General description of viral hepatitis. Clinical description of viral hepatitis with fecal-oral mechanism of transmission. Acute and chronic viral hepatitis with the parenteral way of transmission.

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The problem of the viral hepatitis remains most actual, as these diseases according to spread step down only to acute respiratory and acute intestinal infections. Viral hepatitis is most frequent reason of chronic hepatitis and liver cirrhosis. In  some patients viral hepatitis may have lethal outcomes.

The problem of the viral hepatitis is present under fixed attention of many scientists of the whole world. At present time  definite successes in study of etiology, epidemiology, clinic, diagnostics of this polyetiological viral disease have been possessed.

Hepatitis, a general term referring to inflammation of the liver, may result from various causes, both infectious (ie, viral, bacterial, fungal, and parasitic organisms) and noninfectious (eg, alcohol, drugs, autoimmune diseases, and metabolic diseases); this article focuses on viral hepatitis, which accounts for more than 50% of cases of acute hepatitis in the United States.

In the United States, viral hepatitis is most commonly caused by hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV). These 3 viruses can all result in acute disease with symptoms of nausea, abdominal pain, fatigue, malaise, and jaundice. Additionally, HBV and HCV can lead to chronic infection. Patients who are chronically infected may go on to develop cirrhosis and hepatocellular carcinoma (HCC). Furthermore, chronic hepatitis carriers remain infectious and may transmit the disease for many years.

Other hepatotropic viruses known to cause hepatitis include hepatitis D virus (HDV) and hepatitis E virus (HEV). However, the term hepatotropic is itself a misnomer. Infections with hepatitis viruses, especially HBV and HBC, have been associated with a wide variety of extrahepatic manifestations. Infrequent causes of viral hepatitis include adenovirus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and, rarely, herpes simplex virus (HSV). Other pathogens (eg, virus SEN-V) may account for additional cases of non-A/non-E hepatitis.

Acute versus chronic viral hepatitis

The term viral hepatitis can describe either a clinical illness or the histologic findings associated with the disease. Acute infection with a hepatitis virus may result in conditions ranging from subclinical disease to self-limited symptomatic disease to fulminant hepatic failure. Adults with acute hepatitis A or B are usually symptomatic. Persons with acute hepatitis C may be either symptomatic or asymptomatic (ie, subclinical).

Typical symptoms of acute hepatitis are fatigue, anorexia, nausea, and vomiting. Very high aminotransferase values (>1000 U/L) and hyperbilirubinemia are often observed. Severe cases of acute hepatitis may progress rapidly to acute liver failure, marked by poor hepatic synthetic function. This is often defined as a prothrombin time (PT) of 16 seconds or an international normalized ratio (INR) of 1.5 in the absence of previous liver disease.

Fulminant hepatic failure (FHF) is defined as acute liver failure that is complicated by hepatic encephalopathy. In contrast to the encephalopathy associated with cirrhosis, the encephalopathy of FHF is attributed to increased permeability of the blood-brain barrier and to impaired osmoregulation in the brain, which leads to brain-cell swelling. The resulting brain edema is a potentially fatal complication of fulminant hepatic failure.

FHF may occur in as many as 1% of cases of acute hepatitis due to hepatitis A or B. Hepatitis E is a common cause in Asia; whether hepatitis C is a cause remains controversial. Although FHF may resolve, more than half of all cases result in death unless liver transplantation is performed in time.

Providing that acute viral hepatitis does not progress to FHF, many cases resolve over a period of days, weeks, or months. Alternatively, acute viral hepatitis may evolve into chronic hepatitis. Hepatitis A and hepatitis E never progress to chronic hepatitis, either clinically or histologically.

Histologic evolution to chronic hepatitis can be demonstrated in approximately 90-95% of cases of acute hepatitis B in neonates, 5% of cases of acute hepatitis B in adults, and as many as 85% of cases of acute hepatitis C. Some patients with chronic hepatitis remain asymptomatic for their entire lives. Other patients report fatigue (ranging from mild to severe) and dyspepsia.

Approximately 20% of patients with chronic hepatitis B or hepatitis C eventually develop cirrhosis, as evidenced by the histologic changes of severe fibrosis and nodular regeneration. Although some patients with cirrhosis are asymptomatic, others develop life-threatening complications. The clinical illnesses of chronic hepatitis and cirrhosis may take months, years, or decades to evolve.

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Hepatitis A (HAV)

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Agent  was first discovered in 1973 by Feinstone. This is RNA-containing virus. Complete viral bodies as well as empty parts (capsules) with size of 27-30 nm can be noticed under electronic microscope. On their surfaces capsomeres are seen. Nucleopeptide of VHA(Fig.1) does not possess surface projections and covering. Core structure is not revealed in the virion.

Virus contains 4 peptides (VP1-4), participating  in reactions of immune precipitation. It is assumed that VP1 and VP3 are located pertly on the surface and VP2 and VP4 are present inside the virion. However, up till date, there is not authentic informations about their meaning in relation to antiqenicity and immunogenicity.

 

msotw9_temp0

Fig.1. Electronic microscopy (negative contrast)  hepatitis virus A

VHA is stable during pH 3,0-9,0, sensitive to formaldehyde, may remain preserved for a period of few months or even years during temperature  + 4 °C, for weeks - during room temperature. Complete inactivation  of virus takes place during 85 °C in a period of 5 minutes. VHA is resistant to chlorine, in comparison with other viruses of this group and may enter through barriers of water cleaning stations. Complete inactivation of virus steps on during concentration of chlorine 2,0 - 2,5 mg/l with exposition for a period of 15 minutes, of lime chloride - 10 mg/l through 15 minutes.

Virus of hepatitis A may reproduce in number of human and monkey cellular cultures, from where viral antigen is obtained. It is necessary to remark, that successful adaptation of VHA towards culture of cells is very much necessary for study of biological properties, for obtaining of source of reagents for diagnostics (antigen, antiserum), as well as for construction of vaccines, (live, killed).

Pathophysiology

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 liver cells. 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, and chlorine and iodine are similarly effective.

Hepatitis A virus as viewed through electron microHepatitis A virus as viewed through electron microscopy.

Various genotypes of HAV exist; however, there appears to be only 1 serotype. Virion proteins 1 and 3 are the primary sites of antibody recognition and subsequent neutralization. No antibody cross-reactivity has been identified with other viruses causing acute hepatitis.

Liu et al performed phylogenetic and recombination analyses on 31 complete HAV genomes from infected humans and simians. They identified 3 intra-genotypic recombination events (I-III), which they believe demonstrate that humans can be co-infected with different HAV subgenotypes.

Hepatocyte uptake involves a receptor, identified by Kaplan et al, on the plasma membrane of the cell, and viral replication is believed to occur exclusively in hepatocytes. The demonstration of HAV in saliva has raised questions about this exclusivity. After entry into the cell, viral RNA is uncoated, and host ribosomes bind to form polysomes. Viral proteins are synthesized, and the viral genome is copied by a viral RNA polymerase (see the image below). Assembled virus particles are shed into the biliary tree and excreted in the feces.

Hepatitis A.

Minimal cellular morphologic changes result from hepatocyte infection. The development of an immunologic response to infection is accompanied by a predominantly portal and periportal lymphocytic infiltrate and a varying degree of necrosis.

Many authorities believe that hepatocyte injury is secondary to the host’s immunologic response. This hypothesis is supported by the lack of cytotoxic activity in tissue culture and correlations between immunologic response and manifestations of hepatocyte injury.

Person-to-person contact is the most common means of transmission and is generally limited to close contacts. Transmission through blood products has been described. The period of greatest shedding of HAV is during the anicteric prodrome (14-21 d) of infection and corresponds to the time when transmission is highest (see the image below). Recognizing that the active virus is shed after the development of jaundice is important, although amounts fall rapidly.

Outbreaks of acute hepatitis A have received international attention. The most notable report of transmission appeared in the New England Journal of Medicine. This report described a point source epidemic of HAV infection at a Pennsylvania restaurant where the vehicle for transmission was green onions used to make a mild salsa. The contamination of the onions occurred before the vegetable arrived in the United States.

The incubation period usually lasts 2-6 weeks, and the time to onset of symptoms may be dose related. The presence of disease manifestations and the severity of symptoms after HAV infection directly correlate with patient 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.

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 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.

Prodrome

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.

Icteric phase

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. Itch (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

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).

Hepatitis B (HBV)

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Background

In 1965, Blumberg et al reported the discovery of the hepatitis B surface antigen (HBsAg), also known as Australia antigen, and its antibody, hepatitis B surface antibody (HBsAb). A few years later, in 1970, Dane visualized the hepatitis B virus (HBV) virion.[1] Since then, considerable progress has been made regarding the epidemiology, virology, natural history, and treatment of this hepatotropic virus. The image below depicts a liver biopsy specimen.

Liver biopsy specimen showing the ground-glass appearance of hepatocytes in a patient with hepatitis B.

Hepatitis B is a worldwide healthcare problem, especially in developing areas. An estimated one third of the global population has been infected with the hepatitis B virus (HBV). Approximately 350 million people are lifelong carriers, and only 2% spontaneously seroconvert annually. Ongoing vaccination programs appear to be promising in the attempt to decrease the prevalence of HBV disease.

The hepatitis B virus (HBV) is transmitted hematogenously and sexually. The outcome of this infection is a complicated viral-host interaction that results in either an acute symptomatic disease or an asymptomatic disease. Patients may become immune to HBV, or they may develop a chronic carrier state. Later consequences are cirrhosis and the development of hepatocellular carcinoma (HCC).

Antiviral treatment may be effective in approximately one third of the patients who receive it, and for selected candidates, liver transplantation currently seems to be the only viable treatment for the latest stages of hepatitis B.

Pathophysiology

Hepatitis B virus (HBV) is a hepadnavirus. It is an extremely resistant strain capable of withstanding extreme temperatures and humidity. HBV can survive when stored for 15 years at –20°C, for 24 months at –80°C, for 6 months at room temperatures, and for 7 days at 44°C.

