Fegato Flashcards
What is the virology of hepatitis A virus (HAV)?
What is the most common means of transmission of hepatitis A virus (HAV)?
What is the incubation period of hepatitis A virus (HAV)?
One of the more common causes of acute hepatitis is hepatitis A virus (HAV), which was isolated by Purcell in 1973. Humans appear to be the only reservoir for this virus. Since the application of accurate serologic tests in the 1980s, the epidemiology, clinical manifestations, and natural history of hepatitis A have become apparent.
HAV is a single-stranded, positive-sense, linear RNA enterovirus of the Picornaviridae family. In humans, viral replication depends on hepatocyte uptake and synthesis, and assembly occurs exclusively in the liver cells. Virus acquisition results almost exclusively from ingestion (eg, fecal-oral transmission), although isolated cases of parenteral transmission have been reported.
HAV is an icosahedral nonenveloped virus, measuring approximately 28 nm in diameter (see the image below). Its resilience is demonstrated by its resistance to denaturation by ether, acid (pH 3.0), drying, and temperatures as high as 56°C and as low as -20°C. The hepatitis A virus can remain viable for many years. Boiling water is an effective means of destroying it. Chlorine and iodine are similarly effective.
The incubation period usually lasts 2-6 weeks, and the time to the onset of symptoms may be dose related. The presence of disease manifestations and the severity of symptoms after HAV infection directly correlate with the patient’s age. In developing nations, the age of acquisition is before age 2 years. In Western societies, acquisition is most frequent in persons aged 5-17 years. Within this age range, the illness is more often mild or subclinical; however, severe disease, including fulminant hepatic failure, does occur.
What are the risk factors for the acquisition of hepatitis A?
Most patients have no defined risk factors for hepatitis A. Risk factors for the acquisition of hepatitis A include the following:
Personal contacts
Institutionalization
Occupation (eg, daycare)
Foreign travel
Male homosexuality
Illicit parenteral drug use
HAV has a worldwide distribution, [6, 7] particularly in resource-poor regions. [8, 9] The highest seropositivity (ie, the highest prevalence of antibody to HAV) is observed in adults in urban Africa, Asia, and South America, where evidence of past infection is nearly universal. [10, 11, 12, 13, 14]
Acquisition in early childhood is the norm in these nations and is usually asymptomatic. Factors predisposing humans to early acquisition include overcrowding,
What is the prognosis of hepatitis A virus (HAV) infection?
In general, the prognosis is excellent. Long-term immunity accompanies HAV infection. Recurrence and chronic hepatitis do not usually occur. Typically, there are no lasting sequelae.
Death is rare, though it is more frequent in elderly patients and in those with underlying liver disease. Annually, an estimated 100 people die in the United States as a result of acute liver failure due to HAV infection. Although the case-fatalities from fulminant HAV infection have been reported in all age groups, where overall the mortality is estimated at approximately 0.3%, the rate is 1.8% among adults older than 50 years and is also higher in persons with chronic liver diseases.
What should be included in the history of patients with suspected hepatitis A virus (HAV) infection?
What are the early symptoms of hepatitis A virus (HAV) infection?
How is the icteric phase of hepatitis A virus (HAV) infection characterized?
How is relapsing hepatitis A virus (HAV) infection characterized?
What is the focus of the physical exam in patients with suspected hepatitis A virus (HAV) infection?
What are the typical physical findings in patients with suspected hepatitis A virus (HAV) infection?
Along with outlining the presenting complaint and its severity and sequelae, the history should also initiate a search for the source of exposure (eg, overseas travel, lack of immunization, intravenous [IV] drug use) and attempt to exclude other possible causes of acute hepatitis (eg, accidental acetaminophen overdose). The incubation period is 2-6 weeks (mean, 4 wk). Shorter incubation periods may result from higher total dose of the viral inoculum.
Discussion focusing on excluding other potential causes should be undertaken early in order to guide further investigation. Not every patient with fever, hepatomegaly, and jaundice has hepatitis A virus (HAV) infection. Some of the important differential diagnoses for acute hepatitis warrant early and specific management.
In the prodrome, patients may have mild flulike symptoms of anorexia, nausea and vomiting, fatigue, malaise, low-grade fever (usually < 39.5°C), myalgia, and mild headache. Smokers often lose their taste for tobacco, like persons presenting with appendicitis.
In the icteric phase, dark urine appears first (bilirubinuria). Pale stool soon follows, although this is not universal. Jaundice occurs in most (70%-85%) adults with acute HAV infection; it is less likely in children and is uncommon in infants. The degree of icterus also increases with age. Abdominal pain occurs in approximately 40% of patients. Itching (pruritus), although less common than jaundice, is generally accompanied by jaundice.
Arthralgias and skin rash, although also associated with acute HAV infection, are less frequent than the above symptoms. Rash more often occurs on the lower limbs and may have a vasculitic appearance.
Relapsing hepatitis A is an uncommon sequela of acute infection, is more common in elderly persons, and is characterized by a protracted course of symptoms of the disease and a relapse of symptoms and signs following apparent resolution (see Complications).
Hepatomegaly is common. Jaundice or scleral icterus may occur. Patients may have a fever with temperatures of up to 40°C.
What is the gold standard for diagnosis of viremic stages of hepatitis A infection?
Nucleic acid testing (NAT) is the gold standard for the diagnosis of viremic stages of hepatitis infection. [17]
What is the gold standard for diagnosis of viremic stages of hepatitis A infection?
What are the approach considerations in the workup of hepatitis A?
Which hepatic synthetic function measurements are consistent with hepatitis A?
What is the role of anti-hepatitis A virus (HAV) IgM testing in the workup of hepatitis A?
What is the role of anti-hepatitis A virus (HAV) IgG in the workup of hepatitis A?
Nucleic acid testing (NAT) is the gold standard for the diagnosis of viremic stages of hepatitis infection. [17]
Central to the prevention of any legal problem is establishing the correct diagnosis, which comes from a combination of careful history and subsequent examination. Appearances may be deceiving; therefore, always exclude drugs, particularly acetaminophen, as a cause of acute liver injury. One of the most common reasons for the misdiagnosis of hepatitis A infection is misinterpretation of the serology tests.
Liver biopsy has a minimal role in the diagnosis acute of HAV infection. It may play a part in chronic relapsing HAV infection or in situations where the diagnosis is uncertain. Other investigations (eg, serum acetaminophen) may be necessary, depending on the findings from the history and clinical examination. Molecular diagnostic techniques performed on blood and feces for HAV RNA are purely research tools at present.
Kodani et al have developed an NAT-based assay that may be able to detect five viral genomes of hepatitis simultaneously: HAV RNA, HBV DNA, HCV RNA, HDV RNA, and HEV RNA, [17] Independent validation would have potential clinical implications for wider patient surveillance, donor specimens screening, and its use in the setting of outbreaks. [17]
After establishing a diagnosis of hepatitis A virus (HAV) infection, tracing contacts and notifying local public health authorities are important steps for preventing further cases. Omitting these measures may place the practitioner in a vulnerable situation.
The prothrombin time (PT) usually remains within or near the reference range. Significant rises should raise concern and support closer monitoring. In the presence of encephalopathy, an elevated PT has ominous implications (eg, fulminant hepatic failure [FHF]).
Bilirubin level rises soon after the onset of bilirubinuria and follows rises in ALT and AST levels. Levels may be impressively high and can remain elevated for several months; persistence beyond 3 months indicates cholestatic HAV infection.
Older individuals have higher bilirubin levels. Both direct and indirect fractions increase because of hemolysis, which often occurs in acute HAV infection.
Modest falls in serum albumin level may accompany the illness.
The diagnosis of acute HAV infection is based on serologic testing for immunoglobulin M (IgM) antibody to HAV. Test results for anti-HAV IgM are positive at the time of onset of the symptoms and usually accompany the first rise in the alanine aminotransferase (ALT) level.
