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Cirrhosis

Diagnosis

Clinical Signs and Symptoms

Clinical signs and symptoms of cirrhosis include (NIDDK 2014a; A.D.A.M. 2013):

  • Fatigue/weakness, loss of appetite, weight loss, nausea, abdominal pain, and pruritus (itching), which are common symptoms of cirrhosis, although not specific to cirrhosis
  • Splenomegaly, a palpably enlarged spleen, which can sometimes be felt on physical exam
  • Spider angioma (spider veins) are occasionally seen

The consequences (sequelae) of cirrhosis can also result in distinctive associated symptoms in individuals with advanced disease (Park 2013; NIDDK 2014a; Elwell 2003; Cavanaugh 1990; Yurci, Yucesoy 2011; Stillman 1990; Nayak 2012).

  • Abdominal distention due to the abdomen filling with ascitic fluid
  • Jaundice (Icterus), a yellowing of the skin and sclera (whites of eyes) can be seen in advanced stages of cirrhosis. This is due to the buildup of bilirubin, a yellow waste pigment from the normal breakdown of old red blood cells that is usually removed from the blood by the liver
  • Bruising or excessive bleeding from loss of coagulation (clotting) protein production
  • Melena, or dark stools resulting from digested blood in feces, and “coffee ground” emesis, which is vomiting of digested blood, may result from a combination of coagulopathy and disordered gastrointestinal hemodynamics proceeding from portal hypertension
  • Pale or clay-colored stools that result from lack of bile secretion
  • Altered mental state, including confusion, personality change, slowed or slurred speech, memory loss, trouble concentrating, and changes in sleep habits can result from hepatic encephalopathy
  • Asterixis (flapping tremors), intermittent involuntary muscle contractions, usually of the wrists and hips, can also be caused by hepatic encephalopathy
  • Lower extremity swelling/peripheral edema due to low albumin in the blood leading to abnormal fluid collection in tissues
  • Recurrent infections due to immune dysfunction
  • Dyspnea (difficulty breathing) from hepatopulmonary syndrome
  • Hypogonadism, a syndrome of low testosterone and libido, impotence, and shrinkage of the testes, may also cause gynecomastia (male breast enlargement)
  • Bone loss or fracture from metabolic bone disease

Testing

Several tests, both non-invasive and invasive, can aid in confirming a diagnosis of cirrhosis (Kim 2014).

Biochemical tests. Multiple markers of liver function can be measured from blood samples. Alanine transaminase (ALT or SGPT) and aspartate transaminase (AST or SGOT) are released by damaged or inflamed hepatocytes; gamma-glutamyl transferase (GGT) and bilirubin are indicators of cholestasis (failure of the liver to excrete bile). All four can become elevated during liver disease. Patients with cirrhosis also show increased alkaline phosphatase (ALP) activity. Several compounds synthesized by a healthy liver (haptoglobin, apolipoprotein-A1, albumin, alpha-2-macroglobulin) may fall with the onset of liver damage. Panels that test several markers concurrently (eg, Fibrotest, APRI, or the European Liver Fibrosis Panel) are widely validated and are good predictors of fibrosis and cirrhosis, but are insufficient for evaluating dynamic changes (Kim 2014; Ohkubo 1994).

Diagnostic imaging. Ultrasound (US) is an inexpensive, non-invasive imaging modality that constructs dynamic 2D images using high-frequency sound waves. It can be used to assess several liver parameters (eg, size, bluntness of edges, coarseness of liver tissue, presence of surface nodules) that may be consistent with hepatic fibrosis. Doppler ultrasound can additionally measure velocity of blood flow in the liver, and may detect changes in portal vein volume and velocity and arterial resistance in the liver, which may be evident in portal hypertension. Contrast-enhanced ultrasound is a more recent technique that involves the injection of “microbubbles” intravenously prior to imaging, which enhances the ultrasound signals and allows for more detailed measurements of blood flow. Computed tomography (CT) is a three-dimensional x-ray imaging technique for visualizing internal structures; magnetic resonance imaging (MRI) is an imaging technique that produces cross-sectional images using radio waves in powerful magnetic fields. Both are useful methods for visualizing advanced liver disease and are standard methods for diagnosing hepatocellular carcinoma in cirrhosis patients. Both are suitable for imaging the anatomical features of advanced cirrhosis (surface nodules, prominent fibrous bands, shrinkage of liver volume, and an enlarged portal venous system), but are not as useful for diagnosing early stages of cirrhosis where these features may be absent (Kim 2014).

