia) is a medical sign in which the level of albumin in the blood is low. [1] This can be due to decreased production in the liver, increased loss in the gastrointestinal tract or kidneys, increased use in the body, or abnormal distribution between body compartments. Patients often present with hypoalbuminemia as a result of another disease process such as malnutrition as a result of severe anorexia nervosa, sepsis, cirrhosis in the liver, nephrotic syndrome in the kidneys, or protein-losing enteropathy in the gastrointestinal tract. One of the roles of albumin is being the major driver of oncotic pressure (protein concentration within the blood) in the bloodstream and the body. Thus, hypoalbuminemia leads to abnormal distributions of fluids within the body and its compartments. As a result, associated symptoms include edema in the lower legs, ascites in the abdomen, and effusions around internal organs. Laboratory tests aimed at assessing liver function diagnose hypoalbuminemia. Once identified, it is a poor prognostic indicator for patients with a variety of different diseases. Yet, it is only treated in very specific indications in patients with cirrhosis and nephrotic syndrome. Treatment instead focuses on the underlying cause of the hypoalbuminemia. Albumin is an acute negative phase respondent and not a reliable indicator of nutrition status.

Contents

Signs and symptoms

Pitting edema of the lower extremities commonly seen in conditions associated hypoalbuminemia. Combinpedal.jpg
Pitting edema of the lower extremities commonly seen in conditions associated hypoalbuminemia.

Patients with hypoalbuminemia are more likely to present with it as a sign of an underlying disease process than as a primary disease process. By itself, hypoalbuminemia decreases the total protein concentration in blood plasma, also known as the colloid osmotic pressure, which causes fluid to exit the blood vessels into tissues to equalize the concentrations. This leads to fluid-induced swelling of the extremities known as edema, build-up of fluid in the abdomen known as ascites, and fluid surrounding internal organs known as effusions. Patients also present with nonspecific findings such as fatigue and excessive weakness. Muehrcke's lines are a strong indicator of hypoalbuminemia. [2] Hypoalbuminemia by itself may present without any symptoms, as the congenital and complete loss of albumin seen in analbuminemia can be asymptomatic. Alternatively, it can present with death in utero prior to birth or as a disease of adults characterized by edema, fatigue, and hyperlipidemia. The reason for this heterogeneity of presentation is not well understood. [3]

Complications

By itself, hypoalbuminemia can cause hypovolemia and circulatory collapse secondary to decreased oncotic pressure within the vascular system. [3] Due to its metal-binding properties, hypoalbuminemia may lead to nutritional deficits including zinc deficiency. [4] Hypoalbuminemia associated with the nephrotic syndrome can lead to the development of hyperlipidemia, although this is usually in the absence of atherosclerosis. [3] Further, in patients on dialysis, hypoalbuminemia is associated with more advanced fluid overload. [5] [6]

Causes

Hypoalbuminemia can be caused through a number of different mechanisms, each with the result of decreasing albumin levels. These include: 1) impaired synthesis within the liver, 2) increased utilization by tissue, 3) distributional issues, and 4) increased excretion or loss. [7] Often, the cause is multifactorial as in liver cirrhosis, where reduced hepatic synthesis and increased capillary leakage combine to further decrease albumin levels. [ citation needed ]

Inflammation and infection

Albumin is considered a negative acute phase reactant, which means that as inflammation and other acute physiologic processes occur, its levels decrease. This is in contrast to acute phase reactants like C-reactive protein (CRP), whose levels increase with inflammatory processes. With respect to mechanism, inflammation leads to decreased production of albumin as a result of increased levels of cytokines, specifically IL-1, IL-6, and TNF-α. [7] In patients with the overwhelming infections common in sepsis and septic shock, hypoalbuminemia occurs as a result of the combinatorial effects of decreased synthesis as above, increased utilization by tissues, and increased transcapillary leakage from blood vessels due to increased vascular permeability. [3]

Liver disease

Healthy and cirrhotic liver. If present, hypoalbuminemia suggests advanced liver disease as seen in cirrhosis. Liver Cirrhosis.png
Healthy and cirrhotic liver. If present, hypoalbuminemia suggests advanced liver disease as seen in cirrhosis.

