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Acute viral hepatitis is a systemic illness that mainly affects the liver. Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis D virus (HDV), and hepatitis E virus (HEV) are the viruses that cause almost all instances of acute viral hepatitis. Hepatitis can be present with little or no symptoms, although it frequently results in jaundice, anorexia, and malaise. Hepatitis infection is divided into two types: acute and chronic. Acute hepatitis remains for less than six months, whereas chronic hepatitis stays for an extended period. 

The causes can also be triggered by chemical substances, the 'Drug Induced Liver Injury'.

Acute infectious hepatitis is mainly caused by specific hepatitis viruses: hepatitis A, B, C and E. Associated with the hepatitis B virus (HBV), infection with the delta virus can occur. This virus needs the HBV to replicate and is mainly found in Türkiye  and the Balkan states.

In addition, acute infectious hepatitis can also be triggered by non-specific liver viruses, such as Epstein-Barr virus (causative agent of mononucleosis, which is associated with sore throat and splenomegaly) and cytomegalovirus (CMV), which can flare up mainly after organ transplants.

In addition, there are exceptionally microbial causes, such as Q fever (histologically characterized by fibrin ring granulomas), syphilis (via homophilic contacts) and spirochetosis ictero-hemorragica (transmitted by rats via contaminated water).

The clinical signs are the development of jaundice (on average in one in three), pronounced fatigue and possibly skin rash, joint swelling and gastrointestinal discomfort (mainly due to the hepatitis A virus). The recovery phase lasts several weeks, but may be associated with severe post-viral asthenia. Laboratory tests show a very strong increase in transaminase and, in severe forms, an increase in bilirubin and international normalized ratio (INR). In addition to specific antiviral therapy for some conditions, relative bed rest is recommended and work can be resumed when transaminases are normal.

Since acute infectious hepatitis can make patients more susceptible to the hepatotoxicity of medications, all non-essential medications should be discontinued, including estrogens, which increase the risk of cholestatic hepatitis after hepatitis A. There is no place for the use of corticosteroids.

The infection is fecal-oral. The incubation period is about 2 to 6 weeks. An infected person can be contagious from 2 to 5 weeks before the onset of jaundice, until the disappearance of clinical symptoms. Acute hepatitis A can occur in small epidemics.

The disease never becomes chronic and its evolution depends on the age at which the infection occurs. In children, the disease is usually subclinical, while in people over 45 years of age, there is a mortality of more than 2% (partly due to acute liver failure).

Intake of estrogens (via oral contraception) may lead to cholestasis after the first phase of severe hepatitis. In a minority of adults the disease may be biphasic. Rarely acute hepatitis A provokes chronic autoimmune hepatitis. The diagnosis is made by an increase in bilirubin, a marked increase in transaminases and when the anti-hepatitis A IgM (class M immunoglobulin) becomes positive. Hepatitis A can be prevented by a vaccine. This is recommended when travelling to endemic areas. The first administration should preferably be received fourteen days before departure.

Acute hepatitis A does not require antiviral therapy. Urgent vaccination of the partner would make the course of the disease milder if there had been an infection.

Although this illness has decreased in developed countries due to extensive immunization, numerous developing and under-developed countries are struggling with this virus. HAV infection can be spread by oral-fecal contact, and there are frequent epidemics through nutrition. Improvements in socioeconomic and sanitary circumstances have caused a shift in the disease's prevalence worldwide. Younger children are usually asymptomatic, but as they become older, the infection symptoms begin to appear. Symptoms range from slight inflammation and jaundice to acute liver failure in older individuals. While an acute infection may be self-limiting, unrecognized persistent infections, and the misapplication of therapeutic methods based on clinical guidelines are linked to a higher incidence of cirrhosis, hepatocellular carcinoma, and mortality. Fortunately, most patients recover within two months of infection, though 10–15% of patients will relapse within the first six months. A virus seldom leads to persistent infection or liver damage. The mainstay of therapy is based on supportive care. All children from 12–23 months, as well as some susceptible populations, should receive routine vaccinations, according to the Centers for Disease Control and Prevention and the American Academy of Pediatrics. Laboratory diagnosis of HAV is based on antigen detection, checking liver enzyme levels, and antibody screening. Furthermore, polymerase chain reaction (PCR) technology has identified HAV in suspected nutrition sources; therefore, this technique is used for preventative measures and food-related laws. 

