Acute Viral Hepatitis (PDF)

Denumirea cartii | 1 Acute viral hepatitis Completari Cartea veche Generalities Acute viral hepatitis's are systemic infections that affect mainly the liver through inflammation. They are still...

Denumirea cartii | 1 Acute viral hepatitis Completari Cartea veche Generalities Acute viral hepatitis's are systemic infections that affect mainly the liver through inflammation. They are still a major public health problem due to high morbidity and mortality rates in spite of the existence of efficient vaccines against the two most frequent etiologic agents: Hepatitis A Virus (HAV) and Hepatitis B Virus (HBV); the resulting health costs are high and the treatment resources are limited. Five different viruses are accounting for more than 90% of the hepatitis infections: HAV, HBV, Hepatitis C Virus (HCV), Hepatitis D Virus (HDV) and Hepatitis E Virus (HEV). While HBV is a DNA virus, the rest of these are RNA viruses. This etiologic diversity leads to complex antigenic properties, diverse pathologies, different evolutions; the clinical picture is however similar for all types of hepatitis. The clinical specter spans from asymptomatic infections to extremely severe and rapid evolutions but the main public health burden is due to the possibility of evolution towards chronic infections with B, C and D viruses and the risk of developing hepatocellular carcinoma. 1. Viral hepatitis A Acute viral hepatitis type A is an infectious-contagious disease, transmitted by the enteral route, clinically manifested by general infectious and digestive phenomena, accompanied or not by jaundice. 1.1. Etiology It is a spherical RNA virus with a diameter of 27 nm, with icosahedral symmetry, lacking an envelope. The viral genome contains linear, single-stranded viral RNA, a single reading frame (ORF) with 3 regions (P1, P2, P3). Although 7 different genotypes have been identified, HAV is antigenically unitary, with only one viral serotype and one unique antigenic determinant (HAV Ag). HAV does not induce cytopathic effect, is slowly replicating on cell lines; although it can be cultivated in vitro, this technique is not of diagnostic use; in vivo, it replicates strictly in the liver; it can be detected in the liver, bile and the feces by the end of the incubation period. HAV is thermostable and resistant to acids and organic solvents; it remains viable in the feces several hours at room temperature. It is inactivated by boiling for one-minute, intense chlorination, autoclaving, UV exposure and formaldehyde. 1.2 Epidemiology 2 | Denumirea cartii sau a sectiunii/capitolului HAV infection is widespread around the globe, evolving sporadically or endemo- epidemically, with an autumn-winter seasonality and a periodicity of these outbreaks approximately every 5 years, through the accumulation of the receptive mass. The source of infection is exclusively the diseased patient weather with or without clinical symptoms. HAV is detected in the feces starting two weeks after the infective contact until two weeks after the clinical onset but the infectivity diminishes markedly after the apparition of icterus; fecal excretion of the virus can last for 8 weeks and even longer in children and immunocompromised hosts. There is no chronic excretion of HAV. The route of transmission of HAV infection is fecal-oral, through direct contact or contaminated water and food sources. This mode of transmission still causes an increased prevalence of infection in poor countries with a low socio-economic level. Maternal-fetal transmission is not proven; parenteral transmission is entirely exceptional, the duration of viremia being short (10 days before and 10 days after the cynical onset). Humans are universally susceptible to HAV but no more than 40-50% of the infected persons develop clinical symptoms; these are more frequent and more severe in the elder children and adults. Anicteric, asymptomatic infections are quite frequent in children. There is solid, life long post infection immunity. The following are considered to belong to the risk group: family contacts of a person with HAV infection, medical care staff, unvaccinated travelers from areas with low endemicity of high endemicity infection, homosexuals, intravenous drug users, people from disaster areas or refugees on campuses, institutionalized children. 