Albumin is synthesized in the liver, and low serum albumin can be indicative of liver failure or diseases such as cirrhosis and chronic hepatitis. If present, hypoalbuminemia is generally considered to be a sign of advanced hepatic cirrhosis, or irreversible damage to the liver. [3] Production of albumin can be one 60–80% lower in advanced cirrhosis than in healthy liver, an effect amplified by dilution (salt and water retention), fluid shifts (following the accumulation of albumin in extracellular space and ascitic fluid), and even post-transcriptional changes to albumin itself. [8]

Kidney disease

Kidney biopsy showing focal segmental glomerulosclerosis, one of the causes of nephrotic syndrome commonly seen in children. Focal segmental glomerulosclerosis - high mag.jpg
Kidney biopsy showing focal segmental glomerulosclerosis, one of the causes of nephrotic syndrome commonly seen in children.

Hypoalbuminemia can also present as part of the nephrotic syndrome, in which significant quantities of protein are lost in the urine due to kidney damage. Under normal conditions, less than 30 milligrams per day of albumin are lost via the glomerulus. [3] In nephrotic syndrome, protein loss can be as great as 3.5 grams over 24 hours, much of which is albumin, itself leading to hypoalbuminemia. [3] In children, nephrotic syndrome is commonly a primary disease process that is largely idiopathic, although more genetic causes are being identified with the cost and accessibility of whole exome sequencing. After renal biopsy, these syndromes are commonly diagnosed as minimal change disease, membranoproliferative glomerulonephritis, or focal segmental glomerulosclerosis. [9] In adults, on the other hand, nephrotic syndrome is commonly a secondary disease process due to a variety of inciting factors. These inciting factors can be diverse, including toxins, drugs, heavy metals, autoantibodies, post-infectious antibody complexes, or immune complexes formed after malignancies like multiple myeloma. [3]

Albuminuria and resultant hypoalbuminemia can also occur in chronic kidney disease without protein loss levels as high as seen in nephrotic syndrome. Here, albumin loss from the kidneys occur due to decreased glomerular filtration rate (GFR) and subsequent loss of 30 to 300 milligrams of albumin per day. Over the course of months, this can lead to hypoalbuminemia, a common feature of end-stage renal disease. [3] Alterations in fluid distribution and the presence of ongoing inflammation in chronic kidney disease in combination with hypoalbuminemia make fluid status control especially difficult. [5]

Malnutrition or malabsorption

A girl with the physical signs and symptoms of Kwashiorkor, which is an extreme form of malnutrition-associated hypoalbuminemia. Starved girl.jpg
A girl with the physical signs and symptoms of Kwashiorkor, which is an extreme form of malnutrition-associated hypoalbuminemia.

Kwashiorkor is a disease of malnutrition characterized by decreased protein intake and amino acid deficiency resulting in hypoalbuminemia and a characteristic physical presentation. This is an extreme example of how malnutrition can result in hypoalbuminemia. [3] More typical is malnutrition-associated hypoalbuminemia in the elderly, who appear thin and frail but not with the rounded abdomen and edema seen in Kwashiorkor. Albumin is an acute negative phase respondent and not a reliable indicator of nutrition status. [10]

Low albumin levels can also indicate chronic malnutrition from protein losing enteropathy. [3] This is often caused or exacerbated by ulcerative colitis, [11] but can also be seen in cardiac disease and systemic lupus erythematosus. [3] Broadly, protein-losing enteropathy can be caused by increased lymphatic pressure in the gastrointestinal tract as in lymphangiectasis, mucosal erosion-induced lack of absorption as in Crohn's disease and ulcerative colitis, and other diseases of malabsorption without mucosal erosions as in Celiac disease. [3]

Eosinophilic gastritis presents with epigastric pain, peripheral blood eosinophilia, anemia, and hypoalbuminemia. [12]

Pathophysiology

The liver produces albumin and then secretes into the bloodstream, where it is then distributed into tissues across the body. In the liver, the liver synthesizes albumin as pre-proalbumin, converts it first into proalbumin and then albumin in hepatocytes, and releases it into the blood. [7] The body synthesizes albumin at a rate of 10 to 15 grams per day. In the presence of hypoalbuminemia, the liver can increase production by as much as four times the baseline production rate. [8] Once released, albumin distributes itself between the intravascular space (40%) in blood vessels, and extravascular spaces (60%) within the body's different tissues. In the blood plasma, albumin makes up 55 to 60% of total plasma protein by mass, with globulins making up a large part of the rest. In hypoalbuminemia, the amount of albumin in the intravascular space or blood plasma is what is being measured, meaning that abnormal distribution within the two compartments may contribute to a relative hypoalbuminemia in the bloodstream with a normal level in the whole body. [3]

