Chapter 2 Ying-Ying Yang and Han-Chieh Lin Department of Medical Education, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan There is no single biomarker for liver cirrhosis, but its existence can be suggested by some laboratory abnormalities. We would initiate a series of biochemical investigations for patients in whom clinical symptoms of chronic liver disease are noted or the characteristics of liver cirrhosis are identified by physical examination. Liver function tests commonly includes tests to detect hepatic injury (aminotransferases, alkaline phosphatase, and gamma-glutamyl transpeptidase), tests assessing hepatic metabolism (serum bilirubin and ammonia), and tests assessing hepatic biosynthetic function (albumin and prothrombin time). In addition, the magnitude of the abnormalities in blood cell counts, serum biochemistries, and other tests may suggest the severity and etiology of liver cirrhosis. Table 2.1 Normal range of parameters that detect hepatic injury and metabolism. Female: 0.15–0.75 μkat/L Male: 0.15–1.1 μkat/L Female: 0.25–0.6 μkat/L Male: 0.25–0.75 μkat/L Female: 0–0.63 μkat/L Male: 0–0.92 μkat/L Female: <55 U/L Male: <90 U/L Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are hepatic enzymes that are involved in amino acid metabolism. However, high levels of AST are also found in the myocardium, kidneys, pancreas, skeletal muscle, red blood cells, and other tissues. In these circumstances, ALT is considered to be a specific and cost-effective screening test for hepatic injury but this test has limits when predicting the degree of hepatic inflammation and the severity of liver fibrosis [1,2]. ALT mainly exists in the cytosol of hepatocytes, whereas AST is mainly found in the mitochondria. Both of them are released into the bloodstream when hepatocytes are injured or die. However, normal aminotransferase levels do not preclude a diagnosis of liver cirrhosis [3]. Several studies have investigated AST : ALT ratios to correlate these with the severity of hepatic fibrosis. The ratio is about 0.8 in a healthy subject. In patients with alcoholic hepatitis, the AST : ALT ratio is often greater than 2 [4], whereas patients with most forms of nonalcoholic hepatitis have a ratio of less than 1. However, as the chronic hepatitis progresses to cirrhosis, the ratio of AST : ALT may reverse, with a ratio greater than 1 having a specificity of more than 80% for liver cirrhosis and a sensitivity that varies from 32% to 83% [5–8]. This suggests that we need to check for the presence of cirrhosis in patients with nonalcoholic liver disease when the AST : ALT ratio rises above 1. Bonacini et al. [9] concluded that the modified three-parameter cirrhosis discriminate score (CDS), which is derived from three laboratory parameters –platelet count, AST : ALT ratio, and prothrombin time (PT) – has a high likelihood of detecting liver cirrhosis, with a sensitivity of 46% and a specificity of 98% when the value is 8 or above (possible total score 0∼11) [6,10]. Nevertheless, two other studies have failed to confirm the predictive value of the AST : ALT ratio for liver cirrhosis [11,12]. Therefore, the clinical utility of this ratio needs further investigation and its usefulness still remains uncertain for the diagnosis of liver cirrhosis. Alkaline phosphatase (ALK-P) is present in the bile canaliculi membrane of hepatocytes. It is often mildly elevated, but less than the two or three times the upper normal limit seen in liver cirrhosis. In patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), the serum level of ALK-P is higher than patients with other etiologies of liver cirrhosis. However, ALK-P is not only present in the hepatobiliary system, but also in the intestine, bone, kidneys, and placenta. Thus, ALK-P is likely to be less specific for liver disease. Although gamma-glutamyl transpeptidase (GGT) is also present in many other tissues, such as pancreas, kidneys, heart, and lung, it is considered to be more closely correlated to liver disease [13]. In patients with alcoholic hepatitis or alcoholic liver cirrhosis, the serum level of GGT will be much higher than those having liver