
Albumin in cirrhosis
Fluid needs in cirrhosis
Liver diseases, specifically cirrhosis, have been recognised as very important but underestimated health issues1
Chronic liver disease is very common2, with an estimated 1.5 billion people having this condition in 20173. The most common causes of chronic liver disease are alcoholic and non-alcoholic fatty liver disease, chronic viral hepatitis, genetic predisposition, autoimmune disorders and some drugs. Chronic inflammation and fibrosis result in progressive deterioration of liver function and can lead to cirrhosis2. In cirrhosis, regenerative hepatic nodules replace the normal liver architecture, eventually resulting in liver failure1. Progression to cirrhosis does not occur in all patients with liver disease, but is responsible for approximately half of all deaths from liver disease globally and is the 11th most common cause of death worldwide1.
In the following video, Alastair O’Brien, Professor of Experimental Hepatology at University College London, discusses the increasing prevalence of liver disease and highlights fluid resuscitation as the cornerstone of management. Professor O’Brien defines compensated versus decompensated cirrhosis and introduces albumin and the benefits of treatment for people with cirrhosis.
Decompensated cirrhosis
Improving the understanding of fluid resuscitation in decompensated cirrhosis is key to decreasing morbidity and mortality4
Cirrhosis is typically asymptomatic until portal pressure increases and liver function worsens. In the asymptomatic phase, known as ‘compensated cirrhosis’, the disease may remain undetected for years while continuing to progress, and the person may enjoy a good quality of life during this phase5.
Portal hypertension triggers a chain of events that lead to sodium and fluid imbalances (Figure 1), culminating in acute decompensation. This is associated with potentially life-threatening complications including ascites, gastrointestinal bleeding, infection, particularly spontaneous bacterial peritonitis (SBP), and hepatic encephalopathy4,6–8.
Figure 1. The physiological cascade of events in cirrhosis (Adapted4).
Decompensated cirrhosis is systemic, characterised by an increase in circulating chemokines and pro-inflammatory cytokines, and involves multiple organs and systems5. In 30% of cases there is rapid progression to extra-hepatic organ failure, often involving the kidneys, and acute-on-chronic liver failure (ACLF), which is associated with systemic inflammation and a high 28-day mortality rate6–8.
The detrimental effects of cirrhosis can also be attributed to decreased synthesis of albumin as well as alterations to the structure of albumin resulting from the pro-inflammatory and pro-oxidant states6.
Median survival reduces from 12 years in compensated cirrhosis to approximately 2 years in decompensated cirrhosis5
It is now known that decompensated cirrhosis is a protracted pro-oxidant and pro-inflammatory condition caused by systemic spread of pathogen-associated molecular patterns (PAMPs) from the gut and damage-associated molecular patterns (DAMPs) from the diseased liver, with these mechanisms driving acute decompensation8. Given the non-oncotic properties of albumin, which may counteract pathophysiological mechanisms, long-term administration of human albumin is emerging as a disease-modifying treatment in this condition, extending its function in decompensated cirrhosis beyond volume expansion8.
Experimental models reveal the mechanisms of albumin that contribute to its immunomodulatory properties8. For instance, albumin binds a range of offending molecules in cirrhosis such as PAMPs and DAMPs, it regulates cytokine production and release, and regulates antigen-presenting cell functions8. These mechanisms have been observed in people with decompensated cirrhosis whereby albumin reduces the levels of some cytokines8. Further, the ability of albumin to bind the interstitial matrix and interact with the sub-endothelial space is an important function that helps preserve endothelial functions8.
Albumin synthesis and function in cirrhosis
In liver disease, albumin synthesis, structure and function are altered. In cirrhosis in particular, albumin synthesis can decrease by half and in the decompensated setting patients experience protein malnutrition4.
In cirrhotic patients, the cumulative effects of decreased albumin synthesis, impaired precursor intake and increased proteolysis leads to global hypoalbuminaemia, which reduces effective circulating volume and oncotic pressure, causing renal sodium and water retention with ascites and anasarca, making resuscitation more difficult4.
Figure 2 illustrates the effects of liver disease on albumin synthesis and function.
Figure 2. Albumin in liver disease (Adapted9). ACLF, acute-on-chronic liver failure; ESLD, end-stage liver disease; HNA, human nonmercaptalbumin; PGE2, prostaglandin E2; TNFα, tumour necrosis factor alpha.