This test is sensitive and specific, and the results remain positive for 3-6 months after the primary infection and for as long as 12 months in 25% of patients. In patients with relapsing hepatitis, IgM persists for the duration of this pattern of disease. False-positive results are uncommon and should be considered in the event that anti-HAV IgM
Anti-HAV immunoglobulin G (IgG) appears soon after IgM and generally persists for many years. The presence of anti-HAV IgG in the absence of IgM indicates past infection or vaccination rather than acute infection. IgG provides protective immunity.
Trattamento epatite A
When in immunization against hepatitis A indicated?
Treatment generally involves supportive care, with specific complications treated as appropriate. Liver transplantation, in selected cases, is an option if the patient has fulminant hepatic failure (FHF).
The advent of new antiviral agents, such as direct-acting antivirals (DAAs) and host-targeting agents (HTAs), has expanded the potential therapeutic options available against HAV. [19] Kanda et al noted that amantadine and interferon-lambda 1 (IL-29) inhibit HAV internal ribosomal entry site (IRES)-mediated translation and HAV replication, whereas Janus kinase (JAK) inhibitors inhibit La protein expression, HAV IRES activity, and HAV replication.
Patients at risk of developing acute hepatitis A virus (HAV) infection should undergo immunization for the virus. In addition, immunization of those at greater risk for morbidity from acute HAV infection is important.
Immunization is indicated for individuals traveling to areas of high endemicity who have less than 2 weeks before departure. Both the vaccination and intramuscular (IM) immunoglobulin should be administered to provide long-term immunity, particularly in persons who intend to travel to these areas repeatedly.
People with chronic liver disease of any cause should consider hepatitis A vaccination. Response rates in patients with advanced liver disease and in those on immunosuppressive therapies are likely to be lower. The potentially disastrous outcome of acute HAV infection in this group cannot be overemphasized.
Hepatitis A vaccination in some low-risk groups who are potential sources of larger outbreaks of infection (eg, food handlers) has been implemented by some employers, although cost-benefit analysis for the employer does not seem to support such measures.
What is hepatitis B (HBV) (Hep B)?
What is the pathogenesis of hepatitis B (HBV) (Hep B)?
What is encoded in the pathogenesis of hepatitis B (HBV) (Hep B) infection?
What is the role of S gene (surface gene) in the pathophysiology of hepatitis B (HBV) (Hep B) infection?
What is the role of the C gene (core gene) in the pathophysiology of hepatitis B (HBV) (Hep B) infection?
What is the role of the e antigen, (HBeAg) in the pathophysiology of hepatitis B (HBV) (Hep B) infection?
What is the role of the X gene in the pathophysiology of hepatitis B (HBV) (Hep B) infection?
Hepatitis B infection is a worldwide healthcare problem, especially in developing areas. The hepatitis B virus (HBV) is commonly transmitted via body fluids such as blood, semen, and vaginal secretions. [1]
The hematoxylin and eosin (H&E) stain below depicts “ground-glass” cells seen in approximately 50-75% of livers affected by chronic HBV infection.
The pathogenesis and clinical manifestations of hepatitis B are due to the interaction of the virus and the host immune system, which leads to liver injury and, potentially, cirrhosis and hepatocellular carcinoma. Patients can have either an acute symptomatic disease or an asymptomatic disease.
The pathogenesis and clinical manifestations of hepatitis B infection are due to the interaction of the virus and the host immune system. The immune system attacks HBV and causes liver injury, the result of an immunologic reaction when activated CD4+ and CD8+ lymphocytes recognize various HBV-derived peptides on the surface of the hepatocytes. Impaired immune reactions (eg, cytokine release, antibody production) or a relatively tolerant immune status result in chronic hepatitis. In particular, a restricted T-cell–mediated lymphocytic response occurs against the HBV-infected hepatocytes.
The viral genome of hepatitis B consists of a partially double-stranded, circular DNA molecule of 3.2 kilobase (kb) pairs that encodes the following 4 overlapping open reading frames:
S (the surface, or envelope, gene): Encodes the pre-S1, pre-S2, and S proteins
C (the core gene): Encodes the core nucleocapsid protein and the e antigen; an upstream region for the S (pre-S) and C (pre-C) genes has been found
X (the X gene): Encodes the X protein
P (the polymerase gene): Encodes a large protein promoting priming ribonucleic acid (RNA) ̶ dependent and DNA-dependent DNA polymerase and ribonuclease H (RNase H) activities
The S gene encodes the viral envelope. There are 5 mainly antigenic determinants: (1) a, common to all hepatitis B surface antigens (HBsAg), and (2-5) d, y, w, and r, which are epidemiologically important and identify the serotypes.
The core antigen, HBcAg, is the protein that encloses the viral DNA. It can also be expressed on the surface of the hepatocytes, initiating a cellular immune response.
What is hepatitis B (HBV) (Hep B)?
What is the pathogenesis of hepatitis B (HBV) (Hep B)?
What is encoded in the pathogenesis of hepatitis B (HBV) (Hep B) infection?
What is the role of S gene (surface gene) in the pathophysiology of hepatitis B (HBV) (Hep B) infection?
What is the role of the C gene (core gene) in the pathophysiology of hepatitis B (HBV) (Hep B) infection?
What is the role of the e antigen, (HBeAg) in the pathophysiology of hepatitis B (HBV) (Hep B) infection?
What is the role of the X gene in the pathophysiology of hepatitis B (HBV) (Hep B) infection?
Hepatitis B infection is a worldwide healthcare problem, especially in developing areas. The hepatitis B virus (HBV) is commonly transmitted via body fluids such as blood, semen, and vaginal secretions. [1]
The hematoxylin and eosin (H&E) stain below depicts “ground-glass” cells seen in approximately 50-75% of livers affected by chronic HBV infection.
The pathogenesis and clinical manifestations of hepatitis B are due to the interaction of the virus and the host immune system, which leads to liver injury and, potentially, cirrhosis and hepatocellular carcinoma. Patients can have either an acute symptomatic disease or an asymptomatic disease.
The pathogenesis and clinical manifestations of hepatitis B infection are due to the interaction of the virus and the host immune system. The immune system attacks HBV and causes liver injury, the result of an immunologic reaction when activated CD4+ and CD8+ lymphocytes recognize various HBV-derived peptides on the surface of the hepatocytes. Impaired immune reactions (eg, cytokine release, antibody production) or a relatively tolerant immune status result in chronic hepatitis. In particular, a restricted T-cell–mediated lymphocytic response occurs against the HBV-infected hepatocytes.
The viral genome of hepatitis B consists of a partially double-stranded, circular DNA molecule of 3.2 kilobase (kb) pairs that encodes the following 4 overlapping open reading frames:
S (the surface, or envelope, gene): Encodes the pre-S1, pre-S2, and S proteins
C (the core gene): Encodes the core nucleocapsid protein and the e antigen; an upstream region for the S (pre-S) and C (pre-C) genes has been found
X (the X gene): Encodes the X protein
P (the polymerase gene): Encodes a large protein promoting priming ribonucleic acid (RNA) ̶ dependent and DNA-dependent DNA polymerase and ribonuclease H (RNase H) activities
The S gene encodes the viral envelope. There are 5 mainly antigenic determinants: (1) a, common to all hepatitis B surface antigens (HBsAg), and (2-5) d, y, w, and r, which are epidemiologically important and identify the serotypes.
The core antigen, HBcAg, is the protein that encloses the viral DNA. It can also be expressed on the surface of the hepatocytes, initiating a cellular immune response.
The e antigen, HBeAg, which is also produced from the region in and near the core gene, is a marker of active viral replication. It serves as an immune decoy and directly manipulates the immune system; it is thus involved in maintaining viral persistence. HBeAg can be detected in patients with circulating serum HBV DNA who have “wild type” infection. As the virus evolves over time under immune pressure, core promotor and precore mutations emerge, and HBeAg levels fall until the level is not measurable by standard assays.
Individuals who are infected with the wild type virus often have mixed infections, with core and precore mutants in up to 50% of individuals. They often relapse with HBeAg-negative disease after treatment.