Once released into the body, albumin performs a number of functions that can be negatively affected by the reduced levels seen in hypoalbuminemia. These functions include regulation of colloid osmotic pressure or protein concentration within the blood plasma, transport of free fatty acids and other molecules to the liver (unconjugated bilirubin, metals, ions) for storage or utilization, binding of drugs and alteration of pharmacokinetics (half-life, biological activity levels, metabolism), buffering plasma pH, scavenging reactive oxygen species to avoid inflammation and associated damage, functioning as a reservoir of nitric oxide for the regulation of blood pressure, and prevention of coagulation and platelet aggregation in an action similar to the commonly used anticoagulant heparin. It also inhibits inflammatory mediators such as TNF-α and complement 5a (C5a) to reduce the overall inflammatory response. [7]

A number of hormones (e.g. thyroxine, cortisol, testosterone), drugs, and other molecules are bound to albumin in the bloodstream and must be released from albumin before becoming biologically active. For example, calcium binds to albumin; in hypoalbuminemia, there is an increased amount of free ionized calcium, its biologically active form. In the presence of hypoalbuminemia, these functions are differentially affected, and the mechanisms by which they affect disease outcomes remains an area of active debate. [3]

Diagnosis

The serum albumin level is part of a standard panel of liver function tests (LFT) that also includes levels of plasma protein, bilirubin, alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). This is commonly ordered when liver disease is suspected as part of a comprehensive metabolic panel (CMP) in conjunction with the electrolyte panel known as the basic metabolic panel (BMP). In kidney disease, a CMP may be ordered as a follow-up test when proteinuria is detected by urine dipstick analysis, which may lead to a diagnosis of hypoalbuminemia. [3] Low levels of serum albumin are defined as less than 3.5 grams per deciliter, while clinically significant hypoalbuminemia is generally considered to be less than 2.5 grams per deciliter. [7] Upon discovery of hypoalbuminemia, a common work-up will include liver function tests to assess for liver disease, urine albumin and protein levels to assess for albuminuria and nephrotic syndrome, and brain natriuretic peptide to assess for cardiac failure. [3] If protein-losing enteropathy is suspected based on clinical suspicion, an alpha-1 antitrypsin test can be performed. If stool alpha-1 antitrypsin is elevated, this suggests excessive gastrointestinal protein loss. [3]

Management

Treatment of hypoalbuminemia is largely focused on the underlying cause and not on the hypoalbuminemia itself. [7] Albumin infusions can and are commonly performed although they are expensive and have not been shown to be more effective than colloid solutions in a number of conditions and situations. Examples of indications for albumin infusion include hypoalbuminemia in the context of major surgery such as hepatic resection >40%, nephrotic syndrome in conjunction with diuretics and corticosteroids, spontaneous bacterial peritonitis in combination with antibiotics, and rapidly progressing hepatorenal syndrome (type 1) in combination with terlipressin. [7] It is also used to prevent iatrogenic hypoalbuminemia after therapeutic plasmapheresis if volume plasma exchange is greater than 20 milliliters per kilogram in one session or over one week across multiple sessions and after large volume (>5 liter) paracentesis in ascites. [7] These indications have shown positive outcomes respective to their diseases, while conditions like malnourishment, burns (during the first 24 hours), and shock with traumatic brain injury either show no benefit or harm in randomized controlled trials. [7] In liver disease and cirrhosis, in addition to the above indications, the use of albumin is being considered for bacterial infections other than spontaneous bacterial peritonitis, hepatic encephalopathy, and chronic ascites. Its use in these indications remains controversial. [8] In kidney disease and nephrotic syndrome, albumin infusions as replacement for albumin loss to proteinuria is used in some cases of congenital nephrotic syndrome. [9]

Prognosis

By itself, low albumin levels are associated with increased mortality rate in the general population. [8] In disease states specifically, hypoalbuminemia has been used a predictive factor for poor outcomes in a number of conditions, [3] including periprosthetic joint infection treatment failure, [13] and cirrhosis. [8] Amongst patients admitted to intensive care units (ICUs), hypoalbuminemia is specifically associated with ICU-acquired muscle weakness. [14] In chronic kidney disease, hypoalbuminemia is an indicator of frailty, which is itself associated with complications, mental distress, quality of life impairment, resource utilization, and mortality. [15]

Epidemiology

Hypoalbuminemia is commonly found in hospitalized patients, patients in the ICU, and the elderly within the hospital and the community. [3] Amongst elderly patients, prevalence can be as high as 70%, as shown in a study from Southern Brasil. [3]

Related Research Articles

<span class="mw-page-title-main">Edema</span> Accumulation of excess fluid in body tissue

Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area may feel heavy, and joint stiffness. Other symptoms depend on the underlying cause.

