Evaluating Tests for Cirrhosis Diagnosis

 Introduction

Morbidity and mortality from liver cirrhosis are increasing worldwide. The diagnosis of cirrhosis is important to guide treatment, determine prognosis, and monitor complications in patients with chronic liver disease. The identification of cirrhosis is important for the prescription of medications, since its presence will alter the pharmacokinetics of some drugs.

Regardless of the cause of liver disease, cirrhosis is the result of liver injury that causes inflammation and fibrogenesis. It causes distortion of the liver architecture, with micro and macroscopic nodularity, which leads to portal hypertension. Cirrhosis leaves patients vulnerable to life-threatening complications, including variceal bleeding, ascites, infection and hepatocellular carcinoma, and ultimately death .

Clinical features of cirrhosis

Most chronic liver diseases are asymptomatic until decompensated cirrhosis develops. Therefore, the diagnosis of early cirrhosis requires a clinical suspicion of liver disease. Patients at risk for cirrhosis include those with a history of:

• Chronic alcohol abuse
• Obesity or other features of metabolic syndrome
• Migration from countries with high endemic rates of chronic hepatitis B
• Risk factors for chronic hepatitis C, such as history of intravenous drug use
• Hemochromatosis.

The clinical symptoms of people with early or compensated cirrhosis are usually nonspecific and include anorexia, weight loss, and fatigue. Patients with decompensated cirrhosis may present with jaundice, confusion, abdominal distention, or easy bruising.

Key findings on the physical examination of a patient with chronic liver disease include sarcopenia, spider angiomas, a firm liver edge, splenomegaly, palmar erythema, and parotid enlargement. Signs of decompensated cirrhosis are more obvious, such as ascites, jaundice, and liver flap.

Testing Approach

The gold standard test for diagnosing cirrhosis has been liver biopsy ; However, due to its invasiveness, rare but serious complications, and cost, it is now used less frequently. Nowadays, careful clinical evaluation, biochemical markers, and imaging can provide a reliable evaluation of a patient with cirrhosis.

Biochemical markers

The term ’liver function tests’ is commonly used to group biochemical parameters:

• Aspartate aminotransferase (AST)
• Alanine aminotransferase (ALT)
• Gamma-glutamyl transferase
• Alkaline phosphatase

There may be an excessive focus on these tests when investigating the presence of liver disease. While alterations in liver function tests can provide clues to the etiology of chronic liver disease, synthetic function is more specific in detecting the presence and severity of cirrhosis.

• Aminotransferases (AST and ALT) may be moderately elevated in chronic liver disease, but are often normal in advanced cirrhosis. Typically, ALT is higher than AST, but if alcohol is the primary contributor to cirrhosis, this ratio can be reversed with an AST concentration that is twice that of ALT.
   
• Alkaline phosphatase is usually elevated in cirrhosis. Higher concentrations are seen in patients with cirrhosis secondary to cholestatic disease, such as primary sclerosing cholangitis and primary biliary cholangitis.
   
• Gamma -glutamyl transferase is also increased in cholestatic liver disease, but is less specific. The most significant confounding factor is alcoholic liver disease (recent or chronic alcohol intake) which can significantly increase the concentration.

Biochemical evaluation of hepatic synthetic function is a valuable tool in detecting cirrhosis in a patient. Markers of hepatic synthetic function include serum albumin and coagulation studies .

• Albumin concentration falls as cirrhosis progresses. However, it can be reduced in inflammatory states, malnutrition, protein-losing enteropathy or heart failure.
   
• Prothrombin time and INR are elevated due to impaired hepatic synthetic function. This explains the presence of coagulopathy in established liver disease.
   
• Although serum bilirubin may be normal in compensated cirrhosis, an increasing concentration correlates with disease progression.

Hematological markers

A sensitive marker of cirrhosis is thrombocytopenia . This is secondary to splenic sequestration and congestive splenomegaly resulting from portal hypertension. A platelet count of less than 150 x 10 9 /L is usually the first marker of cirrhosis, but other cytopenias emerge as the disease progresses.

Fibrosis tests

There are several tests that combine serum and clinical parameters to predict the presence of cirrhosis. Indirect tests of serum fibrosis include the AST:ALT ratio, the AST to platelet ratio index (APRI score), and, in nonalcoholic fatty liver disease (NAFLD), the FIB-4 and NAFLD fibrosis score. The normal AST:ALT ratio is less than 1, so a score greater than 1 suggests advanced fibrosis or cirrhosis.

