Compensated cirrhosis

The most common severity assessment tools in use are the Child-Turcotte-Pugh (CTP) score and the Model for End Stage Liver Disease (MELD) score. The CTP score was originally devised to risk stratify cirrhotic patients in need of portocaval shunt surgery due to oesophageal variceal bleeding and incorporates bilirubin, albumin and prothrombin time as well as encephalopathy and ascites measurements (see Table 24.6).

The MELD score was first developed to predict short-term prognosis in patients undergoing TIPS. The MELD score (http://www.unos.org/resources/meldpeldcalculator.asp) is based on three continuous, objective variables: bilirubin, creatinine and the INR of prothrombin time. Patients are assigned a score based on these three variables, from 6 through 40, corresponding to a 3-month survival of nearly zero and over 80% respectively. The MELD score has been validated as an accurate predictor of survival in acute liver failure, alcoholic hepatitis, a variety of chronic liver diseases and variceal bleeding, amongst others.

A patient with cirrhosis who has not developed jaundice or portal hypertensive complications of hepatic encephalopathy, ascites or variceal bleeding is ‘well compensated’, meaning he or she has adequate hepatic reserve. These patients are often categorised as Child-Turcotte-Pugh class (CTP) A. The median survival age in this group is 9–12 years. Since there are no available medical treatments to reverse cirrhosis, most management strategies are directed towards prevention.

Oesophageal varices

Approximately 50% of cirrhotic patients will have gastro-oesophageal varices with the likelihood being higher in more advanced disease. The risk of haemorrhage is approximately 5–15% per year with a 15–20% risk of mortality per episode. Therefore, all patients with a new diagnosis of cirrhosis should undergo oesophagogastroduodenoscopy to screen for varices. If large varices are noted, oral non-selective beta-blockers and/or variceal band ligation are indicated. Findings of red wale markings—longitudinal dilated venules on the variceal surface—and large varices (greater than 5 mm) signify an increased risk of spontaneous haemorrhage. Advanced liver disease (CTP B or C) also places the patient at a higher risk of variceal bleeding. For large varices and other high-risk features (CTP C or red wale markings) variceal banding is preferred whereas non-selective beta-blockers are preferred for large varices without other high-risk features. Small varices require only primary prophylaxis with non-selective beta blockers. When varices are absent at the initial endoscopy, primary prophylaxis is not recommended, but screening should be repeated in 2–3 years if the patient remains compensated.

Options for non-selective beta-blockade include propranolol, which is typically initiated at 20 mg twice daily, or nadolol which can be started at 20–40 mg once daily. Beta-blockers should be titrated to the maximally tolerated dose. A decrease in heart rate does not correlate with a decrease portal pressures, though it is also a common practice to titrate beta-blocker doses to a heart rate of 55–60 beats per minute.

Nutrition

Cirrhotic patients are often catabolic and suffer from severe muscle wasting and cachexia. Cirrhotic patients are often wrongly counselled to restrict protein intake, thus exacerbating this process. Patients with cirrhosis should eat 1.2–1.5 g/kg of protein daily with a well-balanced diet. Many patients require vitamin supplementation, with assessment specifically for vitamins A, D, E and K and zinc deficiency. Patients with fluid retention (ascites, pleural effusions or peripheral oedema) require a sodium restriction outlined below.

Obesity is seen in epidemic proportions in developed countries. Morbid obesity is a relative contraindication to transplant. Ideally a patient’s BMI should be below 35 before transplantation in many centres, although exceptions are made. Patients with a BMI over 35 have increased risk of wound complications and longer hospital stays.

All cirrhotic patients should abstain from alcohol completely and permanently. Continued alcohol use can result in earlier decompensation, increased risk of hepatocellular carcinoma, synergistic effects with hepatitis C on disease progression, an attenuated effect of interferon therapy, secondary psychiatric conditions and denial of liver transplantation. For patients with alcohol addiction issues, many transplant centres require 6 months of alcohol abstinence before liver transplantation can be considered.

