SYMPTOMS [124]

The course of infection has 2 phases termed prodromal and icteric.
• Prodromal-phase symptoms include the following:
o Myalgia
o Arthralgia
o Fever with mild temperature elevations (25-97%)
o Anorexia (66-100%)
o Nausea/vomiting (30-100%)
o Weight loss (typically 2-4 kg)
o Dehydration
o Right upper quadrant pain that increases with physical activity
• Icteric-phase symptoms include the following:
o Jaundice - May be difficult to see with some patients' natural skin color; serum bilirubin level is greater than 3 mg/dL; scleral icterus is present
o Dark urine
o Light-colored stools (20-40%)
o Pruritus (50%)
• Other features include the following:
o Urticarial rash
o Diarrhea
• Symptoms of HEV are similar to other hepatitides and include the following:
o Abdominal pain (35-80% of patients)
o Jaundice
o Anorexia
o Hepatomegaly (10-85%)
o Malaise (95-100%)
o Vomiting
• Some patients have asymptomatic infection.
• Prolonged cholestasis has been described in up to 60 percent of patients [132].
• Infection with HEV can also lead to hepatic decompensation in patients with preexisting liver disease and those who are malnourished [134]
• Fulminant hepatitis can occur, resulting in an overall case fatality rate of 0.5 to 3 percent [132].
• Fulminant hepatitis cases in pregnancy may reach a mortality rate of 20% in the 3rd trimester. Premature deliveries with high infant mortality of up to 33% are also observed [124,127,128,135].The reason for this high mortality is not clear yet.
• Some of the complications of pregnancy are toxemia with hypertension, proteinuria, edema, and kidney lesions.
• By directly or indirectly affecting the kidneys, HEV might precipitate eclampsia and lead to increased mortality in pregnant women [133, 136]
SIGNS [124]:
• Right upper quadrant tenderness
• Possible enlarged liver (palpable edges)
• Possible splenomegaly
• Possible transient spider angiomata

DIFFRENTIAL DIAGNOSIS
The differential diagnosis mainly includes
• Acute viral hepatitis,
• Drug or toxic hepatitis,
• Ischemic hepatitis and
• Other infectious diseases in areas where they are endemic such as leptospirosis, dengue fever, malaria, and typhoid fever

INVESTIGATIONS


• The diagnosis of HEV is based upon the detection of the HEV genome in serum or feces by PCR or by the detection of IgM antibodies to HEV [137].
• Simultaneous assessment of anti IgA HEV has been proposed to increase specificity, especially in patients with IgM rheumatoid factor in serum, which can cause a false-positive result on the IgM based assay [137].
• Persistence of IgG anti-HEV has been noted in different studies for 6 to 12 months, 1 to 4 years, and as long as 14 years [138,139, 140, 141].
• At present, only research-based tests are available for the specific detection of hepatitis E virus antigen (HEVAg) in the serum.
• HEVAg has also been detected in liver tissue using an immunofluorescent probe . Rapid immunochromatographic assays for serologic diagnosis are under development [142,143].
• If patient has HEV infection also get urine bilirubin and urobilinogen,
• If patient has HEV infection, total and direct serum bilirubin, ALT and AST, alkaline phosphatase should be done.
• Rapidly increasing serum amino transferase (alanine aminotransferase [ALT], aspartate aminotransferase [AST]) levels that peak within 4-6 weeks of onset and gradually decrease to normal within 1-2 months
• Viral excretion in stool persisting 14 days from onset
• HEV RNA can be detected in acute phase faeces by PCR in approximately 50% of cases. Immune electron microscopy is positive in only about 10% of cases [124]
• Prothrombin time, total protein, albumin should also be obtained.
• If patient has HEV infection, get complete blood count. More commonly, WBC counts are decreased. Differential counts may show atypical cells and lymphocytosis
• Abdominal ultrasonography is recommended.
o It helps rule out biliary obstruction in cases with significant nausea, vomiting, or fever.
o It can demonstrate the presence of an enlarged liver; echo texture is heterogeneous and coarsened.
o It can demonstrate splenomegaly, if present.

