HEAPTITIS

DEFINITION
Hepatitis is an inflammation of the liver characterized by diffuse or patchy necrosis [1]
Chronic hepatitis is characterized by the presence of hepatic inflammation on liver biopsy and elevation of serum liver enzymes, especially transaminases, generally defined as disease that has lasted for 6 months or longer [2]

APPROACH TO A PATIENT WITH JAUNDICE [3, 4]

• If patient has jaundice, the classic definition of jaundice is a serum bilirubin level greater than 2.5 to 3 mg per dL (42.8 to 51.3 µmol per L) in conjunction with a clinical picture of yellow skin and sclera
• Patient with jaundice may present with no symptoms at all (i.e., the condition is found accidentally), or they may present with a life-threatening condition. The wide range of possibilities is based on the variety of underlying causes and whether disease onset is quick or slow moving.
• If patient with jaundice has acute illness, which is frequently caused by infection, may seek medical care because of fever, chills, abdominal pain, and flu-like symptoms. For these patients, the change in skin color may not be their greatest concern
• Patients with noninfectious jaundice may complain of weight loss or pruritus.
• Abdominal pain is the most common presenting symptom in patients with pancreatic or biliary tract cancers.
• Even something as nonspecific as depression may be a presenting complaint in patients with chronic infectious hepatitis and in those with a history of alcoholism
• Patients may present with jaundice and some extrahepatic manifestations of liver disease. Examples include patients with chronic hepatitis and pyoderma gangrenosum, and patients with acute hepatitis B or C and polyarthralgias
• Jaundice can reflect a medical emergency in a few select situations. These include massive hemolysis (eg, due to Clostridium perfringens sepsis or falciparum malaria), ascending cholangitis and unconjugated hyperbilirubinemia in the neonatal period (which can lead to kernicterus), and fulminant hepatic failure.
• The physical examination should focus primarily on signs of liver disease other than jaundice, including bruising, spider angiomas, gynecomastia, testicular atrophy, and palmar erythema. An abdominal examination to assess liver size and tenderness is important. The presence or absence of ascites also should be noted.
• If patient has jaundice, the initial work-up of the patient with jaundice depends on whether the hyperbilirubinemia is conjugated (direct) or unconjugated (indirect).
• A urinalysis that is positive for bilirubin indicates the presence of conjugated bilirubinemia. Conjugated bilirubin is water soluble and therefore able to be excreted in urine.
• The findings of urinalysis should be confirmed by measurements of the serum total and direct bilirubin levels
• If patient appearing to have jaundice has normal bilirubin and liver enzymes, patient has pseudo jaundice which may be due to high vegetable intake. Unlike true jaundice, carotenemia does not result in scleral icterus or elevation of the bilirubin level
• If patient has unconjugated hyperbilirubinemia in which urine is negative for bilirubin, increased total and normal cojugated bilirubin look for hemolysis, drug toxicity, genetic syndrome(Gilbert's and Crigler-Najjar syndrome) and hematoma
• If urine is positive for bilirubin, increased total and cojugated bilirubin patient has conjugated hyperbilirubinemia, obtain Liver function tests( AST,ALT, AP, GGT) and CBC
• If patient has jaundice, a CBC is useful in detecting hemolysis, which is indicated by the presence of fractured red blood cells (schistocytes) and increased reticulocytes on the smear.
• If patient has jaundice, AST and ALT are markers of hepatocellular injury.
• They can be less helpful in patients with chronic liver disease, because levels can be normal or only slightly elevated when there is little liver parenchyma left to damage.
• Acute viral hepatitis may cause the levels of ALT to raise several thousand units per liter. Levels greater than 10,000 U per L usually occur in patients with acute injury to the liver from another source (e.g., drugs [acetaminophen] or ischemia)
• If patients have acute alcoholic hepatitis, they have AST and ALT levels that rise to several hundred units per liter. With alcohol-induced damage, the ratio of AST to ALT is usually greater than 1, whereas infectious causes of hepatitis typically cause greater elevation in ALT than in AST
• Alkaline phosphatase and gamma-glutamyltransferase are markers for cholestasis. As bile obstruction progresses, the levels of these two markers rise several times above normal
• The disorders associated with isolated conjugated hyperbilirubinemia and normal liver enzymes are Rotor and Dubin-Johnson syndrome.
• If still no cause is apparent obtain viral serology for hepatitis A, B and C
• If patient has jaundice, the second-line serum investigations may include tests for hepatitis A IgM antibody, hepatitis B surface antigen and core antibody, hepatitis C antibody
• If still no cause is appearent screen for autoimmune disorders (ANA, antiLKM and anti-smooth muscle antibodies)
• If patient with jaundice has an elevated amylase level would corroborate the presence of pancreatitis when this condition is suspected based on the history or physical examination.
• Other tests to be carried out include serum levels of iron, transferrin, and ferritin (for hemochromatosis), serum levels of ceruloplasmin (for Wilson's disease) and measurement of alpha-1-antitrypsin activity (for alpha-1-antitrypsin deficiency).
• If no diagnosis is appearent than go for imaging studies like ultrasonography and CT scan to rule out intra and extra hepatic causes of jaundice
• Ultrasonography is typically the first test ordered, because of its lower cost, wide availability, and lack of radiation exposure, which may be particularly important in pregnant patients.
• While ultrasonography is the most sensitive imaging technique for detecting biliary stones, CT scanning can provide more information about liver and pancreatic parenchymal disease. Neither modality is good at delineating intraductal stones
• Further imaging that may be done by a gastroenterologist or interventional radiologist includes endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography
• If patient has jaundice, a liver biopsy provides information on the architecture of the liver and is used mostly for determining prognosis.
• It also may be useful for diagnosis if serum and imaging studies do not lead to a firm diagnosis.
• Liver biopsy can be particularly helpful in diagnosing autoimmune hepatitis or biliary tract disorders (e.g., primary biliary cirrhosis, primary sclerosing cholangitis).