Ascites
Cirrhosis is responsible for approximately 80% of ascites cases in developed countries5,8. Five to 10% of patients with compensated cirrhosis develop ascites, which is the most common complication of decompensation5. Ascites signals a significant worsening of prognosis and requires chronic treatment. Its clinical manifestations impact a person’s ability to work and socialise, can lead to hospitalisation, and can cause further complications such as abdominal hernias, restrictive ventilatory dysfunction, spontaneous bacterial peritonitis (SBP) and hepatorenal syndrome (HRS)5,8. Learn more about guideline recommendations for treatment of decompensated cirrhosis.
With the onset of ascites, 5-year survival reduces from approximately 80% in compensated patients to around 30% in decompensated cirrhosis5
The 1-year mortality rate of cirrhosis with ascites is approximately 40%, the 2-year mortality rate is about 50%, and the 5-year mortality rate around 70%8. It is therefore important that patients with ascites are assessed for liver transplantation8.
Ascites is graded according to the amount present (Table 1) and classified according to treatment responsiveness (Table 2)8.
Table 1. Ascites grades and characteristics8.
Grade | Characteristics |
Grade 1 | Mild: only detectable by ultrasound |
Grade 2 | Moderate: moderate abdominal distension |
Grade 3 | Large or gross: severe abdominal distension |
Table 2. Ascites treatment classifications8.
Responsive ascites |
Can be fully mobilised or confined to grade 1 with diuretic therapy, which may involve dietary sodium restriction |
Recidivant ascites |
Recurs at least three times within 12 months despite satisfactory diuretic dosage and dietary sodium restriction |
Refractory ascites |
Diuretic-resistant Cannot be mobilised, or prevention of early recurrence not possible due to inadequate response to diuretic treatment and sodium restriction Diuretic-intractable Cannot be mobilised, or prevention of early recurrence not possible due to diuretic-induced complications impeding the use of an effective dose of diuretic |
Complications of ascites that further worsen prognosis include SBP, which is established by a neutrophil count of >250/µL in the ascitic fluid and hepatorenal syndrome (HRS)8.
Fluid resuscitation in decompensated cirrhosis
While it is important to determine volume status in cirrhosis, this can be difficult because up to half the extracellular fluid may be in the extravascular space, evidenced as ascites and oedema4. Further, while a patient may appear total volume expanded, they may in fact be intravascularly volume-depleted and therefore at risk of HRS4. In a postoperative patient with liver disease, over-resuscitation risks ascites and hyponatraemia, which are hard to treat4.
Management of hypervolaemic hyponatraemia
In decompensated cirrhosis, portal hypertension leads to increases in plasma volume, which can lead to significant hypervolaemic hyponatraemia4. Hyponatraemia (defined as sodium <130 mmol/L) is an independent predictor of mortality, and the initial step is to determine whether the patient is hypo- or hypervolaemic4.
Hypovolaemic hyponatraemia often occurs secondary to overdiuresis. It is less common than hypervolaemic hyponatraemia, and its hallmark symptoms are low serum sodium in the absence of ascites and oedema. Administration of normal saline and withholding diuretics is the initial management step in this condition. Albumin use in this setting is not supported by evidence4.
Hypervolaemic hyponatraemia occurs when antidiuretic hormone is over-secreted, resulting in unbalanced water and sodium retention4. Restriction of free water to <1000 mL/day is the primary treatment, with no data supporting saline administration. The European Association for the Study of the Liver guidelines support albumin use in this setting for volume expansion4. After over-resuscitation with crystalloid in a perioperative patient, iatrogenic hypervolaemic hyponatraemia may occur; therefore, careful fluid administration and free water restriction are necessary as a preventive measure4.
Management of hepatorenal syndrome
HRS is defined by acute kidney injury (AKI) in cirrhosis. Albumin is used to both treat and prevent HRS, and a randomised trial demonstrated albumin’s ability to prevent HRS and to improve survival in SBP. HRS comprises two types: HRS1, which is more severe, and HRS2. In HRS1, standard treatment involves vasopressin, or a vasopressin analogue such as terlipressin, and albumin administration. HRS tends to occur in postoperative patients; therefore, it is important to investigate postoperative patients with increased creatinine for potential HRS, with aggressive treatment to help reduce mortality4.
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