Viral genome

The viral genome consists of a partially double-stranded, circular DNA of 3.2 kilobase (kb) pairs that encodes 4 overlapping open reading frames, as follows:

An upstream region for the S (pre-S) and C (pre-C,) genes has been found. The structure of this virion is a 42-nm spherical, double-shelled particle consisting of small spheres and rods, with an average width of 22 nm.

The S gene encodes the viral envelope. There are 5 mainly antigenic determinants: (1) a, common to all hepatitis B surface antigen (HBsAg), and (2-5) d, y, w, and r, which are epidemiologically important. 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, comes from the core gene and is a marker of active viral replication. Usually, HBeAg can be detected in patients with circulating serum HBV DNA.

The best indication of active viral replication is the presence of HBV DNA in the serum. Hybridization or more sensitive polymerase chain reaction (PCR) techniques are used to detect the viral genome in the serum.

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.

Antibody production

The production of antibodies against HBsAg 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 is detected in almost every patient with previous exposure to HBV. The immunoglobulin M (IgM) subtype is indicative of acute infection or reactivation, whereas the IgG subtype is indicative of chronic infection. With this marker alone, one cannot understand the activity of the disease. Antibody to HBeAg is suggestive of a nonreplicative state and one in which the antigen has been cleared.

Variant strains

With the newest PCR techniques, scientists are able to identify variations in the HBV genome (variant strains). Mutations of various nucleotides such as the 1896 (precore/core region) processing the production of the HBeAg have been identified (HBeAg negative strain). The prevalence of the HBeAg negative virus varies among different areas. Estimates indicate that 50-60% of the patients from Southern Europe, the Middle East, Asia, and Africa as well as 10-30% of patients in the United States and Europe who have chronic HBV infection have been infected by this strain.

Immune response

The pathogenesis and clinical manifestations of hepatitis B are due to the interaction of the virus and the host immune system. The immune system attacks HBV and causes liver injury. Activated CD4+ and CD8+ lymphocytes recognize various HBV-derived peptides located on the surface of the hepatocytes, and an immunologic reaction occurs. 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 final state of HBV disease is cirrhosis. Patients with cirrhosis and HBV infection are likely to develop hepatocellular carcinoma (HCC). In the United States, the most common presentation is that of patients of Asian origin who acquired the disease as newborns (vertical transmission).

Viral life cycle

Four different stages have been identified in the viral life cycle of hepatitis B and are briefly discussed below.

Stage 1

The first stage is immune tolerance. The duration of this stage for healthy adults is approximately 2-4 weeks and 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

In the second stage, an inflammatory reaction with a cytopathic effect occurs. HBeAg can be identified in the sera, and a decline of the levels of HBV DNA is seen. 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.

Stage 3

In the third stage, the host can target the infected hepatocytes and HBV. Viral replication no longer occurs, and HBeAb can be detected. The HBV DNA levels are lower or undetectable, and aminotransferase levels are within the reference range. In this stage, an integration of the viral genome into the host's hepatocyte genome takes place. HBsAg still is present.

Stage 4

In the fourth stage, the virus cannot be detected and antibodies to various viral antigens have been produced. Different factors have been postulated to influence the evolution of these stages, including age, sex, immunosuppression, and coinfection with other viruses.

Genotypes and disease progression

Eight different genotypes (A through H) representing a divergence of the viral DNA at around 8% have been identified. 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.

It is reported that the risk of HCC might be higher with an increasing level of HBV viral load and the presence of genotype C and common variants in the precore and basal core promoter regions.

Dong et al developed a novel in vitro 1.5X HBV replication system that was capable of consistently generating a high level of HBV. Although the investigators believed this system would help compare the replication capacity among the virus strains associated with high and low risk of HCC, there was no significant difference in the replication capacities among these strains in vitro. The investigators concluded that the HBV-1.5X system may be a useful platform in helping to establish stable cell lines and transgenic mice for the investigation of viral pathogenesis, particularly for the various strains of HBV.

VHB in natural condition is revealed in sick people and carriers, in forest marmots, in carth squirrels, in Peiking ducks. This DHA-containing virus (Fig.2) is pathogenic for human and few types of primates – chimpanzee, gorillas. VHB causes acute and persistent infection, primarily damages liver.

Virus consists of nucleus and covering. Further antigenic structure of VHB is differentiated: HBsAg – surface, HBcAg – internal (care), HBeAg – reflects infectiouness of virus.

Towards these  antigens in organism of patients antibodies are produced: anti-HBs; anti-HBc; anti-HBe.

Presence of HBsAg   in human organism testifies the presence of acute and latent proceeding infection. It  is  assumed, that  prolonged  conservation HbsAg  in  serum  of  the  blood  in  sick  man  may  testify  about transfer  of  the  process  into  chronic  form.  HBsAg is revealed in majority of patients in incubation stage. HBcAg is practically not determined in blood and fixed in directly by DNA-polymerize reactions, falling positive in acute period of disease, as well as after many months and years in carriers. Soon after discovery of HBsAg in blood of patients anti-HBc appear. Most often they are observed in carriers of infection. In early stages of disease HBeAg is revealed, which is then changed by anti-HBe.

Very important diagnostic information may be obtained by using methods of determination of DNA HB. For this purpose molecular hybridization of nucleic acids and polymerize chain reaction (PCR) is used. Genospecific viral DNA is observed in serum of blood, in bioptates of  liver, in lymphocytes of peripheral blood. Mentioned method enables to discover very small quantities of viral DNA in investigated samples, which moderately increases reliability of diagnosis.

hbv2

Fig.2. Electronic microscopy (negative contrast)  hepatitis virus B

The spectrum of the symptomatology of hepatitis B disease varies from subclinical hepatitis to icteric hepatitis to hyperacute, acute, and subacute hepatitis during the acute phase, and from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) during the chronic phase.

Acute phase

The incubation period is 1-6 months in the acute phase.

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:

Patients with hyperacute, acute, and subacute hepatitis may present with the following:

Chronic phase

Patients with chronic hepatitis B disease can be healthy carriers without any evidence of active disease, and they also are asymptomatic.

Patients with chronic active hepatitis, especially during the replicative state, may complain of symptomatology such as the following:

Physical Examination

The physical examination findings in hepatitis B disease vary from minimal to impressive (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:

The physical examination of patients with chronic hepatitis B virus (HBV) infection can reveal stigmata of chronic liver disease such as the following:

Patients with cirrhosis may have the following symptoms:

Staging

Liver damage is graded according to the inflammatory component and is described as follows:

Liver damage staging (ie, fibrosis) is described as follows:

Stage 3 – Septal, bridging fibrosis (see the image below)

Stage 4 – Cirrhosis (see the following image)

 

Hepatitis C  (VHC)

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Practice Essentials

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 3% of the world’s population has been infected with HCV and that there are more than 170 million chronic carriers who are at risk of developing liver cirrhosis and/or liver cancer.

Essential update: Pegylated interferon/ribavirin reduces mortality in patients coinfected with HIV and HCV

In patients coinfected with HCV and human immunodeficiency (HIV) with compensated cirrhosis, sustained virologic response (SVR) to treatment with pegylated interferon plus ribavirin significantly reduces the incidence of liver-related decompensations and overall mortality, according to a recent study. In a prospective cohort study of 166 coinfected patients, 2 (4.6%) patients with SVR to pegylated interferon/ribavirin developed liver decompensation, compared to 33 (26.8%) patients without SVR. The probability of developing hepatic decompensation was 0% at 1 year and 4% at 3 years for SVR patients, compared with 15% and 32%, respectively, for non-SVR patients. Two (4.6%) patients with SVR to interferon/ribavirin died due to any cause, compared to 22 (17.9%) patients without SVR. The probability of overall mortality in the SVR group was 0% at 1 year and 4% at 3 years, whereas the probability in the non-SVR group was 12% at 1 year and 20% at 3 years.[1]

Signs and symptoms

Initial symptoms of hepatitis C are often extrahepatic, most commonly involving the joints, muscle, and skin. Examples include the following:

Symptoms characteristic of complications from advanced or decompensated liver disease are related to synthetic dysfunction and portal hypertension, such as the following:

Physical findings usually are not abnormal until portal hypertension or decompensated liver disease develops. Signs in patients with decompensated liver disease include the following:

Other common extrahepatic manifestations include the following:

Diagnosis

General baseline studies in patients with suspected hepatitis C include the following:

Tests for detecting hepatitis C virus (HCV) infection include the following:

Liver biopsy is not mandatory before treatment but may be helpful. Some restrict it to the following situations:

Management

Treatment of acute hepatitis C includes the following:

The 2 goals of treatment of chronic hepatitis C are as follows :

Treatment of chronic hepatitis C includes the following:

Recommendations for nonresponse or relapse include the following:

Image library

Diagnostic algorithm for hepatitis C virus infection.

 

 

Pathophysiology

The cause of hepatitis C, HCV, is a spherical, enveloped, single-stranded RNA virus belonging to the Flaviviridae family and Flavivirus genus. 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 at least 50% of hepatocytes may be infected with HCV in patients with chronic hepatitis C.

RNA-dependent RNA polymerase, an enzyme critical in HCV replication, 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.

Virion of virus of hepatitis C consists of nucleus and lipid external membrane. Genome is represented by single chain RNA. VHC is heavily resistant in external medium, particularly in biological fluids such as preparations of blood, sperm and others.  It is sensitive to chloroform, to other desinfective solutions and high temperatures (100 °C and more).

Antigenic structure of VHC is less studied. It is established, that to the antibodies are produced (class Ig M and G) to virus in the organism of the patient. Their discovery in blood serum of patient testifies presence of acute or chronic disease. Antibodies may stick to definite level during 6-9 months, and thereafter their titers in serum decrease upto complete disappearance.

History

Acute hepatitis C (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 infection 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. The most commonly occurring extrahepatic manifestations were as follows:

In addition, sensory neuropathy has been reported as an extrahepatic manifestation in 9% of patients with HCV infection. 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, intravenous 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. Patients with the mucosa-associated lymphoma tumors (MALT) syndrome itself tend to have bowel symptoms.

