Which is the most typical prodromal symptom of viral hepatitis A?

Prognosis and Natural History

Acute HAV infection resolves spontaneously and fully in most cases. Few children have the atypical manifestations, as described previously. The most significant complication is fulminant hepatic failure causing death or requiring transplantation. In the United States, fewer than 1% of fulminant hepatic failure cases in children are attributed to hepatitis A.14 This is in contrast to Latin America, where more than 40% of pediatric fulminant liver failure is caused by HAV.15 The risk of hepatic failure is higher in children less than 5 years old16 and patients with chronic hepatitis C infection.17 In 2006 there were five reported deaths in the United States because of acute hepatitis A infection; none of these were in children.3 According to the Studies of Pediatric Liver Transplantation (SPLIT) registry, which collects data from 37 North American pediatric liver transplant centers, only 2 (0.1%) of the 2291 pediatric transplants between 1995 and June 2006 were for fulminant hepatitis A.18

Viral Hepatitis Co-Infections

Acute HAV infections in persons with chronic HBV and HCV infections are associated with more severe disease and a higher risk of death. Acute HAV infection in persons infected with HIV may result in a prolonged HAV viremic stage (median duration 53 days vs. 22 days, p < 0.05) and potentially more severe disease as well as increased transmissibility.

HBV and HCV co-infection may result in more serious medical complications than HCV alone, in that there is an increased chance of progression to cirrhosis and an increased risk of development of hepatocellular carcinoma.

Among HIV-infected persons, chronic HBV infection occurs in 10-15%, and up to 30% may be co-infected with HCV. An increased risk of death has been reported in HIV/HBV co-infected men. Reports from several countries have shown significantly increased rates of death from end-stage liver disease among HIV-infected persons in the era of highly active antiretroviral therapy (HAART) compared with the pre-HAART era. One hypothesis is that chronic HBV and/or HBC infections can potentiate the inherent hepatotoxicity of the antiretroviral therapy drugs.

Clinical Course of Acute Hepatitis A

Acute hepatitis A virus infection causes an acute necroinflammatory process in the liver, which normally resolves spontaneously without chronic sequelae.52-54 The incubation period of acute HAV usually lasts between 14 to 28 days and up to 50 days. The likelihood of symptoms during acute HAV infection is age related. In approximately 70% of children beyond the age of 6 years, the disease is mild and asymptomatic and the remaining patients are usually unicteric.55 In children above the age of 6 years and especially in adults, more than 70% develop jaundice and symptoms that last between 2 and 8 weeks. Prodromal symptoms of acute hepatitis include malaise, fatigue, anorexia, vomiting, abdominal discomfort, diarrhea and, at a later stage and less commonly, fever, headaches, arthralgia, and myalgia53 (Table 29-2). The prodromal symptoms usually regress upon development of jaundice.

Five clinical patterns of hepatitis A are recognized: (1) asymptomatic HAV infection, often present in children under the age of 5 to 6 years; (2) symptomatic HAV infection with the appearance of dark urine and sometimes clay-colored stools, often accompanied or followed by jaundice; (3) cholestatic hepatitis characterized by a protracted course associated with pruritus, prolonged elevation of alkaline phosphates, γ-glutamyl transpeptidase, bilirubinemia, and weight loss56; (4) relapsing hepatitis A infection manifested by reappearance of some or all the clinical, biochemical virologic and serologic markers of acute hepatitis A after initial resolution;46,47 and (5) fulminant hepatitis, which is rare and frequently resolves spontaneously but may be fatal or require liver transplantation.57,58

According to one report, the most common signs on physical examination include hepatomegaly and jaundice present in 78% and 71% of symptomatic adult patients respectively. Splenomegaly and lymphadenopathy, are less common.59

Extrahepatic and atypical manifestations of acute hepatitis A are relatively rare60 and include skin involvement (rash), leukocytoclastic vasculitis, pancreatitis, carditis, glomerulonephritis, pneumonitis, hemolysis (especially in patients with glucose-6 phosphate dehydrogenase deficiency), thrombocytopenia, aplastic anemia, cryoglobulinemia, arthritis, neurologic findings including mononeuritis, encephalitis, Guillain-Barré syndrome, and transverse myelitis. A posthepatitic syndrome may occur in a minority of patients who develop prolonged fatigue, right upper quadrant discomfort, fat intolerance and indigestion, weight loss, emotional instability, and prolonged indirect bilirubinemia. Acute HAV infection resolves spontaneously in more than 99% of infected individuals (overall case fatality ratio approximately 0.3% to 0.6%). Relapsing hepatitis A may develop in 3% to 20% of cases.46,47 The cholestatic and relapsing forms of hepatitis A resolve spontaneously with few exceptions.61 Fulminant hepatitis is very rare with a wide range of estimated rates up to 1 : 10,000 or more in immunocompetent, healthy individuals. Mortality in fulminant hepatitis A is declining mainly because of availability of better intensive care and liver transplantation,57 and is linked to age greater than 50 years (case fatality rate is approximately 1.8%). However, in recent years a rising number of cases with fulminant hepatitis A has been reported in children in South America58,62,63 and Korea.23,64 Major risk factors associated with fulminant hepatitis A include age, underlying chronic liver disease,65,66 intake of paracetamol, co-infection with other viruses such as hepatitis C (HCV),67 and co-infection with other viral agents.

