Management of Liver Cirrhosis in Patients With HCC

Abstract and Introduction

Abstract

Management of hepatocellular carcinoma (HCC) is challenging compared to other common malignancies because of the nature of the associated background of chronic liver dysfunction. Most of the patients with HCC have underlying cirrhosis. While progression of the tumor is a major contributor to mortality, cirrhosis and its complications often accounts for a significant portion of the morbidity and mortality seen in this group of patients. Severity of underlying liver disease and degree of decompensation predicts prognosis and dictates the tumor treatment options and responses. A multidisciplinary approach is considered the standard of care and paramount to optimal patient outcomes. This review provides information on the general management of cirrhosis, cirrhosis-related complications and commonly associated symptoms, mainly focusing when available on high-level evidence and guidelines.

Introduction

Cirrhosis is a common problem worldwide, accounting for significant mortality and hospital admission rate. Estimated prevalence of cirrhosis in the United States is 0.15% of the population and it is estimated that up to 1% have histological cirrhosis that is not yet clinically detected.^[1] Similar numbers have been reported from European countries and even higher numbers are estimated in most Asian and African countries. Main underlying etiology varies geographically; Alcohol consumption and chronic hepatitis C are the leading causes of cirrhosis in western countries. Chronic hepatitis B is highly endemic in the Asian Pacific region and appears to be the commonest cause of liver cirrhosis, with few exceptions. For example hepatitis C is common in Japan accounting for the most common cause of cirrhosis and liver cancer, while alcohol related cirrhosis is more common in China and Korea compared to other Asian countries.^[2]

Hepatocellular carcinoma (HCC) represents the main contributor to liver-related mortality^[3] and tumor progression is the main cause of death in HCC patients,^[4] however a significant percentage of them die from complications relates to cirrhosis. Therefore, managing cirrhosis to delay the advent of complications as well as appropriately treating these complications early in its course both during and after treatment of the HCC is paramount to improve morbidity and mortality.

Liver cirrhosis histologically represents an advanced stage of hepatic fibrosis associated with hepatic nodules that progressively disrupts the normal hepatic architecture and transforms the liver from a low-resistance to a high-resistance organ, this process elevates the sinusoidal pressure causing impaired hepatocyte function and increases the pressure in the portal vein leading to portal hypertension.^[5] Portal hypertension is defined as being 6 mmHg or greater as measured by the wedged hepatic vein gradient. As the portal pressure increases so does the risk for developing complications related to cirrhosis.^[5] This review summarizes the current management strategies that have been shown to be effective at decreasing the morbidity and mortality associated with the development of complications from cirrhosis.

Table 1. General measures in patients with liver cirrhosis. Identification and treatment of underlying etiology
– Avoid "second hit": alcohol cessation, avoid hepatotoxic medications/herbal preparations, immunization against HBV and HAV
– Periodic estimation of severity of disease (using CP or MELD score) and development of complications
– Improve nutritional status and avoid unnecessary dietary restrictions
– Transplant evaluation
– Life style modification that showed proven/probable benefit: avoid smoking, cannabis use, encourage weight loss, coffee, dark chocolate
– Randomized controlled trials on liberal use of other medications as non selective beta blockers, statins, antibiotics and anticoagulation and their role in delaying progression of cirrhosis or side effects

Table 2. Current and future recommendation for common complications of liver cirrhosis
	Current interventions (beside liver transplant)	Future interventions
Ascites	Dietary sodium restriction; Combination oral diuretics; Paracentesis for tense or refractory ascites; TIPS for refractory ascites	Improve diuretic sensitivity using one or more of the following: midodrine, clonidine, vasopressin antagonists
Variceal bleeding	Screening endoscopy; Primary prophylaxis using NSBB and/or EVL; Secondary prophylaxis using NSBB and EVL. TIPS in selected cases; Acute bleeding: vasoconstrictors, antibiotic prophylaxis, urgent endoscopy, +/- emergency TIPS	More definite role for HVPG and variceal pressure measurement; Use of other beta blockers as carvedilol; Endoscopic therapy using laser or Argon plasma photocoagulation for GAVE and portal hypertensive enteropathy; Thrombin injection or retrograde transvenous obliteration for fundal varices
Hepatic encephalopathy	Rule out other diagnoses and specific precipitating factors; Treatment with Non-absorbable disaccharides and antibiotics; Avoid unnecessary protein restriction	Further studies on role of flumazenil, acarbaose and Zinc supplement
Hyponatremia	Free water restriction; Adjusting/holding diuretics; Rare use of hypertonic saline; Tolavaptan is no longer recommended	Evaluation of other vasopression receptor antagonists
Hepatorenal syndrome	Confirm diagnosis, exclude other reversible causes; Rule out infections; Treatment using combination albumin and vasoconstrictor (terlipressin or noradrenaline or both midodrine and octreotide)	Further evaluation of role of TIPS; Evaluation of new alternatives to dialysis as MARS and Prometheus extractorporeal liver support system; New diagnostic tools that offer definite diagnosis as Urinary neutrophil gelatinase-associated lipocalin.
Spontaneous bacterial peritonitis	Confirm diagnosis with ascitic neurtophil count; Start treatment with third generation cephalosporin and albumin; Do not miss secondary peritonitis; Prophylaxis in all survivors and in other selected patients	Evaluating diagnosis using leukocyte esterase dipsticks or ascitic fluid lactoferrin; Evaluate benefits of selective intestinal decontamination on hemodynamics

Table 2. Current and future recommendation for common complications of liver cirrhosis

Current interventions (beside liver transplant)

Future interventions

Ascites

Dietary sodium restriction; Combination oral diuretics; Paracentesis for tense or refractory ascites; TIPS for refractory ascites

Improve diuretic sensitivity using one or more of the following: midodrine, clonidine, vasopressin antagonists

Variceal bleeding

Screening endoscopy; Primary prophylaxis using NSBB and/or EVL; Secondary prophylaxis using NSBB and EVL. TIPS in selected cases; Acute bleeding: vasoconstrictors, antibiotic prophylaxis, urgent endoscopy, +/- emergency TIPS

More definite role for HVPG and variceal pressure measurement; Use of other beta blockers as carvedilol; Endoscopic therapy using laser or Argon plasma photocoagulation for GAVE and portal hypertensive enteropathy; Thrombin injection or retrograde transvenous obliteration for fundal varices

Hepatic encephalopathy

Rule out other diagnoses and specific precipitating factors; Treatment with Non-absorbable disaccharides and antibiotics; Avoid unnecessary protein restriction

Further studies on role of flumazenil, acarbaose and Zinc supplement

Hyponatremia

Free water restriction; Adjusting/holding diuretics; Rare use of hypertonic saline; Tolavaptan is no longer recommended

Evaluation of other vasopression receptor antagonists

Hepatorenal syndrome

Confirm diagnosis, exclude other reversible causes; Rule out infections; Treatment using combination albumin and vasoconstrictor (terlipressin or noradrenaline or both midodrine and octreotide)

Further evaluation of role of TIPS; Evaluation of new alternatives to dialysis as MARS and Prometheus extractorporeal liver support system; New diagnostic tools that offer definite diagnosis as Urinary neutrophil gelatinase-associated lipocalin.

Spontaneous bacterial peritonitis

Confirm diagnosis with ascitic neurtophil count; Start treatment with third generation cephalosporin and albumin; Do not miss secondary peritonitis; Prophylaxis in all survivors and in other selected patients

Evaluating diagnosis using leukocyte esterase dipsticks or ascitic fluid lactoferrin; Evaluate benefits of selective intestinal decontamination on hemodynamics