HAV infection is highly contagious, and it is a leading cause of acute hepatitis. In people with chronic liver disorders, acute HAV infection can induce liver failure. HAV seroprevalence is also relatively low in high-income provinces. Socioeconomic factors, access to clean water, and proper sanitation are all strongly linked to epidemiology. HAV usually causes short-term, self-limiting illnesses that go away without any long-term effects in 4–7 weeks. Dissimilar to HBV and HCV, HAV seems not to cause persistent liver damage. However, particularly in the elderly, severe fulminant hepatitis with possibly fatal liver failure may ensue. The associated risk factors that cause case-to-case variation in the degree of liver disease and recurrence remain unclear. Furthermore, contact with the feces of infected patients with HAV can result in the transmission of the virus, implying that the virus can be spread via oral-fecal transmission. It is widespread, although it is more common in less-developed areas with inadequate sanitary and hygienic conditions. Transfusion transmission of HAV is exceedingly rare due to the short persistence of viremia throughout acute HAV infection (approx. 10–50 days). However, donors should be reminded that if they are identified with blood-borne diseases after donating blood, they must inform the blood center. If a transfused individual shows hepatitis A symptoms with no record of traveling or oral-fecal disease, doctors should evaluate the potential of transfusion-transmitted hepatitis A. 

In collaboration with state and local health departments, CDC launched a large-scale, multidisciplinary response in 2017 to control the ongoing outbreaks associated with person-to-person transmission. To provide hepatitis A vaccination to disproportionately affected populations most affected by the outbreaks, health departments developed and implemented nontraditional vaccination and staffing strategies. These included holding satellite vaccination clinics (e.g., at correctional facilities, substance use treatment facilities, syringe services programs, and homeless shelters) and broadening the scope of health care professionals approved to administer vaccines. To overcome barriers to vaccination, including mistrust, stigma, and vaccine hesitancy, health departments partnered with organizations that have long-standing, trusted relationships with persons at risk for HAV infection. In September 2022, as a result of these intensive and innovative efforts, 24 states have officially declared their outbreaks over, and the remaining 13 states report decreased case counts from the peaks of their outbreaks.

The findings in this report are subject to at least five limitations. First, risk factor data were self-reported and subject to recall and social desirability biases. Second, hepatitis A surveillance in the United States is passive; thus, case counts might underestimate the actual number of cases. Third, a substantial proportion of data was missing; caution should be exercised when interpreting results with high rates of missing data. Fourth, ethnicity was not systematically ascertained and could not be included. Finally, states did not use an identical hepatitis A–related death case classification, which might have resulted in differential classification of deaths as being hepatitis A–related.

Hepatitis A epidemiology in the United States has shifted as a result of the ongoing outbreaks associated with person-to-person transmission. Cases occurred almost exclusively among adults, and HAV transmission was driven primarily by close contact among persons who use illicit drugs and persons experiencing homelessness. Improving services for these populations, including access to substance use treatment and sanitation, are important considerations in mitigating HAV transmission. Many adults at increased risk for HAV infection remain vulnerable to infection, despite long-standing vaccination recommendations. Given the high hospitalization rate during these outbreaks and the high level of susceptibility to HAV infection among adults in the United States, efforts are needed to improve awareness of and adherence to ACIP hepatitis A vaccination recommendations. Increased hepatitis A vaccination coverage, through implementation of nontraditional vaccination strategies to reach disproportionately affected populations, along with improved universal and catch-up childhood vaccination, will be necessary to respond to the current hepatitis A outbreaks and prevent similar outbreaks in the future. Lessons learned during these outbreaks have been reinforced by experiences during the COVID-19 pandemic and other vaccine-preventable disease outbreaks. Disproportionately affected populations often experience stigma, mistrust, and societal barriers that limit adequate access to the health care system. Continued improvements in vaccination infrastructure, immunization information systems, and education and outreach are critically needed to build vaccine confidence and improve vaccine delivery in nontraditional settings.

Risk areas for travellers

Over the last decades, a substantial decrease in incidence of hepatitis A infection has been observed worldwide due to better food and water hygiene, improved sanitation, increasing socio-economic standards and (in few countries) the implementation of hepatitis A vaccine in the childhood vaccination programmes. Therefore, many countries are evolving from high and intermediate endemicity towards intermediate and low endemicity respectively.

