Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Author: Dr. Debottam Bandyopadhyay
Consultant , MBBS, MD, DM, Medical Gastroenterologist AMRI Group of Hospitals, Kolkata.
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Abstract
Human serum albumin, a negatively charged small globular protein encoded on chromosome 4, is the most abundant protein in the blood. Albumin accounts for about 75% of plasma oncotic pressure. Albumin has showed valuable role in managing various disease. Albumin is utilized in patients with liver cirrhosis, hepatic encephalopathy and hepatorenal syndrome. Albuzest an effective plasma volume expander containing albumin 20%, manufactured by SK plasma group which is the second largest business group in Korea. Overall, albumin is effective in treatment of hepatorenal syndrome, hepatic encephalopathy and cirrhosis.
Keywords: Albumin, Liver cirrhosis, Hepatic encephalopathy, Hepatorenal syndrome, Albuzest
Introduction
The most abundant protein in the blood is albumin. Albumin accounts for about 50% of all plasma proteins. Albumin is a small globular protein consisting of a single chain of 585 amino acids organized in three repeated homologue domains (sites I, II and III), each of which comprises two separate sub-domains (A and B).
Under physiological conditions, about 10-15 grams of albumin is produced in the liver by the hepatocytes. Different hormones such as insulin, cortisol and growth hormone stimulates the synthesis of albumin, while pro-inflammatory substances including interleukin-6 and tumor necrosis factor do the inhibition of its synthesis [1,2].
Albumin has been used for many years in the management of patients with cirrhosis and ascites as it is an effective plasma volume expander due to its high oncotic activity and prolonged half-life in the intravascular compartment [3].
The main physiologic function of albumin is to maintain colloid osmotic pressure, but in the past few years, many other functions have been recognized. These other function include ligand binding and transport of various molecules, in addition to antioxidant and anti-inflammatory actions [4]. These functions of albumin could be applied to various clinical situations, including septic shock.
Functions of Albumin
Colloidal Osmotic Pressure
Albumin is essential for maintaining the oncotic pressure in the vascular system. A decrease in oncotic pressure due to a low albumin level allows fluid to leak out from the interstitial spaces into the peritoneal cavity, producing ascites [5].
Antioxidant Effects
The major extracellular source of thiols is albumin. Thiols are scavengers of reactive oxygen and nitrogen species. Albumin can also limit the production of reactive oxidative species by binding free copper (an ion known to be particularly important in accelerating the production of free radicals) [5].
Transport
Albumin is negatively charge, but binds weakly and reversibly to both cations and anions. Therefore, it functions as a transport molecule for an outsized number of metabolites, including fatty acids, ions, thyroxine, bilirubin and amino acids. The glycosylation of albumin, which is to a particular extent age-dependent, affects its charge and therefore, may influence capillary permeability characteristics [1]. Albumin acts as a transporter vehicle and binds with drugs given in Table 1.
Table 1: Albumin acts as a transporter vehicle and binds with drugs [1]
|
Transport vehicle for |
Albumin interacts with |
|
|
Endothelial stabilization
Albumin has the ability to reduce injury to the endothelium caused by reactive oxygen and nitrogen species which means it may stabilize the endothelium and help to maintain capillary permeability. It also interferes with neutrophil adhesion to the capillary endothelium [5], thereby reducing inflammation and aiding the maintenance of endothelial integrity.
Albumin Impact on Osmotic Pressure
Colloid osmotic pressure, or oncotic pressure, is a form of osmotic pressure which is induced by proteins, mainly albumin, in a blood vessel’s plasma that displaces water molecules, thus creating a relative water molecule deficit with water molecules moving back into the circulatory system within the lower venous pressure end of the capillaries. Oncotic pressure has the opposing effect of both hydrostatic blood pressure, pushing water and small molecules out of the blood into the interstitial spaces within the arterial end of capillaries, and interstitial colloidal osmotic pressure, pressure exerted by fluids within the interstitial fluid. These interacting forces determine the partition balancing of total body extracellular water between the blood plasma and the larger extracellular water volume outside the blood stream.
Dissolved compound throughout the body have an osmotic pressure. As large plasma protein cannot cross through the capillary walls so their effect on the osmotic pressure of the capillary interiors will balance out the tendency for fluid to leak out of the capillaries, means the osmotic pressure tends to pull fluid into the capillaries.
The large majority of oncotic pressure in capillaries is generated by the presence of high quantities of albumin. The total oncotic pressure of an average capillary is about 28 mmHg with albumin contributing approximately 22 mmHg of this oncotic pressure. As blood proteins cannot escape through capillary endothelium so oncotic pressure of capillary beds tends to draw water into the vessels. It is necessary to understand the oncotic pressure as a balance; because the blood proteins reduce interior permeability so that less plasma fluid can exit the vessel [6].