1.3. Pathogenesis HAV is orally ingested and the first round of replication is in the oropharynx, salivary glands and the bowel - where it can be recovered at this time. Multiplication in the epithelial cells of the small intestine is follow by transport by way of the port vein to the liver where another round of replication occurs in hepatocytes and Kupfer cells. Transcription of RNA is followed by synthesis of the viral proteins that are assembled into new capsids then virions in the cytoplasm; the virions are excreted in the bile ducts without cell destruction - HAV lacks cytopathic effect. HAV is transported through the bile to the feces or can infect new target cells. The intrahepatic replication is accompanied by viremia that last from week 2 post infection until week 2 after the onset of symptoms (1 week after the apparition of icterus). The hepatic lesions are the result of immunologic mechanisms induced by expression of viral antigens on the surface of hepatocytes; NK cells and cytotoxic T cells are involved in viral clearance through cytokine and interferon action. The humoral immunity is limiting the infection; IgM antibodies appear concomitantly with the clinical onset, during fecal excretion on the virus, and last for 6 months, being thus a marker for current or recent infection; IgG antibodies follow,  Denumirea cartii | 3 are predominant during convalescence and through long life persistence protect against reinfection. Hepatocyte destruction is accompanied by serum increase in lysis specific enzymes and electrolytes (iron, copper). Hepatic injury affects metabolic processes such as the lipid metabolism (increase in triglycerides, decrease of cholesterol), protein metabolism (decrease in albumins and coagulation factors II, V, VII, and IX, increase in globulins), glucidic metabolism (erratic glycaemia) and hydro electrolytic - with a tendency of increase of the extracellular fluid. 1.4. Clinical picture HAV infection, in most cases, is asymptomatic. In cases with clinical expression, a polymorphic symptomatology is encountered, being generally dominated by systemic, non-specific and variable manifestations, which begin 1-2 weeks before the onset of jaundice and which are often associated with digestive disorders; these manifestations tend to decrease in intensity with the onset of jaundice. There are also anicteric forms, these being more common in children. The incubation period is 15-45 days, with an average duration of 21 days. The prodromal (preicteric) period lasts 3-5 days. Acute viral hepatitis with HAV most often begins as a general infectious syndrome, manifested by fever (38-39⁰C), headache, myalgias. At the same time, the non-specific digestive syndrome is most frequently present, manifested by anorexia, nausea, vomiting, bloating, pain in the epigastrium and the right hypochondrium, abdominal flatulence. There can also be a pseudo-influenza onset (fever, myalgias, arthralgias), urticarial, pseudo-surgical (frequent in children – abdominal pain that can mimic acute abdomen), pseudo- rheumatism, neuropsychiatric. The period of the condition (icterus) lasts between 4-21 days in hepatitis A. Concomitant with the alleviation of symptoms from the prodromal period, insidious jaundice sets in, with variable intensity and average duration. Acholic stools and hyperchromic urine accompany jaundice, the intensity of which is an indicator of the severity of the clinical form; if the value of bilirubinemia does not exceed 2-3 mg/dl, jaundice may go unnoticed (anicteric or mild forms), instead in cholestatic forms, which have a much prolonged evolution (3-6 months) and are more common in viral hepatitis A, the intensity of jaundice strikes, it may have a greenish tint (greenish jaundice). The hepatosplenomegaly syndrome consists in the presence of sensitive hepatomegaly; the liver is soft in consistency, the surface is smooth, and there is pain and discomfort in the right hypochondrium. Splenomegaly also occurs in 3-15% of patients. Another 1-2 weeks dyspeptic manifestations may be present. Some patients may present asthenic syndrome, apathy, irritability, insomnia, adynamia. In the common forms, the hemorrhagic syndrome (epistaxis, gingivorrhagia, heavier menstrual bleeding up to metrorrhagia) is rarely encountered. The posticteric period lasts 2-6 months, 1-2 months being necessary for complete clinical-biochemical remission and histological normalization. During convalescence, 4 | Denumirea cartii sau a sectiunii/capitolului some patients may present a complex symptomatology, with fatigue, anorexia, weight stagnation, abdominal discomfort. Clinical forms  The anicteric form clearly predominates in children. The manifestations of the prodromal period are present. Transaminase and histopathological changes usually guide the diagnosis. Often these anicteric forms remain undiagnosed and represent sources of infection.  The form with relapses can occur during the convalescence period, both in children and in adults. The frequency varies between 2 and 20% of cases. Relapses occur either after an apparently complete cure or after a partial remission. They can be single or multiple. In relapse, the intensity of symptoms is lighter compared to the previous episode and the patient recovers without sequelae. HAV can be detected in fecal specimen, the patient being contagious.  