**4. Natural history and clinical presentation**

Hepatitis C is a heterogeneous disease with considerable morbidity and mortality rates. More than 80% of infected individuals develop chronic infection; the remaining 10-20% develop spontaneous clearance with natural immunity. The acute infection has an incubation period of 7 weeks (range, 4-20 weeks) and is symptomatic in only 20% of patients and rarely severely icteric. Serum aminotransferase levels generally increase to more than 10 times the normal range and go back to normal once the disease symptoms resolve themselves. HCV antibodies usually develop at the time of onset of symptoms. HCV RNA appears even earlier, during the incubation period, with an increase in titer at the time of the manifestation of symptoms, and then disappears once the disease disappears. Once acute HCV infection has established itself, around 85% of patients develop chronic infection, which is generally asymptomatic. In these patients, HCV RNA remains present and in approximately 75% of patients, alanine amino‐ transferases (ALT), and aspartate aminotransferases (AST) remain elevated at more than 1.5 times the upper normal limit. The course of chronic hepatitis C is variable, with vague, intermittent, and nonspecific symptoms of chronic fatigue and malaise, which usually present in less than 20% of patients. Extrahepatic manifestations of HCV, including glomerulonephritis and cryoglobulinemia, can develop in a small percentage of patients. The development of progressive liver injury, fibrosis, and cirrhosis can occur in 20% to 30% of chronically infected patients over a period of 20-30 years. In patients presenting with chronic hepatitis C, fibrosis progression is extremely variable over time and can be partially predicted based on the age of the patient at infection, disease duration, liver histologic activity and stage of fibrosis, and ALT profile. However, it is often difficult to predict clinical outcomes in individual cases. In patients who have developed cirrhosis, the 5-year risk of decompensation is between 15% and 20% and that of hepatocellular carcinoma around 10%. The relationship between virus load, HCV genotype, quasi-species variability, and progression of liver disease is controversial. Acquired infection after age 40 years, being male, excessive alcohol consumption, hepatitis B virus (HBV) or HIV coinfection, steatosis, and immunosuppressed state have all been identified as cofactors associated with progression of fibrosis and development of cirrhosis. Once cirrhosis develops, symptoms are more common, and the signs of end-stage liver disease can appear, manifesting themselves as jaundice, weakness, wasting, and gastrointestinal bleeding. The incidence of developing hepatocellular carcinoma is 2-5% per year in patients with hepatitis C-related cirrhosis. Thus, this important liver disease has protean manifestations but is often insidious and can often lead to end-stage liver disease that needs liver transplantation, despite the presence of few overt symptoms and signs of illness [16-20].

#### **5. Risk factors**

The risk factors for the transmission of HCV infection vary substantially between countries and geographic regions. HCV is spread primarily by contact with blood and blood products. With the introduction in 1991 of routine blood screening for HCV antibodies and improve‐ ments in the test in mid-1992, transfusion-related hepatitis C has virtually disappeared. Illicit use of injectable drugs is currently the main source of HCV infections in most developed countries (e.g., Western Europe, US) and is becoming a major source of infection in transitional economy and developing countries, accounting for 40% or more of those infected. Of the estimated 16 million people in 148 countries who actively inject drugs, 10 million are infected with HCV [2,21,22]. In developing and transitional economy countries, the nosocomial transmission of new HCV infections is a major problem because of the reuse of contaminated or inadequately sterilized syringes and needles used in medical, paramedical, and dental procedures, with an estimated 2.3-4.7 million new infections occurring each year [2,23-25]. In patients on chronic hemodialysis, overall, the current prevalence of HCV is below 5% in most of Northern Europe, around 10% in most of Southern Europe and the US, but between 10% and 50% and up to 70% in many parts of the developing world, including many Asian, Latin American, and North African countries. It is important to emphasize that the prevalence of HCV is highly variable from unit to unit within the same country, with recent reports from some dialysis units in the US reporting a prevalence above 20% [26]. The risk of transmission of HCV from a mother to her child occurs in 4-8% of births to women with HCV infection and in 17-25% of births to women with HIV and HCV coinfection. The risk posed to the infant from breastfeeding is negligible, and nonsexual intrafamilial transmission is very rare [27,28]. The risk of heterosexual transmission is low, while recent data indicate that promiscuous male homosexual activity is related to HCV infection [29]. Folk medicine practices, including acupuncture and ritual scarification, as well as body piercing, tattooing, and commercial barbering are potential modes for transmission of HCV infection when performed without appropriate infection control measures [30,31].
