End-stage liver disease

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Chapter 46 END-STAGE LIVER DISEASE

KEY POINTS

• End-stage liver disease is a complication of cirrhosis that is due to a variety of aetiologies, including chronic viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune disease and metabolic disease.
• The manifestations of end-stage liver disease are a consequence of hepatic synthetic failure and portal hypertension.
• Common manifestations of end-stage liver disease include portal hypertensive bleeding, fluid retention and ascites, spontaneous bacterial peritonitis, hepatorenal syndrome and hepatic encephalopathy.
• Patients with cirrhosis should be monitored for manifestations of end-stage liver disease so that appropriate measures can be implemented to prevent and treat complications. This includes screening for oesophageal varices and hepatocellular carcinoma, introduction of prophylactic antibiotics in select circumstances and regular monitoring of renal and liver function. Concomitant therapies should be monitored carefully.

INTRODUCTION

End-stage liver disease is also known as decompensated liver disease. It develops in patients with underlying cirrhosis due to a wide variety of causes, including chronic hepatitis C, chronic hepatitis B, alcoholic liver disease, non-alcoholic fatty disease, autoimmune liver diseases (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) and genetic or metabolic liver diseases (alpha1-antitrypsin deficiency, genetic haemochromatosis, Wilson’s disease). Despite the wide aetiological processes involved in the development of cirrhosis, the manifestations of end-stage liver disease are common to all, and are consequent to the combination of portal hypertension and hepatic synthetic failure (Table 46.1). Extrahepatic manifestations of end-stage liver disease include hepatopulmonary syndrome and portopulmonary hypertension. In addition, the presence of cirrhosis predisposes to hepatocellular carcinoma (HCC), bone disease and malnutrition.

TABLE 46.1 Manifestations of end-stage liver disease

Complications of portal hypertension and portosystemic shunting

• Ascites
• Spontaneous bacterial peritonitis
• Hepatorenal syndrome
• Oesophageal and gastric varices
• Hepatic encephalopathy
• Hepatopulmonary syndrome and portopulmonary hypertension

Consequences of hepatic synthetic failure

• Hypoalbuminaemia
• Hypoprothrombinaemia and coagulopathy
• Hyperbilirubinaemia

ASSESSMENT

History

The essential elements of history taking for patients with end-stage liver disease (Figure 46.1) include:

• Likely aetiology and duration of liver disease:

– History of alcohol intake (age of onset, daily intake, last use)
– History of injection drug use (age of onset, last use)
– Ethnicity and country of birth
– Family history of liver disease
– History of obesity, features of metabolic syndrome.

• Precipitants of recent deterioration:

– Recent alcohol abuse
– Recent illness, including infections, diarrhoea, vomiting, constipation
– Recent medication history, including diuretics, sedatives, analgesics, non-steroidal antiinflammatories
– History of gastrointestinal bleeding
– Nutritional intake, including salt intake, protein intake.

image

FIGURE 46.1 Assessment of end-stage liver disease.

CT = computed tomography; K = potassium, MRI = magnetic resonance imaging; U = urea.

Physical examination

Assessment of patient with end-stage liver disease (Figure 46.1) should include examination for:

• Palmar erythema
• Finger clubbing (presence indicative of hepatopulmonary syndrome)
• Spider naevi
• Gynaecomastia, loss of body hair, testicular atrophy (in males)
• Cardiovascular assessment (usually reveals hyperdynamic circulation, with warm peripheries and mild tachycardia and hypotension)
• Signs of pulmonary hypertension (may be present in 2%–10% of patients with portal hypertension)
• Hepatosplenomegaly
• Fluid retention (ascites, peripheral oedema, pleural effusion)
• Hernias (periumbilical, inguinal)
• Malnutrition (loss of subcutaneous fat deposits, muscle wasting)
• Signs of hepatic encephalopathy (flapping tremor, cognitive changes)
• Fetor hepaticus.

Laboratory evaluation

In addition to the investigations listed, other specific investigations will be required to determine the cause of liver disease (Figure 46.1).

Haematology

• Full blood count (leucopenia and thrombocytopenia reflect portal hypertension).
• Coagulation profile (prolongation of international normalised ratio [INR] reflects hepatic synthetic failure or inadequate vitamin K absorption).