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.

The hepatitis C virus (HCV) is an RNA virus. HCV is a major cause of both acute and chronic hepatitis. Persons become infected mainly through parenteral exposure to infected material by blood transfusions or injections with nonsterile needles. Persons who inject illegal drugs, people who snort cocaine with shared straws, and health care workers who are at risk for needlestick and other exposures are at highest risk for HCV infection. Another major risk factor for HCV is high-risk sexual behavior. The incidence of acute HCV infection has sharply decreased in the United States during the past decade, but its prevalence remains high (approximately 2.7 million Americans) because chronic hepatitis C (CHC) infection develops in approximately 75% of patients acutely infected.

Most patients with acute and chronic infection are asymptomatic. Patients and health care providers may detect no indications of the 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 underlying HCV infection.

Cutaneous symptoms or findings relevant to HCV infection manifest in 20-40% of patients presenting to dermatologists and in a significant percentage (15-20%) of general patients. HCV is suggested and must appear in the differential diagnosis of these patients to avoid missing this important but occult factor in clinical disease in the appropriate setting.

Extrahepatic manifestations of hepatitis C virus are numerous.[1] The most prevalent and most closely linked with HCV is essential mixed cryoglobulins with dermatologic, neurologic, renal, and rheumatologic complications. A less definite relationship to HCV is observed with systemic vasculitis, porphyria cutanea tarda, and the sicca syndromes.

HCV is a major public health problem because it causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). HCV also induces extrahepatic manifestations such as mixed cryoglobulinemia, porphyria cutanea tarda, leukocytoclastic vasculitis, lichen planus (LP), and sicca syndrome, all of which should be regarded as early markers of a potentially fatal chronic liver disease.

Chronic hepatitis C infection is associated with many extrahepatic manifestations in joints, muscles, neural and gastrointestinal tissues, and skin. In this article, the many dermatologic manifestations of hepatitis C virus (HCV) are classified according to diseases with proven or suspected etiology or causation.

Primary causation results from direct infection of HCV in the skin, lymphocytes, dendric antigen-presenting cells, and blood vessels. An example of this type of disorder is the recent finding of epidermal cells with HCV-RNA particles.

Secondary causation occurs when HCV infection manifests in the skin due to epiphenomena resulting from the disruption of immune responses. Leukocytoclastic vasculitis due to cryoglobulinemia is a good example of a specific skin manifestation resulting from the production of immunoglobulins, with rheumatoid characteristics causing an immune complex–mediated vasculitis.

Tertiary causation of dermatologic manifestations results when the disruption of another organ infected or affected by HCV causes skin manifestations that are nonspecific and typical of skin responses to that organ; these responses result from a wide range of causes, including flushing and other findings of thyroid hormone release in early HCV-linked autoimmune thyroiditis. Chronic active hepatitis leading to fibrotic liver disease in chronic hepatitis C infection can also cause cutaneous vascular changes, such as spider nevus and palmar erythema. Arteriovenous hemangioma, a benign acquired cutaneous vascular lesion, has also been reported to be associated with chronic liver disease, including chronic active hepatitis associated with HCV infection.

Another category of dermatologic manifestations in HCV infections in a causative schema includes those diseases in which an association has been identified, but the details of causation have not yet been clarified. Porphyria cutanea tarda (PCT) is a good example of this type of HCV-related disease in which causation is unexplained but undeniable. In patients with PCT, 70% are HCV positive.

Neoplastic dermatologic manifestations are another category of extrahepatic findings.

Dermatologic manifestations are associated with treatments of HCV infection, especially interferon.

The last category is suspected associations of the disorder in a causative schema. HCV genomic analysis by means of arduous gene sequencing of many viruses has led to the division of HCV into genotypes based on homology. Arabic numerals denote the genotype, and a letter denotes the subtype for lesser homology within each genotype.

History

Chronic hepatitis C infection occurs after the acute infection in 70% of patients with hepatitis C virus (HCV), which represents a high rate of chronicity for a viral infection. The development of chronic infection is not matched by the development of symptoms. Patients with chronic hepatitis C infection often have no symptoms for long periods.

Symptoms often first develop as clinical findings of extrahepatic manifestations of HCV. In a large study of the extrahepatic manifestations of HCV, 74% of medical workers with HCV infection demonstrated extrahepatic manifestations. Arthralgias (23%), paraesthesias (17%), myalgias (15%), pruritus (15%), and sicca syndrome (11%) were the most commonly occurring extrahepatic manifestations.

Cryoglobulinemia was demonstrated in 50% of patients, and HCV is the most common cause of this condition. Vasculitis, arterial hypertension, purpura, LP, arthralgias, and low thyroxine levels were associated with titers positive for cryoglobulin. Biologic manifestations common to chronic hepatitis C infection include titers positive for serum cryoglobulins (40-56%), antinuclear antibody (ANA) (10%), low thyroxine (10%), and anti–smooth muscle antibody (7%). Risk factors for manifestations of extrahepatic chronic hepatitis C infection include advanced age, female sex, and liver fibrosis.

Symptoms and clinical findings are most common in the joints, muscle, and skin. Arthralgias occurred in 20% of patients, skin manifestations in 17%, sicca syndrome in 23%, and sensory neuropathy in 9%.

Thrombocytopenia occurs in approximately 10% of patients. One or more autoantibodies frequently occur in chronic hepatitis C infection; these autoantibodies include ANA (41%), rheumatoid factor (38%), anticardiolipin antibody (27%), antithyroid antibody (13%), and anti–smooth muscle antibody (9%). One autoantibody was present in 70% of sera.

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, intravenous drug use, injury of the nasal mucosa from snorting cocaine through shared straws).

Patients with ongoing pathology associated with chronic hepatitis C infection 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.

Patients with the mucosa-associated lymphoma tumors (MALT) syndrome itself tend to have bowel symptoms.

Chronic hepatitis C may be associated with pruritus to the extent that some authorities believe that patients with unexplained pruritus should be investigated for HCV infection.[19]

Dermatologic manifestations of HCV infection

Primary dermatologic disorders associated with chronic hepatitis C infection

Lichen planus

LP is a pruritic papulosquamous disorder involving the skin, scalp, nails, oral mucosa, and genitalia.

The lesions and pathology are often typical unlike many papulosquamous skin disorders, such as seborrhea, atopic dermatitis, and contact dermatitis; these skin disorders have scaling, erythema, and pruritus and are included in the differential diagnosis of LP but lack its pathologic and clinical specificity. Intracellular HCV infection of epithelial cells is proven for LP.

Often, the papular lesions of LP suddenly appear on the volar acral surfaces of the wrists and arms and are pruritic. Oral symptoms are less common, but painful erosions can occur in oral lichen planus (OLP). Hair loss in lichen planopilaris, exquisite pruritus of markedly hypertrophic plaques on the lower legs in hypertrophic LP, and painful genital erosions can be presenting findings.

The prevalence of oral, cutaneous, pharyngeal, and/or vulval LP in 87 HCV-infected patients was 19.5%.Another study found no significant association between cutaneous lichen planus and HCV infection.

A retrospective analysis of 808 Italian patients with oral lichen planus showed that 137 of them were infected with HCV.

Note the images below:

Lichen planus. Courtesy of Walter Reed Army MedicaLichen planus. Lichen planus. Courtesy of Walter Reed Army MedicaLichen planus. Lichen planus. Courtesy of Walter Reed Army MedicaLichen planus. Lichen planus (hypertrophic type). Courtesy of WalLichen planus (hypertrophic type).

Lichen planus (oral lesions). Courtesy of Walter RLichen planus (oral lesions). Lichen planus (volar wrist). Courtesy of Walter ReLichen planus (volar wrist).

Acral necrolytic erythema

The symptomatology of acral necrolytic erythema includes pruritus associated with recurrent, erythematous, papular eruptions with blisters and erosions on the dorsal aspects of the feet and ankles. Pain is common with variable-sized erosions. Chronic lesions are hyperkeratotic plaques with erosions and peripheral erythema preferring the acral parts of the legs. These lesions provide unusually specific markers for HCV infection.

Sialadenitis

Symptoms include dry eye and sicca syndrome due to chronic destruction of the major and minor salivary glands by capillaritis.

Mooren corneal ulceration

Serious corneal ulcerations are often linked to HCV infection. Cross-reactivity to the HCV envelope protein and a corneal antigen appears to be causative. Pain, lacrimation, and loss of sight result.

Leukocytoclastic reactions (some)

This tends to appear as an eruption of palpable purpura on the lower extremities. It may represent an HCV immune complex disease.

Secondary dermatologic disorders of chronic hepatitis C resulting from perturbations of the immune system

Cryoglobulinemia

Leukocytoclastic vasculitis occurs with type II mixed cryoglobulinemia in the skin and mucous membranes. Leukocytoclastic vasculitis also occurs with necrotizing small vessel vasculitis of the skin, kidneys, joints, and eyes. Disorders of this type belong to a group termed mixed cryoglobulinemia syndrome. These disorders display palpable purpura of the legs (which is worse distally and inferiorly), livido reticularis, ulcerations, urticaria, symmetric polyarthritis, myalgias, cutis marmorata, and fatigue. The symptomatology is pruritus, pain, or Raynaud phenomenon resulting from vasculitic sludging in the postcapillary venules of immunologic material.

In all cases of cryoglobulinemia, an inflammatory reaction occurs with an influx of polymorphonuclear cells. Variable vascular damage and occlusion results in worsening degrees of pathology and symptoms; such pathology includes livido vasculitis with perturbation of superficial and deep vascular reflexes and mottling blue changes of the skin (cutis marmorata); pruritus; painful ulcerations of significant size resulting from arteriolar occlusion; and through-and-through necrosis of epidermis, dermis, and fat. Significantly, HCV localized to the intravascular debris and recently to the vessel wall establishes specificity to these reactions. Perhaps the clinical variability of vasculitic reactions is related to the degree of specificity of the vasculitis.