MILD CHRONIC ELEVATION IN SERUM AMINOTRANSFERASES [4]
The laboratory evaluation of patients with chronic (defined as six months or greater), mild elevation (defined as less than 250 U/L) of one or both of the aminotransferases is best achieved in a stepwise fashion to eliminate unnecessary testing.
• Review possible link to medications, herbal therapies or recreational drugs
• Screen for alcohol abuse (screening instruments, AST/ALT ratio >2:1)
• Obtain serology for hepatitis B and C (HBsAg, HBsAb, HBcAb, HCV Ab)
• Screen for hemochromatosis (FE/TIBC >45 percent)
• Evaluate for fatty liver (AST/ALT usually < 1, obtain a RUQ ultrasound)
• If the above is unrevealing confirm that source is hepatic by following:
Exclude muscle disorders (obtain creatinine kinase or aldolase)
Obtain thyroid function tests (TSH if hypothyroidism is suspected otherwise obtain a full set of thyroid function tests)
Consider celiac disease (especially in patients with a history of diarrhea or unexplained iron deficiency - serum anti endomysial IgA or anti tissue transglutaminase IgA antibodies are reasonable screening tests)
Consider adrenal insufficiency

• Consider less common causes of liver disease if now it is confirmed that source is of liver origin :
• Consider autoimmune hepatitis particularly in women and those with a history of other autoimmune disorders (check serum protein electrophoresis, obtain ANA and ASMA if positive)
• Consider Wilson's disease in those <40 (check ceruloplasmin, evaluate for Kayser Fletcher rings)
• Consider alpha-1-antitrypsin deficiency especially in patients with a history of emphysema out of proportion to their age or smoking history (obtain alpha-1-antitrypsin phenotype)
• Observe if ALT and AST are less than two-fold elevated
• Otherwise consider a liver biopsy

ISOLATED ELEVATION OF THE ALKALINE PHOSPHATASE AND/OR GAMMA GLUTAMYL TRANSPEPTIDASE [4]
• The first step in the evaluation of an elevated alkaline phosphatase is to identify its source
• Physiological causes of alkaline phosphatase should be ruled out like pregnancy and after eating a fatty meal. Test should be repeated in a fasting state.
• If gel electrophoresis is not available which is the most specific test, either a 5'-nucleotidase or GGT should be obtained. These tests are usually elevated in parallel with the alkaline phosphatase in liver disorders, but are not increased in bone disorders.
• An elevated serum alkaline phosphatase with a normal 5'-nucleotidase or GGT should prompt an evaluation for bone diseases.
• The most common causes to be considered in patients of elevated alkaline phosphatase include partial bile duct obstruction, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, adult bile ductopenia, and certain drugs such as androgenic steroids and phenytoin.
• Initial testing should include a right upper quadrant ultrasound (which can assess the hepatic parenchyma and bile ducts) and an antimitochondrial antibody (AMA), which is highly suggestive of PBC.
• The presence of biliary dilatation suggests obstruction of the biliary tree.
• In patients with biliary dilatation or choledocholithiasis, an endoscopic retrograde cholangiopancreatogram (ERCP) should be done to identify the cause of obstruction and to allow for an intervention such as stone removal or stent placement.
• Patients with a positive AMA should have a liver biopsy to verify the diagnosis of PBC.
• Suggest a liver biopsy and either an ERCP or magnetic resonance cholangiopancreatogram (MRCP) if the AMA and ultrasound are both negative and the alkaline phosphatase is persistently more than 50 percent above normal for more than six months.
• If the alkaline phosphatase is less than 50 percent above normal, all of the other liver tests are normal, and the patient is asymptomatic, we suggest observation alone

CAUSES OF HEPATITIS [3, 4]
ACUTE HEPATITIS
• Infectious viral hepatitis such as hepatitis A, hepatitis B, hepatitis C, hepatitis D and hepatitis E.
• Other viral diseases such as: mononucleosis and cytomegalovirus.
• Severe bacterial infections.
• Amoebic infections.
• Medicines, eg paracetamol poisoning and halothane (an anaesthetic).
• Toxins: alcohol and fungal toxins, eg toadstool poisoning
CHRONIC HEPATITIS

Chronic hepatitis also has a number of different causes.
• Contagious viral hepatitis such as hepatitis B, hepatitis C and hepatitis D.
• Medicines.
• Toxins such as alcohol.
• Autoimmune hepatitis. This is a disease in which a number of liver cells are destroyed by the patient's own immune system. Autoimmune hepatitis can also sometimes occur as acute hepatitis. The cause is unknown.
• Inborn metabolic disorders, such as Wilson's disease (disorder of the body's copper metabolism) and haemochromatosis (disorder of the body's iron metabolism).

HEPATITIS A
DEFINITION:
Hepatitis A is acute inflammation of liver caused due to RNA virus, causing epidemics or sporadic cases of hepatitis, transmitted by the fecal-oral route, either by direct contact with a person who is infected with hepatitis A virus or by ingestion of food or water that has been contaminated with the virus [5].

DIAGNOSTIC CONSIDERATIONS
Prodrome of anorexia, nausea, vomiting, malaise, aversion to smoking.
Fever, enlarged and tender liver, jaundice.
Normal to low white cell count; abnormal liver tests, especially markedly elevated aminotransferases early in the course.
Evidence of transmission by the fecal-oral route, either by direct contact with a person who is infected with hepatitis A virus or by ingestion of food or water that has been contaminated with the virus, but in approximately 40 percent of reported cases of hepatitis A, the source of infection cannot be identified.
Hepatitis A IgM is positive
Hepatitis never goes into chronic stage.
Incubation period is 14 -21 days
Liver biopsy may show hepatocellular necrosis and mononuclear infiltrate but is very rarely indicated.