Serum biochemistry

• Sodium, potassium, urea, creatinine.
• Bilirubin, albumin, liver enzymes.
• Serum alpha-fetoprotein (elevation may reflect HCC, or be related to liver inflammation in chronic viral hepatitis).

Microbiology

• Fluid cultures (blood, urine, ascites, etc, if sepsis suspected, or change in clinical condition).

Evaluation of ascitic fluid

• A diagnostic paracentesis involves the removal of 20–40 mL of ascitic fluid.
• Fluid should be sent for a cell count, albumin, protein and culture (by inoculation into blood culture bottles).
• An ascitic white cell count (WCC) >500 cells/mm3 or neutrophil count >250 cells/mm3 indicates the presence of infection (usually spontaneous bacterial peritonitis).
• A serum to ascites albumin gradient (SAAG) of >11 g/L is consistent with ascites due to portal hypertension, rather than malignancy or infection.
• An ascites protein concentration of <10 g/L is associated with a high risk for spontaneous bacterial peritonitis.

Radiologic investigations

• Ultrasound of upper abdomen: a screening test to identify space occupying lesions in the liver, portal vein patency, the presence of ascites, splenomegaly.
• Triple-phase computed tomography (CT) scan of the abdomen: a more sensitive test for identification of hepatocellular carcinoma (classically displays enhancement on arterial phase, and a defect on portal phase), lymphadenopathy, ascites, vascular shunts.
• Magnetic resonance imaging (MRI): can be used safely in patients with renal impairment. More sensitive than ultrasound for detection of hepatocellular carcinoma.
• Portal vein pressure measurements: used in some specialist centres for quantitation of portal hypertension. Involves hepatic vein cannulation, usually via the right external jugular vein. Clinically significant portal hypertension is a hepatic vein–portal vein pressure gradient (HVPG) >10 mmHg (normal 3–6 mmHg). Varices rarely bleed until HVPG >12 mmHg.

Cardiorespiratory evaluation

Shortness of breath is a common symptom in patients with end-stage liver disease. Specific investigations of the cardiorespiratory systems may include:

• Chest X-ray
• CT chest
• Echocardiography
• Full respiratory function tests
• Arterial blood gases on room air
• If hepatopulmonary syndrome is suspected then:

– Contrast-enhanced ‘bubble’ echocardiography
– Technetium-99-labelled macroaggregated albumin nuclear scan

• If portopulmonary hypertension is suspected then:

– Right heart catheter study.

Liver biopsy

Liver biopsy is rarely required in patients with end-stage liver disease as a diagnosis of cirrhosis can usually be established with a combination of history, physical examination, laboratory testing and imaging. Where an aetiology is not apparent, liver biopsy may occasionally provide additional information, although this would rarely influence further management. In most cases, percutaneous biopsy is precluded because of ascites, coagulopathy or thrombocytopenia, and a transjugular route should be considered.

In patients with end-stage liver disease and a space occupying lesion, ultrasound- or CT-guided biopsy is usually not required to establish a diagnosis of hepatocellular carcinoma if this diagnosis can be made on characteristic imaging and an elevated alpha-fetoprotein level. Patients with small hepatocellular carcinoma lesions will remain amenable to liver transplantation regardless of confirmation of hepatocellular carcinoma.

Severity scores in end-stage liver disease

A number of scoring systems are used to assess severity of liver failure, and are used to determine prognosis, priority for liver transplantation and risks of procedures such as general anaesthesia or portosystemic shunt procedures. The two most commonly used systems are the Child-Pugh (Child-Turcotte-Pugh) classification (Table 46.2) and the Model for End-stage Liver Disease (MELD).

TABLE 46.2 Child-Pugh score for severity of liver disease. Child-Pugh A: 5–6; Child-Pugh B: 7–9; Child-Pugh C: 10–15

image

image

*To convert μmol/L to mg/dL, multiply by 0.01652. INR = international normalised ratio.

MANAGEMENT

Oedema, ascites and pleural effusions

Cirrhosis is associated with abnormal extracellular fluid volume regulation, which results in accumulation of fluid as oedema, ascites, or pleural effusion. This abnormality in volume regulation is associated with significant changes in the splanchnic circulation and renal circulation that induce sodium and water retention.