Urticarial vasculitis with HCV infection presents with painful urticarial blanching plaques of the limbs and chest that fade to residual hyperpigmented areas. The 2 cases presented lacked cryoglobulins. Complete disappearance of arthralgias and skin and liver disease occurred with clearance of HCV infection, suggesting that urticarial vasculitis may result from HCV immune complex disease.

Note the images below:

Cold agglutinin disease indistinguishable from cryCold agglutinin disease indistinguishable from cryoglobulinemia. Cryoglobulinemia, palpable purpura, dysproteinemicCryoglobulinemia, palpable purpura, dysproteinemic purpura, and leukocytoclastic vasculitis (small vessel vasculitis).

Sialadenitis

Dry mouth without dry eyes is the most prominent symptom of sialadenitis associated with HCV infection. Sialadenitis is an inflammatory disorder of the salivary, parotid, sublingual, and minor glands. Findings include xerostomia resulting from a chronic lymphocytic infiltrate and destruction of the salivary glands. Sjögren disease and its markers ssRo and ssLa are not found. As many as 15% of patients with chronic hepatitis C infections have sicca syndrome.

Mooren corneal ulcer

Serious corneal ulcerations begin at the rim or periphery and can progress singly or multiply and bilaterally to destroy the cornea. Symptoms of ulceration are eye pain, inflammation, tearing, and loss of vision due to corneal opacity and destruction.

Antiphospholipid syndrome

This is a serious multisystemic illness resulting from pathologic production of the antiphospholipids anticardiolipin and lupus anticoagulant. These IgG molecules (sometimes IgM or immunoglobulin A [IgA] in less severe variants) bind to platelets, vascular endothelium, beta-2 lipoproteins, prothrombin, and other phospholipids. The resultant pathologic processes depend on the locale of the process. Severe coagulopathies in the eye, the brain, the kidney, and large vessels result in symptomatology referable to vascular destruction or bleeding in these organs.

Tertiary dermatologic disorders

These are nonspecific disorders manifesting as a result of organ failure or disease of the skin associated with organ diseases. Symptoms are those of disease in the specific organs, as follows:

Dermatologic manifestations in which the exact pathogenesis is not further specified

Behçet syndrome

Symptoms form the major criteria for diagnosis of this disorder (see Behcet Disease). Findings for the major criteria include recurrent oral ulcerations appearing in young adults in their 20s and 30s with uveitis and genital ulcerations. Organs involved include the eyes, brain, lungs, GI tract, and kidneys. Aphthae and genital ulcerations are painful erosions. Uveitis causes pain, vision problems, and lacrimation, as well as other symptoms.

Canities

Graying of hair occurs with various conditions as well as naturally with aging.

Prurigo (prurigo nodularis)

Prurigo nodularis appears as a heaped keratotic inflammatory nodule on the extensor surfaces of the arms, legs, and trunk. Lesions are pruritic, and patients find themselves incessantly picking them with their fingers and nails.

Note the images below:

Prurigo nodularis. Courtesy of Walter Reed Army MePrurigo nodularis. Prurigo nodularis. Courtesy of Walter Reed Army MePrurigo nodularis

Prurigo nodularis. Courtesy of Walter Reed Army MePrurigo nodularis.

Vitiligo. Courtesy of Walter Reed Army Medical CenVitiligo.

Polyarteritis nodosa

PAN is a rare systemic vasculitis caused by necrotizing lesions in small- and medium-sized arteries of the skin, nerves, muscles, joints, kidneys, liver, and GI tract. More often associated with HBV infection, PAN results from aneurysmal dilatation, hemorrhage, or ulceration in the affected artery. In PAN, false-positive results for HCV are more common than true positive results for HCV. Protean manifestations result. Major systemic symptoms of fever, malaise, and prostration occur. Clinical manifestations result from organ involvement. Skin nodulation, ulceration, and palpable purpura are common. Mononeuritis multiplex is a common presentation. Acute muscle and abdominal pain and hypertension often occur.

HCV-polyarteritis nodosa represented about one fifth of HCV vasculitis in one series, tending to be severe with an acute clinical presentation yet with a good clinical remission rate.

Pruritus

Extrahepatic manifestations of HCV infection occur in 74% of patients. Pruritus is one of the most common symptoms, occurring in 15% of patients. A study of HCV infection with pruritus showed that nonspecific lesions were associated with pruritus in two thirds of patients. Urticaria occurred in 5 of 29 patients, with urticarial vasculitis occurring in 1 patient. Atopic dermatitis occurred in 2 of 29 patients with HCV infection. LP was present in 4 of 29 patients, and cryoglobulinemia was present in 10 of 29 patients. Most patients in this group had xerosis and keratosis pilaris that were easily alleviated with emollients. Prurigo nodularis is more common in patients with HCV and pruritus than in other patients.

Urticaria and urticarial vasculitis

A study of 79 patients with urticaria detected anti-HCV antibody in 24% and HCV RNA in 22%. Genotype 1b was present in 71% of patients; genotype 2a, in 24%; and genotype 2b, in 6%. In patients with HCV, urticaria tends to last longer than the typical few hours, is associated with worse liver status, and leaves a brown stain. Clinical findings of urticaria are identical to those of hives.

Note the images below:

Chronic urticaria. Courtesy of Walter Reed Army MeChronic urticaria. Urticaria (secondary to penicillin). Courtesy of WUrticaria (secondary to penicillin).

Erythema nodosum

A nonspecific association, erythema nodosum (EN) has multiple causes considered in the differential diagnosis, including viral infections. EN appears as erythematous, tender, dome-shaped elevations on the skin on the lower legs. EN lesions can be single or multiple, and they can demonstrate a reaction pattern on the skin resulting from panniculitic inflammation generated by various pathologic sources (eg, infections with bacteria, mycobacteria, Protozoa, fungi, viruses).

Erythema nodosa. Courtesy of Walter Reed Army MediErythema nodosa. Erythema nodosa. Courtesy of Walter Reed Army MediErythema nodosa. Courtesy of Walter Reed Army Medical Center Dermatology.

Erythema multiforme[41]

Bull's-eye lesions characterize the skin reaction pattern of erythema multiforme (EM). EM can be asymptomatic, pruritic, or burning. As an immune response to adverse antigenic stimuli from endogenous or exogenous sources, the response can be limited to a few, many, or widespread urticarial lesions with surrounding erythema and central deeply erythematous spots. Overwhelming reactions of this type include oral and anal ulcerations, systemic symptoms, and prostration; this condition is termed Stevens-Johnson syndrome. HCV infection is just one of many possible causes of EM.

Note the images below:

Erythema multiforme. Courtesy of Walter Reed Army Erythema multiforme.

Erythema multiforme. Courtesy of Walter Reed Army Erythema multiforme.

Erythema multiforme. Courtesy of Walter Reed Army Erythema multiforme.

Erythema multiforme of the oral mucosa. Courtesy oErythema multiforme of the oral mucosa.

Erythema multiforme (Stevens-Johnson syndrome). CoErythema multiforme (Stevens-Johnson syndrome).

Autoimmune thrombocytopenia

Symptoms of low platelet counts occur with petechiae and purpura. Ecchymosis occurs without symptoms. Bland petechial and ecchymotic hemorrhage must be included in the differential diagnosis.

Leukocytoclastic vasculitis

Leukoclastic vasculitis occurs as a result of circulating immune complexed depositing with endothelial cell gaps in the skin and mucous membranes. The antigen is usually not known or determined, although it may be HCV.

Dermatologic manifestations of chronic hepatitis C infection in which the cause is unknown

Porphyria cutanea tarda

PCT develops in patients who have 1 or more of the risk factors for PCT; the risk factors include exposure to chemical or toxic agents or drugs, iron overload, or excessive alcohol intake. PCT is manifested by blisters, vesicles, and milia on the acral dorsal surfaces of the extremities, especially the tops of the hands.

Hypertrichosis of the temples, pigmentary changes, scarring, sclerodermatous changes, chloracne, ulcerations, and dystrophic calcifications are commonly the result of skin fragility with symptoms of epidermolysis bullosa.

Uroporphyrins and hepatocarboxyl porphyrins collect in the skin, bones, and teeth after they spill into the blood once the liver is saturated. These pigments, found in the plasma, fluoresce and turn the urine dark red from renal excretion. Mild elevations in the levels of these substances and in urinary aminolevulinic acid (ALA) also occur, but porphobilinogen (PPG) levels are in the reference range.

Variegate porphyria and hereditary coproporphyria have the same clinical presentation, but PPG levels are elevated in these conditions. The prevalence of PCT is related to the relative prevalence of HCV and major hemochromatosis and other iron overload genetic abnormalities.

In southern Europe where HCV is prevalent, 70-90% of patients with PCT have positive results for HCV. Patients with familial PCT had negative results for HCV in one study. All patients with PCT with HCV had active multiplication of HCV.

In northern Europe, Australia, and England where the prevalence of HCV is lower, 20% of patients with PCT have detectable levels of HCV. In these countries, PCT is more closely related to the higher prevalence of the hemochromatosis gene abnormality.

In the United States, the prevalence of HCV in patients with PCT is intermediate at 56%.

Dermatologic manifestations of malignancies associated with chronic hepatitis C disease

Non-Hodgkin B-cell lymphoma

A high prevalence (20-40%) of HCV antibodies occurs in non-Hodgkin B-cell lymphoma (NHLB), and the antibodies are not present in other lymphomas or hematologic malignancies. Lymphomas producing cryoglobulins and low-grade mucosa-associated lymphoma tumors (ie, MALT syndrome) of the GI tract are associated with dermatologic manifestations. Antigen-driven B-cell proliferation from chronic stimulation is the proposed mechanism. NHLB presents like other lymphomas, with lymphoidal masses, gut associated masses, and symptoms of cryoglobulinemia with palpable purpura and ulcers of the lower legs.

