8.0 Managing patients with advanced liver disease

  • Determine the phase of the hepatitis B virus (HBV) infection.
  • Determine the severity of the liver disease.
  • Fully evaluate the patient to identify factors contributing to liver damage.
  • Minimise other hepatic injury:
    • manage other causes of liver disease or damage
    • advise on healthy living.
  • Offer antiviral therapy where appropriate – treat all patients with antiviral therapy if cirrhotic and detectable HBV DNA.
  • Manage the complications of cirrhosis.
  • Implement screening for hepatocellular carcinoma as recommended in Chapter 9.

People with chronic hepatitis B (CHB) virus infection are at an increased risk of developing liver cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC), with 15–40% developing complications during their lifetime. Cirrhosis is a histopathological diagnosis, describing liver fibrosis with nodule formation, subsequent to liver cell necrosis and regeneration. Fibrosis in response to hepatocyte death is due to stellate cell activation; it is at first limited in extent, then forms portal-to-portal or portal-to-central vein bridging, finally leading to nodule formation. Cirrhosis leads to altered liver perfusion, with a decrease in portal vein flow and a compensatory increase in hepatic artery input. This adversely affects hepatocyte function over time. Nevertheless, patients with stable cirrhosis may survive for many years without major complications. When liver inflammation continues, fibrosis worsens and progresses to ‘decompensated cirrhosis’. This refers to the complications of jaundice, ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy or HCC. If the cause of the liver disease can be removed, early cirrhosis may reverse in some patients.

In hepatitis B virus (HBV) infection, progression of the inflammatory and fibrotic processes is more rapid in those with raised alanine aminotransferase (ALT) levels and in those with detectable HBV DNA.

Patients with advanced liver disease, with or without ongoing hepatic inflammation, present clinicians with significant management challenges. Adding to the complexity of the management process are untreated cofactors such as hepatitis C virus (HCV) infection, alcohol use, non-alcoholic fatty liver disease (NAFLD, with its associated insulin resistance) or smoking. With treatment, these patients may still enjoy months or years of an acceptable quality of life, even if the underlying condition cannot be reversed. Liver transplantation can provide a better quality of life, but availability is limited. This chapter focuses on the management of advanced liver disease in patients with CHB infection, assuming that HBV has been identified as an issue.

The phase of the disease must be established, so that appropriate decisions on antiviral therapy can be made (see Chapters 2 and 3). Despite barriers to initiating and maintaining therapy, all patients with advanced liver disease should be treated with an oral antiviral agent. Suppression of HBV DNA to undetectable levels is an important goal in cirrhosis caused by CHB. Engaging the patient in a management plan may increase the possibility of ultimately being able to use antiviral therapy.

Cirrhosis may be present in the absence of symptoms, clinical signs or abnormal liver tests. It is therefore important to determine, where possible, the presence or absence of cirrhosis. Liver biopsy has been the gold standard for determining the degree of hepatic fibrosis, and is frequently recommended before therapy. However, non-invasive examinations such as transient elastography (FibroScan®) are becoming more commonly used and accepted.

Many units do not have access to FibroScan®, and patients may prefer to avoid a biopsy. In these instances, ultrasound performed by experienced technicians may identify cirrhosis and portal hypertension. However, the sensitivity of ultrasound in detecting cirrhosis may be as low as 50%; hence, a normal liver ultrasound cannot be used to exclude the presence of cirrhosis.

Having established the presence or absence of cirrhosis, the severity of the liver disease should be assessed. A full physical and laboratory work-up is needed, so that signs of cirrhosis and portal hypertension, and their complications, can be documented at baseline. This allows relevant management strategies to be offered and progress to be evaluated appropriately.

Assessment of cirrhosis and severity of liver disease

Assessment for the following is required:

    • Chronic liver disease
      – spider naevi
      – hepatic palms (palmar erythema)
      – nail changes (leukonychia)
      – gynaecomastia
      – hepatosplenomegaly.
    • Portal hypertension
      – collateral vessels on anterior abdominal wall
      – caput medusa (venous structures around the umbilicus)
      – ascites
      – varices (evidenced by ultrasound, computed tomography and endoscopy).
    • Fluid and electrolyte and renal problems
      – oedema
      – pleural effusion
      – decreased urine output
      – hyponatraemia
      – hypo/hyperkalaemia
      – rising creatinine.
    • Portal systemic encephalopathy (PSE)
      – be aware of minimal PSE, which by definition is not evident on clinical evaluation; number-connection tests or driving-skill tests may be required
      – reversed sleep pattern (daytime somnolence and nocturnal waking) in early PSE
      – slowing of normal response times, reflexes
      – impaired driving skills
      – lack of energy
      – metabolic flap (asterixis)
      – confusion, disorientation
      – increasing drowsiness
      – coma (hepatic failure).
    • Hepatic decompensation
      – jaundice
      – bruising, bleeding
      – spontaneous bacterial peritonitis
      – hepatocellular carcinoma
      – impaired glucose homeostasis (hypoglycaemia)
      – impaired renal function (hepatorenal syndrome).
    • Extrahepatic manifestations of advanced liver disease
      – cardiomyopathy
      – hepatopulmonary syndrome
      – metabolic bone disease and risk of fractures
      – hormonal complications
         * testicular atrophy and feminisation in men
         * hirsutism and amenorrhoea in women
      – increased risk of serious infections.
    • Nutritional assessment
      – body mass index (may not be useful if there is significant fluid retention)
      – waist circumference (may not be useful if ascites)
      – proximal muscle wasting.