The management of fluid retention in decompensated liver disease usually involves a step-wise approach.

• Salt restriction, aiming for 50–100 mmol sodium/day. It is often useful for the patient to consult a dietitian for advice regarding salt content of specific foods.
• Avoid medications associated with salt and fluid retention, including non-steroidal antiinflammatory drugs, antacids, effervescent preparations.
• Fluid restriction is usually only recommended in the presence of hyponatremia with normal serum creatinine.
• Introduction of diuretics, initially with spironolactone, and later with addition of frusemide. Doses should be increased gradually, and patients should be carefully monitored for the development of renal impairment or electrolyte disturbance (hyponatraemia, hyper/hypokalaemia). Maximum doses of diuretics are spironolactone 400 mg, frusemide 120 mg, although few patients can achieve these doses without development of complications. Diuretics should be reduced or even stopped in the presence of hyponatraemia (sodium <125 mmol/L) or a rising creatinine.
• Patients are considered to have refractory ascites when the ascites cannot be mobilised with reasonable doses of diuretics (diuretic-resistant) or if diuretics cannot be tolerated (diuretic-intolerant) because of cramps, hyponatraemia or renal impairment.
• Management options in refractory ascites include:

– Repeated large volume paracentesis (with intravenous volume expansion, e.g. concentrated albumin 10 g/L ascites removed)
– Transjugular intrahepatic portosystemic shunt (TIPS)
– Refractory ascites may be an indication for liver transplantation.

• Nutritional intake and status should be assessed in patients with ascites, and protein and calorie intake increased in malnourished patients (the majority). This may require use of nutritional supplements. Protein intake of 1–1.5 g protein/kg/day is recommended.
• Pleural effusions in cirrhotic patients (hepatic hydrothorax) are thought to occur when ascitic fluid traverses the diaphragm via small congenital or acquired defects in the diaphragm. They occur more commonly in the right pleural cavity.
• Management options include:

– Salt and fluid restriction
– Diuretic therapy
– Repeated thoracocentesis
– Insertion of pleural drains and thoracoscopic or operative procedures should be avoided as they are associated with high mortality
– TIPS
– Liver transplantation.

Hyponatraemia

Dilutional hyponatraemia is a common manifestation of end-stage liver disease and may occur in the absence of diuretic therapy. Diuretic therapy is the most common precipitant of a falling serum sodium level. It is not uncommon for patients to develop progressive hyponatraemia following admission to hospital without any obvious change to their diuretic dosages. A variety of factors are probably responsible including: adherence to prescribed doses of diuretics, adherence to a salt-restricted diet and intravenous infusions of 5% dextrose while the patient is nil by mouth. Other causes of hyponatraemia should also be considered, such as therapy with other drugs known to cause hyponatraemia (such as SSRI [selective serotonin reuptake inhibitor] antidepressants) or other disease processes, including diarrhoea.

The management of hyponatraemia in patients with marked fluid retention can be extremely difficult. It should be remembered that despite often markedly low serum sodium levels, patients with oedema and ascites have increased levels of total body sodium. Thus attempts at correcting hyponatraemia by infusion of normal saline will result in further exacerbation of the oedema state, but usually with little change in serum sodium level. Appropriate management should include:

• Cessation of diuretics (although further fluid retention is likely to result)
• Fluid restriction (800–1200 mL daily)
• Avoidance of normal saline infusion (use only 5% dextrose if IV fluids are necessary, noting fluid restrictions)
• Dietary salt restriction
• Avoidance of high sodium-containing antibiotics
• Hypertonic saline infusion should not be used, as central pontine myelinolysis may occur on rapid correction of serum sodium.

Patients with renal impairment and hyponatraemia are particularly difficult to manage and should be managed as for hepatorenal syndrome (see below).

Muscle cramps

Painful muscle cramps are a common problem in patients with end-stage liver disease and are often worse during diuretic therapy. Treatment is empirical and no therapies are of proven value. Stretching and massaging the affected muscles may provide relief. Some patients respond to cessation or dose reduction of diuretics or correction of hypomagnesaemia or hypozincaemia. Clinical efficacy of drugs such as quinine has not been established.

Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SBP) is a common life-threatening complication of end-stage liver disease. Patients may be asymptomatic, develop a fever or have worsening encephalopathy. Rarely are there obvious features of peritonitis with fever, chills, abdominal pain and tenderness.

A diagnosis of SBP is made when the ascitic white cell count or neutrophil count is elevated (as discussed previously). Identification of an organism on culture or Gram stain is not required to establish a diagnosis.

Prophylaxis

Prophylaxis with regular daily antibiotics (e.g. norfloxacin, sulfamethoxazole/trimethoprim) should be given in the following situations:

• A previous episode of SBP
• Patients with ascites and very low ascitic protein concentration (less than 10 g/L)
• Patients with ascites who are admitted to hospital with upper gastrointestinal bleeding.

Treatment

Most infections are due to Gram-negative organisms and treatment should be with broad-spectrum intravenous antibiotics, such as a third-generation cephalosporin. In patients receiving prophylactic antibiotics, Gram-positive infection is more common, which will affect choice of antibiotics. The specific choice of antibiotic used will vary according to hospital policy and availability.

The concomitant administration of intravenous concentrated albumin has been shown to significantly reduce the rate of acute renal failure and improve survival in patients with SBP.

Hepatorenal syndrome

Hepatorenal syndrome is a functional renal failure that occurs in patients with end-stage liver disease, almost always in the setting of severe ascites and hyponatraemia. It develops because of marked renal vasoconstriction and concomitant extrarenal vasodilatation that occurs in end-stage liver disease.

Diagnosis

Diagnostic criteria include:

• Low glomerular filtration rate (rising serum creatinine, creatinine clearance <40 mL/min)
• Oliguria, <500 mL/day
• Low urinary sodium concentration, <10 mmol/L.

Hepatorenal syndrome is classified as type 1 (rapid onset of progressive oliguria and rising serum creatinine, associated with extremely high mortality) and type 2 (insidious onset, better prognosis).

Other causes of renal failure should be excluded. These include acute tubular necrosis, hepatitis C- or B-related renal disease (e.g. glomerulonephritis), IgA nephropathy (in alcoholic liver disease), urinary obstruction, drug-induced interstitial nephritis (e.g. proton pump inhibitors, antibiotics).

Potential precipitants of renal failure should be avoided in patients with end-stage liver disease. They should be sought in patients who develop renal failure. These include:

• Infection, including SBP, pneumonia, urinary tract infection, bacteraemia
• Hypotension related to gastrointestinal bleeding
• Nephrotoxic medications, including non-steroidal antiinflammatory drugs and COX 2 inhibitors, aminoglycoside antibiotics, ACE inhibitors and angiotensin receptor antagonists
• Nephrotoxic contrast agents
• Hypovolaemia due to diuretics, limited oral intake, vomiting, diarrhoea, overuse of lactulose, large-volume paracentesis.

Management

• Careful assessment of volume status, including central venous pressure monitoring. Hypovolaemia should be corrected with isotonic saline, however, once euvolaemia has been obtained, sodium intake should be restricted.
• Intravenous antibiotics until infection can be excluded.
• Cessation of nephrotoxic medications.
• Use of splanchnic vasoconstrictors. Choice of agent will depend on availability, but include terlipressin with albumin infusion (the most widely studied), noradrenaline plus albumin or midodrine and albumin. For example:

– Terlipressin 1 mg IV, 4- to 6-hourly with concentrated (20%) albumin 100 mL IV, twice daily for 7–14 days.

• TIPS has been shown to improve renal function in some patients with hepatorenal syndrome, but in very advanced liver disease may be associated with worsening of liver function and development of severe encephalopathy.
• Consideration of renal-replacement therapy (haemofiltration or haemodialysis) in patients with potentially reversible cause of deterioration, or in those being considered for liver transplantation.
• Liver transplantation is the only therapy associated with long-term survival.
• Primary prevention: all patients with cirrhosis and features of portal hypertension, such as platelet count below 100, splenomegaly, varices on abdominal imaging, should undergo endoscopy to assess for oesophageal varices and be considered for primary prevention. Strategies include:

– Non-selective beta-blockers, aiming for reduction in heart rate of 25% or <60 beats/min, or
– Endoscopic band ligation, aiming for eradication of varices.