MALT syndrome

A study concerning the association of HCV and NHLB showed a prevalence of HCV of 37%. Patients were older, and more patients were female than male. A closer association to immunocytoma than to MALT syndrome was found. In 20 patients with immunocytoma, 13 had HCV infection, and localization to the orbit and mucosal surfaces was more common. HCV localized to a parotid lymphoma associated with a mixed cryoglobulinemia showed viral proliferation in parotid epithelial cells and not in NHLB cells.

Epstein-Barr virus and herpesvirus type 6 are the other sialotropic viruses not present in the reported cases. Local carcinogenic functions of HCV, effect on the p53 system, immunoregulation perturbations, and malignant transformation were considered in the etiology of the conditions.

HCV patients with B-cell lymphoma and Sjögren syndrome have a high frequency of parotid enlargement and vasculitis, an immunologic pattern overwhelmingly dominated by the presence of rheumatoid factor and mixed type II cryoglobulins, a predominance of MALT lymphomas, and an elevated frequency of primary extranodal involvement in organs in which HCV replicates (eg, exocrine glands, liver, stomach).

Hepatoma

The progression of HCV infection to chronic hepatitis C infection and then to hepatocellular carcinoma is a well-known sequence. The chronicity of HCV infection occurs in 60% of patients infected by the virus overall, but the rate increases to more than 90% in type 1b infection. Worse hepatocellular disease also resulted from type 1b infections. Hepatic cirrhosis is correlated with inoculation size, being more common in patients with HCV-infected blood transfusions (23%) and organ transplantation than in users of intravenous drugs (9%). Viral species variation, complications, and host antibody response vigor have a role in chronic infection. Cirrhosis develops in approximately 15-20% of patients with chronic hepatitis C. Hepatocellular carcinoma eventually occurs in 5-10% of patients with chronic hepatitis C. Symptoms of hepatoma include rapid decompensation of the liver and metastases, often to the brain.

Squamous cell carcinoma of the tongue

This condition is a rarely coexistent disorder, usually evident as an erosion on the tongue.

Dermatologic manifestations associated with interferon alfa therapy for HCV infection

Erosive OLP and epidermolytic hyperkeratosis may occur with interferon alfa therapy for chronic hepatitis C infection. Capillaritis may be present with interferon alfa treatment of chronic hepatitis C infection. Lichen myxedematosus may worsen during interferon alfa-2a therapy for chronic active hepatitis. Finally, thyroiditis may occur during interferon therapy.

Possible conditions associated with HCV infection

Erythema dyschromicum perstans is an asymptomatic condition of ashy gray discoloration of the skin on the extensor surfaces of the arms and face.

Porokeratosis, the disseminated superficial type, has been associated with HCV infection or hepatocellular carcinoma. Eruptive disseminated porokeratosis in relation to the onset of hepatocellular carcinoma occurred in 3 closely observed patients with chronic hepatitis C infection and persistent HCV hepatitis. Both conditions are believed to be related to immunomodulation of the TP53 gene. HCV core protein may affect cancer transformation directly through an effect on a promoter gene expression. The core protein is a multifunctional protein with the capacity to bind to the so-called death domain of tumor necrosis factor receptor 1 (TNFR1) and the intracellular portion of lymphotoxin-beta receptor. The portion of TNFR1 active in apoptosis and antiapoptosis signaling pathway is the death domain affected by HCV.

Generalized granuloma annulare, an asymptomatic condition with dermal nodule formation resulting from an inflammation of collagen, may be present.

Symmetric polyarthritis and livido reticularis may occur.

Asymptomatic, solitary, dome-shaped reddish papules, 5-10 mm in diameter, may be present on the face in some patients with HCV infection; these papules represent arteriovenous hemangiomas, which are seen with increased frequency in these patients.

Progressive pigmented purpura (Gougerot-Blum disease) is demonstrated as lesions of capillaritis on the lower legs with fine petechiae in various distributions.

A possible association between erythema induratum (nodular vasculitis) and HCV infection has been suggested.

Sarcoidosis may occur in HCV patients, especially in association with antiviral immunotherapy.

Hepatitis D (VHD)

http://www.niaid.nih.gov/topics/hepatitis/hepatitisD/Pages/Default.aspx

http://emedicine.medscape.com/article/185463-overview#aw2aab6b6

Background

Hepatitis D virus (HDV) is an RNA virus that is structurally unrelated to hepatitis A, hepatitis B, or hepatitis C virus. It was discovered in 1977. HDV causes a unique infection that requires the assistance of viral particles from hepatitis B virus (HBV) to replicate and infect other hepatocytes. Its clinical course is varied and ranges from acute, self-limited infection to acute, fulminant liver failure. Chronic liver infection can lead to end-stage liver disease and associated complications.

There are 3 known genotypes of hepatitis D. Genotype I has a worldwide distribution; genotype 2 exists in Taiwan, Japan, and northern Asia; and genotype 3 is found in South America.

Simultaneous infection with HBV and HDV is known as coinfection and results in fulminant liver failure in 1% of patients. Complete clinical recovery and clearance of HBV and HDV coinfection is the most common outcome. Chronic infection with HBV and HDV occurs in less than 5% of patients.

Infection with HDV in a patient who is already positive for the hepatitis B surface antigen (HBsAg) is known as superinfection and results in fulminant liver failure in 5% of patients. Approximately 80-90% develop chronic HDV infection. These patients progress more rapidly to develop cirrhosis and may develop hepatocellular carcinoma.  

A study from The Netherlands suggested HDV may hinder the control of HBV. Xiridou et al used a mathematical model for the transmission of both viruses and calculated the reproduction numbers of single HBV infections and dual HBV/HDV infections. The investigators looked at the endemic prevalences of both viruses and found that HDV modulates HBV epidemic severity and also hampers impact on HBV interventions. Xiridou et al concluded that in endemic populations with HDV, control programs that ignore HDV presence may lead to underestimation of the HBV epidemic and overestimation of positive results, as control of HBV is dependent on the reproduction numbers of dual HBV/HDV infections.

Complications

Complications may include the following:

Patient education

Modify high-risk behaviors, including intravenous drug use and unsafe sexual practices.

Promote the use of universal precautions for health care workers.

Patients with chronic HDV and HBV infection should not donate blood, share toothbrushes or razors, or consume alcohol. Precautions should be observed.

Etiology

Hepatitis D virus (HDV) infection is an acute and chronic inflammatory process involving the liver. HDV is transmitted parenterally; it can replicate independently within the hepatocyte, but it requires HBsAg for propagation. Hepatic cell death may occur due to the direct cytotoxic effect of HDV or via a host-mediated immune response.

Risk factors include intravenous drug use and multiple blood transfusions.

Sexual transmission is less efficient than with HBV.

VHD represents itself defective virus particle of size 30 - 35 nm, contains internal antigen (HDAg), made up of small circular RNA and surface covering, which is HBsAg VHB. It is considered that reproduction of virus is possible only during presence of HBsAg in organism of patient, therefore hepatitis D proceeds always as a coinfection or superinfection, joining to VHB.

Human’s organism replies on internal VHD by production of antibodies of class IgM, which used in diagnostics  of  the disease.

Hepatitis E (VHE)

Background

Hepatitis E is an enterically transmitted infection that is typically self-limited. It is caused by the hepatitis E virus (HEV) and is spread by fecally contaminated water within endemic areas. Outbreaks can be epidemic and individual. Hepatitis E has many similarities with hepatitis A. Hepatitis E has been associated with chronic hepatitis in solid-organ transplant recipients, patients infected by HIV, and an individual on rituximab treatment for non-Hodgkin lymphoma. A study has shown that among patients receiving hemodialysis, the seroprevalence of anti-HEV immunoglobulin G (IgG) was found to be high. However, no evidence of chronic infection was found.

The course of infection has 2 phases, the prodromal phase and the icteric phase. The infection is self-limited. Whether protective immunoglobulins develop against future reinfection remains unknown. The overall case fatality rate is 4%, although pregnant women and liver transplant recipients may be at substantially higher risk.

Therapy should be predominantly preventive, relying on clean drinking water, good sanitation, and proper personal hygiene. A successful recombinant hepatitis E vaccine has been developed.

Pathophysiology and Etiology

The hepatitis E virus (HEV) genome contains 3 open reading frames (ORFs). The largest, ORF-1, codes for the nonstructural proteins responsible for viral replication. ORF-2 contains genes encoding the capsid. The function of ORF-3 is unknown, but the antibodies directed against ORF-3 epitopes have been identified.

Hepatitis E results from HEV infection and is spread by fecally contaminated water within endemic areas. On the other hand, in nonendemic areas, the major mode of the spread of HEV is foodborne, especially undercooked pork.

HEV is an RNA virus of the genus Hepevirus. It was discovered during electron microscopy of feces contaminated with enteric non-A, non-B hepatitis. The virus is icosahedral and nonenveloped. It has a diameter of approximately 34 nanometers, and it contains a single strand of RNA approximately 7.5 kilobases in length. Four HEV genotypes have been identified. Genotypes 1 and 2 are considered human viruses; genotypes 3 and 4 are zoonotic and have been isolated from humans and animals.

http://www.niaid.nih.gov/TOPICS/HEPATITIS/HEPATITISE/Pages/Default.aspx

http://emedicine.medscape.com/article/185463-overview#aw2aab6b7

Virus of hepatitis E has been isolated from feces of patients with jaundice. Spherical particles similar to virus were able to discover due to the method of immune electronic microscopy. Material for investigation was collected from volunteers, infected by material from patients with jaundice with assumed diagnosis of viral hepatitis E. It is supposed, that VHE may be caused by few strains of virus of different antigens.

At present time a test-system, giving the possibility of discovering antigens of virus in fecal matter has been elaborated. Serums of  reconvalescenes  are  used  for  that.

Epidemiology

Viral hepatitis A – antroponosis. The source of disease is sick person in prejaundice period and in 15-20 days of climax period of the disease and virus carrier. Primary localization of virus is gastrointestinal tract. Mechanism of transmission is fecal-oral. Virus is excreted from the organism of sick person with fecal matter. Specific final factors of transmission of hepatic A virus are water and blood. Character of infection of water depends upon conditions of water supply and its relation with fecal contamination. Intermediate factors of transmission are flies, transferring virus together with fecal matter on products of nutrition, dishes.