The role of the X gene is to encode proteins that act as transcriptional transactivators that aid viral replication. Evidence strongly suggests that these transactivators may be involved in carcinogenesis.
What does the presence of antibodies against HBsAG (anti-HBs) indicate in the pathogenesis of hepatitis B (HBV) (Hep B) infection?
What does the presence of anti-HBc subtype IgM or IgG suggest in the pathogenesis of hepatitis B (HBV) (Hep B) infection?
What does the presence of antibodies to the e antigen (HBeAg) suggest in the pathogenesis of hepatitis B (HBV) (Hep B)?
How are hepatitis B (HBV) (Hep B) genome variants identified?
How does the global prevalence of the HBeAg-negative strain of hepatitis B (HBV) (Hep B) vary among regions?
The production of antibodies against HBsAg (anti-HBs) confers protective immunity and can be detected in patients who have recovered from HBV infection or in those who have been vaccinated.
Antibody to HBcAg (anti-HBc) is detected in almost every patient with previous exposure to HBV and indicates that there is a minute level of persistent virus, as demonstrated by the risk of reactivation in individuals who undergo immune suppression regardless of their anti-HBs status.
The immunoglobulin M (IgM) subtype of anti-HBc is indicative of acute infection or reactivation, whereas the IgG subtype is indicative of chronic infection. The activity of the disease cannot be understood using this marker alone, however.
Antibody to HBeAg may be suggestive of a nonreplicative state if there is undetectable HBV DNA or the emergence of the core/precore variants and of chronic HBV HBeAg-negative disease.
The prevalence of the HBeAg-negative virus varies from one region to another. Estimates indicate that among patients with chronic HBV infection, 50-60% of those from Southern Europe, the Middle East, Asia, and Africa, as well as 10-30% of patients in the United States and Europe, have been infected with this strain.
What is the final state of hepatitis B (HBV) (Hep B) disease?
What are the five stages in the life cycle of hepatitis B virus (HBV) (Hep B)?
What are the genotypes hepatitis B (HBV) (Hep B)?
Which factors increase the risk for hepatocellular carcinoma (HCC) in patients with hepatitis B (HBV) (Hep B)?
The final state of HBV disease is cirrhosis. With or without cirrhosis, however, patients with HBV infection are likely to develop hepatocellular carcinoma (HCC). [4, 5, 6] In the United States, the most common presentation of these patients with HCC is that they are of Asian origin and acquired HBV disease as newborns (vertical transmission).
The 5 stages that have been identified in the viral life cycle of hepatitis B infection are briefly discussed below. Different factors have been postulated to influence the development of these stages, including age, sex, immunosuppression, and coinfection with other viruses.
Stage 1: Immune tolerance
This stage, which lasts approximately 2-4 weeks in healthy adults, represents the incubation period. For newborns, the duration of this period is often decades. Active viral replication is known to continue despite little or no elevation in the aminotransferase levels and no symptoms of illness.
Stage 2: Immune active/immune clearance
In the immune active stage, also known as the immune clearance stage, an inflammatory reaction with a cytopathic effect occurs. HBeAg can be identified in the sera, and a decline in the levels of HBV DNA is seen in some patients who are clearing the infection. The duration of this stage for patients with acute infection is approximately 3-4 weeks (symptomatic period). For patients with chronic infection, 10 years or more may elapse before cirrhosis develops, immune clearance takes place, HCC develops, or the chronic HBeAg-negative variant emerges.
Stage 3: Inactive chronic infection
In the third stage, the inactive chronic infection stage, the host can target the infected hepatocytes and HBV. Viral replication is low or no longer measurable in the serum, and anti-HBe can be detected. Aminotransferase levels are within the reference range. It is most likely at this stage that an integration of the viral genome into the host’s hepatocyte genome takes place. HBsAg still is present in the serum.
Stage 4: Chronic disease
The emergence of chronic HBeAg-negative disease can occur from the inactive chronic infection stage (stage 3) or directly from the immune active/clearance stage (stage 2).
Stage5: Recovery
In the fifth stage, the virus cannot be detected in the blood by DNA or HBsAg assays, and antibodies to various viral antigens have been produced. The image below depicts the serologic course of HBV infection.
Ten different genotypes (A through J), representing a divergence of the viral DNA of about 8%, have been identified. [19] The prevalence of the genotypes varies in different countries. The progression of the disease seems to be more accelerated and the response to treatment with antiviral agents is less favorable for patients infected by genotype C, compared with those infected by genotype B. However, much of this can be explained by the presence of core and precore mutations found in multivariate analysis. [20, 21]
It has been confirmed that the risk of HCC is related to higher HBV DNA levels in the serum, when DNA is present for longer periods—with an even higher risk if there is an increasing level of hepatitis B viral load, the presence of genotype C, and the presence of mutations in the precore and basal core promoter regions.
Even the presence of hepatitis B surface antibody (anti-HBs) in the absence of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA is significantly related to an increased risk for HCC, although surveillance for HCC is not recommended in the affected group unless cirrhosis is present. In the United States, the estimated annual incidence of HCC in patients infected with hepatitis B is 818 cases per 100,000 persons. In Taiwan, the annual incidence of this malignancy in patients with hepatitis B and cirrhosis is 2.8%. Familial clustering of HCC has been described among families with hepatitis B in Africa, the Far East, and Alaska.
Ruolo di HBxAg
Most likely, the HBxAg produced by these sequences is the transactivating factor, because it has been found to bind to a variety of transcription factors such as CREB (cyclic adenosine monophosphate [cAMP]–response element-binding protein) and ATF-2 (activating transcription factor 2), which alters their DNA-binding specificity. Thus, the ability of the HBV pX protein to interact with cellular factors broadens the DNA-binding specificity of these regulatory proteins and provides a mechanism for pX to participate in transcriptional regulation. This shifts the pattern of host gene expression relevant to the development of HCC.
Additionally, HBxAg has been postulated to bind to the C-terminus and inactivate the product of the tumor suppressor gene TP53, as well as to do the following:
Sequester TP53 in the cytoplasm, resulting in the abrogation of TP53 -induced apoptosis (although controversy exists regarding this concept)
Reduce the ability for nucleotide excision repair by directly acting with proteins associated with DNA transcription and repair such as XPB and XPD
Reduce p21WAF1 expression, which is a cell cycle regulator
Bind to protein p55sen, which is involved in the cell fate during embryogenesis and is found in the liver of patients with hepatitis B, thus altering its function
The levels of tumor necrosis factor-alpha (TNF-a), a proinflammatory cytokine, are also upregulated. The transcriptional transactivation of nitric oxide (NO) synthetase II by pX and the elevated levels of TNF-a are responsible for the high levels of NO found in these patients. NO is a putative mutagen through several mechanisms of functional modifications of TP53, DNA oxidation, deamination, and formation of the carcinogenic N-nitroso compounds. A second transactivator is encoded in the pre-S/S region of the HBV genome, stimulating the expression of the human proto-oncogenes c-fos and c-myc; this upregulates the expression of TGF-a by transactivation.
How is hepatitis B (HBV) (Hep B) transmitted?
What is the incidence of hepatitis B (HBV) (Hep B) in the US?
What are the risk factors for hepatitis B (HBV) (Hep B) infection in the US?
How has routine vaccination of infants for hepatitis B (HBV) (Hep B) infection affected the prevalence in the US?
What is the global prevalence of hepatitis B (HBV) (Hep B) infection?
Hepatitis B infection, caused by the hepatitis B virus (HBV), is commonly transmitted via body fluids such as blood, semen, and vaginal secretions. [1] Consequently, sexual contact, accidental needle sticks or sharing of needles, blood transfusions, and organ transplantation are routes for HBV infection. Infected mothers can also pass the infection to their newborns during the delivery period. [1]
Because of the implementation of routine vaccination of infants in 1992 and of adolescents in 1995, the prevalence of HBV infection has significantly declined in individuals born in the United States.