EPIDIMEOLOGY
Worldwide, four major patterns of HAV infection can be described based on the age-specific prevalence of antibodies to HAV. These range from high endemicity, such as in Africa and parts of Asia and Latin America, where the majority of infections occur in early childhood, to low and very low endemicity, such as in North America and Western Europe, where few persons are infected in childhood, and the majority of the population remains susceptible throughout adulthood [6]
In 2003 in US, the incidence of Hepatitis A was 2.6 per 100,000 which has declined due to introduction of vaccine against it
Persons aged 5-14 years are most likely to acquire acute HAV infection. Over the last 40 years, the average age of infected persons has steadily increased [6]
Over last 20 years, shifting patterns in the prevalence of antibodies to HAV (anti-HAV) are seen throughout South-East Asia and China. In general in the late 1970s and early 1980s, 85-95% of the population of developing countries like the Philippines, Korea, China and Thailand were anti-HAV-positive by age 10-15 years, compared with only about 50% in the more affluent countries like Malaysia and Singapore. In the early 1990s, 85-95% of the population was immune by age 30-40 years in the Philippines, Korea, China and Thailand and by 50 years of age and above in Malaysia and Singapore. Similar trends were noted in Hong Kong, Taiwan and Japan [7].
Race: Immigrants from countries of high endemicity to countries of low endemicity may be responsible for some of the periodicity observed with outbreaks of infection. In this setting, affected individuals tend to be infants born since the last outbreak or susceptible adults who moved to the area.
Sex: Except for persons in high-risk populations (eg, sewage workers, childcare workers, aid workers, male homosexuals), no sexual predilection is apparent.
Age: With increasing age of acquisition, both symptomatic disease and adverse sequelae increase [8]
TRANSMISSION
• Hepatitis A virus is transmitted by the fecal–oral route, either by direct contact with a person who is infected with hepatitis A virus or by ingestion of food or water that has been contaminated with the virus.
• Contaminated food is identified as the source of transmission for less than 5 percent of cases reported in the United States [9]. Spread is favored by crowding and poor sanitation
• It can spread by [6]
1. Person to person contact
2. Homosexual contact
3. Contact with contaminated food or water
4. Raw or undercooked shellfish (oysters, clams, mussels)
5. Foods contaminated by infected food handlers
6. Persons in daycare centers
7. Persons in institutions
8. Military personnel
9. Through blood transfusions
10. Via intravenous drug use
11. No identifiable risk factor


CLINICAL FEATURES
• HAV infection usually results in an acute, self-limited illness and only rarely leads to fulminant hepatic failure.
• Fulminant hepatic failure occurs more commonly in patients with underlying liver disease, particularly chronic hepatitis C virus infection
• The manifestations of Hepatitis A infection vary with age.
• HAV infection is usually silent or subclinical in children. In contrast, infection in adults can vary in severity from a mild flu-like illness to fulminant hepatitis.

SYMPTOMS
• The incubation period averages 30 days (range 15 to 49 days).
• After incubation period the illness begins in symptomatic patients with the abrupt onset of prodromal symptoms including, fatigue, malaise, nausea, vomiting, anorexia, fever, and right upper quadrant pain [11].
• Within a few days to one week, these patients enter icteric phase and note dark urine, acholic stool (light-colored stools lacking bilirubin pigment), jaundice, and pruritus. The prodromal symptoms usually diminish when jaundice appears; jaundice typically peaks within two weeks [12]
• In convalescent phase, there is an increasing sense of well-being, return of appetite, and disappearance of jaundice, abdominal pain and tenderness, and fatigability.
• Three atypical clinical manifestations of acute infection are recognized: prolonged cholestasis, relapsing hepatitis, and extra hepatic disease associated with acute infection [13].
• A relapsing form of hepatitis is observed in 3 to 20 percent of patients with HAV infection. The clinical course is usually preceded by an apparent full clinical recovery with near normalization of the serum aminotransferases lasting 4 to 15 weeks, followed by biochemical and, in some cases, clinical relapse, which is often milder than the initial episode.
• Variety of extrahepatic manifestations of hepatitis A virus has been described [13]
• Evanescent rash and arthralgias are the most common, occurring in approximately 11 and 14 percent of patients, respectively [13]
• Extra hepatic manifestations also include toxic epidermal necrolysis, myocarditis, optic neuritis, transverse myelitis, thrombocytopenia, aplastic anemia and red cell aplasia [13]
• Acute renal failure, interstitial nephritis, pancreatitis, transient heart block, Guillain-Barré syndrome, lupuslike syndrome, and Sjögren syndrome have been reported in association with HAV infection. These complications are all rare



SIGNS:
The two most common physical examination findings are jaundice and hepatomegaly, which occur in 70 and 80 percent of symptomatic patients, respectively [18].
Less common findings include splenomegaly, cervical lymphadenopathy, evanescent rash, arthritis, and, rarely, a leukocytoclastic vasculitis.