Susceptibility to the disease is high. Mainly children and adults up to 30 year fall sick.

The source of hepatitis B virus in nature is sick person with acute or chronic form, healthy carrier. Natural path of transfer is sexual. Infection may be transferred even during kisses through traumatized mucous, through milk of mother, through placenta from sick mather to fetus (vertical path of transmission). Parenteral path of the transmission has blood transfusion and its preparations, meaning to injections, manipulation, operative intervention.

Susceptibility to the disease is high. Most  often drug addicts, homosexuals, prostitutes, medical personnål (surgeons, obstetrician  - gynecologists, workers of hemodialysis departments, manipulative nurses, doctors-infectionists) often fall sick with hepatitis B.

Epidemiology of viral hepatitis D has been studied insufficiently. It is assumed, that source of infection is sick person, basic path of transmission is parenteral.

Persons  suffering from VHB or HBsAg – carriers are more susceptible.

Epidemiology of viral hepatitis E is  identical to epidemiological laws of HAV, and hepatitis C – to hepatitis B.

Pathogenesis

Pathogenesis of viral hepatitis is still not studied completely due to big difficulties, caused by absence of accessible experimental model of the disease. At the base of existing notions about  pathogenesis of acute  viral  hepatitis lay clinical observations, life time investigations of liver tissue and comparative study of viral hepatitis in animals.

Entrance of the agent of the disease into the organism of patient takes place perorally (HAV, HEV), by sexual way (HBV, HCV), parenteral by (HBV, HCV, HDV and not excluded for HAV - HEV), vertically (not excluded for all viral  hepatitis).

The agent approaches regional lymphatic glands, where its massive reproduction takes place the second phase of pathogenetic process. The agent causes damage of cells and their death. Organism replies on this negative influence by immune reaction of reticular tissue of the lymphatic glands, executing “barrier” function. This corresponds to period of incubation. On this level infections process may stopped. In insufficiency of “barrier” function the phase of generalization of infection (primary virusemia) begins.

Virus continues to enter from lymphatic glands into blood in a large quantities. Clinically this phase is manifested by signs of intoxication and beginning of the damage of liver. In this phase viruses of hepatitis are connected  with thrombocytes. Due to composition of their phospholipid membrane they violate, metabolism of arachidonic acid is intensified, that leads to increase in their adhesive and aggregate activeness. Viruses of hepatitis also render action on cells of endothelium of small vessels, cause destruction of the structure of their biomembrane. As a result of such influence, highly active endoperoxides are formed from arachidonic acid (compulsory component of phospholipids of membrane), rendering powerful influence on adhesion and aggregation of thrombocytes, erythrocytes. Such influence of viruses of hepatitis on the cells of blood  cells of endothelium of vessels already in the phase of virusemia renders essential influence on coagulative and anticoagulative system of the blood causes disseminated intravascular coagulopathy. The first stage of DIÑ-syndrome develops. Degree of these disorders depends on massivity of virusemia and determines the disease.

The phase of virusemia is confirmed by relevation HBsAg in the blood of the patients. Besides virusemia parenchymatous diffusion happens too. Viruses of hepatitis penetrates into the liver cells, at first, into erythrocytes. Reproduction of virus is realized in hepatocytes. Virus also revealed in erythrocytes, thrombocytes, in the cells of pancreas, reticuloendothelial system. The inculcation of virus into hepatocytes leads to disorder of intracellular metabolic process, especially in  membranes of hepatocytes. The lesion of membranes accelerates destruction of hepatocytes.

The mechanism of the damage of hepatocytes, other cells  of the organs and systems in studied insufficiently. Syndrome of cytolisis also plays the leading role in pathogenesis of viral hepatitis B. However, virus of hepatitis B doesn’t possess the direct cytopathogenic action.

F.Dubleu, A. Bluger consider that immune reactions, connected with T-cells, have the leading meaning in the pathogenesis of syndrome of cytolisis. The penetration of virus into hepatocytes and reproduction in hepatocytes leads to accumulation of viruses in surface membrane. Circulation of antigens in the blood causes sensibilization of T-lymphocytes. The activation of T-lymphocytes leads to distinction and depression of the agent and to differention of subpopulation of T-lymphocytes. Effect of T-killer  causes  cytolisis  of hepatocytes. Autoimmune reactions intensify cytolitic syndrome and necrosis of liver.

Pathogenesis of viral hepatitis B is explained from viral-immunogenetic position, because it is known that power of immune response is genetically determinated. Immune reaction may be strong (in fulminate form of hepatitis), flabby and adequate. Only adequate immune reaction promotes cyclic course and favorable outcomes of the disease.

The scientific achievements of the last years opened new points of view to pathogenesis and therapy of different forms of viral hepatitis. The study of metabolic processes on the level of cell allowed to open new aggressive components having negative influence on its structure and functions.

The surplus activity of the processes of freeradical oxygenation renders destructive influence on cell’s membranes. As a result free radicals are accumulated in the cells. The process oxygenation of lipids is intensified (peroxide oxygenation lipids – POL). It is known that lipids are the basic structural component of the cells. Antioxydant system of the organism is defending mechanism, supporting free radical oxygenation of the physiological level. Due to investigations of the last years it was shown that activation of the processes of peroxide oxygenation of lipids plays the essential role in the pathogenesis of viral hepatitis and leads to alteration of structure and functions of membrane of hepatocytes, thrombocytes and other cells. It’s worth to underline that simultaneously with activation of POL the considerable depression of antioxydantic activity of the blood serum is marked.

In case of extremely high activity of POL exhaustion of AOS takes place, which leads to disorder of activity of cellular ferments, particullary of glucolysis, glucohenolysis and to rupture of phoshorilation. As a result, cell loses energetic potential. It leads to destruction of cell. Along with this permeability of membrane of hepatocyte and its internal structural components are disturbed. Corrosion of hepatocyte takes place, its synthetic, disintoxicative and other function are lost. Disturbance of permeability of lysosomal membranes causes exit proteolytic ferment into cytoplasm, which complete the death of hepatocyte.

At the last years data about molecular mechanism of the damage of hepatocyte’s membranes were received. It  is known that interferones cause depression of reproduction of viruses.

Leukocytaric and fibroblastic interferones may be produced practically by all cells. Immune  gamma-interferon is  produced  by  gamma-interferon immunocompetentive cells during immune response.

Interferon may influence to complex of defensive reaction (phagocytosis, inflammation, antigen expression). Interferon is the most important factor of nonspecific resistance. However, interferon has influence to differentiation and activation of effectoric cells of immune system. The activation of monocytes (macrophages), increased generation of peroxide radicals, increased phagocytes activity are observed under influence of interferon. Thus, at the present time interferon is considered not only as antiviral remedy, but also as important regulator of interaction between cells. Due to investigations of the last time it was established that antiviral effect of interferon is not connected with direct interaction with viruses. Antiviral effect is connected with change of metabolic processes in the cells.

It is established that there is decreased produce of interferon in the patients with viral hepatitis B, especially in patient with severe course of the disease. In fulminate course of acute viral hepatitis B interferon is not revealed in the blood serum.

 

Pathological anatomy

Morphological changes in liver take place in all tissual components - parenchyma, connective tissue, reticuloendothelium, in lesser degree in bile pathway, i. e. diffuse damage of the organs is possessed. Degree of damage fluctuates from insignificant dystrophic and single necrotic changes of epithelial tissue of lobules of liver during light forms till massive and submassive necroses of liver parenchyma. Three variants of acute form of the disease are differentiated: acute cyclic, cholestatic and massive necrosis of liver (Fig.3).

 

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Fig.3. Massive hepatonecrosis

During acute cyclic form diffuse damage of epithelial and mesenchymial elements are observed. Decompensation of beam structure with orderly placement of hepatocytes with their considerable polymorphism is noted.

Along with the dystrophic changes, expressed processes of regeneration with figures of mitosis and abundance of double nuclear cells are determined. Characteristics are presence of scattered necrosis hepatocyties in all lobules. Changes of mesenchymial elements inside  the lobules are expressed in proliferation of Kupffer’s cells with their change into macrophages. Cytoplasm of these cells are basophilic, contains bile pigment. Capillaries in the center of lobules are dilated. Proliferation  of lymphohistocytary elements with admixtures of plasmatic cells  eosinophills and neutrophils are marked in the portal tract. Along with this, reticular hyperplasia of spleen and portal lymphatic vessels is observed. Clinical manifestations of the disease correspond to the severity of destructive changes in parenchyma of liver.

During cholestatic variant of viral hepatitis majority of morphological changes are observed in intrahepatic bile passages with picture of cholangitis and pericholangitis.

 

Clinical manifestations

Clinical picture of all viral hepatitis is very much similar and differs in percent relation by severity of the course of the disease and its outcomes. Viral hepatitis A and E are characterized by cyclic benign course with complete reconvalescence. In hepatitis B, C and D medium serious and serious course, lingering and chronic forms of disease and lethal consequences are inrarely observed.

Depending upon the expressiveness of clinical manifestations of the disease and degree of functional disorders of liver, established by biochemical tests, light, medium serious, serious and  malignant (fulminate) forms of viral hepatitis are differentiated. All atypical cases of the disease (non-jaundice, obliterated, subclinical) are concerned to light forms, because as clinical manifestations and functional changes are weakly expressed in such patients.

During evaluation of severity of the disease expressiveness of intoxication and jaundice is taken into attention along with enlargement of sizes of liver and spleen, loss in weight, level of bilirubin in blood serum.

High intoxication, polyarthralgia, expressed dyspeptic symptomocomplex are typical for fulminate and serious forms of viral hepatitis. Prolonged intensive jaundice, hypotonia, bradycardia, changing into tachycardia, slackness, subfebrile temperature, decrease in diuresis, testifies about serious or even malignant course of viral  hepatitis with indefinite prognosis.

Laboratory tests are used for evaluation of severity of disease: tests of concentration of general bilirubin in blood serum of patients, the prothrombin index.