The CDC reported 3322 new cases of acute hepatitis B in 2018; however, it is believed that a large percentage of cases go unreported. [32] Two million or more people in the US have chronic HBV infection; it is estimated that foreign-born persons from high endemic areas represent more than half of the total cases. [33] The prevalence of the disease is higher among black individuals and persons of Hispanic or Asian origin.
HBV disease not only accounts for 5-10% of cases of chronic end-stage liver disease and 10-15% of cases of hepatocellular carcinoma (HCC) in the United States, it is also the dominant cause of cirrhosis and HCC worldwide.
HBV is blamed for at least 5000 US deaths annually. The prevalence is low in persons younger than 12 years born in the United States, with the subsequent increase being associated with the initiation of sexual contact (the major mode of transmission in adults, along with intravenous drug abuse [IVDA]). It is also associated with the occurrence of first intercourse at an early age. Additional risk factors, as identified in the National Health and Nutrition Examination Survey (NHANES) III, are as follows:
Non-Hispanic black ethnicity
Cocaine use
High number of sexual partners
Divorced or separated marital status
Foreign birth
Low educational level
Globally, chronic HBV infection affects 350-400 million people, [34] with disease prevalence varying among geographic regions, from 1-20%. A higher rate exists, for example, among Alaskan Eskimos, Asian Pacific islanders, Australian aborigines, and populations from the Indian subcontinent, sub-Saharan Africa, and Central Asia. In some locations, such as Vietnam, the rate is as high as 30%. Such variation is related to differences in the mode of transmission, including iatrogenic transmission, and the patient’s age at infection.
The lifetime risk of HBV infection is less than 20% in low prevalence areas (< 2%; generally, 0.1-2%), [8] and sexual transmission and percutaneous transmission during adulthood are the main modes through which it spreads. About 12% of HBV-infected individuals live in low-prevalence areas, which include the United States, Canada, western Europe, Australia, and New Zealand. [8]
What is the spectrum of symptoms of hepatitis B (HBV) (Hep B) infection?
What are the multisystem manifestations of hepatitis B virus (HBV) (Hep B) infection?
What are the cutaneous symptoms of the early course hepatitis B (HBV) (Hep B) infection?
What is the incubation period in the acute phase of hepatitis B (HBV) (Hep B) infection?
What is icteric hepatitis?
What is the presentation of fulminant and subfulminant hepatitis B (HBV) (Hep B)?
What are the signs and symptoms of chronic hepatitis B (HBV) (Hep B)?
Which symptoms may be present in chronic hepatitis B (HBV) (Hep B) with progressive liver disease?
The spectrum of the symptomatology of hepatitis B disease varies from subclinical hepatitis to icteric hepatitis to fulminant, acute, and subacute hepatitis during the acute phase, and from an asymptomatic chronic infection state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) during the chronic phase.
Papular acrodermatitis, also recognized as Gianotti-Crosti syndrome, has been associated with hepatitis B, most commonly in children with acute infection. [37]
The following multisystem manifestations may occur in hepatitis B virus (HBV) infection:
Pleural effusion and hepatopulmonary and portopulmonary syndrome may occur in patients with cirrhosis
Diffuse intravascular coagulation may occur in patients with fulminant hepatitis
Myocarditis, pericarditis, and arrhythmia occur primarily in patients with fulminant hepatitis
Arthralgias and arthritic (serum sickness) subcutaneous nodules may also occur, but these are rare
Guillain-Barre syndrome, encephalitis, aseptic meningitis, and mononeuritis multiplex may occur in patients with acute hepatitis B
Pancreatitis may develop
Aplastic anemia is uncommon, and agranulocytosis is extremely uncommon
A variety of cutaneous manifestations have been recognized during the early course of viral hepatitis, including hives and a fleeting maculopapular rash. These various lesions are episodic, palpable, and, at times, pruritic. A discoloration of the skin can be identified after the resolution of the exanthem, particularly on the lower extremities. Women are more prone to developing cutaneous manifestations.
Acute phase
The incubation period is 1-6 months in the acute phase of hepatitis B infection. Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic, but patients with anicteric hepatitis have a greater tendency to develop chronic hepatitis. Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis.
Icteric hepatitis is associated with a prodromal period, during which a serum sickness –like syndrome can occur. The symptomatology is more constitutional and includes the following:
Anorexia
Nausea
Vomiting
Low-grade fever
Myalgia
Fatigability
Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)
Right upper quadrant and epigastric pain (intermittent, mild to moderate)
Patients with fulminant and subfulminant hepatitis may present with the following:
Hepatic encephalopathy
Somnolence
Disturbances in sleep pattern
Mental confusion
Coma
Ascites
Gastrointestinal (GI) bleeding
Coagulopathy
Chronic phase
Patients with chronic hepatitis B disease can be immune tolerant or have an inactive chronic infection without any evidence of active disease; they are also asymptomatic.
Patients with chronic active hepatitis, especially during the replicative state, may complain of symptomatology such as the following:
Symptoms similar to those of acute hepatitis
Fatigue
Anorexia
Nausea
Mild upper quadrant pain or discomfort
If progressive liver disease is present, the following symptomatology may appear:
Hepatic decompensation
Hepatic encephalopathy
Somnolence
Disturbances in sleep pattern
Mental confusion
Coma
Ascites
GI bleeding
Coagulopathy
The physical examination findings in hepatitis B disease vary from minimal to impressive (in patients with hepatic decompensation), according to the stage of disease.
Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following:
Low-grade fever
Jaundice (10 days after appearance of constitutional symptomatology, lasting for 1-3 mo)
Hepatomegaly (mildly enlarged, soft liver)
Splenomegaly (5-15%)
Palmar erythema (rarely)
Spider nevi (rarely)
The physical examination of patients with chronic hepatitis B virus (HBV) infection can reveal stigmata of chronic liver disease such as the following:
Hepatomegaly
Splenomegaly
Muscle wasting
Palmar erythema
Spider angioma
Vasculitis (rarely)
Patients with cirrhosis may have the following findings:
Ascites
Jaundice
History of variceal bleeding
Peripheral edema
Gynecomastia
Testicular atrophy
Abdominal collateral veins (caput medusa)
What is the role of lab testing in the workup of hepatitis B (HBV) (Hep B)?
How is severity determined in hepatitis B virus (HBV) (Hep B)?
How is a patient’s level of infectivity determined in hepatitis B (HBV) (Hep B) infection?
What is the role of DNA testing in the evaluation of hepatitis B (HBV) (Hep B)?
Laboratory evaluation of hepatitis B disease generally consists of liver enzyme tests, including levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT), as well as liver function tests (LFTs) that include total and direct serum bilirubin, albumin, and the measurement of the international normalized ratio (INR). [38] Hematologic and coagulation studies also include a platelet count and a complete blood count (CBC). Ammonia levels may be obtained, but the results often create diagnostic confusion in clinicians. [39]
Serologic tests for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) immunoglobulin M (IgM) are required for the diagnosis of acute hepatitis B virus (HBV). [1, 40, 41] HBsAg is positive in both acute and chronic HBV infection; however, the presence of IgM anti-HBc is diagnostic of acute or recently acquired infection. [40] Antibody to HBsAg (anti-HBs) is produced after a resolved infection and is the only HBV antibody marker present after vaccination. The presence of HBsAg and total anti-HBc, with a negative test for IgM anti-HBc, indicates chronic HBV infection; the absence of IgM anti-HBc or the persistence of HBsAg for 6 months indicates chronic HBV infection. The presence of anti-HBc alone might indicate acute, resolved, or chronic infection or a false-positive result. [40]
To evaluate the patient’s level of infectivity, quantification of hepatitis (HBV) DNA is essential, and the presence of hepatitis B e antigen (HBeAg) should be determined. Indeed, the best indication of active viral replication is the presence of HBV DNA in the serum. Hybridization or more sensitive polymerase chain reaction (PCR) assay techniques are used to detect the viral genome in the serum, as well as specific genotypes, mutants resistant to oral nucleoside and nucleotide analogues, and core and precore mutations.