Regions with high endemicity are sub-Saharan Africa and parts of South Asia (Afghanistan, Bangladesh, Bhutan, India, Nepal, Pakistan). Hepatitis A is typically acquired during childhood, providing immunity for nearly all adults. Considering most children experience an asymptomatic disease course, outbreaks are rather exceptional.

Intermediate endemic areas are Latin America, North Africa, the Middle East and multiple countries in Asia. The infection is less frequently acquired during childhood, leaving more adults susceptible to hepatitis A. Hence, outbreaks are more common.

Western Europe, Canada, USA, Australia, New Zealand and some high income countries in Asia (Japan, South Korea, Brunei, Singapore) have a low to very low endemicity. The risk of getting infected with hepatitis A virus in these areas is thus low.

Infection occurs through blood contact, sexual contact and transmission from mother to child (vertical transmission). The incubation period is 8 to 24 weeks. The diagnosis is made by a very strong increase in transaminases, which may or may not be accompanied by an increase in bilirubin. The hepatitis B surface antigen becomes positive, as does the hepatitis B DNA. 

The course of the disease is determined by the age at which you come into contact with the virus. In newborns, the infection is usually subclinical, but leads to chronicity in 90% of babies. In children, the chance of chronicity is 20% and in the elderly less than 10%. Acute hepatitis B is a rare cause of acute liver failure (ALF).

Mother-to-child transmission is virtually universal. Transmission occurs during childbirth and therefore a caesarean section* is of no benefit. All children of a hepatitis B surface antigen-positive mother should be vaccinated and given immunoglobulins immediately after delivery. Mothers with very high viraemia (> 200,000 IU/ml) are best treated with a polymerase inhibitor in the third trimester of pregnancy.

Acute hepatitis B should not be treated with antiviral therapy unless after several weeks it appears that the serum hepatitis B DNA is still strongly positive. In that case, antiviral therapy can be considered.

Hepatitis C virus (HCV) chronically infects 58 million people worldwide, and chronic hepatitis C (CHC) is a major cause of serious liver diseases such as potentially fatal hepatic cirrhosis and hepatocellular carcinoma (HCC). HCV infection accounts for one in four cases of liver cancer (Bartenschlager et al, 2018).

Although the cure rate of CHC patients has significantly improved with the use of directly acting antiviral agents (DAAs), there is currently no prophylactic vaccine available. Additionally, cured patients may still be at risk for reinfection due to lack of protective immunity (Farci et al, 1992; Page et al, 2009). Moreover, the persistent risk of HCC development post‐treatment, emergence of drug resistance‐associated substitutions (RAS) and new subtypes, as well as limited access to DAA therapy in underdeveloped regions pose significant challenges to achieving the goal of eliminating viral hepatitis as a public health threat by 2030 (Bartenschlager et al, 2018; Shah et al, 2021). Therefore, HCV infection will continue to be a global public health concern.  

The mode of infection is mainly through contaminated blood, including needle stick injuries or intravenous/intranasal drug use. Hepatitis C is not a classic sexually transmitted disease (STD), but can be transmitted through rough anal contact. It can also be transmitted through vertical contamination, but this is generally low (< 5%).

Diagnosis is made by a marked increase in transaminases, possibly accompanied by an increase in bilirubin and hepatitis C RNA that becomes positive. Hepatitis C antibodies appear after 4 to 12 weeks. 75% of infections become chronic. There is no vaccine.

Antiviral therapy is started when the disease becomes chronic.

Pathogenesis|clinical picture

In most cases (80%), HCV infection becomes chronic, despite the presence of antibodies and HCV-specific T cells. After an incubation period of 2 months (range 2 to 26 weeks), infection with HCV leads to jaundice (icterus) in only 10% of cases. In half of the HCV carriers, ALT values ​​remain more or less elevated.

The physician encounters HIV mainly in the form of chronic hepatitis and cirrhosis (20% after 20 years). The chance of developing cirrhosis is higher in men, in HCV infection at an older age and if the HCV carrier uses alcohol. Modest alcohol use and diabetes mellitus also worsen the prognosis of hepatitis C initially. In addition to liver disease, HCV infection is associated with several other conditions. A significant proportion of patients with membranoproliferative glomerulonephritis type 1 and 'mixed cryoglobulinemia' are found to be HCV positive [Mixed cryoglobulinemia can evolve into a florid B-cell malignancy in up to 11% of cases].