See standard texts on liver disease for a more detailed description of these manifestations (1-5).

All patients should have a detailed history and examination performed to establish:

  • underlying medical conditions including co-infection with hepatitis C or D viruses, or human immunodeficiency virus, which will influence the course of the disease
  • medication use
    – prescribed
    – alternative or complementary medicine and over-the-counter drugs
  • tobacco use
  • alcohol use (there is no safe alcohol consumption in cirrhosis)
  • recreational drug use (especially cannabis which promotes fibrosis)
  • family history of liver disease, diabetes
  • weight, body mass index
  • evidence of diabetes or other organ system disease
  • other forms of liver disease (e.g. haemochromatosis, autoimmune liver disease).

Cofactors for liver disease should be addressed in patients with advanced liver disease, as far as possible. Specifically, obesity should be controlled, and alcohol and cannabis use ceased (or markedly reduced if abstinence is not an option). Paracetamol can be used at a reduced dose, and non-steroidal anti-inflammatory (nephrotoxic) therapy should be avoided. Drugs known to cause liver disease should be used with caution, although underlying liver disease does not increase the risk of hepatotoxicity. Exercise should be maintained, where possible, to help preserve muscle mass, cardiovascular fitness, functional status and quality of life.

Having advised the patient about other factors that can aggravate liver disease, the clinician must then focus on a specific management plan for the advanced liver disease.

The treatment of CHB is discussed in detail in Chapter 7. All patients should be evaluated for possible antiviral therapy with an oral nucleos(t)ide analogue (entecavir or tenofovir), because these drugs will significantly modify the progression of the disease. Pegylated interferon is contraindicated in patients with decompensated cirrhosis, but oral antiviral agents are generally well tolerated. All cirrhotic patients with detectable HBV DNA should be placed on antiviral therapy.

8.6.1  Management strategies

Following the diagnosis of cirrhosis,the following steps should be taken.

a. A gastroscopy or endoscopy.
This should be considered, to detect oesophageal or gastric varices.

b. HCC screening (see Chapter 9).
The risk of HCC must be addressed in patients with CHB infection. Both cirrhotic and, to a lesser extent non-cirrhotic, patients are at risk of this complication. Recommended screening comprises 6-monthly abdominal ultrasound examinations and serum alpha-fetoprotein levels (6).

c. If the liver disease is advanced, referral to a liver transplant unit for assessment should be considered.
Not all patients will be suitable for transplant or even for referral to a transplant unit. However, this decision should be considered and documented. Two means of objectively assessing severity of liver disease are the Child Pugh Turcotte score and the Model of End-Stage Liver Disease (MELD) score. The scoring system for the Child Pugh Turcotte model is shown in Table 8.1. The MELD score is calculated using data for serum bilirubin, serum creatinine and the international normalised ratio (INR). Online calculators can easily provide a score if these results are available. Patients who have a high Child’s B or Child’s C score and MELD score of over 15 should be referred for consideration of transplantation if there are no contraindications. Table 8.2 demonstrates the link between MELD scores and life expectancies.

Table 8.1 Child Pugh Turcotte scoring system for cirrhosis
Measure1 point2 point3 pointUnits
Bilirubin (total) <34 (<2) 34–50 (2–3) >50 (>3) μmol/L (mg/dL)
Serum albumin >35 28–35 <28 g/L
International normalised ratio <1.7 1.71–2.20 >2.20 No unit
Ascites None Mild Mod/severe No unit
Hepatic encephalopathy None Grade I–II (or suppressed with medication) Grade III–IV (or refractory) No unit


PointsClassOne-year survival
Two-year survival
5-6 A 100 85
7-9 B 81 57
10-15 C 45 35


Table 8.2 Model of End-Stage Liver Disease score and prognosis in chronic liver disease
MELD scorePredicted 6-month
12-month survival
24-month survival
0-9 98 93 90
10-19 92 86 80
20-29 78 71 66
30-39 40 37 33
MELD, Model of End-Stage Liver Disease

8.6.2 Dietary modification in advanced liver disease

Patients with advanced liver disease often eat poorly, and in the past this has been complicated by advice to reduce protein and sodium intake. It is clear that patients do better if they can eat frequent small protein-containing meals daily. Evening food intake enhances hepatic regeneration and recovery from hepatic insults and, in hospital patients, it reduces morbidity and mortality.