A positive result suggests not only the likelihood of active hepatitis but also that the disease is much more infectious, as the virus is actively replicating. [41]
HBV DNA testing is also recommended when occult HBV is suspected (positive anti-HBc and negative antibody to HBsAg [anti-HBs] and HBsAg) or in cases in which all of the serologic tests are negative. [42]
What are the AASLD recommendations for the initial evaluation of HBsAg-positive patients with hepatitis B (HBV) (Hep B)?
What are the AASLD recommendations for evaluation of hepatitis B (HBV) (Hep B) in HBsAg-positive patients with elevated LFTs?
The current AASLD recommendations for the initial evaluation of HBsAg-positive patients is summarized below. [38]
All patients
History and physical examination: Thoroughly evaluate for the following:
Alcohol, metabolic, and other risk factors for HBV infection
Patient’s HBV vaccination status
Family history of HBV infection and hepatocellular carcinoma
The presence of symptoms/signs of cirrhosis
Routine laboratory studies
CBC, platelet count; INR
Levels of AST, ALT, total bilirubin, ALP, and albumin
Serologic/virologic studies
Hepatitis B e antigen (HBeAg)/anti-HBe
HBV DNA level
Anti-hepatitis A virus (anti-HAV) (to determine need for vaccination)
Imaging/staging studies
Abdominal ultrasonography
Vibration-controlled transient elastography (eg, FibroScan) or a serum fibrosis marker panel (APRI [AST-to-platelet ratio index], FIB-4 [platelet count, ALT, AST, age], or FibroTest [gamma-2 macroglobulin, gamma-2 globulin, gamma globulin, apolipoprotein A1, gamma-GGT, total bilirubin])
Select patients
Routine laboratory studies: In the setting of elevated liver function test results, obtain tests to exclude other causes of chronic liver disease. Obtain levels of alpha-fetoprotein (AFP) and GGT.
Serologic/virologic studies
HBV genotyping
Tests for coinfection with hepatitis C virus (HCV), hepatitis D (delta) virus (HDV), and/or human immunodeficiency virus (HIV) in at-risk individuals aged 13-64 years who have not undergone one-time screening
Test diagnostici sierici epatite B
Acute hepatitis B disease
High levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), within a range of 1000-2000 IU/mL, is the hallmark of this stage of HBV disease, although values 100 times above the upper limit of normal (ULN) can be also be identified. Higher values are found in patients with icteric hepatitis. ALT levels are usually higher than AST levels.
Gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) levels may be elevated, but they are usually not more than 3 times the ULN.
Albumin levels can be slightly low, and serum iron levels may be elevated as an acute phase reactant. In the preicteric period (ie, before the appearance of jaundice), leukopenia (ie, granulocytopenia) and lymphocytosis are the most common hematologic abnormalities and are accompanied by an increase in the erythrocyte sedimentation rate (ESR).
Anemia due to a shortened red blood cell survival period is an infrequent finding, although hemolysis may be noted. Thrombocytopenia is a rare finding. Patients with severe hepatitis experience a prolongation of the international normalized ratio (INR).
Several viral markers can be identified in the serum and the liver. Hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) (marker of infectivity) are the first markers that can be identified in the serum in acute disease. Hepatitis B core antibody (anti-HBc) immunoglobulin M (IgM) follows.
For patients who recover, seroconversion to hepatitis B surface antibody (anti-HBs) and hepatitis B e antibody (anti-HBe) is observed. The anti-HBc is of the IgG class. Patients with persistent HBsAg lasting more than 6 months are considered to have chronic hepatitis.
Inactive hepatitis B disease
The term “healthy carriers” is no longer used due to the fact that a person who is positive for HBsAg has a high risk of cirrhosis and hepatocellular carcinoma (HCC) and, therefore, cannot be defined as healthy. Such individuals have normal AST and ALT levels, with markers of infectivity, such as HBeAg, being negative and HBV DNA going undetected or being detected at very low levels (usually below 2,000 IU/ml). HBsAg, anti-HBc of IgG type, and anti-HBe are present in the serum. A minimum follow-up of these patients for 1 year with laboratory evaluation every 3 to 4 months is recommended.
Chronic active hepatitis B disease
Chronic active HBV disease is categorized into HBeAg-positive and HBeAg-negative disease.
Subtype “wild type” or HBeAg-positive disease
Patients have mild to moderate elevation of the aminotransferases (≤5 times the ULN). The ALT levels are usually higher than the AST levels. Extremely high levels of ALT can be observed during exacerbation or reactivation of the disease, and they can be accompanied by impaired synthetic function of the liver (ie, decreased albumin levels, increased bilirubin levels, and prolonged prothrombin time [PT]).
HBV DNA levels are high during this phase. HBsAg and anti-HBc of IgG or IgM type (in case of reactivation) are identified in the serum.
If the AST levels are higher than the ALT levels, the diagnosis of cirrhosis must be considered. Hyperglobulinemia is another finding, predominantly with an elevation of the IgG globulins. Tissue-nonspecific antibodies, such as anti–smooth muscle antibodies (ASMAs) (20-25%) or antinuclear antibodies (ANAs) (10-20%), can be identified. Tissue-specific antibodies, such as antibodies against the thyroid gland (10-20%), can also be found. Mildly elevated levels of rheumatoid factor (RF) are usually present, indicating the presence of cryoglobulins on further assessment.
Subtype chronic HBV HBeAg-negative disease
Note that although the HBeAg result is negative in this stage, HBeAg negativity can be associated with greater HBV DNA replication and more rapid disease progression in patients who carry mutations in either the precore or the basic core promoter region of the HBV genome. [42]
Cirrhosis
In the early stages of cirrhosis, findings of chronic viral hepatitis can be found. Later, as the disease progresses, low albumin levels, hyperbilirubinemia, prolonged PT, low platelet and white blood cell counts, and AST levels higher than ALT levels can be identified. Alkaline phosphatase (ALP) and GGT levels can be slightly elevated.
Biopsia epatite B e stadiazione
Acute hepatitis B
The hallmark of acute hepatitis B is liver cell death. Scattered within the lobule are small, individual clusters of dying hepatocytes in apoptosis. (When the nucleus is extruded, it is an eosinophilic, or Councilman, body). Many of the surviving hepatocytes show hydropic swelling known as ballooning degeneration. Lymphocytes diffusely infiltrate the lobule, with macrophages and neutrophils seen occasionally.
Chronic hepatitis B
The hallmark of chronic hepatitis B infection is lymphoid inflammation, mostly involving the portal tracts. However, occasional Councilman bodies are seen in the lobule. Hepatocytes that are distended with viral particles may acquire an unusual “ground-glass” appearance on the hematoxylin and eosin (H&E) stain (see the following image). Ground-glass cells are seen in approximately 50-75% of livers affected by chronic HBV infection, and they stain positive for hepatitis surface B antigen (HBsAg). Immunohistochemical staining of the specimen can help to identify the presence of HBsAg or hepatitis B core antigen (HBcAg) (ie, chronic infection).
As the severity of the histologic changes advance, interface hepatitis (piecemeal necrosis) appears, with erosion of the limiting plate by chronic inflammation from the portal side of the lobule. Over time, this ongoing type of inflammation may lead to increasing degrees of fibrosis that spreads out from that portal tract to connect with other nearby portal tracts (bridging fibrosis). When the fibrosis advances further in severity, regenerating nodules of hepatocytes appear; this constitutes cirrhosis (see the image below).