Treatment HCV

The highly effective oral agents used in HCV (effective in 80-100% of treated patients) cannot all be used safely in the more advanced stages of fibrosis and cirrhosis. Liver biopsy in chronic HCV infection has the main role to grade fibrosis and inflammation and to establish a competing diagnosis (alcoholic liver disease or drug hepatitis). In addition, liver biopsy can be used to document progression of liver disease over time, which is not possible with serum transaminase determination. In addition to liver biopsy, ultrasound fibroscan and various blood tests can be used. The degree of fibrosis plays a role in determining the degree of urgency to proceed with treatment. From mild to moderate fibrosis, treatment is urgently needed. In severe fibrosis, liver transplantation should be considered.

Prevention

Passive or active immunization against hepatitis C is not available. The chance of infection with HCV after a needle stick injury with HCV-positive blood is 1-10%. Depending on the type of accident and the amount of infectious material transmitted.

Young people are usually infected by staying in endemic areas. Sporadic forms are increasingly appearing in adults. The infection is transmitted by zoonosis, including contact with infected pork. The virus can also be transmitted by blood transfusion.

The diagnosis is made by a marked increase in transaminases, which may be accompanied by an increase in bilirubin, the appearance of anti-hepatitis E virus IgM antibodies and a positive hepatitis E virus RNA. The most common genotype in the West is genotype 3.

Acute hepatitis E usually does not become chronic. The HEV RNA remains in the blood for 2 to 3 weeks. Only in patients under immunosuppression, for example after a transplant, can it become chronic.

An important complication is the development of serious neurological abnormalities, including Guillain-Barré syndrome. This is also called Hepatoneural syndrome.

There is no vaccine yet in the West. Acute hepatitis E does not need to be treated either. When hepatitis E becomes chronic, it can be cured by an antiviral drug. This is successful in 75% of cases.

Characteristics|epidemiology

Hepatitis delta virus (HDV) is not related to any other human or animal virus. HDV more or less parasitizes HBV, because it uses the envelope of HBV as an envelope. Infection with HDV is therefore only possible in the presence of infection with HBV.

Sporadic cases of HDV infection occur worldwide. The virus is found relatively often in intravenous drug users. HDV spreads mainly through blood-to-blood contact.

Hepatitis Delta virus life cycle HDV is the smallest human infecting virus and the sole member of the Deltavirus genus. HDV is characterized as a “satellite” or “defective” virus as it is dependent on HBV co-infection for viral assembly and persistence. HDV has an approximate 1.7 kb circular, single-stranded, negative-sense RNA genome that encodes for a single protein of two isoforms: The small and large delta antigens (S-HDAg and L-HDAg, respectively). Viral entry occurs similarly to HBV due to HDV’s co-opted use of the envelope HBsAg protein. Following viral entry, HDV uncoats in the cytoplasm and the ribonucleoprotein complex consisting of the HDV viral genome and HDAg complex is imported into the nucleus. Rolling-circle replication occurs in the nucleolus using the host RNA polymerase II to produce antigenomic positive sense HDV RNA that serves as a template for genomic HDV RNA synthesis and protein production. The antigenome can be edited by host protein adenosine deaminase acting on RNA 1 (ADAR1) to change adenine to inosine in the UAG stop-codon to produce the L-HDAg. The edited and non-edited antigenomes are then linearized by the HDV associated ribozyme, exported to the cytoplasm, and translated to HDV antigens. The non-edited transcript produces S-HDAg (24 kDa) and the transcript modified by ADAR1 produces the L-HDAg (27 kDa). Following extensive post-translational modifications, the viral antigens associate with the HDV RNA in the cytoplasm to form the ribonucleoprotein complex. The ribonucleoprotein is trafficked through the ER and Golgi apparatus where it co-opts the HBsAg envelope produced by HBV, and then buds out of the cell.

D'souza S, Lau KCK, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol 2020; 26(38): 5759-5783 [PMID: PMC7579760 DOI: 10.3748/wjg.v26.i38.5759] 

This presents as abnormal liver tests (all types) after taking medication.

The provoking substances themselves are usually of little or no toxicity, but toxic metabolites may be formed. Rarely, there is idiosyncrasy (immunoallergy), which is characterized by eosinophilia, but usually the toxicity is dose-dependent. The amount and activity of some metabolizing enzymes in the liver are genetically determined. A person who has a genetic predisposition to rapid conversion to a toxic liver product is more likely to have toxic side effects. Elderly and patients with cirrhosis are at increased risk. For example, the maximum daily dose of paracetamol in cirrhotic patients is 2 g instead of 4 g. Certain medications can induce or inhibit the microsomal enzymes that detoxify the metabolites (see drug interactions when taking antiviral medication for hepatitis C).