<span class="mw-page-title-main">Proteinuria</span> Presence of an excess of serum proteins in the urine

Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy. Severe proteinuria can cause nephrotic syndrome in which there is worsening swelling of the body.

<span class="mw-page-title-main">Ascites</span> Abnormal build-up of fluid in the abdomen

Ascites is the abnormal build-up of fluid in the abdomen. Technically, it is more than 25 ml of fluid in the peritoneal cavity, although volumes greater than one liter may occur. Symptoms may include increased abdominal size, increased weight, abdominal discomfort, and shortness of breath. Complications can include spontaneous bacterial peritonitis.

Liver function tests, also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin time (aPTT), albumin, bilirubin, and others. The liver transaminases aspartate transaminase and alanine transaminase are useful biomarkers of liver injury in a patient with some degree of intact liver function.

<span class="mw-page-title-main">Nephrotic syndrome</span> Collection of symptoms due to kidney damage

Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy urine. Complications may include blood clots, infections, and high blood pressure.

<span class="mw-page-title-main">Serum protein electrophoresis</span> Laboratory test

Serum protein electrophoresis is a laboratory test that examines specific proteins in the blood called globulins. The most common indications for a serum protein electrophoresis test are to diagnose or monitor multiple myeloma, a monoclonal gammopathy of uncertain significance (MGUS), or further investigate a discrepancy between a low albumin and a relatively high total protein. Unexplained bone pain, anemia, proteinuria, chronic kidney disease, and hypercalcemia are also signs of multiple myeloma, and indications for SPE. Blood must first be collected, usually into an airtight vial or syringe. Electrophoresis is a laboratory technique in which the blood serum is applied to either an acetate membrane soaked in a liquid buffer, or to a buffered agarose gel matrix, or into liquid in a capillary tube, and exposed to an electric current to separate the serum protein components into five major fractions by size and electrical charge: serum albumin, alpha-1 globulins, alpha-2 globulins, beta 1 and 2 globulins, and gamma globulins.

<span class="mw-page-title-main">Budd–Chiari syndrome</span> Medical condition

Budd–Chiari syndrome is a very rare condition, affecting one in a million adults. The condition is caused by occlusion of the hepatic veins that drain the liver. The symptoms are non-specific and vary widely, but it may present with the classical triad of abdominal pain, ascites, and liver enlargement. It is usually seen in younger adults, with the median age at diagnosis between the ages of 35 and 40, and it has a similar incidence in males and females. The syndrome can be fulminant, acute, chronic, or asymptomatic. Subacute presentation is the most common form.

<span class="mw-page-title-main">Portal hypertension</span> Abnormally increased portal venous pressure

Portal hypertension is defined as increased portal venous pressure, with a hepatic venous pressure gradient greater than 5 mmHg. Normal portal pressure is 1–4 mmHg; clinically insignificant portal hypertension is present at portal pressures 5–9 mmHg; clinically significant portal hypertension is present at portal pressures greater than 10 mmHg. The portal vein and its branches supply most of the blood and nutrients from the intestine to the liver.

<span class="mw-page-title-main">Anasarca</span> Medical condition of severe edema

Anasarca is a severe and generalized form of edema, with subcutaneous tissue swelling throughout the body. Unlike typical edema, which almost everyone will experience at some time and can be relatively benign, anasarca is a pathological process reflecting a severe disease state and can involve the cavities of the body in addition to the tissues.

Spontaneous bacterial peritonitis (SBP) is the development of a bacterial infection in the peritoneum, despite the absence of an obvious source for the infection. It is specifically an infection of the ascitic fluid – an increased volume of peritoneal fluid. Ascites is most commonly a complication of cirrhosis of the liver. It can also occur in patients with nephrotic syndrome. SBP has a high mortality rate.

<span class="mw-page-title-main">Serum albumin</span> Type of globular protein produced by the liver

Serum albumin, often referred to simply as blood albumin, is an albumin found in vertebrate blood. Human serum albumin is encoded by the ALB gene. Other mammalian forms, such as bovine serum albumin, are chemically similar.