All cirrhotic patients should be counselled on avoidance of raw seafood due to risk of Vibrio vulnificus septicaemia, which carries a particularly high rate of mortality in cirrhotic patients (about 50%). Swimming in contaminated water can also result in wound infections or cellulitis, and should be avoided.

Osteoporosis

Chronic liver disease predisposes patients to the development of hepatic osteodystrophy by multiple pathways that cause decreased bone formation and increased bone resorption. Patients with chronic liver disease plus one of the following: prolonged corticosteroid use (over 3 months), low-trauma fracture, a postmenopausal female or male older than 50 years or hypogonadism should be screened for osteoporosis with a dual energy x-ray absorptiometry. All patients should receive calcium supplementation 1200–1500 mEq/day and vitamin D 1000 IU/day. Counselling on smoking cessation and weight-bearing exercise is appropriate. Bisphosphonates should be considered for patients with known osteoporosis, non-traumatic fractures or inability to withdraw from corticosteroids.

Medication counselling

Paracetamol (acetaminophen) can be hepatotoxic above a dose of 4 g/day. Certainly, patients with concurrent alcohol use or malnutrition can experience additional liver injury at lower doses of paracetamol. In this subset of patients, it is probably safest to avoid chronic dosing of paracetamol, but a low dose (2 g/day) one time or infrequent dosing appears safe. In other cirrhotic patients, paracetamol at doses under 4 g/day for short periods of time appear safe, but less than 2.6 g/day is now the standard of care. The chronic use of paracetamol has not been studied in cirrhotic patients, thus most hepatologists will recommend dose reduction (2 g/day in divided doses) for longer term dosing. Many over-the-counter herbal medications can be hepatotoxic and can cause acute liver failure and thus should be avoided.

Surgery counselling

Patients with cirrhosis are at an increased risk of complications and mortality from surgery. Reasons for this are multiple, but include altered drug metabolism and preexisting hyperdynamic circulation that responds atypically to the stress of surgery and pharmacologic support. The MELD and CTP scores are reasonably accurate in predicting operative risks. In a retrospective study, the risk of 30-day mortality in patients undergoing intraabdominal non-transplant surgery was 5% at a MELD under 10 and 14% for a MELD over 15. In the interpretation of this study, it was suggested that for each increase in MELD score from 6–20 there is a 1% increase in 30-day mortality, and MELD scores over 20 give an additional 2% risk per point. For example, a patient with a MELD score of 7 has an approximately 7% risk of death whereas a MELD score of 25 would correlate to an approximate 30-day mortality of 50% It has been suggested that patients with CTP class A or MELD score less than 10 are acceptable candidates for elective surgery. Elective surgery for patients with CTP class B or MELD over 10 but under 15 should be approached with caution and, if surgery is necessary, work-up for transplant should be completed; performing the operation in a transplant centre is optimal. Elective surgery should not be performed on cirrhotic patients with CTP class C cirrhosis or a MELD score over 15.

Hepatocellular carcinoma

Approximately 80–90% of hepatocellular carcinomas (HCCs) occur in patients that have cirrhosis. Patients with cirrhosis, regardless of aetiology should have HCC surveillance every 6 months with an ultrasound of the liver. The alpha-fetoprotein test has recently fallen out of favour for use in HCC surveillance programs. Non-cirrhotic patients with hepatitis B are also at risk of developing HCC and should also undergo screening if they are in one of the following categories: Asian females over 50 years old, Asian males over 40 years old, Africans over 20 years old, or with a family history of HCC.

The alpha-fetoprotein measurement for screening of HCC is an imperfect test. An alpha-fetoprotein level over 20 ng/mL alone has a sensitivity of 60%. However, in the setting of a liver lesion over 2 cm in diameter, this carries a very high positive predictive value for the diagnosis of HCC.

Ultrasonographic findings in HCC are variable, ranging from an echogenic lesion in small HCCs (due to tumoural fat) to hypoechoic in larger lesions. These findings can be difficult to distinguish from those seen in macronodular cirrhosis and a CT scan is recommended for further evaluation. CT findings of arterial enhancement and venous wash-out are highly specific for HCC.