The APRI score is validated in chronic viral hepatitis. An APRI score greater than 1 has a sensitivity of 76% and a specificity of 72% for predicting cirrhosis.

The FIB-4 is a composite of age, AST, and platelet count, while the NAFLD fibrosis score is a composite of age, body mass index, presence or absence of diabetes, serum aminotransferase concentrations, platelet count, and albumin. serum. These scores are useful to rule out the presence of advanced fibrosis with negative predictive values ​​greater than 90%.

Proprietary tests for fibrosis include Fibrotest , the Enhanced Liver Fibrosis Score (ELF), Fibrospect II and Hepascore, which was developed in Western Australia. 1 These composite scores use a variety of clinical parameters and specialized serum markers, some of which are only available in tertiary referral centers.

Ultrasound

Abdominal ultrasound is generally the first imaging modality recommended when liver disease is suspected. It is widely available, low cost, and has good sensitivity in excluding biliary obstruction. Features suggestive of cirrhosis on ultrasound include a nodular liver edge, splenomegaly, portal vein dilation, and umbilical vein recanalization. Limitations include missing mild hepatic steatosis (<2.5 to 20%).

Elastography

Elastography is a relatively new imaging modality, but now widely used to non-invasively estimate liver stiffness . Increased liver stiffness correlates with more advanced fibrosis. Elastography does not determine the cause of cirrhosis, but by measuring the speed of propagation of mechanical waves through the liver parenchyma, it can give a measure of the stiffness of the liver. Elastography is available alongside ultrasound evaluation in many radiology practices or as FibroScan in most tertiary referral centers.

There are two different types of elastography techniques, based on ultrasound or magnetic resonance imaging .

• Ultrasound generates transverse waves that travel through liver tissue at a speed determined by the stiffness of the tissue . The faster the speed, the greater the stiffness of the liver.
   
• In MRI elastography , mechanical vibration produces waves in the liver that become a stiffness map of the tissue. This technique is not yet widely available due to its cost.

Transient elastography , known by its trade name FibroScan (Echosens), is the most widely used form of elastography. It is a one-dimensional form of shear wave elastography that measures stiffness in kilopascals (kPa). Results range from 2.5 to 75 kPa, with a normal value of approximately 5 kPa. Cutoffs for fibrosis severity (F0-F4) vary depending on the etiology of the liver disease and are best validated in chronic viral hepatitis. In stage 2 or 3 fibrosis, the stiffness is 7 to 11 kPa and in stage 4 fibrosis (cirrhosis) it is more than 11 to 14 kPa. Limitations of FibroScan include its low reliability in patients with obesity, ascites, and artificially elevated stiffness due to severe liver inflammation or steatosis .

Liver biopsy

Liver biopsy is rarely needed for the diagnosis of cirrhosis, but still has a role in definitively diagnosing the underlying cause of liver disease. It is performed percutaneously with ultrasound guidance after verifying that there is no significant coagulopathy .

A transjugular liver biopsy performed at a tertiary referral center is safer in patients with a higher risk of hemorrhage. It also allows measurement of hepatic vein pressure gradient , which is the most accurate measure of portal hypertension, but is primarily used in research rather than clinical practice.

Surveillance

Once the diagnosis of cirrhosis is made, it is important to monitor for deterioration in liver function or complications. This includes referral to a gastroenterologist to consider gastroscopy to look for esophageal varices . These develop as a complication of portal hypertension and are an important cause of mortality in patients with cirrhosis. Preventive treatment of varicose veins with a nonselective beta-blocker or band ligation reduces the risk of hemorrhage and morbidity.

Patients with cirrhosis should be monitored for hepatocellular carcinoma . The guidelines recommend a biannual abdominal ultrasound to detect the presence of a new liver lesion and urgent referral to a hepatologist if hepatocellular carcinoma is suspected. Measuring alpha-fetoprotein as a screening test is no longer recommended . Hepatocellular carcinoma is often asymptomatic until very advanced, so surveillance allows for earlier diagnosis, better treatment options, and improved survival.

Referral to specialist

Referral to a hepatologist should be considered for evaluation of all patients with liver cirrhosis, when the diagnosis of chronic liver disease is uncertain, and for management of complications. Patients with early or well-compensated cirrhosis have a good prognosis , particularly if the underlying liver disease is controlled by treatment of chronic hepatitis B or C or lifestyle modification, such as stopping alcohol. Early intervention can stabilize disease progression and help prevent or delay hepatic decompensation.