TREATMENT
NON PHARMACOLOGICAL TREATMENT
• Therapy should be predominantly preventive, relying on clean drinking water, good sanitation, and proper personal hygiene [144].
• Travelers to endemic areas should avoid drinking water or other beverages that may be contaminated and should avoid eating uncooked shellfish. Care should be taken while preparing uncooked fruits or vegetables. Boiling water may prevent infection, but the effectiveness of chlorination is unknown.
• The acute illness may result in anorexia, nausea, and vomiting, predisposing patients to dehydration [144].
• These symptoms tend to be worse in the afternoon or evening. Patients should attempt to ingest significant calories in the morning. As they improve, frequent small meals may be better tolerated [144].
• Neither multivitamins nor specific dietary requirements are required
• Patients should be given a detailed explanation of their condition with particular emphasis on the long-term implications for the health. This should be reinforced by giving them clear and accurate written information.
• Hepatitis E is a notifiable disease.
• Patients should be allowed to function at whatever levels they can tolerate [144].
• No evidence indicates that bed rest hastens recovery. It actually may retard recovery [144].
PHARMACOLOGICAL TREATMENT
Acute Icteric Hepatitis [155]

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.

FOLLOW UP
• Serum ALT concentrations should be monitored weekly until they start to decline .

PREVENTION
Immune prophylaxis
There is no available immunoglobulin (IG) prophylaxis at present.
• IG prepared from donors in non-HEV-endemic countries does not prevent infection [124]
• The efficacy of IG prepared from donors in HEV-endemic areas is unclear, although convalescent human sera have given promising preliminary results for passive protection.10
• Experimental immune prophylaxis against HEV based on recombinant antigens appears to confer short-term protection and may be useful for pregnant women in endemic areas and travellers coming into these regions.
Vaccination
• A vaccine against HEV is not yet commercially available.
• In a high-risk population, the rHEV vaccine was effective in the prevention of hepatitis E in a trial [146]
PROGNOSIS
• No chronic cases of acute hepatitis E have been reported. The infection is self-limited.
• Hepatitis E is a mild to moderate disease in severity (mortality rate of 0.4-4.0%) except in pregnancy, where the mortality rate is progressively higher in each succeeding trimester and may reach 20% [145].
PATIENT EDUCATION
• Travelers should be educated about good hygiene and clean, safe water supplies.
• 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 HEV 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.
• If patient develops Hepatitis E, 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 HEV on the liver.
• Avoid prolonged, vigorous exercise until symptoms start to improve.
• Take complete rest at least 10 days after appearance of jaundice



AUTOIMMUNE HEPATITIS
DEFINITION
Autoimmune hepatitis (AIH) is an unresolving inflammation of the liver of unknown cause. It is characterized by the presence of interface hepatitis and portal plasma cell infiltration on histologic examination, hypergammaglobulinemia and autoantibodies [147]

DIAGNOSTIC CONSIDERATIONS [148]
Diagnosis requires the presence of characteristic features and the exclusion of other conditions that resemble AIH.

Usually young to middle-aged women.
Chronic hepatitis with high serum globulins.
Positive antinuclear antibody (ANA) and/or smooth muscle antibody in most common type.
Responds to corticosteroids.
DIAGNOSTIC CRITERIA
The diagnostic criteria for AIH that should be applied to all patients. Definitive criteria include
• Patient should not have any genetic liver disease i.e. Normal alpha1-antitrypsin phenotype and normal serum ceruloplasmin, iron, and ferritin levels
• Patient should not have active viral infection (No markers of current infection with hepatitis A, B, and C viruses)
• Patient’s daily alcohol consumption should be < 25 g/d and no recent use of hepatotoxic drugs
• On lab investigations Predominant serum aminotransferase abnormality should be present and globulin, gamma-globulin or immunoglobulin G level > 1.5 times normal
• ANA, SMA, or anti-LKM1 > 1:80 in adults and > 1:20 in children; no AMA
• Histological findings should include interface hepatitis and no biliary lesions, granulomas, or prominent changes suggestive of another disease

