Hepatorenal Syndrome

Etiology

Viral hepatitis is the most common cause of liver failure, thus hepatorenal-syndrome, in developing countries. Most commonly, it is caused by Hepatitis B or, less commonly, Hepatitis C. In the developed world, the most common causes are drugs/medications; most commonly acetaminophen, chronic alcoholism or any drugs that induce cytochrome p450; and non-alcoholic steatohepatitis (NASH). Less common causes of liver failure leading to HRS include viruses such as CMV, HHV6, and Parvovirus B19. Alternatively, vascular phenomenon like hepatic/portal vein thrombosis and metabolic causes such as nonalcoholic fatty liver disease.[2]

Epidemiology

The incidence of hepatorenal syndrome in patients with decompensated liver disease is approximately 4%. Most of these patients have portal hypertension from alcoholic hepatitis, cirrhosis, or metastatic cancers. The cumulative probability of developing HRS at 1 year is 18% and at 5 years is 39% in patients with decompensated liver disease. The highest risk patients were those with hyponatremia and high plasma renin activity. One third of patients that have spontenous bacterial pertionitis can go on to develop HRS. [3]

Pathophysiology

Cirrhosis and portal hypertension can trigger the neurohormonal cascade which leads to the development of HRS. This, in turn, causes the production and release of vasodilators and cytokines like nitric oxide and prostaglandins which cause splanchnic and systemic vasodilation. The systemic drop in circulating pressure triggers the carotid and aortic arch baroreceptors to activate three separate compensatory mechanisms. These include the renin-angiotensin-aldosterone system, vasopressin release, and activation of the sympathetic nervous system (SNS). The progression of the cirrhosis causes the fall in cardiac output and the fall in systemic vascular resistance in a cycle that induces further renal vasoconstriction.[3] This leads to further renal hypoperfusion, worsened by renal vasoconstriction with the end point of renal failure.

The most common precipitating factors of HRS are spontaneous bacterial peritonitis, large volume paracentesis of ascites without plasma expansion and gastrointestinal bleeding.[4]

Toxicokinetics

Any form of sepsis can cause HRS in patients with liver cirrhosis, as it can trigger the systemic release of sepsis-related vasoactive mediators, similar to those released in portal hypertension.[5]

History and Physical

Patients with hepatorenal syndrome present with signs and symptoms of severe liver failure. These patients initially can present with fatigue and lethargy which can be multifactorial. This may be contributed to by loss of appetite due to increasing nausea. Over time, patients become increasingly more jaundiced, originating in the sclera and then spreading from head-to-toe. The liver's synthetic function becomes affected, and patients become coagulopathic and more likely to bleed. As all this occurs, there is a very slow, gradual build-up of ascitic fluid in the peritoneum due to the intravascular loss of albumin. Confusion due to hepatic encephalopathy is likely the last and most severe stage of the liver disease as a result of the liver failing to break down toxic metabolites. Most importantly these patients notice they urinate less frequently in smaller and smaller volumes as they become oliguric.  [6]

Evaluation

Hepatorenal syndrome has two types and is a diagnosis of exclusion. Type 1 is characterized by rapid and progressive decline in renal function defined by doubling of the serum creatinine to at least greater than 2.5 or a decrease in the creatinine clearance by half or more over a two week period. This is usually associated with a urine output of less than 500mL/day, a normal urine sediment and a low urinary sodium excretion. Type 2 typically involves less severe kidney injury, and patients ordinarily present with diuretic-resistant ascites. Other apparent causes of acute kidney injury need to be excluded, including pre-renal, nephrotoxic drugs, obstructive nephropathy, and renal parenchymal disease.[7]

Treatment / Management

First and foremost, HRS involves establishing euvolemia while stopping all nephrotoxic agents. The active medical treatment of HRS is directed at splanchnic vasoconstriction which results in increased systemic vascular resistance and mean arterial pressure. This via counter-regulatory mechanism suppresses the renin-angiotensin-aldosterone system (RAAS) and the SNS. In turn, this reduces renal vasoconstriction and improves renal blood flow. This is achieved with several different combinations of medical therapy. In Europe, a combination of terlipressin and albumin improves renal perfusion in patients with HRS Type 1 and can work in some patients with HRS Type 2.[8] In North America, noradrenaline and midodrine or octreotide are used for the same purpose as terlipressin.[9]

When medical management fails, surgical/interventional management involves placement of a transjugular intrahepatic portosystemic shunt (TIPS). This type of surgical treatment is established with the insertion of an intrahepatic stent to connect the portal vein to the hepatic vein. The shunt redirects portal blood into the systemic circulation, reducing portal pressure and increasing systemic venous return. This reduces the arterial hypoperfusion and thereby downregulates stimulation of the RAAS and SNS.[7]

Definitive treatment for HRS is established through liver transplantation and provides the best long-term survival benefit.

Other experimental techniques such as molecular adsorbent recirculating system, a modified dialysis technique aimed at removing substances causing vasodilation like nitric oxide, tumor necrosis factor, and cytokines have not been shown to improve overall survival. Renal replacement therapy has been tried in patients that do not respond to the vasoconstrictors above or are poor candidates for TIPS. However, both these therapies may be considered more appropriate as a bridge to transplant.[10]

Patients with spontaneous bacterial peritonitis should be treated promptly and remain on long-term antibiotic therapy to prevent the development of HRS. Those with sepsis from other sources should also be treated promptly to limit the release of sepsis-related vasoactive mediators.

Differential Diagnosis

• Acute glomerulonephritis

• Acute tubular necrosis

• Chronic glomerulonephritis

• Crescentic glomerulonephritis

• Diffused proliferative glomerulonephritis

• Membranoproliferative glomerulonephritis

• Membranous glomerulonephritis

• Poststreptococcal glomerulonephritis

• Rapidly progressive glomerulonephritis

Prognosis

Prognosis for Type 1 HRS is poor, with an average survival of just less than 2 weeks. Type 2 HRS survival is dependent on the severity of the Child-Pugh class of liver disease, but generally more chronic and median survial was 6 to 12 months without treatment. [11]

Complications

Renal failure and death.[12]