The prolonged form is characterized by the persistence of clinical (physical asthenia) and/or biological changes characteristic of the acute period for several weeks or months. The prognosis is good, with no risk of chronicity.  The cholestatic form is characterized by an intense, prolonged jaundice with a green tint. They occur in 4-10% of hepatitis A cases in adults.  The fulminant form is extremely rare in hepatitis A, being more common in adults. Fulminant hepatitis is the consequence of massive liver necrosis and is defined by numerous severe dyshomeostasis, among which coagulation disorders and neuropsychiatric disturbances are dominant. In most cases, fulminant hepatitis occurs within the first month after the onset of viral hepatitis A. Particular situations:  Acute hepatitis A in pregnant women has no teratogenic risk for the fetus. HAV infection in the last trimester of pregnancy can sometimes lead to infection of the fetus, which may develop an asymptomatic form of the disease, but with longer elimination of HAV in the feces.  Acute hepatitis A in patients with HIV infection: people with HIV do not seem to develop a more severe form compared to the rest of the population, but they may show persistent elevations of transaminases (> 280 days).  Acute hepatitis A in patients with chronic liver diseases may have a more severe evolution than in individuals without underlying liver pathology, the fulminant form being the most common. Patients with chronic liver diseases should be vaccinated against hepatitis A and hepatitis B. 1.5. Laboratory diagnosis The positive diagnosis is established on epidemiological, clinical and paraclinical data.  Denumirea cartii | 5 Epidemiological data refer to the notion of contact, absence of disease in the antecedents, lack of vaccination. Also, travel to an area with high endemicity (Asia, Africa, South America). The clinical data reveal the previously described symptomatology. Laboratory data a) Non-specific laboratory data The non-specific laboratory changes in acute viral hepatitis are similar between the different types of acute hepatitis (A, B, C, D, E). These are mentioned more extensively for hepatitis A, following that for acute hepatitis B, C, D, E, only some particularities will be pointed out. Confirmation of the positive diagnosis of hepatitis requires complex paraclinical data, which are the consequence of the physiopathological processes taking place:  Hepatocytolysis syndrome: - the increase of transaminases (AST, ALT) is often marked (20-30 times) from the prodromal period, preceding jaundice; - the ALT level reaches very high values, in acute hepatitis A, the values being significantly higher than those in acute hepatitis B, C or E; - gradually remits during convalescence without being correlated with the degree of liver damage.  Biliary retention syndrome: - increased bilirubin (both fractions, sometimes with the predominance of direct bilirubin); jaundice becomes obvious at more than 4-5 mg/dl; - high (> 20 mg/dl) and persistent levels of bilirubinemia correlate with severe forms; In HAV the average values of serum bilirubin levels are lower than in acute HBV.  The cholestatic syndrome - is associated with significant increase in serum bilirubin; the gammaglutamyltranspeptidase (GGT), alkaline phosphatase (ALP) and cholesterol are also increased in the serum; - if the cholestatic syndrome is more important than hepatocytolysis syndrome, it is most likely not an acute viral hepatitis. It is recommended to perform an abdominal ultrasound to detect a possible biliary obstruction.  Hematological syndrome: - the number of leukocytes can be normal or low, with lymphocytosis, neutropenia. Rarely, "atypical lymphocytes", with a lymphoblastoid appearance, can be detected on the peripheral smear; - thrombocytopenia, hemolytic anemia, aplastic anemia, pancytopenia can sometimes be found in complicated forms of the disease.  The liver failure - reflects severe hepatic injury and affects several liver functions: a. synthesis of the serum proteins, their values decrease: 6 | Denumirea cartii sau a sectiunii/capitolului - prothrombin - as reflected by the reduction of the prothrombin index (PI), increase in INR (international normalized ratio); it is an early marker for severe prognosis and anticipates the liver failure; - proconvertin; - Christmas factor (IX) b. detoxification: increase in serum ammonium c. metabolic: decrease of bilirubin conjugation.  