**7. Assessment of liver disease severity**

Acute HCV infections are often oligo- or asymptomatic. The long incubation period makes difficult to link related cases to the source of infection, and despite the high prevalence of disease, most infected people are unaware of their infection. The long-term impact of HCV infection is highly variable, ranging from minimal histological changes to extensive fibrosis and cirrhosis with or without HCC [31]. Spontaneous clearance in the chronic phase of the infection is rare and occurs only in 15–25% of cases. In 70–80% of infected patients, the virus persists and the infection becomes chronic. In most patients, CHC leads to different degrees of liver fibrosis, and one third (15–25%) of them could develop liver cirrhosis and HCC at a rate of 2–4% after 10 to 40 years (Figure 1) [10,18]. The progression of liver disease occurs over decades and is accelerated by alcohol consumption, diabetes/obesity, coinfections (human immunodeficiency virus [HIV] and hepatitis B virus), old age at the time of infection, cumu‐ lative exposure to hepatotropic viruses, and environmental hepatotoxins [32,33]. The extra‐ hepatic manifestations of HCV infection include cryoglobulinemia, membranous glomerulonephritis, and some non-Hodgkin lymphomas [34]. In Europe, about 1/4 of HIVinfected patients have an HCV coinfection. Patients coinfected with HIV/HCV have a higher risk of cirrhosis and AIDS and a higher overall mortality [35]. Thanks to the growing knowl‐ edge on the pathophysiology of the disease, the development of diagnostic procedures, and the improvements in therapy and prevention, the clinical care for patients with HCV-related

**Figure 1.** Natural history of HCV infection. In patients with HCV infection, the spontaneous clearance after the acute phase occurs only in 15–25% of cases; during the chronic phase, extrahepatic manifestations might occur. For patients who progress to decompensated cirrhosis, the survival rate at 5 years is about 50%, and among them, 2–4% per year

Since many infected people are unknown to health care systems due to the asymptomatic nature of the disease, the management of HCV infection should focus not only on therapy but

liver disease has considerably advanced during the last years.

develop hepatocellular carcinoma

**6. Screening and diagnosis**

28 Recent Advances in Liver Diseases and Surgery

Due to the particularly high cost of the new DAAs, in the last 3 years, the access to treatment has been restricted and strictly regulated. For this reason, the decision regarding treatment initiation with DAAs mainly focus on the assessment of liver disease severity. In particular, individuals at more advanced stages and with compensated cirrhosis benefit more than people with less advanced cirrhosis since they are at higher dying risk.

Well-established panels of direct and indirect biomarkers have been studied for the assessment of fibrosis progression and for the diagnosis of cirrhosis. Indirect biomarkers reflect liver function while direct biomarkers reflect extracellular matrix turnover and include many molecules involved in hepatic fibrogenesis. The most commonly used indirect serum bio‐ markers comprise the following: (i) the AST platelet ratio index [APRI = (AST/upper limit of normal)× 100/platelet count] that was extensively validated in chronic HCV; (ii) Fibrotest, a patented biomarker panel using five biochemical markers and two clinical parameters, which was validated in several etiologies of cirrhosis and in the monitoring of fibrosis progression; and (iii) FIB4, a biomarker panel using age, AST, platelet count, and ALT [FIB4 = (age× AST) / (platelets × √ALT)], originally developed and validated in a cohort of HIV/HCV-coinfected patients [40]. The blood tests needed for calculating APRI and FIB4 scores are inexpensive and are available at the health facilities that provide treatment for HCV infection since they are also used to monitor patients before and after the commencement of treatment [18,26]. Liver biopsy remains the reference method for grading the activity and histological progression (staging) of the disease [30,31,41]. However, because of its invasiveness, patient discomfort, risk of complications, as well as the need for expert histological interpretation, transient ultrasound elastography (Fibroscan) is now used to assess liver disease severity prior to therapy at a safe level of predictability [42,43]. Fibroscan is a noninvasive method of measuring the mean stiffness of hepatic tissue, with hepatic rigidity considered a marker of progressive fibrosis. There are different scoring systems for assessing the severity of chronic liver disease. The major approach to classify CHC involves three separate considerations: (1) the etiology, which is determined on the basis of histological appearance and laboratory tests; (2) the severity and distribution of necroinflammatory activity; and (3) the degree of fibrosis [44]. The most common scoring methods to interpret a liver biopsy include the Metavir, the histologic activity index (HAI), also known as Knodell score, and the modified hepatic activity index (Ishak-modified Knodell score) [45].

Metavir is a scoring system used to assess inflammation and fibrosis by histopathological evaluation of a liver biopsy of patients with HCV. The scoring from A0 to A3 represents a grading system that gives an indication on the activity and degree of inflammation. The amount of inflammation is relevant since it is considered a precursor of fibrosis (Table 2). Metavir also includes a staging system that indicates the amount of fibrosis or scarring [46].

The Knodell score is a semiquantitative and reproducible histological scoring of liver biopsies, also commonly used for staging liver disease, that includes three categories of necroinflam‐ matory activity: periportal injury with or without bridging necrosis, lobular injury, and portal inflammation. Lesions are assigned weighted numeric values that resulted in a combined score, the hepatic activity index (HAI) [47].

In the last years, the Knodell score has been partially replaced by the Ishak score, in which the major changes concern the modification of the HAI and the further division of necroinflam‐ matory assessment in four categories [45].


**Table 2.** Metavir liver biopsy scoring system