Viral hepatitis have principally cyclic course. Incubation period is different. In  hepatitis A it is in average 15-30 days, during viral hepatitis B  30-180 days. The disease begins with signs of general intoxication - so called pre-jaundice period. There  are the next some variants of prejaundice period:

1)     Dyspeptic variant. – The patients complain of appetite absence, nausea, sometimes vomiting. Temperature is subfebrile. Duration of period is 3-7 days.

2)     Astenovegetative variant. – The patients complain of weakness, headache, malaise,  decrease of appetite. Body temperature  is subfebrile or 37-38 ˚C;

3)     Influenza-like variant. – The patients complain of headache, weakness; muscular pain, decrease of appetite. Body temperature is 37.5-39 °C, and in separate cases 39-40 °C. Duration of 2nd  and 3rd variant of prejudice period is of 5-7 days;

4)     Polyarthralgic variant. –  It is observed principally during hepatitis B and C. Patients complain of pain in joints, sometimes muscular pain is troubling, weakness, decrease of appetite. During this subfebrile temperature is in majority of the patients. Duration of this period is composed of  7-14 days;

5)     Mixed type –  All above indicated signs of intoxication are of different degree.

The next period of the disease is climax period. The state of the majority of the patient becomes better. The temperature is normalized, urine becomes dark, colorness stool. Scleras are icteric, jaundice grows gradually (Fig.4). The further course of the disease depends on degree of liver damage by the virus, which determines the severity of the disease. During light course of viral hepatitis jaundice grows in a period of 3-5 days. It is present on one level during one week. Disappearance of jaundice is observed on 15-16 day. Urine becomes more light at the end of the first-second week of the jaundice period, it is of yellow or orange color.

During medium serious and serious course of the disease yellowish coloring of scleras and skin is more intensive, jaundice period is prolonged (20-45 day). In majority of the patients the signs of cardiovascular system disorder are observed. There are hypotonia, bradycardia, muffed hearts sounds. In 80-90 % of the patients liver is enlarged, its surface is smooth, borders are curved, moderately painful. In 30-40 % of patients spleen is palpated. During serious course of viral hepatitis in some patients meteorism of abdomen, caused by disorders of digestion (signs of damage of pancreas, secretory glands of stomach and disorders of biocenosis of gastro-intestinal tract) is observed. In some patients jaundice is very intensive (Fig.5) and skin itch is observed (so called cholestatic variant of the course of the disease).

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Fig.4. Icteric sclera

Different changes are observed from central nervous system. Already during light course of viral hepatitis changes adynamia, slackness, disorders of sleep may be present.

In serious cases clear cerebral disorders caused by considerable dystrophic changes in the liver, endogenic intoxication and increase of the activity of the processes of  POL are observed.

In the period of reconvalescence reverse development of symptomatic of disease, normalization of biochemical indices is marked.

 

 

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Fig.5. Jaundice of skin

Complications

The most threatening outcome of viral hepatitis is acute or subacute massive nercosis of liver, during which picture of acute or subacute hepatic encephalopathy is observed. An acute hepatic encephalopathy (AHE) is typical for acute hepatites.

The term “acute hepatic encephalopathy” denotes unconscious condition of  the patient with violation of reflex activity, convulsions, disorder of life vital functions as a result of deep brake  of action of  cerebral cortex with its spread on to subcortex and below laying parts of central nervous system. This sharp brake  action of  nervous-psychic activity is characterized by disorder of movements, sensibility, reflexes and by absence of reactions on different irritators.

Hepatic coma is an endogenic coma, caused by endogenic intoxication as a result of loss of function and breakdown of liver.

There  are the next stage of AHE  – precoma I, precoma II and properly coma.

Precoma I is characterized by non constant disorder of consciousness, unsuitability of mood, depression, lowered capability towards orientation, tremors, inversion of sleep. Patients are irritated, sometimes - euphoric. They are troubled by paroxysms of depression, doom, presentiment of death. Fainting, short time unconsciousness, giddiness, hiccup, nausea, vomiting may be observed.  Jaundice  grows. Bradycardia is changed by tachycardia. Tendon reflexes are raised. Such condition prolongs from few hours to 1 - 2 day with moving into second stage.

In the second stage of precoma consciousness is more hampered, losses in memory is a characteristic feature, alternated with attacks of tachymotor and sensory exciment till delirium. During awakening orientation in time, space and action is absent. Tendon reflexes are high. Jaundice raises sharply.  Muffed  heart sounds, tachycardia, hypotonia are revealed.

Rhythm of respiration is disturbed. Liver begins to decrease in size. Hepatic insufficiency is inrarely accompanied with hemorrhagic syndrome due to development DIC-syndrome. In 1/3 of patients nasal hemorrhages, gastrointestinal hemorrhages, uterine bleeding and hemorrhages of other localization are observed. Diuresis decreases. Abdomen is inflated; peristaltic of intestine is decreased. Such condition continues for 12 hours - 2 days.

During the third stage – properly coma - complete loss of consciousness and disappearance of reflexes is marked. Pathological reflexes may be too. Rigidity of muscles of extremities, hyperkineses, convulsive syndrome, and thereafter complete areflexia are observed. Expressed tachycardia, hypotonia, disorder of rhythm of respiration are revealed. Diuresis decreased considerably till anuria. The death of the patients is through 6-24 hours. The patients perish from massive hemorrhages or in development of severe metabolic acidosis.

 

 

Diagnosis

Preliminary diagnosis of viral hepatitis is based on epidemiological anamnesis, finding of the development of the disease, clinical picture with account of peculiarities of the ways of the transmission, duration of incubation period, presence of prejaundice period, presence of typical subjective and objective signs with account of the patients age.

Diagnosis is confirmed by routine and specific laboratory tests. In routine blood test of the patients with viral hepatitis lymphocytosis is observed with moderately expressed course and in serious course of the disease - anemia and leucopenia. ESR is slightly decreased. In urine urobilin and bile pigments are observed. During climax period, particularly during medium serious and serious forms, there are no stercobilin in stool.

 Increased content of general bilirubin, primarily on account of its direct fraction is observed in blood serum during all jaundice period. Ratio of direct and indirect fraction composes 3:1. In all patients already in pre-jaundice period of the disease, during all jaundice period and in the period of early reconvalescence increased activity of ALT, AST is observed, testifying about the presence of cytolytic processes in liver.

Specific antigens (HBsAg) and antibodies to antigens of all known at present time viruses of hepatitis are revealed in the blood of patients with help of these methods. Discovery of antibodies of class of IgM testifies about acute disease. Discovery of other  classes of immunoglobulins antibodies testifies about lingering or chronic course of viral hepatitis or about earlier infectious process or about disease in the past.

 

Differential diagnosis

Differential diagnosis of viral hepatitis is necessary to perform with diseases like leptospirosis, yersiniosis, mononucleosis, malaria, mechanic and hemolytic jaundice, toxic hepatoses.

Leptospirosis is characterized by acute beginning of the disease, often with chill, continuation of fever during of climax of the disease and jaundice, pain in muscles, especially in calfs, hemorrhagic syndrome. In blood leucocytosis with neuthrophillosis and shift in the formula to the left, accelerated ESR are observed. Activity of ALT and AST is moderately raised or normal relation of direct and indirect bilirubin 1:1. In blood serum concentration of urea and residual nitrogen increases. Stool is colored. In urine erythrocytes, leukocytes, like wax cylinders are marked in large quantity. Diuresis decreased till anuria.

In generalized forms of yersiniosis jaundice may be also observed, however it is accompanied by fever, metastatic focuses in other organs and tissues, leucocytosis with nuetrophilosis, accelerated ESR, aggravations and relapses. Diagnosis is confirmed by serological methods with specific yersiniotic antigen.

In malaria there are clear alternation of attacks fever with chills, replaced by heat and sweat and periods of apyrexia. Often painful, increased in size spleen is marked. In blood hemolytic anemia, in fat drop blood and smear different forms of malarial plasmodia are reveled. In blood serum indirect fraction of bilirubin predominates.

In mechanic jaundice stones in gall bladder and bile passages, enlargement of head of pancreas and other signs are revealed with help of ultrasound investigation. In majority of the patients moderate increase of activity of ALT, AST, leukocytosis, accelerated ESR are marked. Hemolitic jaundice is characterized by anemia, accelerated ESR, increase of indirect fraction of bilirubin. Stercobilin is always present in stool. 

Differential diagnosis of VH with hepatoses is complicated and demands from doctor thoughtful and painstaking work. During this essential significance possesses correctly taken anamnesis.

Outcomes of the disease

Viral hepatitis most often ends with complete reconvalescence. In some patients may be cholecystitis, cholangitis, pancreatitis, dyskinesia of bile excreting pathways after an acute hepatitis. In 5-10 % of patients lingering course with periodical aggravations, caused by prolonged persistence of virus is observed. In such cases chronic hepatitis develops. This variant of the course of the disease is typical of viral hepatitis B and C chronic hepatitis may end up by liver cirrhosis.

 

 

Treatment

Treatment is used complex and depends on the clinical form and gravity of disease current. At mild current of a viral hepatitis in the acute period it is possible to prescribe only semi-bed regime, diet ¹ 5, polyvitamines and desensitizing preparations: calcium gluconate, Diazolin, Diprazin or Tavegil. In case of meteorism, feeling of gravity in epigastrium area after the meal, unstable feces - Festal, Pancurmen, Allochol, Cholenzym are indicated.