Inflammatory syndrome: - Increase of serum IgG, IgM - alteration of the albumin/globulin ratio - hipoalbuminemia and hypergammaglobulinemia are considered to be signs of chronic liver injury. b) Specific laboratory data The etiologic diagnostic is based on serology: IgM anti-HAV antibodies are detectable since the clinical onset and up to 3-6 months later; they signal acute or recent infection. IgG antibodies signify residual immunity post infection or post vaccination, HAV antigen can be detected in stools by immune electron microscopy or in serum by ELISA. The virus can be cultivated and the viral RNA can be detected by RT-PCR but these techniques are not used for the routine diagnostic. HAV RNA is detected more frequently than HAV Ag. 1.6. Differential diagnosis The differentiation of acute viral hepatitis from other pathologies must be carried out according to the period of the disease:  In the prodromal period come into discussion, depending on the initial symptomatology: respiratory viruses, flu, food poisoning, biliary dyskinesias, cholecystitis, appendicitis, mental disorders, urticaria, acute articular rheumatism.  During the period of the condition, the differentiation must be made between the various types of jaundice: hemolytic jaundice, hepatocellular jaundice, obstructive jaundice. Hepatocellular jaundice can occur in both infectious and non-infectious pathologies. a) Infectious: viral (cytomegalovirus, infectious mononucleosis, enteroviruses, arboviruses, herpes virus infection), bacterial (systemic salmonellosis, septicemia, typhoid fever, tuberculosis), spirochetes (leptospirosis, Lyme disease, secondary syphilis), brucellosis. b) Non-infectious: toxic hepatitis (mushrooms, carbon tetrachloride, white phosphorus, mercury, etc.), medicinal hepatitis (antidiabetic drugs, anesthetics,  Denumirea cartii | 7 antimetabolites, isoniazid, antithyroid drugs, etc.), alcoholic hepatitis, genetic diseases (Rotor syndrome, Gilbert's disease, Crigler-Najjar syndrome). Other differential diagnoses: - Budd-Chiari syndrome – suprahepatic vein occlusion; - Wilson's disease – autosomal recessive disease, characterized by a decrease in the biliary elimination of Cu and its accumulation in the liver, eyes, kidneys, central nervous system. Features: Kaiser-Fleischer ring, low ceruloplasmin values. - Autoimmune hepatitis –jaundice is present, significant increase in serum transaminases, detection of antinuclear antibodies, anti-smooth muscle fiber guide the diagnosis. - Recurrent jaundice of pregnancy (cholestatic). 1.7. Prognosis The otherwise healthy patients that develop this form of disease recover completely with no sequels. Elder age, preexisting chronic liver disease and hypo or agammaglobulinemia are predisposing factors for more severe evolution, with mortality of 0.1-1%, sometimes through fulminant evolution. 1.8 Prophylaxis  Non-specific prophylaxis The prevention of hepatitis A consists in: ensuring potable water, the correct storage, removal and neutralization of fecaloid-household residues in communities; hygienic food storage and handling; periodic disinsections; compliance with the rules of individual hygiene. Passive pre-exposure prophylaxis can be done with standard immunoglobulins (Ig), administered prior to possible exposure. In post-exposure prophylaxis, administration of Ig within the first 2 weeks after exposure to a source of HAV protects most recipients from disease. The anti-HAV vaccine can also be used in post- exposure prophylaxis in immunocompetent individuals aged 1 to 40 years without other previous liver disease.  Specific prophylaxis There are several hepatitis A vaccines on the market that contain inactivated virus and are given by injection, intramuscularly. Both monovalent (Havrix, Avaxim, etc.) and bivalent products are available: vaccine against hepatitis A and hepatitis B, as well as against hepatitis A and typhoid fever. 1.9. Treatment The treatment of acute hepatitis A is similar to that of acute hepatitis B, C and E (see the subsection Treatment of acute hepatitis B). 2. Acute viral hepatitis B 2.1. Etiology 8 | Denumirea cartii sau a sectiunii/capitolului Hepatitis B virus (HBV) is the only DNA virus of the 5 hepatitis viruses, belonging to the Hepadnaviridae family, along with distinct genera that cause hepatitis in mammals and birds. In its complete form (Dane particle), it is small (42 nm) and contains an outer shell (envelope) and viral core (core, nucleocapsid). The Dane particle is infectious Fig. 6.1. HBV structure The envelope embeds the surface antigen HBsAg that has three forms: large (″L″), medium (″M″) and small (″S″). The large peptide displays several epitopes: a (which is present in all strains) d/y and w/r, respectively; their combination defines the 8 subtypes and 8 genotypes (A-H) that have distinct geographical distribution and differ in terms of chronic evolution vs. clearance of the virus. The A (adw) and D (ayw) genotypes predominate in Europe. HBsAg can be identified both in the serum and in the cytoplasm of infected hepatocytes. The viral nucleocapsid (core) is 27 nm large, is localized in the nucleus of the hepatocyte and consists of: - HBc Ag – core protein: it is located strictly in the hepatocyte and cannot be