The outcome of viral hepatitis A in pregnancy is usually unaltered and favorable although the clinical course may be more severe in older women. Cases of vertical transmission from infected mothers to their newborns or perinatal transmission are very rare,68-71 but premature labor and increased gestational complications have been reported in the second and third trimesters of pregnancy.72-74

Hepatitis A

Acute hepatitis A virus (HAV) infection is usually self-limiting. However, elderly patients with acute HAV infection seem to show hepatocellular dysfunction with frequent jaundice and coagulopathy, as well as an increased incidence of complications, such as prolonged cholestasis, pancreatitis, and ascites (Brown and Persley, 2002). Higher hospitalization and mortality rates have been reported in elderly patients with HAV; 42% of patients aged 70 years or older required hospitalization compared with 3–20% of adults aged 40–49 years during an outbreak of HAV infection in the United States (Willner, 1998). Age-related differences in outcomes were also reported: 0.004% deaths in individuals 5–14 years old and 2.7% in those older than 49 years of age (Brown and Persley, 2002). Data from the Centers for Disease Control and Prevention (CDC, 2009 Surveillance) also indicate that mortality rate due to HAV increases with age with no fatalities reported in patients younger than 34 years of age. The mortality rates are estimated to be 0.05 per 100,000 patients aged between 45 and 54 years, and 0.11 per 100,000 patients older than 75 years of age. Vaccination for hepatitis A should, therefore, be considered for people, especially the elderly, planning to travel to endemic areas (Mahon and James, 1994).

23.1 Hepatitis A Virus

HAV is a RNA virus, which belongs to the family Picornaviridae (see Table 23.1). HAV is transmitted via the oral-fecal route from contaminated water or foods, and its infection causes acute hepatitis, and was formerly known as infectious hepatitis.

Epidemiology: HAV is usually spread by eating or drinking food or water contaminated with infected feces. Shellfish which have not been sufficiently cooked is a relatively common source. It may also spread through close contact with an infectious person. Most of the infected individuals (ie, 90% of children and 25–50% of adults) are asymptomatic. A person is immune for the rest of their life after a single infection. Globally around 1.5 million symptomatic cases occur each year with likely tens of millions of infections in all (Fig. 23.2). It is prevalent in regions with poor sanitation and not enough clean water. In the developing world about 90% of children have been infected by age 10 and thus are immune by adulthood. HAV outbreaks often occur in moderately developed countries where children are not exposed when young and there is not widespread vaccination. In the year 2010, acute hepatitis A (AHA) resulted in 102,000 deaths.

Pathogenesis: Many cases show little or no symptoms especially for youngsters. The incubation period is typically 2 to 7 weeks until serum ALT (ie, alanine aminotransferase) value is abnormally high (Fig. 23.3). Most symptoms last 8 weeks and may include nausea, vomiting, diarrhea, yellow skin, fever, and abdominal pain. Following ingestion, HAV enters the bloodstream through the epithelium of the oropharynx or intestine. The blood carries the virus to its target organ, the liver, where it multiplies within hepatocytes and Kupffer cells (liver-resident macrophages) (Box 23.1). Virions are secreted into the bile and released in stool. HAV is excreted in large quantities approximately 11 days prior to the appearance of symptoms or anti-HAV IgM antibodies in the blood (see Fig. 23.3). Thus, the diagnosis relies on the IgM in the blood.

Box 23.1

Cells Constituting Liver

The liver is often called the “chemical factory” of our body, because the liver fulfills diverse metabolic functions (ie, carbohydrate, proteins, and lipids). The metabolic functions of the liver are largely carried out by the hepatocytes, liver parenchymal cells. In addition to liver parenchymal cells, however, diverse nonparenchymal cells (NPCs) constitute the liver. In fact, hepatocytes constitute only 40% of the cells in the liver, while NPCs constitute 60% of the cells in the liver. The representative NPCs include the liver sinusoid endothelial cells (LSEC), hepatic stellate cells (HSC), and Kupffer cells. In addition, immune cells from the bloodstream such as dendritic cells, NK cell, and T cells infiltrate the liver, responding to invading pathogens. The liver clears blood-borne pathogens through uptake by hepatic scavenger cells, such as LSEC and Kupffer cells. Nonetheless, some pathogens (such as hepatitis viruses) can escape immune control and persist in hepatocytes, causing the diseases. Lifelong persistent infections caused by some viruses (HBV and HCV) lead to liver cirrhosis and HCC. Liver cirrhosis results from transformation of HSC to myofibroblasts, while liver cancer or HCC results from neoplastic transformation of hepatocytes.