An algorithmic approach to diagnosing HCC has been recommended by the American Association for the Study of Liver Diseases. For lesions smaller than 1 cm in diameter identified by ultrasound, surveillance ultrasound should be performed every 3 months and, if stable over 1–2 years, reversion to standard 6–12-month surveillance interval is recommended. If a lesion over of 1 cm diameter is identified by ultrasound, it is recommended that a CT or MRI be obtained. If an atypical vascular pattern is noted on one imaging test (CT or MRI), the other imaging modality should be used for further clarification. If a typical vascular pattern (arterial phase enhancement with venous phase washout) is seen on both CT and MRI, the lesion should be treated as HCC, and biopsy is not needed. If imaging does not provide diagnostic features, a biopsy should be pursued. If biopsy results are non-diagnostic, ultrasound on 3-month intervals is recommended. Biopsy confirmation is rarely needed if imaging is characteristic and may cause needle-tract seeding, spreading the cancer. If a liver biopsy is considered under any of the aforementioned circumstances, the authors recommend that this be discussed with a hepatologist before proceeding.

Several treatment options are available for HCC including resection, locoregional therapy such as transarterial chemoembolisation (TACE), radiofrequency ablation (RFA) and liver transplantation. Radiofrequency ablation technique utilises a probe inserted percutaneously into the tumour with ultrasound or CT guidance and induces coagulative necrosis from heat generated by electromagnetic radiation. TACE delivers small embolic particles and a chemotherapeutic agent (cisplatin or doxorubicin commonly) to deprive the tumour of its vascular supply and concomitantly deliver cytotoxic therapy, resulting in tumour hypoxaemia and necrosis.

The optimal use of conventional strategies and novel therapies is evolving. A careful multidisciplinary approach involving a transplant surgeon, transplant hepatologist, interventional radiologist, and oncologist results in the best outcome.

A system to guide HCC treatment, known as the Barcelona Clinic Liver Cancer staging system, has been adopted at many centres and takes into account the number and size of tumours, liver function, comorbidities, and performance status of the patient, which is summarised below. An otherwise healthy patient with a small solitary lesion, without portal hypertension or bilirubin elevation, is a candidate for resection and has the highest rate of cure. The optimal size parameters for resection remain undefined, but a lesion less than 2 cm in diameter has been suggested. The presence of portal hypertension or elevated bilirubin portends a poor outcome in resection due to subsequent liver decompensation. Patients with similar tumour characteristics, but with underlying portal hypertension or elevated bilirubin, may be candidates for RFA, TACE or liver transplantation. Generally speaking, a patient with HCC and without other contraindications (listed below) can be considered for liver transplantation if they fulfil the Milan criteria, which is 3 lesions smaller than 3 cm or one lesion smaller than 5 cm in diameter. It is very important to note that some centres carry out successful transplantation for HCC with characteristics exceeding those of the Milan criteria and discussion with the transplant centre is crucial. In patients with an expected waiting time for the transplant greater than 6 months, it is recommended that locoregional therapy be performed before transplantation although there is little evidence to support the benefit of this practice.

In patients who are not candidates for resection or transplantation, Child-Turcotte-Pugh (CTP) status, location and size of the tumours, ascites and portal vein thrombus are some of the important factors in deciding whether to perform RFA or TACE. Optimal outcomes for RFA are seen in patients with an HCC less than 3 cm in diameter. Technical challenges may prevent use of RFA in patients with ascites, lesions near the surface of the liver, or lesions near the hilum or gallbladder. Guidelines have recommended that TACE should ideally be performed in CTP class A patients with multifocal involvement confined to the liver. However, TACE can be used in a variety of different circumstances including in solitary tumours, depending on the centre. Performing TACE in patients with CTP class B or C cirrhosis or those with portal vein thrombus increases the risk of decompensation and is not recommended. Recently, transarterial radioembolisation (TARE) has garnered attention as an alternative to TACE and RFA. This modality is under continued investigation and its role in treatment of HCC is not yet defined. For patients with advanced disease with good underlying liver function (CTP class A), sorafenib, a multikinase inhibitor, has shown modest improvement in survival and time to progression.