DIFFRENTIAL DIAGNOSIS [14]
Hepatitis A should be differentiated from other causes of acute hepatitis:
Acute Viral Hepatitis like hepatitis B, C , E
Acute drug-induced liver injury (e.g., Paracetamol, ecstasy)
Acute HIV infection
Drug-induced hypersensitivity reactions (e.g., sulfasalazine hypersensitivity)
Viral hepatitis (e.g., cytomegalovirus [CMV], Epstein-Barr virus [EBV])
Budd Chiari syndrome

INVESTIGATIONS

• Hepatitis A infection is confirmed by a positive serum hepatitis A virus-specific immunoglobulin M (HAV-IgM) which remains positive for 6 months or more.
• Hepatitis A virus-immunoglobulin G (HAV-IgG) does not distinguish between current or past infection and may remain positive for life.
• If patient has hepatitis A, serum/plasma aminotransferases (AST/ALT) can range from 500 to 10,000 IU/L.
• Bilirubin can be up to 500 micromoles/L.
• Both direct and indirect fractions increase because of hemolysis, which often occurs in acute HAV infection
• Alkaline phosphatase levels are usually <2x the upper limit of normal, but higher if there is cholestasis
• Modest falls in serum albumin level may accompany the illness
• If in a patient of Hepatitis A, prothrombin time (PT) is prolonged by more than 5 seconds, suggest developing hepatic decompensation
• If patient has Hepatitis A, advise CBC. Blood picture may show mild lymphocytosis is not uncommon. Pure red cell aplasia and pancytopenia may rarely accompany infection. Indices of low-grade hemolysis are not uncommon
• An ultrasound scan may be required when alternative diagnoses warrant exclusion and should assess vessel patency and evaluate any evidence supporting unsuspected underlying chronic liver disease. Ultrasound scanning is essential in patients with fulminant hepatic failure.
• Blood urea and serum creatinine should be obtained at baseline.
• Screen for other sexually transmitted infections in cases of sexually-acquired hepatitis or if otherwise appropriate.

TREATMENT
If patient has Hepatitis A, he/she should be advised against handling food, keeping cleanliness, avoiding unprotected intercourse. Treat the patient symptomatically and maintain oral rehydration. If patient develops fulmanent hepatic failure admit the patient. Contacts should be given immunoglobulins and vaccination and other people vaccinated.

NON PHARMACOLOGICAL TREATMENT
• Patients should be advised to avoid food handling and unprotected sexual intercourse until they have become non-infectious [15].
• Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partner(s). This should be reinforced by giving them clear and accurate written information.
• Hepatitis A is a notifiable disease [15].
• Encourage an adequate diet. Patients should avoid alcohol and medications that may accumulate in liver disease. Otherwise, no specific dietary restrictions are necessary
Bed rest during the acute illness may be important, although data to support this practice are lacking. Restricting transmission is important, especially in the early phases of the illness. Returning to work should probably be delayed for 10 days after the onset of jaundice [15]
PHARMACOLOGICAL TREATMENT
Acute Icteric Hepatitis [15]

Mild/moderate (80%), manage as an outpatient emphasising rest and oral hydration.
Nausea and vomiting are treated with antiemetics
Paracetamol may be cautiously administered but is strictly limited to a maximum dose of 3-4 g/d in adults
Severe attack with vomiting, dehydration, or signs of hepatic decompensation (change in conscious level or personality), admit to hospital.
If patient has cholestatic type of hepatitis, cholestyramine should be administered if the pruritus is bothersome.
Pregnancy and Breast Feeding [15]

• Pregnant women should be advised of the increased risk of miscarriage/premature labor and the need to seek medical advice if this happens.
• Breast-feeding can be continued but consider giving human normal immunoglobulin (HNIG) 125 mg intramuscularly (i.m.) to the baby, although most children will have mild or asymptomatic infection.
Sexual and Other Contacts [15]
• Partner notification should be performed for at-risk homosexual contacts (oro/anal, digital/rectal, and penetrative anal sex) within the period 2 weeks before to 1 week after the onset of jaundice. This to be documented and the outcome documented at subsequent follow-up.
• Other people thought to be at risk (household contacts, those at risk from food/water contamination) to be contacted via the public health authorities.
• Hepatitis A vaccine may be given up to 7 days after exposure providing exposure was within the infectious period of the source case (during the prodromal illness or first week of jaundice).
• HNIG, 250 to 500 mg intramuscularly, should be considered for patients at higher risk of complication (concurrent chronic hepatitis B or C, chronic liver disease, or age >50 yr) or if there has been a delay of more than 7 days after exposure.
• HNIG works best if given in the first few days after first contact, with an efficacy of 90%, and is unlikely to give any protection more than 2 weeks after first exposure, but may reduce disease severity if given up to 28 days after exposure
• Patients are most infectious for 2 weeks before the jaundice (i.e., before the illness is recognized).
• Hepatitis A vaccine 3 scheduled doses provide 95% protection for at least 5 years. Current advice is to revaccinate after 10 years; however there is increasing evidence that vaccine-induced immunity may be >20 years and possibly lifelong, so no further booster doses may be needed after the primary course in immunocompetent patients.
• Human immunodeficiency virus (HIV)-positive patients respond (antibody production) in 73 to 88%, but titers are lower than in HIV-negative individuals.
• If patients with a low CD4 count (<300 cells/mm3) are vaccinated, they should be revaccinated if the CD4 count rises above 500/mm3 as a result of highly active antiretroviral therapy (HAART).
• There is a combined hepatitis A+B vaccine given on the same schedule as the hepatitis B vaccine and has similar efficacy to the individual vaccines although early immunity to hepatitis B may be impaired
• If an outbreak is suspected or if the index case is a food handler, notify the local public health department.

• Relapsing HAV infection
o This complication occurs in 3-20% of patients with acute HAV infection and uncommonly takes the form of multiple relapses.
o Following a typical acute course of HAV infection, a remission phase occurs, with partial or complete resolution of clinical and biochemical manifestations. The initial flare usually lasts 3-6 weeks; relapse occurs after a short period (usually <3 wk) and mimics the initially presentation, although it usually is clinically milder.
A tendency to greater cholestasis exists in these patients. Vasculitic skin rashes and nephritis may be additional clinical clues to this syndrome.
During relapses, shedding of virus can be detected. IgM antibody test findings are positive.
The clinical course is toward resolution, with lengthening periods between flares. The total duration is 3-9 months.
Liver transplantation has been performed in patients with this condition when signs of significant decompensation have occurred. Corticosteroid treatment has been shown to improve the clinical course, although the course is generally benign without treatment.