• Initial management of bleeding:

– Urgent evaluation of haemodynamic state
– Fluid resuscitation, via large bore cannulas
– Blood tests for full blood count, electrolytes and creatinine, liver function tests and cross-match
– Central venous pressure, arterial monitoring
– Consideration of endotracheal intubation depending on level of consciousness, and degree of bleeding
– To reduce portal pressure, commence intravenous administration of:

• Octreotide 50 μg IV, immediately, then 25–50 μg/h IV for 5 days, or
• Terlipressin 2 mg IV, 6-hourly for 2–3 days

– Urgent endoscopy to confirm source of bleeding and management with endoscopic band ligation.

• Continued or recurrent bleeding:

– Repeat endoscopy and band ligation
– Balloon tamponade
– Emergency TIPS or surgical portosystemic shunt (depending on local expertise).

• Secondary prevention:

– Repeated endoscopic band ligation to eradication of varices
– Non-selective beta-blocker
– Consider TIPS.

Hepatic encephalopathy

Hepatic encephalopathy is a common manifestation of end-stage liver disease. It has a spectrum of presentations from grade 1 (sleep inversion, poor concentration, personality change) through to grade 4 (deep coma). Sudden development or worsening of encephalopathy should prompt a search for a precipitant such as:

• Gastrointestinal bleeding
• Dehydration or electrolyte disturbance
• Renal impairment
• Use of sedatives or narcotics
• Sepsis, including SBP, urinary tract infection, respiratory infection, cellulitis
• Constipation
• Recent TIPS insertion
• Worsening of liver failure.

In the absence of a readily identifiable precipitant, infection should be assumed and the patient should be started on broad-spectrum intravenous antibiotics, such as a third-generation cephalosporin, according to hospital guidelines.

Management should be directed at correction of the precipitant, airway support if required and the use of lactulose at a dose required to promote two to three loose stools per day. In a deteriorating patient, lactulose 30 mL orally, rectally or via nasogastric tube, may be required every 1–2 hours to induce a rapid laxative effect. Care should be taken not to induce severe diarrhoea, and the patient should be monitored for development of bowel distension.

Protein restriction is not recommended in the management of hepatic encephalopathy. In acute, severe encephalopathy, protein should only be withheld for a maximum of 24–48 hours, then progressively increased to normal intake as recovery occurs. Protein intake should not be restricted in patients with chronic encephalopathy, as these patients are usually markedly malnourished. A protein intake of 1–1.5 g protein/kg/day is recommended.

Hepatocellular carcinoma

See Chapter 44.

Nutritional management

See Chapter 45.

SUMMARY

The manifestations of end-stage liver disease are common to all aetiologies and result from a combination of portal hypertension and hepatic synthetic failure. Clinicians should be aware of clinical signs and laboratory findings in end-stage liver disease, and actively seek precipitants when sudden deterioration occurs. A patient’s status can change rapidly from being relatively stable, to being critically unwell. Management of bleeding gastro-oesophageal varices, hepatic encephalopathy, spontaneous bacterial assessment and acute renal failure for example, require rapid assessment and introduction of life-saving interventions. Less acute, long-term management requires careful attention to diet to ensure appropriate salt and fluid restrictions, and adequate protein and caloric intakes, as well as monitoring for complications such as hepatocellular carcinoma.

FURTHER READING

Cordoba J, Lopez-Hellin J, Planas M, et al. Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. 2004;41:38-43.

Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology. 2001;120:726-748.

Gines P, Cardenas A, Arroyo V, et al. Management of cirrhosis and ascites. N Eng J Med. 2004;350:1646-1654.

Gines P, Torre A, Terra C, et al. Review article: pharmacological treatment of hepatorenal syndrome. Aliment Pharmacol Ther. 2004;20(Suppl 3):57-62. discussion: 63–4

Moore KP, Wong F, Gines P, et al. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology. 2003;38:258-266.

Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N Engl J Med. 2001;345:669-681.

Wong F, Bernardi M, Balk R, et al. Sepsis in cirrhosis: report on the 7th meeting of the international ascites club. Gut. 2005;54:718-725.

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