<span class="mw-page-title-main">Minimal change disease</span> Medical condition

Minimal change disease is a disease affecting the kidneys which causes nephrotic syndrome. Nephrotic syndrome leads to the loss of significant amounts of protein in the urine, which causes the widespread edema and impaired kidney function commonly experienced by those affected by the disease. It is most common in children and has a peak incidence at 2 to 6 years of age. MCD is responsible for 10–25% of nephrotic syndrome cases in adults. It is also the most common cause of nephrotic syndrome of unclear cause (idiopathic) in children.

<span class="mw-page-title-main">Hepatorenal syndrome</span> Human disease

Hepatorenal syndrome is a life-threatening medical condition that consists of rapid deterioration in kidney function in individuals with cirrhosis or fulminant liver failure. HRS is usually fatal unless a liver transplant is performed, although various treatments, such as dialysis, can prevent advancement of the condition.

Transudate is extravascular fluid with low protein content and a low specific gravity. It has low nucleated cell counts and the primary cell types are mononuclear cells: macrophages, lymphocytes and mesothelial cells. For instance, an ultrafiltrate of blood plasma is transudate. It results from increased fluid pressures or diminished colloid oncotic forces in the plasma.

Hypoproteinemia is a condition where there is an abnormally low level of protein in the blood. There are several causes that all result in edema once serum protein levels fall below a certain threshold.

<span class="mw-page-title-main">Human serum albumin</span> Albumin found in human blood

Human serum albumin is the serum albumin found in human blood. It is the most abundant protein in human blood plasma; it constitutes about half of serum protein. It is produced in the liver. It is soluble in water, and it is monomeric.

Congenital nephrotic syndrome is a rare kidney disease which manifests in infants during the first 3 months of life, and is characterized by high levels of protein in the urine (proteinuria), low levels of protein in the blood, and swelling. This disease is primarily caused by genetic mutations which result in damage to components of the glomerular filtration barrier and allow for leakage of plasma proteins into the urinary space.

Glomerulonephrosis is a non-inflammatory disease of the kidney (nephrosis) presenting primarily in the glomerulus as nephrotic syndrome. The nephron is the functional unit of the kidney and it contains the glomerulus, which acts as a filter for blood to retain proteins and blood lipids. Damage to these filtration units results in important blood contents being released as waste in urine. This disease can be characterized by symptoms such as fatigue, swelling, and foamy urine, and can lead to chronic kidney disease and ultimately end-stage renal disease, as well as cardiovascular diseases. Glomerulonephrosis can present as either primary glomerulonephrosis or secondary glomerulonephrosis.

<span class="mw-page-title-main">Cirrhosis</span> Chronic disease of the liver, characterized by fibrosis

Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage to the liver leads to repair of liver tissue and subsequent formation of scar tissue. Over time, scar tissue can replace normal functioning tissue, leading to the impaired liver function of cirrhosis. The disease typically develops slowly over months or years. Early symptoms may include tiredness, weakness, loss of appetite, unexplained weight loss, nausea and vomiting, and discomfort in the right upper quadrant of the abdomen. As the disease worsens, symptoms may include itchiness, swelling in the lower legs, fluid build-up in the abdomen, jaundice, bruising easily, and the development of spider-like blood vessels in the skin. The fluid build-up in the abdomen may develop into spontaneous infections. More serious complications include hepatic encephalopathy, bleeding from dilated veins in the esophagus, stomach, or intestines, and liver cancer.

<span class="mw-page-title-main">Hepatic hydrothorax</span> Medical condition

Hepatic hydrothorax is a rare form of pleural effusion that occurs in people with liver cirrhosis. It is defined as an effusion of over 500 mL in people with liver cirrhosis that is not caused by heart, lung, or pleural disease. It is found in 5–10% of people with liver cirrhosis and 2–3% of people with pleural effusions. It is much more common on the right side, with 85% of cases occurring on the right, 13% on the left, and 2% on both. Although it is most common in people with severe ascites, it can also occur in people with mild or no ascites. Symptoms are not specific and mostly involve the respiratory system.