At medioserious and serious current of the acute form of hepatitis a bed regime is provided together with the specific treatment. Desintoxication  therapy consists of plentiful drink; 5 % solution of glucose, saline solutions, Ringer’s solution, Trisault, Quartasault, 20 % solution of Sorbit (or. Sorbitoli), donor Albumin (given in vein), one of enterosorbents  SKN of different brands, carbaphosfer, Carbosilan, Sillard P, Enterosgel, Polyphepan. The quantity of drunk liquid should be balanced with a daily urine. Polarizing admixture: 3.7 gm potassium of Sody chlorid and 12 UN of insulin on 1 liter of 5 %  solution of  glucose was recommended. There are indicated the preparations improving metabolism in hepatocytes: Ascorbinic acid, Thiamin chlorid, Pyridoxine hydrochloride, cocarboxylase, Potassy Orotat, Riboxin, Citochrom C, Lipamid, Calcy Pangamat. Last two preparations are indicated mainly at accompanying hepatoses with fatty infiltration of liver (alcoholism, diabetes,  thyrotoxicosis, an obesity etc.). For acidosis decreasing 2 %  solution of  sodium of a hydrocarbonate  25-50 mL (P.R.) 3-4 times per day or on 150-200 mL (I.V.) should be infused.

Among etiotropic agents moderate medical effect at acute virus hepatitis has human recombinative  α-2-interferon - Reaferone, Intron A, Realdironi or analogue Laferone in powder, in amp.  1 000 000 IUN: from 1-st to 5-10-th day of the icteric period. Next days their efficiency falls. At acute hepatitis B Laferon is infused  1 000 000 IUN 2 times per day during 5-6 days, then  1 000 000 IUN 1 time per day during 5 days. If medical effect is insufficient, there should be  continued infusing 1 million UN 2 times per week during 2 weeks. It is worthy to use Leicinferone as the basic component which is the admixture of natural α-interferons of donor leucocytes, the factor of necrosis of tumours and Interleicin-1. However many clinicians challenge expediency of indication of interferon at the hepatitis of acute period. More physiologic is the stimulation of endogenic interferonogenesis with the help of such inductores, as Mefanam acid, Prodigiosan, Pyrogenal, Nifluril, Cycloferon.

At threat of hepatonecrosis - glucocorticoids  150-200 mg are prescribed. The dose of prednisolon per day, must be reduced after the patient gets out of extremely serious condition. The volume of infusion solutions is enlarged up to 30-50 mL/kg per day. Ornithin (ornicetyl) promotes a linkage and removing out of organism nitrous bonds and improves a metabolism.

A lactulose reduces an adsorption of ammonia from  intestine in blood, especially in combination with Neomycin. With the aim of oppression of processes of an autolysis there should be used inhibitors of proteolytic enzymes Contrical or Gordox each 8 hours (I.V.) intravenous dropping, at improvement of a condition synthetic inhibitors. At retention of liquid in organism it is required to use Spironolacton (Veroshpiron), Kaliumsaving  diuretics, or saluretics-Furosemid, Etacrinic acid. Psychomotor exaltation is stopped by Sody  hydroxybutyrate in combination with Sibazon (Seduxen), Haloperidol. At increasing of hepatic failure  there are used antilymphocytic gamaglobulin during 1-5 days with the control of quantity of lymphocytes in a pereferic blood, apparatus methods of clearing of patients blood, hyperbaric oxygenation.

At cholestatic  form of a virus hepatitis the are effective preparations which form complexes inside intestine with cholic acids which can not be soaked up, cholestiramin and Bilignin. Fenobarbital is used which is the inductor of synthesis of Glucouroniltransferas. This enzym is necessary for conjugation of bilirubin with glucuronic acid, and stimulating its egestion with bile. Fenobarbital is indicated with combination of Cyanocobalamin. Simultaneously for intensifying secretion of bile Nospan and Cholenzym are indicated. After the termination of an acholia duodenal tubages 5-10 %  solution of magnesy sulfat (1/4-1/2 glasses), Sorbit or Xilit (20 gr on 100 mL of hot water) 1 hour before breakfast are applied.

Bioflavonoids – Convaflavin, Carsili, Legalone, Silibor, Quercetin are indicated in case of the alonged reconvalescence. At hyperaminotransferasaemia – Aevit or Tocopherol acetas, Thymalin, T-activin, Dipiridamol (Curantyl), Isoprinosin (has also antiviral property) - give positive effects. There are used also Saparal, Methyluracil (or. Methacil), Natry nucleinic, Thymalin in a combination with Dipiridamol, Hofitol.

 Cholagogue agents - broths of flowers of immortele, hips, thyme, mints peppery at the rate of 1 dining spoon of a herb or a mixture to 1 glass of water are indicated for convalescents Fenobarbital with Cyanocobalamin are applied during 10 days in case of hyperbilirubinemia with prevalence of untied fraction of pigment; preparations of choice can be Cordiamin or Sibazone (Seduxen) which also stimulate glucoruniltransferase of  hepatocytes. At hyperbilirubinemia mainly at the expence of connected fraction stimulate a bile secretion using oxygen cocktails with cholagogue herbs and honey. Vitohepat or Cobamamid stimulate neogenesis and hemopoes, accelerate regenerative processes in liver, course of treatment lasts 15-20 days. At astenia and hypoproteinemia, and also for elimination of catabolitic influences of glucocorticoids which were used at the acute period, anabolic hormones: such as methandrostenolon (Nerobol), Phenobolin (Nerobolil) or Retabolil are indicated. For elimination of the asthenic phenomena,  there are used Novopasit, tinctura of Valeriana root (20 gm: 200 mL), herbs of neetle, Thyme, Bromidums, and in rather serious cases - Chlozepid (or. Eleny), Sibazon (or. Seduxen), Relany, Barbiturates.

At the dyspeptic phenomena caused by oppression of secretory function of digestion organs, also Allochol, Liobily, Cholenzym, Festal, Panzynorm forte, Pancurmen, Pancreatin, Pancitratit, Vobensym are widely used.

At posthepatitic hepatomegalias without signs of cytolisis it is not reasonable to indicate Lydase - promoting a resorption of a fibrous tissue, 10 injections every     2-nd day. It can be infused only after exception of inflammatory process in hepatobiliar ways (will carry out control duodenal intubation).

Chemotherapeutic preparations are indicated in case of the bacterial cholecystitis. At mild current of disease it is possible to use only a fortnight course of Nicodin, at appreciable changes antibiotics or Nitrofurans preparations are indicated.

 It is possible to make antibioticosensetivity of microorganisms allocated from bile. For definition there are used mediums, which content bile of the patient as it  influences on essentially activity of antibiotics. Use Ampicillin, Carbenicilin Dinatry salt, Erythromicin, Cefazolin, Furazolidone, Furagin, at Candida infection sody salt of Levorin. Chemiopreparations indicate in average therapeutic doses during 7 - 8 days.

Specific therapy of chronic virus hepatitises is carried out by preparations of α-interferon (Intron A, Roferon, Realdiron, Reaferon, Laferon). They are effective in case of low replicative activity of the virus determined in blood virus DNA (HBeAg) at a hepatitis B and virus RNA at  hepatitis C. The additional indication is high activity of serum Alanineaminotransferase. One of the specified preparations inject (I.M.) or subcuteneous  3 - 5 million IUN per day 3 times per week during 6 months. Treatment should be stopped, if positive results were not observed after 3 months. The positive effect is observed at 40-50 % of patients with hepatit B and at 20-30 % of patients with hepatit C. At chronic hepatit D less than 10 % of patients are released from viruses even if treatment lasts 1 year. In some cases the success of immunotherapy of virus hepatitises may be increased if preliminary indicate short course of treatment about 6 weeks of glucocorticoids. Combined usage of interferon and Thymalin, Essentiale, Lamivudin, Chenodesoxycholyc acids has been proved.

The side-effects of α-interferon are noticed at half patients right after injection, among them are headache, fever, myalgia, arthralgia, general delicacy. They can be prevented by means of analgetics. Among the remote side-effects are: nausea, diarrhea, depression, irritability, leuco- and thrombocytopenia. Decreasing of a dose of  preparation allows to weak these disorders. There are serious complications (sepsis, psychosis, autoimmune diseases), that demand an immediate cancellation of interferonotherapy.

At  chronic hepatitis B in a phase of replication there are applied a peroral preparation Lamivudin (Zeffix). It provides the same level of seroconversion, as standard course of treatment by interferon.

At chronic hepatitis with low replicative activity of a virus preference is given to pathogenetic agents improving metabolic and reparative processes in  liver, such as: Silibor, Carsil, Liv-52, Hepatofalk, Planta, Hepabenne, Antral, Tocopherol Acetat etc.

 

Prophylaxis

http://www.cdc.gov/hepatitis/HAV/HAVfaq.htm#travel

If the patient is hospitalized, he should be placed in a private room with separate toilet facilities. The major reason for such isolation is to prevent the spread of type A hepatitis. Even with lax precautions, such spread is very rare; most patients with type A hepatitis are no longer excreting virus once they have become symptomatic. Nevertheless, there are exceptions, and isolation is prudent. Secretions and blood products should be handled with care gowns, masks, and gloves are not neces­sary, but a prominent sign reading “needle and blood precautions” is appropriate. Labeling of blood specimens from a patient with hepatitis, is a common practice. It should be stressed, however, that all blood from any patient should be handled as if potentially infectious.

If   the  patient  with  viral  hepatitis  is  at home, the patient should be advised about care in per­sonal hygiene - careful hand washing. Attention also should be paid to blood and blood products and the handling of cuts and lacerations.

Recommendations regarding the prevention of acute hepatitis are governed by the type of viral hepatitis that is being considered. In the case of acute type A hepatitis, all family members, and close personal contacts should receive immune serum globulin (ISG) at a dosage of 2-5 mL in as soon as possible after exposure. Office, factory, and school contacts do not need to be treated. Immune serum globulin can be given for up to 4 weeks after exposure, but it probably is only effective if given within 7-14 days.

In the case of acute type  hepatitis, prophylaxis only needs to be provided for "regular" sexual contacts. The best form of protection is argued Hepatitis  immune globulin (HBIG) at a dosage of 5 mL in as soon as possible and again 1 month later has been the conventional recommendation in this situation. However, the efficacy of HBIG in preventing the sexual spread of acute type  hepatitis has not been well proved. In addition, there is now evidence that postexposure immunization with  HBV vaccine, can attentuate or prevent acute type  hepatitis. Vaccine should be given as soon as possible and then 1 month and 6 months later.