Management of liver cirrhosis

This article discusses a practical, evidence-based approach to the diagnosis and management of liver cirrhosis by focusing on etiology, severity, presence of complications, and potential home-managed treatments. Relevant literature from 1985 to 2010 (PubMed) was reviewed. The search criteria were peer-reviewed full papers published in English using the following MESH headings alone or in combination: “ascites”, “liver fibrosis”, “cirrhosis”, “chronic hepatitis”, “chronic liver disease”, “decompensated cirrhosis”, “hepatic encephalopathy”, “hypertransaminasemia”, “liver transplantation” and “portal hypertension”.

Forty-nine papers were selected based on the highest quality of evidence for each section and type (original, randomized controlled trial, guideline, and review article), with respect to specialist setting (Gastroenterology, Hepatology, and Internal Medicine) and primary care. Liver cirrhosis from any cause represents an emerging health issue due to the increasing prevalence of the disease and its complications worldwide. Primary care physicians play a key role in early identification of risk factors, in the management of patients for improving quality and length of life, and for preventing complications. Specialists, by contrast, should guide specific treatments, especially in the case of complications and for selecting patient candidates for liver transplantation. An integrated approach between specialists and primary care physicians is essential for providing better outcomes and appropriate home care for patients with liver cirrhosis.

Keywords: Ascites, Family medicine, Hepatic encephalopathy, Hypertransaminasemia, Portal hypertension

INTRODUCTION

Liver cirrhosis is defined in histology as a bridging fibrosis-a late stage of hepatic fibrosis-leading to deranged liver architecture and regenerative nodules. Liver cirrhosis is considered the end stage of a variety of chronic liver diseases, and is irreversible in its advanced stages[1]. Cirrhosis is characterized by poor life expectancy and is a leading cause of morbidity and mortality: in the United States liver cirrhosis is the 12th most common cause of death (9.5/100 000 individuals), while in Italy the incidence of liver cirrhosis is over 26 000 new cases each year, with a prevalence over 120 000 cases (7000 below 45 years), and 20 deaths/100 000 individuals.

Figures are likely to be even higher in Asia and Africa. Liver cirrhosis carries the risk of life-threatening complications, partly due to a number of co-morbidities. Medical treatments that may halt the progression of compensated cirrhosis to decompensated cirrhosis are currently being developed[1]. Liver transplantation, however, is the only option in a selected subgroup of patients with end-stage disease. Because of the increasing prevalence of chronic viral hepatitis and (alcoholic- nonalcoholic) steatohepatitis and their high risk evolution toward liver cirrhosis and end-stage liver disease, preventive programs and early management of these conditions are considered an emerging health issue. It is essential that primary care physicians (PCPs) be optimally trained to identify patients with chronic liver disease as early as possible, and to properly manage those with liver cirrhosis.

A close interaction is therefore required between PCPs and specialists (i.e. gastroenterologists, hepatologists, and internists) who have a fundamental role as consultants and guides for specific treatments, i.e. in the case of complications and the management of patients approaching liver transplantation.

This article is based on a PubMed search to provide an updated view for comprehensive management of several aspects of liver cirrhosis in different settings.

DATA SOURCES

Full papers were searched on Medline (http://www.ncbi.nlm.nih.gov/PubMed) for guidelines, randomized controlled trials (RCTs), and authored review articles published in English-language journals in the past 25 years. The following MESH headings were used: “ascites”, “liver fibrosis”, “cirrhosis”, “chronic hepatitis”, “chronic liver disease”, “decompensated cirrhosis”, “hepatic encephalopathy”, “hypertransaminasemia”, “liver transplantation”, and “portal hypertension”. The reference list was updated as of November 2010. Authors independently assessed articles for relevance and study quality. For each section, evidence levels were scored as follows: (1) LEVEL I (at least one properly conducted RCT, systematic review, or meta-analysis); (2) LEVEL II (other comparison trials, non-randomized, cohort, case-control, or epidemiologic studies, and preferably more than one study); and (3) LEVEL III (expert opinion or consensus statements).

 APPROACH TO PATIENTS WITH LIVER CIRRHOSIS

The clinical presentation of liver cirrhosis is often asymptomatic until complications appear. The presence of liver cirrhosis should be suspected in any patient with chronic liver disease and abnormal aminotransferases and/or alkaline phosphatase. Chronic liver disease stigmata should be searched for, and include vascular spiders, palmar erythema, and muscle wasting. Also, a palpable left lobe of the liver, hepatomegaly and splenomegaly are suggestive for liver cirrhosis.

The diagnosis becomes much easier in the presence of signs of decompensation, namely jaundice, ascites, and asterixis. Additional laboratory tests include those exploring liver synthetic function, such as serum albumin and prothrombin time, while serum bilirubin investigates the ability of the liver to conjugate and excrete bilirubin. A low platelet count is suggestive of portal hypertension and hypersplenism. An AST/ALT ratio above 1 is indicative of liver cirrhosis, but its absence does not exclude cirrhosis (i.e. low specificity).