In 70% of cases, toxicity is caused by one specific drug and in 20% of cases by a combination of different drugs. In 10% of cases, toxicity is provoked by dietary supplements or herbs.

The most frequent medications that cause hepatotoxicity are:

1) antibiotics (45%): such as amoxicillin-clavulanic acid, flucloxacillin and macrolides;

2) antiepileptics (15%): such as valproate and carbamazepine;

3) anti-inflammatory drugs: such as diclofenac and nimesulide.

DILI can result in several types of biochemical abnormalities. It can cause liver steatosis, including by mitochondrial toxicity, such as by taking steroids, tetracyclines, methotrexate and non-steroidal antiphlogistics (NSAID). It can give a picture of hepatitis, such as in the case of an overdose of paracetamol, antituberculostatics and antiepileptics. Finally, it can lead to cholestasis, such as by the intake of estrogens and amoxicillin-clavulanic acid.

Diagnosis is made by exclusion diagnosis. Accurate history and heteroanamnesis are crucial. In case of acute presentation, a toxicology screen of urine should be performed.

Almost 80% of DILI cases recover spontaneously. Very rarely, permanent damage to the small bile ducts (vanishing bile duct syndrome) may occur. DILI is a not infrequent cause of acute liver failure.

Small acetaminophen are efficiently processed in the liver to glucuronide or sulphate derivatives and removed via the urine. Paracetamol is processed via the microsomal cytochrome P-450 system, whereby potentially toxic derivatives are formed. By binding with glutathione, these can be detoxified. If this does not happen, an irreversible binding with liver cell proteins occurs. This leads to cell necrosis.

The causes of paracetamol intoxication are:

1) 50% accidental;

2) 50% suicide.

Characteristics of patients with paracetamol intoxication:

1) 50% with alcohol or drug problems;

2) 60% take antidepressants.

Laboratory tests show a very strong increase in transaminases (> 1000), an increase in creatinine and the development of metabolic acidosis. The toxicology screen on urine can show paracetamol.

Treatment consists of nasogastric lavage (if paracetamol was taken less than 4 hours before) and administration of activated charcoal (1 g/kg). Intravenous acetylcysteine ​​(glutathione donor) should be administered if liver function tests are impaired.

The combination of amoxicillin and clavulanic acid is a frequent cause of cholestatic hepatitis in the elderly. There may be an interval of several weeks between taking the medication and noticing cholestasis. Cholestatic hepatitis is associated with typical histological abnormalities.

Acute liver failure has been reported when isoniazid and rifampicin are co-administered to patients taking other enzyme inducers.

ALF manifests as jaundice with increased INR and decreased consciousness.

ALF is present when there is an increase in the INR (> 1.5) and when hepatic encephalopathy appears in a patient previously not known to have serious underlying liver disease.

The interval between the first increase in bilirubin and the onset of hepatic encephalopathy also determines the prognosis. Hyperacute liver failure is present if this interval is less than 1 week. This may be accompanied by cerebral edema and cerebral compression. If the interval is longer than 6 to 8 weeks, subacute liver failure is present. The clinical picture then corresponds to the end stage of a patient with cirrhosis, without cirrhosis being present. Mortality in this type is caused by bacterial infections.

Hepatitis A and acetaminophen cause hyperacute liver failure. Hepatitis B usually leads to acute liver failure. Liver failure provoked by DILI leads to subacute liver failure. This type is now considered the most important cause of ALF.

If the patient meets the criteria for urgent liver transplantation, he has a mortality of more than 90% within 2 weeks if he does not receive a transplant. However, if the patient recovers, a complete spontaneous recovery follows.

Scores that help to assess the need for liver transplantation include the King's College Criteria. They are based on age, etiology, the interval between the rise in bilirubin and the finding of hepatic encephalopathy, the INR and bilirubin level. The subacute forms have the worst prognosis.

Therefore, a patient without previous liver disease who develops an INR > 1.5 should be referred immediately to a centre where urgent liver transplantation is possible. In that case, supportive therapy with N-acetylcysteine ​​can be given. This results in an improvement of peripheral tissue oxygenation.

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