Decompensated cirrhosis

Compensated cirrhosis eventually decompensates, manifested by progressive jaundice, hepatic encephalopathy, gastro-oesophageal variceal bleeding or ascites. Decompensation may arise as a natural progression of disease, or be triggered by events such as infection, hepatoma, medications, other organ failure or surgery. Decompensation heralds a major change in the prognosis of the cirrhotic patient with a 5–year survival rate of 20–50%. Any decompensating event warrants a referral to a transplant hepatologist.

Jaundice

Jaundice can be a result of the natural progression of disease or a manifestation of acute or chronic liver failure. A careful search for infection, gastrointestinal bleeding or HCC is warranted. Cirrhotic patients are also not exempt from other common problems, such as choledocholithiasis, as a cause for jaundice. Biliary obstruction should be ruled out with an ultrasound. A history of recent alcohol use or new medications and over-the-counter drugs should be elicited, as superimposed alcoholic hepatitis or drug hepatotoxicity should be considered.

Hepatic encephalopathy

Hepatic encephalopathy is a set of potentially reversible neuropsychiatric symptoms seen in patients with liver dysfunction. The symptoms can range from mild inattention and disorientation to coma. Hepatic encephalopathy may also be accompanied by an elevation in venous ammonia values, but these values have not been found to correlate well with the presence, absence or grade of encephalopathy. Treatment requires correction of precipitating factors such as gastrointestinal haemorrhage, uraemia, hypoxia, use of psychoactive medication, infection, constipation, electrolyte disturbance and, very rarely, high protein intake. Treatment should include lactulose (oral, nasogastric or rectal) until the bowels begin to move, and then titrated to 2–3 loose stools per day. An alternative therapy is neomycin, but this is rarely used due to the risk of ototoxicity and nephrotoxicity. For lactulose refractory cases, rifaximin has been used with some success. Rifaximin is not superior to lactulose, and is much more expensive. Nonetheless, some data suggest that use of rifaximin (when added to lactulose) is effective for secondary prophylaxis of acute hepatic encephalopathy and may prevent recurrent hospitalisation for hepatic encephalopathy. L-ornithine L-aspartate (LOLA) is another option for lactulose refractory hepatic encephalopathy, and stimulates the urea cycle, leading to decreased ammonia levels. Administration of LOLA for treatment of overt hepatic encephalopathy has been shown to be superior to placebo although the beneficial effects when combined with lactulose remain unknown. Diet is thought to play an important role in hepatic encephalopathy, although it is rare to see a high-protein meal trigger worsening encephalopathy. Skeletal muscle is important for removing ammonia from the blood stream and low protein intake may result in muscle mass loss. Vegetable proteins produce less ammonia than animal proteins and may be preferred. As a rule, protein restriction is rarely required.

Oesophageal variceal haemorrhage

Cirrhotic patients with gastrointestinal bleeding are assumed to have an oesophageal variceal bleed until proven otherwise, due to the 15–20% mortality per episode of variceal haemorrhage. Management should begin with admission to an intensive care unit, the establishment of two large bore intravenous lines (18 gauge or greater), fluid resuscitation, correction of significant coagulopathy, endotracheal intubation for massive bleeds or the inability to protect the airway, and preparation for upper endoscopy. Over-replacement of packed red blood cells is a common mistake as this can lead to increased portal pressure and an increased risk of re-bleeding. The goal haemoglobin level should be about 8 g/dL. Bacterial infections can complicate up to 50% of variceal bleeds and therefore ceftriaxone (or norfloxacin) is recommended for infection prevention. Octreotide, vasopressin, terlipressin or somatostatin may be used to decrease portal inflow. All are equivalent in their efficacy, but the risk of side effects is higher with vasopressin. Oesophageal variceal band ligation should be performed for active bleeding or a clot from a varix, or a non-bleeding varix in the absence of other causes of upper gastrointestinal bleeding. In 10–20% of patients, bleeding cannot be controlled by these measures and salvage measures include balloon tamponade with a Sengstaken-Blakemore or Linton tube, transjugular intrahepatic portal systemic shunt or a surgical shunt. To reduce recurrent bleeding, octreotide or similar agents should be continued for 3–5 days as 50% of early re-bleeding occurs during the first 5 days. Non-selective beta-blockers should be initiated when haemodynamically feasible. After the initial oesophageal variceal band ligation, the patient should undergo repeat oesophageal variceal band ligation every 4–6 weeks until varices are obliterated and then every 6–12 months thereafter.