Follow-up
• See at 1 or 2 weekly intervals until aminotransferase levels are normal (usually 4-12 weeks) [15].
• Immunity is lifelong [15].

Primary Prevention
• Health/sex education should stress the routes of transmission and the higher incidence in developing countries [15]
• Clinicians should offer the hepatitis A vaccine to patients who are at increased risk of hepatitis A infection [16]:
1. Persons with chronic liver disease (e.g., hepatitis B or C)
2. Men who have sex with men
3. Travelers to countries with high endemicity of infection
4. Persons who live in a community experiencing an outbreak of HAV infection
5. Illicit drug users, particularly injection drug users
6. Persons who have clotting-factor disorders
7. Persons at occupational risk for infection
• The full series should be given (initial dose and a second dose 6 to 12 months later) to ensure maximal antibody response [16].
• Non-immune patients who are at increased risk for both hepatitis A and hepatitis B infection may be given the combined hepatitis A and B vaccine in a total of three doses at 0, 1, and 6 months [16].
• If patient has to be vaccinated against Hepatitis A, different vaccines in use are: formalin-inactivated vaccines with and without aluminum hydroxide as an adjuvant, live attenuated vaccines, and combined hepatitis A and hepatitis B vaccines.
• Clinicians should administer HAV vaccination early in the course of human immunodeficiency virus (HIV) infection [16]
• If a patient's CD4 count is <300 cells/mm3 or the patient has symptomatic HIV disease, it is preferable to defer vaccination until several months after initiation of antiretroviral (ARV) therapy in an attempt to maximize the antibody response to the vaccine [16]
• Routine post-vaccination antibody measurement is not recommended because of the generally high efficacy of the vaccine [16]
RECOMMENDATIONS FOR TRAVELLERS TO ENDEMIC AREAS FROM LOW PREVALENCE AREAS [17]:
• All susceptible persons traveling to or working in countries with intermediate or high HAV endemicity (countries other than the United States, Australia, Canada, Japan, New Zealand, and countries in western Europe and Scandinavia) should be vaccinated with HAV vaccine or receive IG before departure.
• If hepatitis A vaccine has to be given, HAV vaccine at the age-appropriate dose is preferred for persons who plan to travel repeatedly to or reside for long periods in these high-risk areas; IG is recommended for travelers less than two years of age
• If hepatitis A vaccine is given, after receiving the initial dose of the HAV vaccine, persons are considered to be protected after four weeks. A booster dose at 6 to 12 months is required for long-term protection
• If persons who will travel to high-risk areas less than four weeks after the initial vaccine dose, IG (0.02 mL/kg) should be administered simultaneously with the first vaccine dose but at different injection sites.
• If persons are allergic to a vaccine component or otherwise elect not to receive vaccine should receive a single dose of IG (0.02 mL/kg IM) shortly before departure. This approach provides effective protection against HAV for approximately four to six months.
PROGNOSIS

• Prognosis is excellent. Long-term immunity accompanies infection. Recurrence and chronic hepatitis does not usually occur.

• Approximately 85 percent of individuals who are infected with hepatitis A have full clinical and biochemical recovery within three months, and nearly all have complete recovery by six months [14].
• Serum aminotransferase concentrations decrease more rapidly than the serum bilirubin; the latter normalizes in more than 85 percent of individuals by three months.
• Fatalities due to hepatitis A are more common with advancing age and, as noted above, in patients with chronic hepatitis C [18]. Reported case fatality rates are 0.1 percent in infants and children, 0.4 percent between the ages of 15 and 39, and 1.1 percent in those over age 40 [19].

COUNCELLING
Travelers should be educated about good hygiene and clean, safe water supplies. Advice should be provided regarding the benefits of immunization, particularly in high-risk individuals.
Travelers should avoid uncontrolled water sources, raw shellfish, and uncooked food.
Boiling water or adding iodine inactivates the virus. Chlorination and certain disinfecting solutions (household bleach 1:100 dilution) are sufficient to inactivate the virus
All fruit should be washed and peeled.
• People with HAV infection who are treated at home and those around them should follow strict enteric precautions.
• Improved sanitary conditions, adherence to sanitary practices such as hand washing, heating foods appropriately, and avoidance of water and foods from endemic areas should be practiced strictly.
• Handwashing is highly effective in preventing the transmission of the virus since hepatitis A virus may survive for up to four hours on the fingertips
• If patient develops Hepatitis A, advise to drink plenty of clear fluids to prevent dehydration.
• Avoid medicines and substances that can cause harm to the liver.
• Avoid alcoholic beverages, as these can worsen the effects of HAV on the liver.
• Avoid prolonged, vigorous exercise until symptoms start to improve.
• Take complete rest at least 10 days after appearance of jaundice




HEPATITIS B
DEFINITION
Acute Hepatitis B
Acute hepatitis B is hepatitis due to Hepatitis B virus lasting < 6 months [20]
Chronic hepatitis B
Chronic necroinflammatory disease of the liver caused by persistent infection with hepatitis B virus for > 6 months. Chronic hepatitis B can be subdivided into HBeAg positive and HBeAg negative chronic hepatitis B [21].
Inactive HBsAg carrier state
Persistent HBV infection of the liver without significant, ongoing necroinflammatory disease [21]
Resolved hepatitis B
Previous HBV infection without further virological, biochemical or histological evidence of active virus infection or disease [21]
Acute exacerbation or flare of hepatitis B
Intermittent elevations of aminotransferase activity to more than 10 times the upper limit of normal and more than twice the baseline value [21]
Reactivation of hepatitis B
Reappearance of active necroinflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved hepatitis B [21]
HBeAg clearance
Loss of HBeAg in a person who was previously HBeAg positive [21]
HBeAg seroconversion
Loss of HBeAg and detection of anti-HBe [21]
HBeAg reversion
Reappearance of HBeAg in a person who was previously HBeAg negative, anti-HBe positive [21]