Staging
Liver damage is graded according to the inflammatory component and is described as follows:
Grade 0 – Portal inflammation only, no activity
Grade 1 – Minimal portal inflammation and patchy lymphocytic necrosis, with minimal lobular inflammation and spotty necrosis
Grade 2 – Mild portal inflammation and lymphocytic necrosis involving some or all portal tracts, with mild hepatocellular damage
Grade 3 – Moderate portal inflammation and lymphocytic necrosis involving all portal tracts, with noticeable lobular inflammation and hepatocellular change
Grade 4 – Severe portal inflammation and severe lymphocytic bridging necrosis, with severe lobular inflammation and prominent, diffuse hepatocellular damage
Liver damage staging (ie, fibrosis) is described as follows:
Stage 0 – No fibrosis
Stage 1 – Portal fibrosis
Stage 2 – Periportal fibrosis
Stage 3 – Septal, bridging fibrosis
Stage 4 – Cirrhosis
Trattamento dell’epatite B
The primary treatment goals for patients with hepatitis B (HBV) infection are to prevent progression of the disease, particularly to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). [2, 38, 55] Risk factors for progression of chronic HBV include the following [2, 38, 55] :
Persistently elevated levels of HBV DNA and, in some patients, alanine aminotransferase (ALT), as well as the presence of core and precore mutations seen most commonly in HBV genotype C and D infections
Male sex
Older age
Family history of HCC
Alcohol use
Elevated alpha-fetoprotein (AFP)
Coinfection with hepatitis D (delta) virus (HDV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)
A synergistic approach of suppressing viral load and boosting the patient’s immune response with immunotherapeutic interventions is needed for the best prognosis. [34] The prevention of HCC often includes the use of antiviral treatment using pegylated interferon (PEG-IFN) or nucleos(t)ide analogues. [35]
HBV infection can be self-limited or chronic. [40] No specific therapy is available for persons with acute hepatitis B; treatment is supportive. [40]
Therapy is currently recommended for patients with evidence of chronic active hepatitis B disease (ie, abnormal aminotransferase levels, positive HBV DNA findings, positive or negative hepatitis B e antigen [HBeAg]). Various algorithms have been proposed
Se pz HBeAg+, T normali e HBV-DNA alto titolo= immunotolleranza=osservazione ogni sei mesi. Trattamento solo se anamnesi familiare positiva
Se portatore inattivo=osservazione
Se HBeAg+ e - con Ishak 0-1-2= trattamento se fattori prognostici favorevoli (dna basso, A,B,C)
Se ishak 5-6 allora terapia immediata
The following are medications approved for the treatment of chronic hepatitis B in adult and/or pediatric patients (adjust all dosing in the setting of renal dysfunction). [38]
Preferred agents
Pegylated interferon (PEG-IFN)-alpha-2a (adults) or IFN-alpha-2b (children) – Adult dose 180 μg weekly; pediatric dose (age ≥1 year): 6 million IU/m 2 three times weekly
Entecavir – Adult dose: Daily 0.5 mg (lamivudine-/telbivudine-naive persons) or 1.0 mg (those with lamivudine/telbivudine experience or decompensated cirrhosis); pediatric dose (age ≥2 years): Weight-based to 10-30 kg; for children weighing more than 30 kg, use 0.5 mg daily
Tenofovir dipovoxil fumarate – Adult and pediatric (age ≥12 years) dose: 300 mg daily
Tenofovir alafenamide – Adult dose only: 25 mg daily; no pediatric dosing
Nonpreferred agents
Adefovir – Adult and pediatric dose (age ≥12 years): 10 mg daily
Lamivudine – Adult dose: 100 mg daily; pediatric dose (age ≥2 years): 3 mg/kg daily (maximum: 100 mg)
Telbivudine – Adult dose only: 600 mg daily; no pediatric dosing
World Health Organization (WHO) recommendations
First-line antiviral treatment (Strong recommendations)
All individuals aged 12 years or older who are eligible for antiviral therapy are recommended to receive therapy with tenofovir or entecavir, the nucleos(t)ide analogs (NAs) with a high barrier to drug resistance. Entecavir is recommended in children aged 2-11 years.
NAs with a low barrier to drug resistance (lamivudine, adefovir, or telbivudine) are not recommended owing to their potential for drug resistance.
In HBV/human immunodeficiency virus (HIV)-coinfected individuals aged 3 years or older, a fixed-dose combination of tenofovir/lamivudine (or emtricitabine)/efavirenz is the preferred option for initiation of ART.
Second-line antiviral treatment for managing treatment failure (Strong recommendation)
For individuals with confirmed or suspected antiviral resistance (ie, history of prior exposure or primary nonresponse) to lamivudine, entecavir, adefovir, or telbivudine, the WHO recommends switching to tenofovir.
Definizione di epatite C. Come varia l’incidenza?
Hepatitis C is an infection caused by the hepatitis C virus (HCV) that attacks the liver and leads to inflammation. The World Health Organization (WHO) estimates that about 71 million people globally have chronic hepatitis C, with approximately 399,000 dying from this infection, primarily due to cirrhosis and hepatocellular carcinoma.
Hepatitis C is a worldwide problem. The hepatitis C virus (HCV) is a major cause of both acute and chronic hepatitis. The World Health Organization (WHO) estimates about 71 million people globally have chronic hepatitis C, with approximately 399,000 dying from this infection, primarily due to cirrhosis and hepatocellular carcinoma (HCC). [1]
The prevalence of HCV infection varies throughout the world. For example, Frank et al reported in 2000 that Egypt had the highest number of reported infections, largely attributed to the use of contaminated parenteral antischistosomal therapy. [2] This led to a mean prevalence of 22% of HCV antibodies in persons living in Egypt.
In the United States, the incidence of acute HCV infection has sharply decreased during the past decade, but its prevalence remains high. According to US Centers for Disease Control and Prevention (CDC) estimates, 2.7-3.9 million people (most of whom were born from 1945 through 1965) in the United States have chronic hepatitis C which develops in approximately 75% of patients after acute infection. [3] This virus is the most common blood-borne pathogen in the United States [4] and a leading cause of morbidity and mortality, primarily through the development of liver fibrosis and cirrhosis; persons with chronic infection live an average of 2 decades less than healthy persons. [4]
Infection due to HCV accounts for 20% of all cases of acute hepatitis, an estimated 30,000 new acute infections, and 8,000-10,000 deaths each year in the United States.
Most patients with acute and chronic infection are asymptomatic. Patients and healthcare providers may detect no indications of these conditions for long periods; however, chronic hepatitis C infection and chronic active hepatitis are slowly progressive diseases and result in severe morbidity in 20-30% of infected persons. Astute observation and integration of findings of extrahepatic symptoms, signs, and disease are often the first clues to the underlying HCV infection. [11]
Although acute HCV infection is usually mild, chronic hepatitis develops in at least 75% of patients.
What is the pathophysiology of hepatitis C virus (HCV) infection?
What is the role of hepatitis C viral (HCV) proteins in the pathogenesis of infection?
What are the most common hepatitis C virus (HCV) genotypes?
Hepatitis C virus (HCV) is a spherical, enveloped, single-stranded RNA virus belonging to the family Flaviviridae, genus Flavivirus. Lauer and Walker reported that HCV is closely related to hepatitis G, dengue, and yellow fever viruses. [13] HCV can produce at least 10 trillion new viral particles each day.
The HCV genome consists of a single, open reading frame and two untranslated, highly conserved regions, 5’-UTR and 3’-UTR, at both ends of the genome. The genome has approximately 9500 base pairs and encodes a single polyprotein of 3011 amino acids that are processed into 10 structural and regulatory proteins (see the image below).
The natural targets of HCV are hepatocytes and, possibly, B lymphocytes. Viral clearance is associated with the development and persistence of strong virus-specific responses by cytotoxic T lymphocytes and helper T cells.
In most infected people, viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis. Findings from studies suggest that at least 50% of hepatocytes may be infected with HCV in patients with chronic hepatitis C.