Use of Albumin in Liver Cirrhosis
The reduced albumin concentration is typically a feature of cirrhosis and represents an important and adverse prognostic factor. It results from both a decreased hepatocyte production and various events closely related to the course of the disease. For example, renal sodium and water retention leads to plasma volume expansion and dilution of extracellular fluid protein content, thus contributing to lower serum albumin concentration. Another factor, at least in the most advanced stage of cirrhosis, is represented by an increase in the trans-capillary escape rate of the molecule that leads the protein to be lost towards the extravascular space.
Albumin has been used as the treatment for many complications of cirrhosis and ascites, such as spontaneous bacterial peritonitis and HRS [7, 8]. As the basic pathophysiological process that leads to the development of ascites is a reduction of the effective arterial blood volume, [9] it makes physiological sense to use albumin in the management of ascites, although this has been controversial.
One randomized, controlled trial checked out the effect of albumin along with standard diuretic therapy in cirrhotic patients with ascites; weekly infusion of 25g of albumin added to diuretic produced a significantly better diuretic response, shorter hospital stays and a lower likelihood of readmission to hospital, but no effect on survival [9] when compared with diuretic alone. Suppression of the activity of anti-natriuretic systems, particularly the renin-angiotensin aldosterone system, probably accounts for a rise in the natriuretic response to diuretics with repeated albumin infusions [9]. Survival, however, was not affected by the addition of albumin [6]. Moreover, compared with the simple performance of paracentesis during a day-care unit, the logistic problems of intravenous albumin administration on a weekly basis, and its lack of cost-effectiveness, render this indication unjust and impractical in clinical practice [10]. For this reason, there's currently no standard recommendation to use albumin as an adjunct therapy to diuretics within the treatment of uncomplicated ascites [6].
Albumin in Hepatic Encephalopathy
Neuropsychiatric syndrome – Hepatic encephalopathy plays a prime role in complicating acute and chronic liver dysfunction and is associated with a wide range of other severe manifestations. In course of cirrhosis, hepatic encephalopathy is very common [11]. Three types of hepatic encephalopathy are noted, type A (acute liver failure), type B (portosystemic shunting), and type C (cirrhosis) [12].
According to the West-Haven criteria, the severity of hepatic encephalopathy is categorized into grade I, II, III and IV [13].
The occurrence of hepatic encephalopathy in patients having liver cirrhosis is apparently 30-45% [14-16]. Numerous substances (mostly ammonia) are liable for the pathophysiology of hepatic encephalopathy which are produced in GUT and metabolized by liver. Newly, other reasons, such as inflammation driven by bacterial translocation and oxidative stress have assumed to play a vital role [17].
Clinical trial was done including 15 patients having hepatic encephalopathy prompted because of diuretic, 4.5% of human serum albumin infused has shown a noticeable progress in hepatic encephalopathy beside showing a reduction in oxidative stress indicators as matched to colloid group. By using volume expansion, the levels of plasma ammonia exhibited a decrease and there was an increase in urinary excretion of ammonia. The noticeable progress in the albumin group may propose an antioxidant role of albumin in the treatment of hepatic encephalopathy [18].
In a current multicenter prospective double blind control trial, 56 cirrhotic patients having acute hepatic encephalopathy were randomized to take either albumin (1.5 g kg–1 on day 1 and 1 g kg–1 on day 3) or isotonic saline in addition to the standard treatment. The results came with negotiable difference in percentage of patients with hepatic encephalopathy on 4th day (albumin 57.7% vs. 53% in saline), But there was a pointedly improved survival rate after three months of continuation in the albumin group [19]. Improvement in hepatic encephalopathy is more frequent and earlier with extracorporeal albumin dialysis [20]. In added prospective randomized controlled multicenter trial, albumin dialysis with molecular adsorbent recirculating system displayed progress in hepatic encephalopathy, but the outcome was non-noteworthy [21].
Albumin in Hepatorenal Syndrome
Development of renal failure in patients with severe liver disease is prominent with Hepatorenal syndrome. It is a life-threatening state with poor prognosis. Hepatorenal syndrome is a possibly reversible renal failure considered by severe intra-renal vasoconstriction that develops in patients with advanced cirrhosis and ascites [22-23].
Hepatorenal syndrome (HRS) is classified into two types. Type 1 hepatorenal syndrome is well defined as the severe, rapid worsening in renal function in which there is doubling of serum creatinine value in less than two weeks and achieving a final value more than 2.5 mg dl-1 in the absence of reasons of renal failure. This typically happens secondary to an acute insult for example spontaneous bacterial peritonitis or acute gastrointestinal bleed and brings a poorer prognosis than type 2 Hepatorenal syndrome. Type 2 hepatorenal syndrome is a slow progressive worsening of renal function with creatinine levels ranging between 1.5 and 2.5 mg dl-1. Even though it may be caused by a precipitating incident. Ascites and hyponatremia is typically more frequent in these patients. In the existence of an acute insult such as spontaneous bacterial peritonitis type 2 hepatorenal syndrome can convert into type 1. In a study by Gines et al., the rate of hepatorenal syndrome was found to be around 18% at one year and 39% at five years in 234 non-azotemic patients with cirrhosis and ascites [24-26].