cirrhosis due to other etiologies. Serum bilirubin levels may be normal in patients with well-compensated liver cirrhosis. It becomes raised later than ALK-P and GGT as the severity of liver cirrhosis progresses. The hyperbilirubinemia in decompensated liver cirrhosis is related to persist cholestasis, hepatocellular dysfunction, and decreased renal excretory function. As one of the parameters in Child–Pugh–Turcotte score, the serum total bilirubin level is also an important predictor of survival in cirrhotic patients. In particular, in patients with PBC, an elevated serum bilirubin level suggests a poor prognosis [14]. Ammonia is produced by enterocytes from glutamine and by colonic bacterial catabolism of nitrogenous sources, such as ingested protein and secreted urea. The intact liver will convert nearly all ammonia to urea or glutamine via the urea cycle. Elevation of blood ammonia is a common feature in patients with liver cirrhosis. Hepatic dysfunction, shunting of blood around the liver, and muscle wasting, is a common characteristic of these patients and decreases the extrahepatic removal of ammonia. Patients with hepatic encephalopathy often have hyperammonemia. Treatments that lower plasma ammonia will improve the clinical status of encephalopathy. However, cerebral ammonia metabolism is not the only causal factor that is related to the development of hepatic encephalopathy [15]. Blood ammonia is not required to make a diagnosis of hepatic encephalopathy and neither does it indicate during long-term follow-up. Furthermore, there are many nonhepatic conditions, such as infection or intestinal bleeding, that can elevate a patient’s blood ammonia level. It is important to be aware of these possible precipitating factors when treating hepatic encephalopathy in cirrhotic patients. These two dye tests have been used to quantify the excretory capacity of the liver. They assess reserved hepatic function during advanced liver disease, particularly among patients who will undergo resection of the liver. The bromsulphalein (BSP) test is seldom performed now because of the possibility of an anaphylactic reaction. The indocyanine green (ICG) test is able to provide a good prediction of hepatic blood flow in healthy adults, but gives low readings in patients with liver cirrhosis, who show a marked decrease in extraction of ICG [16]. Table 2.2 Normal range of parameters that detect hepatic biosynthetic function, coagulating factors, cell counts and others. Male: 2.02–2.79 mmol/L Female: 1.86–2.48 mmol/L Albumin is exclusively synthesized in the liver with approximately 15 g produced per day (200 mg/kg of body weight per day). Hypoalbuminemia that is a consequence of decreased production often reflects severe liver damage, such as liver cirrhosis [17]. Thus, a lower serum albumin level is indicative of more severe liver cirrhosis. As one of the parameters in the Child–Pugh score, just like bilirubin, the serum albumin level also suggests the survival probability in patients with liver cirrhosis. However, cirrhotic patients with massive ascites may have hypoalbuminemia but still have adequate hepatic synthetic function because of hypervolemic dilution via a remarkable increase in plasma volume [18]. On the other hand, hypoalbuminemia is not specific for liver disease; it could be caused by nephrotic syndrome, protein losing enteropathy, malnutrition, congestive heart failure, severe sepsis, and various other diseases. Therefore it is necessary to exclude these nonhepatic etiologies before evaluating the severity or prognosis of liver cirrhosis using the patient’s serum albumin level. Liver synthesizes most of the blood coagulating proteins. These include eight coagulating factors, factor I (fibrinogen), factor II (prothrombin), factor V, factor VII, factor IX, factor X, factor XII, and factor XIII, as well as three anti-thrombotic agents, anti-thrombin III, protein C, and protein S. Among them, synthesis of factors II, VII, IX, and X is dependent on the presence of vitamin K. The reduced ability of a cirrhotic liver to synthesize these coagulating factors will result in a longer PT. However, a