The proteolytic cleavage of the virus results in two structural envelope glycoproteins (E1 and E2) and a core protein. [14] Two regions of the E2 protein, designated hypervariable regions 1 and 2, have an extremely high rate of mutation, believed to result from selective pressure by virus-specific antibodies. The envelope protein E2 also contains the binding site for CD-81, a tetraspanin receptor expressed on hepatocytes and B lymphocytes that acts as a receptor or coreceptor for HCV. HCV core protein is an important risk factor in the development of liver disease; it can modulate several signaling pathways affecting cell cycle regulation, cell growth promotion, cell proliferation, apoptosis, oxidative stress, and lipid metabolism. [15]
Other viral components are nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, NS5B, and p7), whose proteins function as helicase-, protease-, and RNA-dependent RNA polymerase, although the exact function of p7 is unknown. These nonstructural proteins are necessary for viral propagation and have been the targets for newer antiviral therapies, such as the direct-acting antiviral agents (DAAs). NS2/3 and NS3/4A are proteases responsible for cleaving the HCV polyprotein. NS5A is critical for the assembly of the cytoplasmic membrane-bound replication complex; one region within NS5A is linked to an interferon (IFN) response and is called the IFN sensitivity–determining region. NS5B is an RNA dependent RNA polymerase required for viral replication; it lacks proofreading capabilities and generates a large number of mutant viruses known as quasispecies. These represent minor molecular variations with only 1%-2% nucleotide heterogeneity. HCV quasispecies pose a major challenge to immune-mediated control of HCV and may explain the variable clinical course and the difficulties in vaccine development.
Genotypes
HCV genomic analysis by means of an arduous gene sequencing of many viruses has led to the division of HCV into six genotypes based on homology. Numerous subtypes have also been identified. Arabic numerals denote the genotype, and lower-case letters denote the subtypes for lesser homology within each genotype. [12]
Molecular differences between genotypes are relatively large, and they have a difference of at least 30% at the nucleotide level. The major HCV genotype worldwide is genotype 1, which accounts for 40%-80% of all isolates. Genotype 1 also may be associated with more severe liver disease and a higher risk of hepatocellular carcinoma. Genotypes 1a and 1b are prevalent in the United States, whereas in other countries, genotype 1a is less frequent. Genotype details are as follows:
Genotype 1a occurs in 50%-60% of patients in the United States.
Genotype 1b occurs in 15%-20% of patients in the United States; this type is most prevalent in Europe, Turkey, and Japan.
Genotype 1c occurs in less than 1% of patients in the United States.
Genotypes 2a, 2b, and 2c occur in 10%-15% of patients in the United States; these subtypes are widely distributed and are most responsive to medication.
Genotypes 3a and 3b occur in 4%-6% of patients in the United States; these subtypes are most prevalent in India, Pakistan, Thailand, Australia, and Scotland.
Genotype 4 occurs in less than 5% of patients in the United States; it is most prevalent in the Middle East and Africa.
Genotype 5 occurs in less than 5% of patients in the United States; it is most prevalent in South Africa.
Genotype 6 occurs in less than 5% of patients in the United States; it is most prevalent in Southeast Asia, particularly Hong Kong and Macao.
Within a region, a specific genotype may also be associated with a specific mode of transmission, such as genotype 3 among persons in Scotland who abuse injection drugs.
How is hepatitis C virus (HCV) infection transmitted?
What is the prevalence of hepatitis C virus (HCV) infection in the US?
What is the global prevalence of hepatitis C virus (HCV) infection?
What are the racial predilections for hepatitis C virus (HCV) infection?
Which age group has the highest prevalence of hepatitis C virus (HCV) infection?
ransfusion of blood contaminated with hepatitis C virus (HCV) was once a leading means of HCV transmission. Since 1992, however, the screening of donated blood for HCV antibody sharply reduced the risk of transfusion-associated HCV infection. With the advent of more advanced screening tests for HCV such as polymerase chain reaction (PCR), the risk is considered to be less than 1 per 2 million units transfused. The newer assays have decreased the window after infection to 1-2 weeks.
Persons who inject illicit drugs with nonsterile needles are at the highest risk for HCV infection. In developed countries, most of the new HCV infections are reported in injection drug users (IDUs). The most recent surveys of active IDUs in the United States indicate that approximately one third of young (aged 18–30 years) IDUs are HCV-infected. [16] Older and former IDUs typically have a much higher prevalence (approximately 70%-90%) of HCV infection, attributable to needle sharing during the 1970s and 1980s, before greater understanding of the risks of blood-borne viruses and the implementation of public educational strategies. The additional risk of acquiring hepatitis C infection from noninjection (snorted or smoked) cocaine use is difficult to differentiate from that associated with injection drug use and sex with HCV-infected partners. [16]
Transmission of HCV to healthcare workers may occur via needle-stick injuries or other occupational exposures. Needle-stick injuries in the healthcare setting result in a 3% risk of HCV transmission. According to Rischitelli et al, however, the prevalence of HCV infection among healthcare workers is similar to that of the general population. [17] Nosocomial patient-to-patient transmission may occur by means of a contaminated colonoscope, via dialysis, or during surgery, including organ transplantation before 1992.
HCV may be transmitted via sexual transmission. However, studies of heterosexual couples with discordant serostatus have shown that such transmission is extremely inefficient. [18] A higher rate of HCV transmission is noted in men who have sex with men (MSM), particularly those who practice unprotected anal intercourse and have infection with the human immunodeficiency virus (HIV). [19]
HCV may also be transmitted via tattooing, sharing razors, and acupuncture. The use of disposable needles for acupuncture, now the standard practice in the United States, should eliminate this transmission route. Maternal-fetal HCV transmission may occur at a rate of approximately 4%–5%. [20] Breastfeeding is not associated with transmission. [21] Casual household contact and contact with the saliva of those infected are inefficient modes of transmission. No risk factors are identified in approximately 10% of cases.
Worldwide, more than 170 million persons have hepatitis C virus (HCV) infection, [27] of whom 71 million have chronic infection. [1] The Eastern Mediterranean region and Europe have the highest prevalence (2.3% and 1.5%, respectively), with other regions having an estimated prevalence of 0.5%-1.0%. [1] Jeddah City, Saudi Arabia, has a reported HCV prevalence of 0.38%. [28]
The prevalence rates in healthy blood donors are 0.01%-0.02% in the United Kingdom and northern Europe, 1%-1.5% in southern Europe, and 6.5% in parts of equatorial Africa. [29] Prevalence rates as high as 22% are reported in Egypt and are attributed to the use of parenteral antischistosomal therapy. [2]
Race-, sex-, and age-related differences in incidence
In the United States, HCV infection is more common among minority populations, such as black and Hispanic persons in association with lower economic status and educational levels. In addition, in the United States, genotype 1 is more prevalent in black individuals than in other racial groups.
In the United States, 65% of people with HCV infection are aged 30-49 years.
What is the prognosis of hepatitis C (hep C) infection?
Infection with hepatitis C virus (HCV) is self-limited in 15% to 50% of patients. [1, 16, 34, 35] In a review of HCV infection, it was reported that chronic infection developed in 70%-80% of patients. [12] Cirrhosis develops within 20 years of disease onset in 20% of persons with chronic infection. [36] The onset of chronic hepatitis C infection early in life often leads to less serious consequences. [32, 33] Hepatitis B virus (HBV) coinfection, iron overload, and alpha 1-antitrypsin deficiency may promote the progression of chronic HCV infection to HCV-related cirrhosis. [34, 35]
Two studies of compensated cirrhosis in the United States and Europe showed that decompensation occurred in 20% of patients and that hepatocellular carcinoma (HCC) occurred in approximately 10% of patients. [37, 38] The survival rate at 5 and 10 years was 89% and 79%, respectively. HCC develops in 1-4% of patients with cirrhosis each year, after an average of 30 years.
The risk of cirrhosis and HCC doubles in patients who acquired HCV infection via transfusion. [39] Progression to HCC is more common in the presence of cirrhosis, alcoholism, and HBV coinfection.
Bellentani et al [40] and Hourigan et al [41] reported that the rate and likelihood of disease progression is influenced by alcohol use, immunosuppression, sex, iron status, concomitant hepatitis, and age of acquisition.
Qual è la storia clinica dell’infezione da epatite C?
Acute hepatitis C virus (HCV) infection becomes chronic in 70% of patients, which represents a high rate of chronicity for a viral infection. Most patients with chronic hepatitis C are asymptomatic or may have nonspecific symptoms such as fatigue or malaise in the absence of hepatic synthetic dysfunction. Patients with decompensated cirrhosis from HCV infection frequently have symptoms typically observed in other patients with decompensated liver disease, such as sleep inversion and pruritus.