detected in the blood, it is highly immunogenic, eliciting anti-HBc - HBe Ag – pre-core protein: it is the soluble form of HBc Ag, it is a replication marker, its presence indicates high infectivity; it is transiently present early in the infection; its clearance indicates recovery but its persistence for more than 3 months is predictive for chronic evolution. - HBV DNA (viral genome): its presence in blood accounts for the contamination risk; it is small (3200 ntd), asymmetric, closed and circular, partially double stranded. The negative strands codes for 4 overlapping ORFs: - S: codes the M, L and S proteins (HBs) of the viral anvelope - P: codes for the DNA poyimerase - C: codes for HbcAg and HbeAg (pre-C segment) - X: codes the HbxAg - The DNA polymerase: intervenes in the viral replication that occurs in the liver and in the lymph nodes. HBV and the other hepadnaviruses are unique  Denumirea cartii | 9 among DNA viruses because this enzyme mediates a replication process that includes reverse transcription of the RNA- very much like it is performed by retroviruses. - The HbxAg: is a protein involved in the hepatocyte apoptosis induces activation of cytolytic T cells and is associated with liver ontogenesis. Hepatitis B virus can survive and retain its infectious potential for up to 7 days on inorganic surfaces even in the absence of visible traces of blood. It is resistant to some common disinfectants (e.g., sanitary alcohol), as well as to different physicochemical agents. 2.2. Epidemiology Although the HBV infection is globally spread with a human reservoir of more than 350 million carriers its prevalence varies substantially in different geographic regions. It is only 0.5-1% in Western Europe and the USA as compared with 5-10-20% in Far East Asia. The prevalence in Romania is 3-5% with slight zonal variations and a decrease after a vaccination program for the newborns was introduced. The source of infection is represented by the patients with acute or chronic disease and the carriers. HBV is detectable in the blood and in most of the body fluids: saliva, sperm – both sources of infection as well as in milk, genital secretions, tears, CSF. There are several transmission routes: - The Parenteral - percutaneous or per mucosal, through blood and contaminated blood products most commonly during: a. medical interventions: transfusions, use of incorrectly sterilized instruments in stomatology, invasive investigations, parenteral treatment professional accidents: cuts or punctures of the medical staff b. non medical interventions: nail treatment, piercing, shaving, tattooing, sharing of needles by IV drug users, exposure of wounds to biological fluids within the family - Non-parenteral - sexual (heterosexual or same sex) through genital secretions and saliva - Vertical - perinatal: a. in utero: it accounts for 10% of the vertical transmission cases; the risk when the pregnant woman is infected during the last three months of pregnancy; in mothers that are carriers of HBsAg the risk is correlated with the presence of HBeAg (90% risk when it is present vs. 10% when it is absent); b. intrapartum – during delivery; the most frequent route of infection; c. postpartum - the risk of transmission during breastfeeding has not been documented enough. The categories of people at increased risk of acquiring HBV infection are: patients on dialysis, with multiple transfusions (risk: 1/230,000 transfusions); intravenous drug users; medical personnel; children born from mothers carrying HBsAg; prostitutes, homosexuals; family members of HBV-infected patients. 10 | Denumirea cartii sau a sectiunii/capitolului Receptivity is universal. Immunity after the disease is durable, solid, for life, being ensured by the presence of anti-HBs antibodies. They are also the only antibodies that appear after the vaccine. It seems that after primary vaccination with 3 doses of anti-HBV vaccine carried out in the nursery, the anti-HBs antibody titer remains above the protective level for 30 years. 2.3. Pathogenesis The hepatocytes are the main site of replication for HBV; the infection has several stages: Replicative with immune tolerance. It corresponds to the incubation period, lasts for 2-4 weeks, and is characterized by active viral multiplication with minimal cytolysis, therefore with little if any hepatic lesions and no symptoms. Replicative with immunological clearance. The immune system reacts through TCL with the viral proteins as targets. The markers of viral replication disappear and the HBe antibodies appear; cytolysis is exacerbated and symptoms of acute hepatitis are prominent. The stage lasts for 2-4 weeks in patients that clear the virus is indefinite in patients that are becoming chronic carriers. The immune clearance and the destruction of infected hepatocytes are followed by remission of the symptoms