prolonged PT is not specific for liver disease only. It also may be caused by increased consumption of coagulating factors (such as disseminated intravascular coagulation, severe sepsis, or severe bleeding), congenital or acquired coagulopathy, and side effects of certain drugs (e.g., flomoxef, cefmetazole). After excluding these conditions, there are two common causes of prolonged PT: vitamin K deficiency and severe liver dysfunction such as liver cirrhosis. The vitamin K deficiency-related PT prolongation is caused by malnutrition, prolonged obstructive jaundice, and so on, and can be normalized within 24 hours after a single parenteral administration of vitamin K. This typically good response of vitamin K deficiency-related PT prolongation could help us differentiate that from severe hepatic dysfunction-related PT prolongation. Severe hepatic dysfunction-related PT prolongation arises from poor utility of vitamin K and cannot be corrected by exogenous vitamin K administration. The PT can help to predict survival probability in patients with liver cirrhosis when used as a parameter of Child–Pugh score and model for end-stage liver disease (MELD) score. In patients with fulminant hepatic failure, a PT of more than 100 seconds indicates high priority for a liver transplantation [19]. Croquet et al. [19] have found that the PT is well correlated with histologic liver fibrosis score and has a high diagnostic accuracy for severe fibrosis or cirrhosis, especially in alcoholic liver cirrhosis. Nevertheless, the PT cannot completely represent the whole picture of the coagulating status of the patient with liver cirrhosis [21]. The occurrence of bleeding will be inferred by the decreased levels of protein C, protein S, and anti-thrombin III, which favors thrombosis and a possibly superimposed infection or other conditions [22]. The international normalized ratio (INR) is adopted in the MELD score, which is used to prioritize patients in the waiting list for liver transplant [23]. Utilization of INR in patients with liver disease has the shortcoming that it will vary wildly because of the different types of thromboplastin used in this test [24,25]. Subsequently, it will influence the MELD score. As a result, several studies have tried to develop a standard form, such as “INR liver” to avoid this kind of variation [24]. However, it is still uncertain whether the widely implementation of the INR liver for the calculation of the MELD score is essential for all cirrhotic patients [25].
Diagnostic Laboratory Tests
Introduction
Tests that Detects Hepatic Injury (Table 2.1)
Hepatic injury
Hepatic metabolism
Parameter
Normal range
Parameter
Normal range
SI units
Usual units
SI units
Usual units
Serum ALT
3–55 U/L
Serum bilirubin
1.7–17 μmol/L
0.1–1 mg/dL
Serum AST
12–48 U/L
Serum amonia
17–60 μg/dL
10–35 μmol/L
Serum ALK-P
0.6–1.8 μkat/L
80–280 U/L
ICG test
Retention at 15 min <8% (3.5–10.6%)
Serum GGT
BSP test
Retention at 45 min <3.5%
ALK-P, alkaline phosphate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BSP, bromsulphalein; GGT, gamma-glutamyl transferpeptidase; ICG, indocyanine green.
Serum Aminotransferases
Serum Biliary Enzymes
Tests of Hepatic Metabolism (Table 2.1)
Serum Bilirubin
Serum Ammonia
Indocyanine Green and Bromsulphalein Tests
Tests of Hepatic Biosynthetic Function (Table 2.2)
Serum Albumin
Hepatic biosynthetic function
Cell counts and others
Parameter
Normal range in SI units
Parameter
Normal range in SI units
Serum albumin
3.5–5.0 g/dL (usual units: 540–740 μmol/L)
Serum platelet count
15–45 × 1010/L
Serum PT
8.3–10.8 seconds, INR: 0.9–1.2
Serum WBC count
4500–11 000 × 106/L
Serum factor VIII
50–200% of normal (control sample) activity
Serum hemoglobin
Serum factor V
70–130% of normal (control sample) activity
Serum globulin levels
23–35 g/L
Serum factor VII
60–140% of normal (control sample) activity
Serum sodium concentration
135–145 mmol/L
INR, international normalized ratio; PT, prothrombin time; WBC, white blood cells.
Prothrombin Time and International Normalized Ratio
Individual Serum Coagulating Factor Levels
Factor VIII
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