Elastography. Elastography is a newer ultrasound-based method that measures liver stiffness as a marker for fibrosis, enabling diagnosis of liver fibrosis in earlier stages before obvious changes in liver architecture like surface nodules may be present (Adebajo 2012; Sirli 2012). Two newer technologies, transient elastography and acoustic radiation force impulse elastography, utilize different ultrasonic strategies to obtain stiffness measurements; both have similar sensitivity and specificity for the diagnoses of liver fibrosis and cirrhosis (Bota 2013; Sirli 2012).

Liver biopsy. Biopsy remains the gold standard for assessing liver fibrosis. It allows direct examination of inflammatory and architectural changes due to fibrosis, and allows staging of the liver disease, which may guide treatment. Biopsies are not without limitations, however, as they are invasive and have potential for complications. Because the biopsied sample is representative of only a very small fraction of liver tissue, biopsies are subject to sampling error (Kim 2014). Three biopsy approaches are used. Percutaneous biopsies use a hollow cutting needle inserted through skin and into the liver to take one or more samples. Laparoscopic biopsy is a minimally invasive surgical technique used to obtain samples from a specific area of the liver or to avoid disrupting a tumor or site of infection (NIDDK 2014b).

For patients with ascites or a clotting disorder, a transjugular biopsy may be taken; here the biopsy needle is threaded down the neck through the jugular vein into the liver, and samples are taken under x-ray guidance. Transjugular biopsy allows measurement of the hepatic venous pressure gradient, which is a good predictor of portal hypertension and thus of clinical prognosis. Because it is an accurate prognostic test but invasive and not widely available, attempts have been made to use ultrasound measurements of liver stiffness (such as elastography) as a proxy to estimate hepatic venous pressure gradient (Tsochatzis 2014).

Other diagnostic techniques. Other techniques may also be used in liver disease or related pathology:

  • Upper GI endoscopy. Direct visualization of dilated or ruptured blood vessels in the esophagus or stomach by a flexible camera (endoscope) is the gold standard for identifying varices, a common, serious complication of portal hypertension and cirrhosis (Berzigotti 2013).
  • Autoantibody testing. Anti-mitochondrial antibody (AMA) is found in the blood of 90-95% of patients with primary biliary cirrhosis, a condition that creates a chronic obstruction of bile ducts, which can lead to cirrhosis (Tanaka 2002).
  • Molecular analysis. Genomic analysis is available for inherited disorders of metabolism that increase cirrhosis risk. These include tests for Wilson’s disease (copper storage disease); HFE gene mutations, the most common cause of hereditary hemochromatosis (iron overload); alpha-1 antitrypsin deficiency; and cystic fibrosis (Santos 2012; Zarrilli 2013).
  • Ferritin and transferrin saturation (TSAT) testing. Both of these iron transport proteins are elevated in individuals with hereditary hemochromatosis, a risk factor for cirrhosis (Zarrilli 2013).

Prognostic Scores

Prognostic scoring combines laboratory and qualitative measurements of liver function to estimate the survival of a cirrhosis patient within a given time period (Durand 2008). Two systems are in use. An older system, the Child-Pugh (or Child-Turcotte-Pugh) score considers albumin and bilirubin levels, clotting (international normalized ratio; INR) time, and the degree of ascites and encephalopathy in its scoring system. The Child-Pugh score ranges from 5-15, with the lowest scores of 5-6 (class A) indicating a better rate of survival after one year (81%) than the highest scores of 10-15 (class C), which indicate a one-year survival rate of 45% (Huo 2006; Fox 2014). Child-Pugh has largely been replaced by the Model for End-Stage Liver Disease (MELD) score, as MELD is a more accurate predictor of survival (Lee 2013). It is derived from an equation that accounts for the biomarkers creatinine, bilirubin, and prothrombin time (international normalized ratio; INR). It is used to predict short-term (3-month) survival in patients with liver disease. MELD scores range from 6 to 40 on a continuous scale, with higher scores indicating greater risk of mortality within a three-month period (a MELD score of 40 indicates a 71.3% risk of mortality, while a score <9 indicates a 1.9% risk) (Wiesner 2003; Fox 2014). The MELD system is used in the United States for ranking patients for liver transplants (Durand 2005). Other permutations of the MELD score are also in use, including MELD-Na (which incorporates blood sodium levels into the MELD equation to prioritize patients with low blood sodium for transplants), MELDNa (which further refines MELD-Na), and DeltaMELD (which monitors MELD changes over time and is useful in predicting intermediate outcomes in patients with advanced cirrhosis) (Lee 2013).