References

  1. ↑ Anderson, Douglas M. (2000). Dorland's illustrated medical dictionary (29. ed.). Philadelphia [u.a.]: Saunders. p.  860. ISBN   0721682618.
  2. ↑ Williams, Vijai; Jayashree, Muralidharan (October 2017). "Muehrcke Lines in an Infant". The Journal of Pediatrics. 189: 234. doi: 10.1016/j.jpeds.2017.05.039 . ISSN   0022-3476. PMID   28595765.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Gounden, Verena; Jialal, Ishwarlal (2019), "Hypoalbuminemia", StatPearls, StatPearls Publishing, PMID   30252336 , retrieved 2019-11-04
  4. ↑ Himoto, Takashi; Masaki, Tsutomu (2018-01-14). "Associations between Zinc Deficiency and Metabolic Abnormalities in Patients with Chronic Liver Disease". Nutrients. 10 (1): 88. doi: 10.3390/nu10010088 . ISSN   2072-6643. PMC   5793316 . PMID   29342898.
  5. 1 2 Kooman, Jeroen P.; van der Sande, Frank M. (2019). "Body Fluids in End-Stage Renal Disease: Statics and Dynamics". Blood Purification. 47 (1–3): 223–229. doi:10.1159/000494583. ISSN   1421-9735. PMC   6492508 . PMID   30517920.
  6. ↑ Dekker, Marijke J. E.; van der Sande, Frank M.; van den Berghe, Florence; Leunissen, Karel M. L.; Kooman, Jeroen P. (2018). "Fluid Overload and Inflammation Axis". Blood Purification. 45 (1–3): 159–165. doi:10.1159/000485153. ISSN   1421-9735. PMC   6492921 . PMID   29478061.
  7. 1 2 3 4 5 6 7 8 9 Gatta, Angelo; Verardo, Alberto; Bolognesi, Massimo (2012). "Hypoalbuminemia". Internal and Emergency Medicine. 7 (Suppl 3): S193–199. doi:10.1007/s11739-012-0802-0. hdl:11577/2572741. ISSN   1970-9366. PMID   23073857. S2CID   262218475.
  8. 1 2 3 4 5 Carvalho, Joana R.; Verdelho Machado, Mariana (2018). "New Insights About Albumin and Liver Disease". Annals of Hepatology. 17 (4): 547–560. doi: 10.5604/01.3001.0012.0916 . ISSN   1665-2681. PMID   29893696.
  9. 1 2 Cil, Onur; Perwad, Farzana (2018). "Monogenic Causes of Proteinuria in Children". Frontiers in Medicine . 5: 55. doi: 10.3389/fmed.2018.00055 . ISSN   2296-858X. PMC   5858124 . PMID   29594119.
  10. ↑ Bharadwaj, Shishira; Ginoya, Shaiva; Tandon, Parul; Gohel, Tushar D.; Guirguis, John; Vallabh, Hiren; Jevenn, Andrea; Hanouneh, Ibrahim (11 May 2016). "Malnutrition: laboratory markers vs nutritional assessment". Gastroenterology Report. 4 (4): 272–280. doi:10.1093/gastro/gow013. PMC   5193064 . PMID   27174435.
  11. ↑ Ungaro R, Babyatsky MW, Zhu H, Freed JS (January 2012). "Protein-losing enteropathy in ulcerative colitis". Case Reports in Gastroenterology. 6 (1): 177–82. doi:10.1159/000338191. PMC   3364098 . PMID   22679407.
  12. ↑ Collins, Margaret H.; Capocelli, Kelley; Yang, Guang-Yu (2017). "Eosinophilic Gastrointestinal Disorders Pathology". Frontiers in Medicine. 4: 261. doi: 10.3389/fmed.2017.00261 . ISSN   2296-858X. PMC   5775510 . PMID   29379785.
  13. ↑ Fagotti, Lorenzo; Tatka, Jakub; Salles, Mauro Jose Costa; Queiroz, Marcelo C. (2018). "Risk Factors and Treatment Options for Failure of a Two-Stage Exchange". Current Reviews in Musculoskeletal Medicine. 11 (3): 420–427. doi:10.1007/s12178-018-9504-1. ISSN   1935-973X. PMC   6105486 . PMID   29934884.
  14. ↑ Barreiro, Esther (2018). "Models of disuse muscle atrophy: therapeutic implications in critically ill patients". Annals of Translational Medicine. 6 (2): 29. doi: 10.21037/atm.2017.12.12 . ISSN   2305-5839. PMC   5799135 . PMID   29430446.
  15. ↑ Wu, Patrick Yihong; Chao, Chia-Ter; Chan, Ding-Cheng; Huang, Jenq-Wen; Hung, Kuan-Yu (2019). "Contributors, risk associates, and complications of frailty in patients with chronic kidney disease: a scoping review". Therapeutic Advances in Chronic Disease. 10: 2040622319880382. doi:10.1177/2040622319880382. ISSN   2040-6223. PMC   6778996 . PMID   31632625.
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