The imaging studies include abdominal ultrasound, CT scan or magnetic resonance and might reveal a nodular liver and splenomegaly. The differential diagnosis of advanced chronic hepatitis relies on liver biopsy, which is still the gold standard for end-stage chronic liver disease. Percutaneous liver biopsy is not necessary in the presence of decompensated cirrhosis or when imaging studies have confirmed the presence of cirrhosis. Thus, liver biopsy is reserved for selected patients and can also be performed in out clinic settings.

Histology provides information on etiology, disease stage and grade of inflammation. Although the ultimate decision is not currently taken by PCPs, they should repeatedly check the patient with blood tests before referral for liver biopsy (at least two times and at least 2-3 mo apart). If abnormalities persist in spite of second step analyses and a liver ultrasonography has been inconclusive, the decision to perform a liver biopsy must be taken on an individual basis and rely on the patient’s age and general health status, as well as the need for prognostic information (LEVEL III).

According to the American Association for the Study of Liver Disease (AASLD), liver biopsy has a major role in diagnosis, assessment of prognosis, assistance in therapeutic decisions, and reinforcement of the patient’s compliance (LEVEL II). Biopsy, however, is a costly procedure which is not free of potential side effects and risks, and is often refused by the patient. A French survey, which interviewed over one thousand PCPs, concluded that liver biopsy may be refused by up to 59% of patients with chronic hepatitis C and that 22% of PCPs share a similar concern.

Novel non-invasive methods might provide preliminary information with good diagnostic accuracy for further selection of patients at risk for progressive liver disease. For example, tests might help to evaluate the presence and extent of liver fibrosis, and to differentiate cirrhosis from chronic hepatitis (positive predictive values exceed 85%-90%). Such policy may be helpful in the primary care setting. Transient elastography (FibroScan®), for example, assesses liver stiffness, with some limitations in the case of morbid obesity, small intercostals spaces, and ascites.

Ongoing liver fibrosis is also predicted by using specific algorithms of surrogate serum markers or by the application of standardized procedures (e.g. APRI: the aspartate transaminase to platelets ratio index; FibroTest: haptoglobin, α2-macroglobulin, apolipoprotein A1, γGT, bilirubin: Hepascore: bilirubin, γGT, hyaluronic acid, α2-macroglobulin, age, gender; BARD: Body mass index (BMI), AST/ALT ratio, diabetes). A novel technique based upon ultrasound-based elastography (Fibroscan, Echosens, Paris, France) can assess mean hepatic tissue stiffness[11]. Results are expressed in kilopascals (kPa) and the harder or stiffer the tissue, the faster a shear wave propagates, as a marker of hepatic fibrosis. Similar results have been reported with magnetic resonance elastography (MRE). Likely, the combination of elastography with one of these indices will also help specialists to better select patients suitable for liver biopsy.

Life expectancy and quality of life in patients with advanced cirrhosis remains poor, despite diagnostic advancement. Patients experience fatigue, pruritus, ascites, bleeding and encephalopathy. Dyspepsia and malnutrition are common. Whereas liver transplantation has changed life expectation for a number of patients, many transplantable patients still die due to long waiting lists. Targeted therapy is crucial in slowing or even halting disease progression and to provide standard medical care. PCPs should identify and address alcohol abusers early, while conditions like nonalcoholic steatohepatitis (NASH), B and C hepatitis, autoimmune disorders, and hemochromatosis should be appropriately counseled and treated. Attention should be given to active immunization, nutrition, and general healthcare.

MANAGEMENT OF PERSISTENT ASYMPTOMATIC ELEVATION OF SERUM TRANSAMINASES

Measurement of serum ALT is part of standard laboratory tests in asymptomatic outpatients, and is a sensitive screening tool for chronic liver disease[13]. Between one and four percent of asymptomatic subjects may have elevated ALT (LEVEL III)[7,14,15]. In a recent survey in the Mediterranean area, the most likely cause of elevated serum ALT was an excessive alcohol intake (45.6%), nonalcoholic fatty liver disease (NAFLD) (24%), and HCV infection (18.6%).

Over 20% of subjects with elevated ALT show signs suggestive of relevant chronic liver disease. PCPs are required to carefully investigate most common causes of elevated ALT and for early identification of treatable chronic liver diseases. Patient histories should focus on the use of medications, herbal extracts, and alcohol consumption. The presence of diabetes and thyroid disease (hypothyroidism) must be considered.

The problem, however, may be underestimated as about 38% of patients with occasional ALT elevation show normal values at next measurement[16]. Despite the very high number of subjects showing such liver test abnormality in family practice, only a few will need referral, i.e. those patients with doubtful diagnosis after initial evaluation and patients with established diagnosis requiring therapy (LEVEL III).

THE IMPORTANCE OF IDENTIFYING ETIOLOGY

 The identification of the cause underlying liver cirrhosis is essential in starting preventive measures and designing specific intervention (LEVELI).