8.6.3 Fluid and electrolyte problems

Fluid and electrolyte problems are managed by:

  • salt and water restriction where necessary
  • ensuring electrolyte balance
    – cautious diuretic usage to minimise the risk of hepatorenal syndrome
     * spironolactone is the preferred agent, in doses of 25–400 mg/day
     * initial low dose frusemide

– potassium supplementation if required
– low dietary saturated fat with adequate dietary protein, fruit and vegetables
– monitoring of serum creatinine and urine electrolytes (frequency determined by acuteness and severity of fluid overload and need for reversal).

Additional therapy for ascites may be required with regular large volume paracentesis (‘ascitic tap’). Medications to avoid in ascites include angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs (NSAIDs) and beta blockers. Some patients are treated with transjugular intrahepatic portosystemic shunt (TIPS) to lower portal pressure and decrease ascites accumulation.

– All patients presenting with ascites should have a diagnostic tap to exclude or diagnose spontaneous bacterial peritonitis.
– Patients with recurrent ascites should be referred to a specialist unit, as transplantation may need to be considered at this stage.

8.6.4 Portal hypertension

Portal hypertension is managed by:

  • non-selective beta blockers (propranolol and possibly carvedilol)
  • prophylactic variceal band ligation of high-risk oesophageal varices
  • treating acute bleeding when it occurs
  • considering TIPS if conservative measures fail.

Cirrhotic patients with portal hypertension have a definite risk of portal vein thrombosis (PVT). Currently, there are no formal recommendations about use of low molecular weight heparin in this situation, but there is increasing interest in its use, because it appears to reduce risk of both PVT and mortality from other causes (3).

8.6.5 Portal systemic encephalopathy

Portal systemic encephalopathy is managed by:

  • maintaining electrolyte balance
  • using lactulose to clear the colon and alter ammonia metabolism and diffusion (use doses to ensure two to three soft stools per day, and continue use long term)
  • considering use of rifaximin, a non-absorbable antibiotic; this is now funded by the Pharmaceutical Benefits Scheme (PBS) for the prevention of hepatic encephalopathy in patients with a prior episode and in whom lactulose is not tolerated or is ineffective
  • continuing normal protein intake, which is critical for hepatic regeneration.

8.6.6 Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SBP) is managed by:

  • having a low threshold of suspicion in a patient with ascites presenting with fever, abdominal pain, vomiting, onset of or worsening of encephalopathy, deteriorating renal function, renal failure or generally unwell
  • early referral to emergency department or for hospital admission if diagnosis is suspected
  • confirmation of diagnosis by ascitic tap (white cell count >500/mm3 or neutrophils >250/mm3)
  • treatment of acute episode with appropriate IV antibiotics, +/– albumin
  • prophylaxis with co-trimoxazole (alternative norfloxacin) for all patients with previous proven episode of SBP, and patients with ascites and low ascitic protein concentration (<10 g/L).

8.6.7 Advancing hepatic failure

Advancing hepatic failure is managed by:

  • avoiding and managing factors that aggravate the liver disease
    – alcohol, cannabis, tobacco
    – some medications (e.g. excess paracetamol, ibuprofen, anti-tuberculosis agents)
    – obesity
    – injecting drug use
    – iron overload
    – diabetes
    – hepatitis C infection
  • monitoring Mg, Zn, Ca and fat-soluble vitamins
  • regularly checking for infection (e.g. cellulitis, chest infection)
  • avoiding certain infection risks (e.g. avoid uncooked oysters because of the risk of Vibrio vulnificus infection)
  • providing routine vaccination against influenza and pneumonia
  • ongoing screening for the risk of HCC.
  1. Bajaj JS. Review article: the modern management of hepatic encephalopathy. Aliment Pharmacol Ther. 2010;31(5):537–47.
  2. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42(5):1208–36.
  3. Jairath V, Burroughs AK. Anticoagulation in patients with liver cirrhosis: complication or therapeutic opportunity? Gut. 2013;62(4):479–82.
  4. Schiff ER, Sorrell MF, Maddrey WC. Schiff’s Diseases of the Liver (10th edition). Philidephia: Lippincott Williams & Wilkins; 2007.
  5. Sherlock S, Summerfield JA. A colour atlas of liver disease. London: Wolfe Medical Publications Ltd; 1979.
  6. Wong GL, Chan HL, Tse YK, Chan HY, Tse CH, Lo AO, et al. On-treatment alpha-fetoprotein is a specific tumor marker for hepatocellular carcinoma in patients with chronic hepatitis B receiving entecavir. Hepatology. 2014;59(3):986–95.

Robert G Batey, Department of Medicine, Alice Springs Hospital, Alice Springs, NT, and Drug and Alcohol Services, John Hunter Hospital, Newcastle, NSW

& David Iser, Department of Gastroenterology, St Vincent’s Hospital, and Infectious Diseases Unit, Alfred Hospital, Melbourne, VIC