DIAGNOSTIC CONSIDERATIONS

• The spectrum of clinical manifestations of hepatitis B virus (HBV) infection varies in both acute and chronic disease.
• During the acute phase, manifestations range from subclinical or anicteric hepatitis to icteric hepatitis and, in some cases, fulminant hepatitis.
• During the chronic phase, manifestations range from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Extrahepatic manifestations also can occur with both acute and chronic infection.
• Perinatal infection in high prevalence areas [22], horizontal transmission, particularly in early childhood in intermediate prevalence areas, while unprotected sexual intercourse and intravenous drug use in adults are the major routes of spread in low prevalence areas [23]. Also spread by transfusion and needle stick injuries
• Incubation period is 1 to 6 months (average 12–14 weeks)

Diagnostic criteria for various types of Hepatitis B are:
Chronic hepatitis B
1. HBsAg _ _ 6 months
2. Serum HBV DNA _20,000 IU/ml (105copies/ml), lower values 2,000-
20,000 IU/ml (104-105 copies/ml) are often seen in HBeAg-negative chronic hepatitis B
3. Persistent or intermittent elevation in ALT/AST levels
4. Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation

Inactive HBsAg carrier state
1. HBsAg_ _ 6 months
2. HBeAg-, anti-HBe_
3. Serum HBV DNA _2,000 IU/ml
4. Persistently normal ALT/AST levels
5. Liver biopsy confirms absence of significant hepatitis

Resolved hepatitis B
1. Previous known history of acute or chronic hepatitis B or the presence of anti-HBc +/- anti-HBs
2. HBsAg negative
3. Undetectable serum HBV DNA
4. Normal ALT levels

EPIDEMIOLOGY
• The prevalence of HBV carriers varies from 0.1 percent to 2 percent in low prevalence areas (United States and Canada, Western Europe, Australia and New Zealand), to 3 to 5 percent in intermediate prevalence areas (Mediterranean countries, Japan, Central Asia, Middle East, and Latin and South America), to 10 to 20 percent in high prevalence areas (southeast Asia, China, sub-Saharan Africa) [23]
• An estimated 350 million persons worldwide are chronically infected with HBV [26].
• The 10th leading cause of death worldwide, HBV infections result in 500 000 to 1.2 million deaths per year caused by chronic hepatitis, cirrhosis, and hepatocellular carcinoma; the last accounts for 320,000 deaths per year[24,25, 27]
Race:
African Americans have a higher prevalence of the disease than persons of Hispanic origin or white persons.
Sex:
More cases occur in males than in females.
Age:
The earlier the disease is acquired, the greater the chance of developing chronic infection. Infants (mainly infected through vertical transmission) have a 90% chance, children have a 25-50% chance, adults have an approximately 5% chance, and persons who are elderly have an approximately 20-30% chance of developing chronic disease.

TRANSMISSION
• Perinatal transmission
• Horizontal transmission
• Transfusion
• Sexual transmission
• Percutaneous inoculation
• Nosocomial infection
• Organ transplantation


CLINICAL FEATURES

The spectrum of the symptoms varies from subclinical hepatitis to icteric hepatitis to fulmanant hepatitis during the acute phase and from an asymptomatic carrier state to chronic hepatitis, cirrhosis, and HCC during the chronic phase.
• Acute phase [28]
o The incubation period is 1-6 months.
o Anicteric hepatitis is the predominant form of expression for this disease. The majority of the patients are asymptomatic about 70%.
o Patients with symptomatology have the same symptoms as patients who develop icteric hepatitis.
o Patients with anicteric hepatitis have a greater tendency to develop chronic hepatitis.
o Icteric hepatitis is associated with the prodromal period, during which a serum sickness–like syndrome can occur. The symptoms are more constitutional and includes the following:
 Anorexia
 Nausea
 Vomiting
 Low-grade fever
 Myalgia
 Fatigability
 Disordered gustatory acuity and smell sensations (aversion to food and cigarettes)
 Right upper quadrant and epigastric pain (intermittent, mild to moderate)
 Extrahepatic manifestations of acute hepatitis may be heralded by a serum sickness-like syndrome manifested as fever, skin rashes, arthralgia and arthritis, which usually subside with the onset of jaundice. The two major extrahepatic complications of chronic HBV are polyarteritis nodosa and glomerular disease [30, 31].
o Fulminant hepatic failure is unusual, occurring in approximately 0.1 to 0.5 percent of patients. They can present with [29]:
 Hepatic encephalopathy
 Somnolence
 Deepening jaundice
 Mental confusion
 Coma
• Chronic phase
o Patients with chronic hepatitis can be healthy carriers without any evidence of active disease, and they also are asymptomatic.
o Patients with chronic active hepatitis, especially during the replicative state, may complain of symptoms such as the following:
 Symptoms similar to those of acute hepatitis
 Fatigue
 Anorexia
 Nausea
 Mild upper quadrant pain or discomfort
 Hepatic decompensation