Diagnosis is probable if
Partial alpha1-antitrypsin deficiency or nonspecific serum copper, ceruloplasmin, iron, and/or ferritin abnormalities
Daily alcohol < 50 g/d and no recent use of hepatotoxic drugs
Predominant serum aminotransferase abnormality but hypergammaglobulinemia of any degree
ANA, SMA, or anti-LKM1 > 1:40 in adults or other autoantibodies (Includes perinuclear anti-neutrophil cytoplasmic antibodies and the not generally available antibodies to soluble liver antigen/liver pancreas, actin, liver cytosol type 1, and asialoglycoprotein receptor.) present
Revised scoring system for diagnosis of autoimmune hepatitis [159]
Parameters/features Score
Female sex +2
ALP:AST (or ALT) ratio:
<1.5 +2
1.5-3.0 0
>3.0 -2
Serum globulins or IgG above normal
>2.0 +3
1.5-2.0 +2
1.0-1.5 +1
<1.0 0
ANA, SMA or LKM-1
>1:80 +3
1:80 +2
1:40 +1
<1:40 0
AMA positive -4
Hepatitis viral markers:
Positive -3
Negative +1
Drug history:
Positive -4
Negative +1
Average alcohol intake
<25 g/day +2
>60 g/day -2
Liver histology:
Interface hepatitis +3
Predominantly lymphoplasmacytic infiltrate +1
Rosetting of liver cells +1
None of the above -5
Biliary changes -3
Other changes -3
Other autoimmune disease(s) +2
Optional additional parameters:
Seropositivity for other defined auto antibodies +2
HLA DR3 or DR4 +1
Response to therapy:
Complete +2
Relapse +3
Interpretation of aggregate scores:
Pre-treatment:
Definite AIH >15
Probable AIH 10-15
Post-treatment:
Definite AIH >17
Probable AIH 12-17

EPIDEMIOLOGY
• The incidence of autoimmune hepatitis among white northern Europeans is 1.9 cases per 100,000 persons per year, and its point prevalence is 16.9 cases per 100,000 persons per year [149]
• In the United States, autoimmune hepatitis affects 100,000 to 200,000 persons, and it accounts for 6% of the liver transplantations [150]. The frequency of autoimmune hepatitis among patients with chronic liver disease in North America is between 11% and 23%.
• The incidence of type 1 autoimmune hepatitis is estimated to be 0.1-1.9 cases per 100,000 persons per year in Caucasian populations. The incidence is lower in Japan.
• Kosar et al found 17 Turkish patients with autoimmune hepatitis by a retrospective analysis of referrals to a liver clinic in Ankara during a 6-year period. HLA DR3, HLA DR4, or both were found in 15 patients, but none had HLA B8 compared with 11% of the healthy Turkish population [151].

Race:
• The disease is most common in Caucasians of northern European ancestry with a high frequency of HLA-DR3 and HLA-DR4 markers. The Japanese population has a low frequency of HLA-DR3 markers. In Japan, autoimmune hepatitis is associated with HLA-DR4 [147].
• Ethnic background may influence the clinical presentation and outcome. African American patients have a higher frequency of cirrhosis and poorer hepatic synthetic function at presentation than white North Americans [152]. Alaskan natives have a higher occurrence of acute icteric disease and advanced fibrosis than nonnative counterparts [153]; nonwhite, non-European patients frequently have cholestatic features [154, 155]; Asians tend to have late-onset, mild disease [156]; and South American patients are commonly young children with severe disease [157]
Sex:
Women are affected more often than men (70-80% of patients are women) [147].
Age:
Classic descriptions of type 1 autoimmune hepatitis spoke of a bimodal age distribution (ages 10-30 y and 40-50 y). However, more recent work shows that infants, young children, and older adults may be affected. The diagnosis should not be overlooked in individuals older than 70 years. Men may be affected more commonly than women in older age groups [147].