AHA is accompanied with severe liver injury in adults. However, little is known about the underlying mechanism of liver injury, except that hepatocyte injury is T cell-mediated. A recent study showed that the suppressive activity of peripheral regulatory T cells3 is attenuated during acute hepatitis, implicating that the lack of Treg activity is responsible for liver injury (see Journal Club).

Prevention and Treatment: The hepatitis A vaccine is effective for prevention. Some countries recommend it routinely for children and those at higher risk who have not been previously vaccinated. HAV vaccination appears to be effective for life. Other preventative measures include hand washing and properly cooking food. There is no specific treatment, with rest and medications for nausea or diarrhea recommended. Infections usually resolve completely and without ongoing liver disease. The mortality is less than 0.5%.

DIAGNOSIS

Acute hepatitis A is clinically indistinguishable from other forms of viral hepatitis. The diagnosis of infection is based on the detection of specific antibodies against HAV (anti-HAV) in serum (Fig. 77-2). A diagnosis of acute hepatitis A requires demonstration of IgM anti-HAV in serum. The test result is positive from the onset of symptoms47 and usually remains positive for approximately 4 months.48 Some patients may have low levels of detectable IgM anti-HAV for more than a year after the initial infection.48 IgG anti-HAV is also detectable at the onset of the disease, remains present usually for life, and, after clinical recovery, is interpreted as a marker of previous HAV infection (as demonstrated by a positive result on a commercial assay for total anti-HAV and negative result for IgM anti-HAV).

Testing for HAV RNA is limited to research laboratories. HAV RNA has been detected in serum, stool, and liver tissue. Viral RNA can be amplified by polymerase chain reaction (PCR) methodology.49 With a PCR assay, HAV RNA has been documented in human sera for up to 21 days after the onset of illness.50 The use of HCV RNA testing has been described in a report of 76 French patients with acute HAV infection seen between January 1987 and April 2000; 19 had FHF,51 10 of whom required liver transplantation and 1 of whom died while awaiting liver transplantation. The HAV RNA status was determined in 39 of the 50 patients in whom sera and clinical data were available, including the 19 with FHF. HAV RNA was detected in 36 of these 50 patients (72%). The likelihood that HAV RNA was undetectable was greater in patients with FHF than in those with nonfulminant hepatitis (P < .02). Of those in whom HAV RNA was detectable, titers were lower in patients with encephalopathy than in patients with nonfulminant hepatitis (3.6 log vs 4.4 log; P = .02). These data suggest that detection of IgM anti-HAV coupled with nondetection or finding of low-titer HAV RNA in patients with severe acute hepatitis may signal an ominous prognosis and the need for early referral for liver transplantation. As in other studies, HAV genotype did not seem to play a role in the severity of clinical manifestations.52

Acute viral hepatitis

Acute viral hepatitis accounts for 40–70% of patients with ALF worldwide.

Acute hepatitis A (HAV) infection rarely leads to ALF (0.35% of infections), but continues to account for up to 10% of cases; morbidity increases with the age of infection. It is hoped that the prevalence will decrease with improving hygiene standards generally and the uptake of vaccination.

Acute hepatitis B (HBV) causes 25–75% of viral hepatitis-induced ALF. The liver injury is immunologically mediated with active destruction of infected hepatocytes. Diagnosis is by the presence of the IgM antibody (HBcAb) to hepatitis B core antigen. Hepatitis B surface antigen (HbsAg) is frequently negative by the time of presentation. Hepatitis B DNA should also be assayed. ALF may also be seen with hepatitis D, as either a co-infection or supra-infection.

Re-activation of hepatitis B is an increasing cause of ALF and should always be considered in a patient who has received steroids or chemotherapy. High-risk patients should be screened for sAg and HBV DNA and treated with antiviral agents if they are positive. This is a recognised problem in oncology and haematology but it is also a potential risk to patients in intensive care where steroids may be administered.

Hepatitis C (HCV) infection is commonly associated with chronic liver disease but not with ALF. It is detected by the presence of antibodies to HCV in serum. HCV-related cirrhosis will be discussed in detail in the subsequent chapter.

Hepatitis E (HEV), like hepatitis A, is transmitted via the faecal–oral route. It is particularly prevalent in the Indian subcontinent and Asia generally and is responsible for sporadic instances of ALF in the western world. It can be diagnosed by the detection of antibodies to HEV in serum.

Other viruses, such as herpes simplex 1 and 2, varicella zoster virus, cytomegalovirus, Epstein–Barr virus and measles virus, may all rarely cause ALF, but may be seen especially in the immunocompromised patient. Diagnosis is by serological and polymerase chain reaction (PCR) testing. Rift Valley fever, dengue, yellow fever, lassa fever and the haemorrhagic fevers should be considered in those who are at risk.

What is prodromal hepatitis A?

What is the most noticeable symptom of hepatitis A?

What are early prodromal clinical manifestations of hepatitis?

What is the most common symptom of acute hepatitis during the prodromal phase?