SIGNS
The physical examination findings vary from minimal to impressive (patients with hepatic decompensation) according to the stage of disease [28].
• Patients with acute hepatitis usually do not have any clinical findings, but the physical examination can reveal the following:
Low-grade fever
o Jaundice (10 d after the appearance of constitutional symptomatology and lasting for 1-3 mo)
o Hepatomegaly (mildly enlarged soft liver)
Splenomegaly (5-15%)
o Palmar erythema (rarely)
Spider nevi (rarely)
• The physical examination of patients with chronic hepatitis B can reveal stigmata of chronic liver disease such as the following:
o Hepatomegaly
o Palmar erythema
o Spider angioma
• Patients with cirrhosis may have the following symptoms:
o Ascites
o Jaundice
o History of variceal bleeding
o Peripheral edema
o Gynecomastia
o Testicular atrophy
o Abdominal collateral veins (caput medusa)
COMPLICATIONS
1. Hepatocellular carcinoma [33]
• Even the presence of HBsAb in the absence of HBsAg or HBV DNA is significantly related to an increased risk for HCC. The annual incidence of this malignancy in patients with HBV infection and cirrhosis
• HCV along with HBV increases the risk of HCC
2. HDV Super / Co infection
The prevalence of hepatitis D virus (HDV) co-infection among patients infected with HBV worldwide is 0-20%.
2. Glomerulonephritis [34]
• The most common type of glomerulonephritis (GN) described is membranous GN (MGN), mainly in children.
• However, membranoproliferative GN (MPGN) and, even more rarely, immunoglobulin A (IgA) nephropathy, have been identified.
• The prevalence rate of GN among patients with chronic HBV infection is not well known, although observations have been made in children that suggest a range of 11-56.2% but lower in US.
4. Polyarteritis nodosa [35]
• An association between HBV and arteritis has been described when HBsAg is present in serum and in vascular lesions. Evidence for a cause-and-effect relationship is further supported by a high prevalence (36-69%) of HBsAg in patients with polyarteritis nodosa (PAN).
• The clinical manifestations of the disease include cardiovascular (eg, hypertension [sometimes severe], pericarditis, heart failure), renal (eg, hematuria, proteinuria, renal insufficiency), gastrointestinal (eg, abdominal pain, mesenteric vasculitis), musculoskeletal (eg, arthralgias, arthritis), neurological (eg, mononeuritis), and dermatological (eg, rashes) involvement. Significant proteinuria (>1 g/d), renal insufficiency (serum creatinine >1.58 mg/dL), gastrointestinal involvement, cardiomyopathy, and CNS involvement are associated with increased mortality.
5. Skin manifestations
o A variety of cutaneous manifestations are recognized, among which are hives and fleeting maculopapular rash, during the early course of viral hepatitis. Women are more prone to developing cutaneous manifestations.
o The various cutaneous lesions are episodic, palpable, and, at times, pruritic. Although they are transient, a discoloration of the skin can be identified after the resolution of the exanthem, particularly on the lower extremities.
o Papular acrodermatitis, also recognized as Gianotti-Crosti syndrome, has been associated with hepatitis B, more commonly with acute infection in children.
6. Cardiopulmonary manifestations
o Pleural effusion, hepatopulmonary, and portopulmonary syndrome may occur in patients with cirrhosis.
o Myocarditis, pericarditis, and arrhythmia occur primarily in patients with fulminant hepatitis.
7. Joint and neurologic manifestations
o Guillain-Barré syndrome, encephalitis, aseptic meningitis, and mononeuritis multiplex may occur in patients with acute hepatitis.
o Arthralgias and arthritis (serum sickness) subcutaneous nodules also may occur but are rare.
8. Hematologic and gastrointestinal tract manifestations
o Patients may develop pancreatitis.
o Aplastic anemia is uncommon, and agranulocytosis is extremely uncommon.
o Diffuse intravascular coagulation may occur in patients with fulminant hepatitis.


DIFFRENTIAL DIAGNOSIS [36]
If patient has Hepatitis due to HBV, consider following differential diagnosis:

Alcoholic Hepatitis
Autoimmune Hepatitis
Cholangitis
Cirrhosis
Hemochromatosis
Hepatic Carcinoma, Primary
Hepatitis A
Hepatitis C
Hepatitis D
Hepatitis E
Hepatitis, Viral
Primary Sclerosing Cholangitis
Wilson Disease
Drug hepatotoxicity
Congestive heart failure
INVESTIGATIONS
Acute Hepatitis B [15]
• If patient has acute hepatitis B in early stages surface antigen(HBsAg), e antigen(HBeAg), IgM and IgG anticore antibodies and Hepatitis B viral DNA(HBV DNA) will be positive but Anti Hbe and Anti HBs will be negative
• If patient has acute resolving Hepatitis B HBsAg and IgM and IgG anti core antibodies will be positive, Anti Hbe may or may not be positive and HBV DNA and Anti HBs will be negative
• If patient has hepatitis B, serum/plasma aminotransferases (AST/ALT) can range from 500 to 10,000 IU/L.
• Bilirubin can be upto 500 micromoles/L.
• Both direct and indirect fractions increase because of hemolysis, which often occurs in acute HBV infection
• Alkaline phosphatase levels are usually <2x the upper limit of normal, but higher if there is cholestasis
• Modest falls in serum albumin level may accompany the illness
• If in a patient of acute Hepatitis B, prothrombin time (PT) is prolonged by more than 5 seconds, suggest developing hepatic decompensation
• If patient has Hepatitis B, advise CBC. Blood picture may show mild lymphocytosis is not uncommon. Indices of low-grade hemolysis are not uncommon
• An ultrasound scan may be required when alternative diagnoses warrant exclusion and should assess vessel patency and evaluate any evidence supporting unsuspected underlying chronic liver disease. Ultrasound scanning is essential in patients with fulminant hepatic failure.
• Blood urea and serum creatinine should be obtained at baseline.
• Screen for other sexually transmitted infections in cases of sexually-acquired hepatitis or if otherwise appropriate