There is an upsurge in the efficacy of vasoconstrictor drugs by using albumin. Treatment of cirrhotic patients with hepatorenal syndrome for several days or weeks with a combination of vasoconstrictors and plasma volume expansion with albumin grades a noticeable progress in circulatory and renal functions in most cases, with normalization of plasma levels of vasoconstrictor factors and serum creatinine have been illustrated by two studies. Yet, the need for a plasma expander agent as a co-therapy remains uncertain. The administration of vasoconstrictors with albumin has been shown to reverse type 1 hepatorenal syndrome and stabilize renal function in 60-70% of treated patients. Small numbers of patients were there in these studies, some of whom were not randomized, and the impression on long-term (> 1 month) survival has not been shown. Type 2 hepatorenal syndrome treatment data are much uncommon than for type 1 hepatorenal syndrome [27-28]. To achieve the advantageous effect of vasoconstrictor therapy in hepatorenal syndrome by using albumin is not well-known. But, the therapeutic efficacy of vasoconstrictors probably to be improved with albumin, as the improvement in circulatory and renal functions is more noticeable in patients preserved with terlipressin and albumin than that in patients preserved with terlipressin alone. Specified that albumin has volume-expanding, antioxidant and ligand-binding properties, it appears sensible to use albumin infusions in the treatment of hepatorenal syndrome except there is evidence that albumin actually does some harm. As per the American Association for the Study of Liver Disease (AASLD) infusion of albumin plus administration of vasoactive drugs such as octreotide and midodrine should be considered in the treatment of type 1 hepatorenal syndrome (level II-I) [13].
Albuzest – An Effective Plasma Volume Expander
Albumin is an effective plasma volume expander due to its high oncotic activity and prolonged half-life in the intravascular compartment. Seeing these aspects, it is not astonishing that albumin has been used for many years in the management of patients with cirrhosis and ascites [5]. Albuzest 20% contains human serum albumin 20g in each 100mL. Human serum albumin in Albuzest is broadly used in treatment of serious burn injuries, hypoproteinemia, hemorrhagic shock, fetal erythroblastosis and ascites caused by liver cirrhosis [3]. Albuzest is manufactured by SK plasma group which is the second largest business group in Korea, and had revenue of 154 billion US dollar in 2019. SK plasma is contributing 12.9% to the Korean economy. Albuzest is approved by European union standard and USA plasma pool.
Albuzest Dosage and Administration
Albuzest 20% injection 125-375mL, equivalent to human serum albumin 25-75g should be administered by intravenous drip infusion or by slow direct intravenous injection. The recommended infusion rate is 2-4mL/min. It may be diluted with 5% glucose and 0.9% sodium chloride when necessary.
The dosage may be adjusted according to body weight, age, symptoms and existing comorbid conditions of patient (table 2).
Table 2: Dosing of Albumin in different diseases [29]
|
ADULTS DOSE |
|
|
Cirrhotic Ascites and Paracentesis |
Human albumin 6-8 g/liter of removed ascites if paracentesis >4 liter |
|
Spontaneous Bacterial Peritonitis |
Human albumin 1.5 g/kg at diagnosis and 1 g/kg on third day + antibiotic therapy |
|
Hepatorenal Syndrome |
Human albumin 1 g/kg at diagnosis followed by 20–40 g/die + vasoconstrictors |
|
Hypovolemia |
Initial dose 25 g (125 mL of a 20% solution), repeat after 15–30 minutes if necessary |
|
Acute Respiratory Distress Syndrome |
25 g of albumin IV over 30 minutes, every 8 hours for 3 days |
|
Hypoproteinemia |
50–75 g daily, larger amounts may be required in those with severe hypoproteinemia who continue to lose albumin |
|
PEDIATRIC DOSE |
|
|
Hypovolemia |
Initial dose of 0.5–1 g/kg or 2.5–12.5 g, repeat after 15–30 minutes if necessary |
|
Hypoproteinemia |
0.5–1 g/kg given over 0.5–2 hours and repeat after 1–2 days if necessary |
Conclusion
The most abundant protein in the blood is albumin that constitutes about 50% of the total plasma protein. Albumin is essential for maintaining the oncotic pressure in the vascular system. Albumin can also limit the production of reactive oxidative species by binding free copper and it also stabilize the endothelium. For cirrhosis there's currently no standard recommendation to use albumin as an adjunct therapy to diuretics within the treatment of uncomplicated ascites. Albumin dialysis with molecular adsorbent recirculating system displayed progress in hepatic encephalopathy, but the outcome was non-noteworthy. Infusion of albumin plus administration of vasoactive drugs such as octreotide and midodrine should be considered in the treatment of type 1 hepatorenal syndrome (level II-I). Overall, the use of albumin seems to be useful in the patients with liver cirrhosis, hepatic encephalopathy and hepatorenal syndrome.
Reference