and cytolysis and a limited reversion of the histologic modifications: a degree of fibrosis is present but it does not affect the hepatic architecture although theHBsAg can be shed for years. If the immune response of the host is very active the integrative stage follows: HBs seroconversion occurs, the HBsAg disappears, the HBV DNA becomes undetectable in the serum but still detectable in the liver cell where activation can occur if immunosuppression is present (HIV infection, immunosuppressive therapy, cytostatic treatment). The secondary, extra hepatic, sites of replication - lymph nodes, circulating lymphocytes, bone marrow, spleen, pancreas) can act as a virus reservoir although they do not undergo inflammatory lesions; they can be the origin of extra hepatic syndromes and post-transplant activation of infection HBV does not have a direct cytopathic effect; the lesions, the evolution and the symptomatology are triggered by the immune response of the host. The cytolysis is mediated by cytotoxic CD8 lymphocytes that recognize on the cell surface nucleocapsid proteins (AgHBc, AgHBe) and by NK cells. The cytotoxic aggression is associated with inflammatory lesions induced my macrophages that infiltrate the periportal areas. The type of immune response determines the clinical picture and possible chronicization. To some extent, the destruction of the infected hepatocytes is also mediated by early activity of the inflammatory cytokines and components of the innate immunity. The humoral immunity does not directly elicit cytolysis. HBc and HBe antibodies mediate the cytotoxic cellular response. The only protective antibodies are against HBs.  Denumirea cartii | 11 The existence of a direct pathogen effect of the virus is suggested by the association between certain mutations in the pre-core region and a higher incidence of severe and fulminant evolutions. 2.4. Clinical picture The clinical picture of HBV infection is very polymorphic, and the clinical expression can be acute, subacute or chronic. The incubation period is on average between 60-90 days, with limits between 45-180 days. Its duration is determined by the size of the infecting inoculum, the way of transmission, coinfection with other viruses, viral pathogenicity. The patient being asymptomatic. The prodromal (preicteric) period – lasting 2-3 weeks, includes symptoms similar to other forms of acute viral hepatitis. The pseudorheumathoid syndrome or the skin syndrome are specific to the onset of acute hepatitis B. The pseudoinfluenza syndrome (fever, cough, headache, myalgias, physical asthenia) is rarely encountered at the onset of hepatitis B, being specific to the onset of acute hepatitis A. Symptoms may be present simultaneously that belong to several onset syndromes. Hyperchromic urine and discolored stools can be reported by the patient 1-5 days before the onset of clinical jaundice. In children, the Gianotti-Crosti syndrome (papular acrodermatitis) is described, manifested by an erythematous-papular rash on the face and trunk and generalized adenopathy. Period of condition (jaundice). Clinically, sclero-tegumentary jaundice is present, which is usually more intense, more prolonged and often has an undulating evolution; painful hepatomegaly, discomfort in the right hypochondrium, and in some patients splenomegaly and cervical adenopathy may be present. The symptoms in the prodromal phase usually decrease in intensity with the appearance of jaundice. The convalescent period is characterized by the disappearance of constitutional symptoms, but with the persistence of a degree of hepatomegaly and a discrete hepatocytolysis. The duration is between 3-6 months. The evolution in 90% of cases is self-limiting and favorable within a few weeks. In 5-10% of cases, it will progress to chronicity and later to liver cirrhosis and hepatocellular carcinoma. Complications of acute hepatitis B are:  Chronification  Liver cirrhosis and hepatocellular carcinoma  Aplastic/hemolytic anemias  Neuritis, polyradiculoneuritis, myelitis  Periarteritis nodosa  Chronic membranous glomerulonephritis  Subacute cholangitis  Serum sickness: arthritis and urticarial rash  Autoimmune thyroiditis 12 | Denumirea cartii sau a sectiunii/capitolului  Essential mixed cryoglobulinemia  Chronic non-Hodgkin's lymphoproliferations 2.4.1. Clinical forms of acute HBV hepatitis:  Common form – clinical picture similar to the one described, with prothrombin concentration (CP) values above 60%.  Anicteric form - frequently encountered, associated with increased risk of chronification.  Prolonged form, manifests clinically in the following ways: cholestatic (intense and prolonged jaundice), relapsing/with relapses (undulating evolution).  Severe form (fulminant) - rarely encountered (1% of cases). This form is characterized by the presence of coagulation disorders (CP