Ascites

The diagnosis of ascites is suggested if flank dullness, bulging flanks, shifting dullness or a fluid wave is present. Ultrasound is the safest and most inexpensive modality to confirm or dismiss ascites. The 1-year survival rate is approximately 50% once ascites has developed. Treatment of ascites does not influence this survival. Treatment should begin with dietary sodium restriction of less than 2 g/day. Spironolactone (starting at 50–100 mg/day) is the most effective diuretic in patients without acute renal failure or hyperkalaemia. The dose may be titrated every 4–7 days, to a weight loss of 0.5 kg/day in patients without oedema, or 1.0 kg/day in those with oedema. If desired results are not achieved or hyperkalaemia develops, furosemide should then be added at 20–40 mg/day. Maximum recommended dosing is 400 mg/day of spironolactone and 160 mg/day of furosemide. Dose adjustments or diuretic ‘breaks’ are commonly needed due to hyperkalaemia, hyponatraemia or renal dysfunction. If diuretics are maximised, and a patient is not losing fluid weight, a 24-hour urine collection revealing more than 78 mmol/day of sodium indicates dietary non-compliance.

The term ‘refractory ascites’ encompasses diuretic resistant and diuretic intractable (intolerable) ascites. Diuretic resistant ascites fails to resolve despite maximal medical therapy whereas diuretic intractable ascites refers to failure to control ascites due to medication side effects. In this setting, intermittent large volume paracenteses are the next step. Diuretics, if tolerated, should be continued if urinary excretion of sodium is more than 30 mEq/L. A transjugular intrahepatic portal systemic shunt procedure is second-line therapy for refractory ascites, but should be considered in patients requiring over one or two large volume paracenteses per month and is more likely to be effective in the setting of normal renal function. Contraindications for transjugular intrahepatic portal systemic shunt are shown in Table 25.1.

Ascitic fluid from a diagnostic paracentesis should always be sent for cell count, albumin levels, total protein levels and culture. Blood culture bottles should be inoculated with fluid at the bedside to improve the sensitivity for detecting an organism. A serum albumin–ascitic fluid albumin gradient (SAAG) greater than 1.1 g/L is consistent with portal hypertension. A SAAG less than 1.1 g/L merits consideration of other causes for ascites. Therapeutic paracentesis need only be sent for cell count if the patient is well otherwise. If more than 5 litres of fluid is removed, 6–8 g of intravenous albumin per litre removed should be administered. If there is any concern for spontaneous bacterial peritonitis (see below) or renal dysfunction, smaller volumes of fluid may be extracted to avoid postparacentesis circulatory dysfunction, which can worsen renal failure and hasten the re-accumulation of ascitic fluid.

Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SPB) can complicate ascites and historically resulted in mortality greater than or equal to 80%. With heightened clinical suspicion for SBP and early antibiotic therapy, mortality can be reduced drastically. Blood cultures may be positive in about 50% of cases and should be obtained around the time of paracentesis. The diagnosis of SBP is made if the cell count reveals more than 250 polymorphonuclear cells per mm³ or the patient has positive ascitic fluid cultures in addition to clinical symptoms/signs of SBP. Symptoms and signs of SBP include worsening hepatic encephalopathy, fever, elevated/reduced white count, abdominal pain or tenderness, and renal dysfunction. It is important to note that patients with this infection may also be asymptomatic. Once the diagnosis is made, treatment should be initiated with intravenous cefotaxime or the equivalent. Intravenous albumin infusions should be administered at 1.5 g/kg on the day of diagnosis followed by 1.0 g/kg on day 3 to prevent further renal dysfunction. Reassess after 5 days of therapy. If symptoms or white count persist, repeating paracentesis and the cell count will determine whether or not the infection has been eradicated. Primary antibiotic prophylaxis for patients with low ascitic fluid total protein (under 1.5 g) is recommended. Secondary prophylaxis (after first episode) is recommended for all patients due to the high (about 70%) 1-year recurrence rate. Norfloxacin 400 mg/day is the most studied in this setting, but other quinolones (ciprofloxacin) or sulfamethoxazole/trimethoprim can be used.

Renal failure

Renal failure in the cirrhotic patient is an important prognostic sign. Evidence consistently shows that renal failure, now called acute kidney injury, predicts early mortality in cirrhotic patients and is one of three variables used in the Model for End Stage Liver Disease (MELD) score. Aetiologies of acute kidney injury include hypovolaemia, sepsis, acute tubular necrosis, nephrotoxic drugs, and hepatorenal syndrome (Fig 25.1). Evaluation of acute kidney injury should begin by ruling out infection, and urinalysis and urine sodium measurement should also be performed. In all forms of acute kidney injury, the clinician should discontinue diuretics, lactulose and nephrotoxic agents.

Figure 25.1 Acute kidney injury in hospitalized cirrhotics. ARF = acute renal failure; AKI = acute kidney injury; ATN = acute tubular necrosis; GMN = glomerulonephritis; HRS = hepatorenal syndrome. ∗ Volume-responsive prerenal failure is precipitated by infection in 51% of cases.

From Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008; 48(6):2064-2077. © 2008 American Association for the Study of Liver Diseases.

Hypovolaemia should not be overlooked as it accounts for approximately 70% of acute kidney injury in cirrhotic patients; thus all patients should receive volume expansion with 1 g/kg of albumin. Additional colloid or crystalloid fluid may be necessary in addition to the minimum requirement. Sepsis or systemic inflammatory response syndrome will result in systemic vasodilation and a further decrease in effective circulating volume resulting in acute kidney injury. If sepsis is suspected, broad spectrum antibiotic coverage and aggressive fluid resuscitation should be commenced. Patient with spontaneous bacterial peritonitis are at increased risk of hepatorenal syndrome requiring specific measures outline below. Acute tubular necrosis may be the result of sustained hypovolemia, severe sepsis or exposure to nephrotoxic agents. Patients with acute tubular necrosis will not respond to fluid resuscitation and may require renal replacement therapy, usually better tolerated as continuous renal replacement therapy rather than intermittent haemodialysis due to haemodynamic instability.

Patients with hepatorenal syndrome also do not respond well to intravascular volume expansion. This syndrome is unique to liver disease patients and occurs due to renal vasoconstriction in reaction to systemic vasodilation (decreased effective circulating volume). Type 1 hepatorenal syndrome occurs in patients with advanced liver disease and ascites. It is by definition rapidly progressive and results in a median survival of approximately 4 weeks without liver transplantation. Diagnostic criteria are listed in Box 25.1. Type 2 hepatorenal syndrome is a milder form of renal failure that occurs over a period of months. Hepatorenal syndrome is potentially reversible. There is usually a precipitating event (spontaneous bacterial peritonitis, gastrointestinal bleeding). If this inciting factor is addressed, and adequate intravenous albumin has not resulted in improvement in the creatinine (and other causes are ruled out), then hepatorenal syndrome treatments should be initiated. Terlipressin or the combination of octreotide plus midodrine is initiated in conjunction with intravenous albumin infusions. The goal is to increase the mean arterial pressure by 15 mmHg. Treatment should be continued for 7–14 days or until liver transplantation. Liver transplantation is the only definitive treatment for type 1 hepatorenal syndrome.