Symptoms characteristic of complications from advanced or decompensated liver disease are related to synthetic dysfunction and portal hypertension. These include mental status changes (hepatic encephalopathy), ankle edema and abdominal distention (ascites), and hematemesis or melena (variceal bleeding).
Symptoms often first develop as clinical findings of extrahepatic manifestations of HCV and most commonly involve the joints, muscle, and skin. In a large study of the extrahepatic manifestations of HCV, 74% of medical workers with HCV infection demonstrated extrahepatic manifestations, of which the following were the most common [46] :
Arthralgias (23%) Paresthesias (17%) Myalgias (15%) Pruritus (15%) Sicca syndrome (11%) In addition, sensory neuropathy has been reported as an extrahepatic manifestation in 9% of patients with HCV infection. [47] Risk factors for manifestations of extrahepatic chronic hepatitis C infection include advanced age, female sex, and liver fibrosis.
Patients also present with symptoms that are less specific and are often unaccompanied by discrete dermatologic findings. Pruritus and urticaria are examples of less specific clues to underlying HCV infection in the appropriate setting (eg, posttransfusion, organ transplantation, surgery, injection drug use, injury of the nasal mucosa from snorting cocaine through shared straws).
Patients with ongoing pathology associated with chronic hepatitis C that eventually results in organ failure can present with symptoms and signs in the skin. Pruritus, dryness, palmar erythema, and yellowing of the eyes and skin are examples of less specific findings in patients with end-stage liver disease with cirrhosis; these findings provide clues that lead to further evaluation of the underlying causes.
Chronic hepatitis C has a strong association with pruritus. Indeed, some authorities believe that all patients with unexplained pruritus should be investigated for HCV infection. [48]
Most patients with hepatitis C virus (HCV) infection do not have abnormal physical examination findings until they develop portal hypertension or decompensated liver disease. One exception is patients with extrahepatic manifestations of HCV infection, such as porphyria cutanea tarda or necrotizing vasculitis. Signs in patients with decompensated liver disease include the following:
Hand signs: Palmar erythema, Dupuytren contracture, asterixis, leukonychia, clubbing
Head signs: Icteric sclera, temporal muscle wasting, enlarged parotid, cyanosis
Fetor hepaticus
Gynecomastia, small testes
Abdominal signs: Paraumbilical hernia, ascites, caput medusae, hepatosplenomegaly, abdominal bruit
Ankle edema
Scant body hair
Skin signs: Spider nevi, petechiae, excoriations due to pruritus
Other common extrahepatic manifestations include the following:
Cryoglobulinemia Membranoproliferative glomerulonephritis Idiopathic thrombocytopenic purpura Lichen planus Keratoconjunctivitis sicca Raynaud syndrome Sjögren syndrome Porphyria cutanea tarda Necrotizing cutaneous vasculitis Approximately 10%-15% of affected patients have symptoms/signs such as weakness, arthralgias, and purpura; these are often related to vasculitis. The precise pathogenesis of these extrahepatic complications has not been determined, although most are the clinical expression of autoimmune phenomena
What guidelines have been published for the diagnosis of hepatitis C (hep C) infection?
WHO guidelines
The World Health Organization (WHO) recommends nucleic acid testing for qualitative or quantitative HCV RNA detection as well as for test of cure at 12 or 24 weeks following antiviral treatment completion. [50] In areas with limited resources, the WHO suggests using the aminotransferase/platelet ratio index (APRI) or the fibrosis-4 (FIB-4) score for evaluating hepatic fibrosis rather than other noninvasive tests that require more resources (eg, elastography, FibroTest), as follows [50] :
APRI = [(AST (IU/L)/AST_ULN (IU/L))×100]/platelet count (10 9 /L)
FIB-4= age (years) × AST (IU/L)/platelet count (10 9)/L × [ALT (IU/L)1/2]
where ALT is alanine aminotransferase, AST is aspartate aminotransferase, IU is international unit, and ULN is the upper limit of normal.
Serologic screening for HCV involves an enzyme immunoassay (EIA). These assays are 97% specific but cannot distinguish acute from chronic infection. A rapid antibody test for HCV is available. The recombinant immunoblot assay is used to confirm HCV infection.
A meta-analysis comparing point-of-care screening tests (POCTs) with rapid diagnostic tests (RDTs) indicated that POCTs are highly accurate for diagnosing hepatitis C. [51, 52] POCTs do not require special equipment or electricity and are more robust than RDTs at high temperatures; thus, they may enable expanded screening.
Healthcare personnel who sustain a needle-stick injury involving an HCV-infected patient should undergo PCR testing for HCV immediately and then every 2 months for 6 months. If HCV infection is diagnosed, therapy can be instituted.
Other baseline studies include the following [9] :
Complete blood cell (CBC) count with differential
International normalized ratio (INR)
Liver function tests, including levels of ALT and AST, alkaline phosphatase, albumin, and total and direct bilirubin
Calculated glomerular filtration rate (eGFR)
Thyroid function studies
Screening tests for coinfection with human immunodeficiency virus ( HIV) or hepatitis B virus (HBV)
Screening for alcohol abuse, drug abuse, and/or depression
Hepatitis B virus (HBV) testing with hepatitis B surface antigen (HBsAg) (to identify coinfection), as well as hepatitis B surface antibody (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) (for evidence of previous infection)
Serum pregnancy testing in women of childbearing age before initiating a treatment regimen that includes ribavirin or that includes direct-acting antiviral agents (DAAs) without ribavirin
The CBC demonstrates thrombocytopenia in approximately 10% of patients. Low thyroxine levels are found in approximately 10% of patients, as well. Stress testing may be necessary in appropriate patients. An ophthalmologic examination may also be necessary.
Qual è il trattamento dell’epatite C?
Antiviral therapy for chronic hepatitis C should be determined on a case-by-case basis. However, treatment is widely recommended for patients with elevated serum alanine aminotransferase (ALT) levels who meet the following criteria [6] :
Age older than 18 years
Positive HCV antibody and serum HCV RNA test results
Compensated liver disease (eg, no hepatic encephalopathy or ascites)
Acceptable hematologic and biochemical indices (hemoglobin at least 13 g/dL for men and 12 g/dL for women; neutrophil count >1500/mm 3, serum creatinine < 1.5 mg/dL)
Willingness to be treated and to adhere to treatment requirements
No contraindications for treatment
The two most frequently used recombinant interferon (IFN) preparations in clinical trials have been IFN alfa-2b (Intron-A) and IFN alfa-2a (Roferon-A), which differ from each other by only a single amino acid residue. IFN alfacon-1 (Infergen), or consensus IFN, is a genetically engineered compound synthesized by combining the most common amino acid sequences from all 12 naturally occurring IFNs.
Direct-Acting Antiviral Agents (DAAs)
Relatively recently, several antiviral agents have been developed to specifically target various sites of hepatitis C (HCV) viral replication. Similar to the antiretroviral drugs, these agents have been approved by the FDA in various combinations to interrupt HCV replication at different sites, with reported 90%-95% sustained virologic response (SVR) rates in treated patients versus 40%-55% in those completing treatment with dual-therapy pegylated interferon (PEG-IFN) plus ribavirin. [100] However, clinicians should be aware that baseline resistance-associated substitutions (RASs) may impair treatment response to direct-acting antiviral agents (DAAs), particularly baseline NS5A resistance in DAA-naïve HCV patients. [101]
Currently available agents and their target sites are outlined below.
NS3/4 targeting protease inhibitors
Simeprevir
Paritaprevir
Grazoprevir
Glecaprevir
NS5B targeting polymerase inhibitors
Nucleotide: Sofosbuvir
Non-nucleotide: Dasabuvir
NS5A targeting agents
Ledipasvir Ombitasvir Elbasvir Velpatasvir Pibrentasvir