Chronic Hepatitis B [15]

• In most cases the only abnormality to be found will be mildly abnormal aminotransferase levels (usually <100 IU/L) and in many the liver function tests will be normal. Only in severe late stage liver disease do the liver function tests become grossly abnormal
• If patient has chronic Hepatitis B having high infectivity HBsAg, IgG anticore antibody and HBV DNA will be present in blood, HBeAg may or may not be positive and IgM anti core antibody, Anti Hbe and Anti HBs will be negative.
• If patient has chronic Hepatitis B having low infectivity HBsAg and IgG anticore antibody will be positive, Anti HBe may or may not be positive and HBeAg, IgM anticore antibody, HBV DNA and Anti HBs are negative
• If patient had Hepatitis B which has now resolved IgG anticore antibodies will be present, Anti Hbe and Anti HBs may or may not be present and HBsAg, HBeAg, IgM anti core antibodies and HBV DNA will not be present
• If person is successfully vaccinated against Hepatitis B only Anti HBs will be present but all other markers of HBV will be negative
• If patient has Hepatitis B other tests like liver biopsy (for assessment of chronic disease) should be performed only by specialists in this field
• If patient has Hepatitis B, liver biopsy should be considered in HBeAg negative patients who have serum HBV DNA levels of 10(4) to 10(5) copies/mL and normal or mildly elevated ALT to determine if treatment is warranted.


TREATMENT
If patient has Hepatitis B he/ she should be given detailed education about their disease, modes of spread and things to be avoided. If patient has acute hepatitis B treatment is symptomatic with oral hydration, rest and admission if patient is severely ill. If patient has chronic hepatitis B treatment is with alpha interferon. Other promising treatments, alone or in combination with interferon, include lamivudine, famciclovir, thymosine alpha, adefovir and ribavarin
NON PHARMACOLOGICAL TREATMENT
• Patients should be advised to avoid unprotected sexual intercourse, including oro-anal and oro-genital contact, until they have become non-infectious or their partners have been successfully vaccinated [15].
• Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health of themselves and their partner(s) and routes of transmission of infection and advised not to donate blood
• Hepatitis B is a notifiable disease.
• Patient should avoid alcohol
• Patient should avoid hepatotoxic drugs

PHARMACOLOGICAL TREATMENT

Acute Icteric Hepatitis [15]

• Mild/moderate (80%), manage as an outpatient emphasizing rest and oral hydration.
• Nausea and vomiting are treated with antiemetics
• Paracetamol may be cautiously administered but is strictly limited to a maximum dose of 3-4 g/d in adults
• Severe attack with vomiting, dehydration, or signs of hepatic decompensation (change in conscious level or personality), admit to hospital.
• Specific Treatment is only indicated for patients with fulminant hepatitis B and those with protracted, severe acute hepatitis B.
• Lamivudine, telbivudine or entecavir is preferred.
a. Treatment should be continued until HBsAg clearance is confirmed or indefinitely in those who undergo liver transplantation.
b. IFN-alpha is contraindicated.

Chronic Hepatitis B

• All persons with chronic hepatitis B not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6 to 18 months apart [21].
• Treatment options include interferon, lamuvidine, adefovir and other new drugs.

EVALUATION FOR TREATMENT
Patients Not Initially Considered for Treatment [21]
HBeAg positive, HBV DNA _> 20,000 IU/ml and normal ALT
● ALT every 3-6 months, more often if ALT becomes elevated
● If ALT levels are between 1-2 times ULN, recheck ALT 1-3 months; consider liver biopsy if age >40, ALT borderline or mildly elevated on serial tests.
Consider treatment if biopsy shows moderate/severe inflammation or significant fibrosis
● If ALT _> 2 times ULN for 3-6 months and HBeAg_positive, HBV DNA >_ 20,000 IU/ml,
consider liver biopsy and treatment.
● Consider screening for HCC in relevant population
Inactive HBsAg carrier state (HBeAg-negative, anti-HBe Positive Patients with
Normal ALT Levels and HBV DNA <2,000IU/ml)
● ALT every 3 months for 1 year, if persistently normal, ALT every 6-12 months
● If ALT > 1-2 times ULN, check serum HBV DNA level and exclude other causes of liver disease.
Consider liver biopsy if ALT borderline or mildly elevated on serial tests or if HBV DNA persistently >20,000 IU/ml.
Consider treatment if biopsy shows moderate/severe inflammation or significant fibrosis
● Consider screening for HCC in relevant population

Recommendations for Monitoring Patients with Chronic HBV Infection [21]
• HBeAg-positive and HBeAg-negative patients who meet criteria for chronic hepatitis B should be evaluated for treatment.
HBeAg-positive patients:
• HBeAg-positive patients with persistently normal ALT should be tested for ALT at 3-6 month intervals.
• ALT along with HBV DNA should be tested more often when ALT levels become elevated. HBeAg status should be checked every 6-12 months.
• Patients who remain HBeAg positive with HBV DNA levels >20,000 IU/ml after a 3-6 month period of elevated ALT levels between 1-2 times ULN, or who remain HBeAg positive with HBV DNA levels >20,000 IU/ml and are>40 years old, should be considered for liver biopsy, and treatment should be considered if biopsy showsmoderate/severe inflammation or significant fibrosis.
• Patients who remain HBeAg positive with HBV DNA levels >20,000
IU/ml after a 3-6 month period of elevated ALT levels >2 times ULN should be considered for treatment.
• HBeAg-negative patients:
● HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/ml should be tested for ALT every 3 months during the first year to verify that they are truly in the “inactive carrier state” and then every
6-12 months.
● Tests for HBV DNA and more frequent monitoring should be performed if ALT or AST increases above the normal limit.