SURVEILLANCE

• HBV carriers at high risk for HCC such as men over 45 years, persons with cirrhosis, and persons with a family history of HCC, should be screened periodically with both AFP and US.
• While there are insufficient data to recommend routine screening in low-risk patients with chronic HBV infection, periodic screening for HCC with AFP in carriers from endemic areas should be considered.

PROGNOSIS
• The rate of progression from acute to chronic hepatitis B is primarily determined by the age at infection. The rate is approximately 90 percent for perinatally acquired infection [57], 20 to 50 percent for infections between the age of one and five years [58,59], and less than 5 percent for adult-acquired infection
• Approximately 30 to 50 percent of patients with chronic HBV infection have a past history of acute hepatitis
• In a 16-year follow-up study of 317 HBsAg positive blood donors from Montreal, for example, only three died from HBV-related cirrhosis and none developed HCC [60]. Another report included 296 potential blood donors who were excluded from donation after they were found to be HBsAg positive and were followed for 30 years [61]. The incidence of clinically significant liver disease, HCC, or other liver-related morbidity or mortality was not significantly greater than a control population of HBV negative blood donors.
• The prognosis is not so good in HBV-infected patients from endemic areas and in patients with chronic hepatitis B [62-65]. The estimated five-year rates of progression are: Chronic hepatitis to cirrhosis — 12 to 20 percent, Compensated cirrhosis to hepatic decompensation — 20 to 23 percent, Compensated cirrhosis to HCC — 6 to 15 percent.


COUNCELLING
• Patients with chronic HBV infection should be counseled regarding lifestyle modifications and prevention of transmission.
• There are no specific dietary measures that have been shown to have any effect on the progression of chronic hepatitis B. However, heavy use of alcohol (>40 g/day) has been associated with higher ALT levels and development of cirrhosis. In addition, the development of cirrhosis and HCC occurs at a younger age in heavy drinkers with chronic hepatitis B. So advise abstinence or only limited use of alcohol is recommended in hepatitis B carriers
• Persons who are HBsAg-positive should
1. Have sexual contacts vaccinated
2. Use barrier protection during sexual intercourse if partner not vaccinated or naturally immune
3. Not share toothbrushes or razors
4. Cover open cuts and scratches
5. Clean blood spills with detergent or bleach
6. Not donate blood, organs or sperms
• Children and adults who are HBsAg-positive:
1. Can participate in all activities including contact sports
2. Should not be excluded from daycare or school participation and should not be isolated from other children
3. Can share food, utensils or kiss others

HEPATITIS D
• Hepatitis D which is an incomplete ribonucleic acid (RNA) virus that requires the hepatitis B virus outer coat so cannot occur without it and is cleared when the latter is cleared [66].
EPIDEMIOLOGY [67]
• Available data suggest that approximately 5 percent of the HBV carriers worldwide may be infected with HDV [31].
• Since the number of HBV carriers has been estimated to be around 300 million, the number of individuals infected with HDV worldwide is estimated to be 15 million.
• The geographical distribution of HDV infection, however, does not parallel that of HBV, as areas endemic for HBV may be almost HDV-free. The level of HDV endemicity is partly related to the route of transmission.
RISK FACTORS
• Intravenous drug users (IVDUs)
• Their sexual partners but also is seen in
• Female sex workers, and
• Sporadically occurs in other groups

CLINICAL FEATURES
• Due to its dependence upon HBV, HDV infection always occurs in association with HBV infection. The clinical and laboratory findings vary with the type of infection
• Coinfection — Coinfection of HBV and HDV in an individual susceptible to HBV infection (ie, anti-HBs-negative) results in acute hepatitis B + D. This entity is clinically indistinguishable from classical acute hepatitis B and is usually transient and self-limited. However, a high incidence of liver failure has been reported among drug addicts [68].
• Superinfection — HDV superinfection of a chronic HBsAg carrier may present as an unusually severe acute hepatitis in a previously unrecognized HBV carrier, or as an exacerbation of preexisting chronic hepatitis B. Progression to chronic HDV infection occurs in almost all patients [69]. However, HBV replication is usually suppressed by HDV.
• Helper-independent latent infection — A third form of infection is a helper-independent latent infection which can be rescued by the helper virus at a later time. This form of infection was initially observed in the liver transplantation setting.[70]




SYMPTOMS
• If patient of Hepatitis B develops acute hepatitis, if chronic hepatitis B carriers get a further attack of acute hepatitis, or if the liver disease in chronic hepatitis B virus is rapidly progressive suspect Hepatitis D [71]
• If patient has Hepatitis D there is a high rate of fulminant hepatitis and progression of chronic hepatitis to cirrhosis
• If patient has Hepatitis long-standing chronic hepatitis D and B often have inactive cirrhosis [71].
• If patient has Hepatitis D, they have a threefold increased risk of hepatocellular carcinoma.

INVESTIGATIONS
• In acute HDV infection, serum HDAg appears early but is very short-lived and may escape detection if repeated testing is not performed [72].
• In chronic HDV infection, anti-HDV is present in high titers.
• Diagnosis is confirmed by a positive - anti-HDV antibody or hepatitis delta virus - ribonucleic acid (HDV-RNA) test

TREATMENT
• If patient has Hepatitis D response to anti-viral therapy is poor
• There is no specific treatment for acute hepatitis D. In one report, all three patients treated with foscarnet for fulminant hepatitis due to HDV recovered, as did two additional patients with fulminant hepatitis due to HBV alone. Although these results are encouraging, they need to be confirmed [73].
• The only drug approved at present for treatment of chronic hepatitis D is interferon alfa (IFNa). There is no experience with either IFN beta or gamma in this disorder [74].
• If patient has Hepatitis D, the recommended dose regimen is standard IFNa 9 MU TIW for at least 12 months, although longer treatment has been advocated [74].
• If patient has Hepatitis D, in light of new data, pegylated IFN may replace standard IFNa as the treatment of choice for chronic hepatitis D [74].
• If patient has Hepatitis D, early attempts to treat hepatitis D with immunomodulatory drugs, such as corticosteroids or levamisole, were unsuccessful [74].
• If patient has Hepatitis D, several drugs have been evaluated as alternatives to interferon. They include ribavarin, foscarnet, acyclovir, Suramin, THF gamma 2, lamivudine, and famciclovir and Antisense therapy. Overall, the results are discouraging.

FOLLOW UP
• If patient is asymptomatic HDV carriers with normal ALT levels, they do not require therapy but should be monitored for signs of active disease [74].
PRIMARY PREVENTION
• If patient is to be prevented from Hepatitis D, the mainstay of prevention of HDV infection is vaccination against its helper virus, the HBV [75].
PREVENTION AFTER LIVER TRANSPLANTATION
• If patient has Hepatitis D, passive prophylaxis with hepatitis B immunoglobulin has not completely prevented reinfection of transplanted livers by HDV [76].
• In some patients, HDV virions were able to infect and replicate within the liver allograft. Nonetheless, HDV infection is abortive and does not result in recurrent liver disease unless the allograft is simultaneously reinfected with HBV [76].



PROGNOSIS
• If patient has Hepatitis D, in view of the poor overall response, it is difficult to identify factors that may predict response. The only feature which may be associated with an increased likelihood of response is a short duration of disease [74]


HEPATITIS C

• Hepatitis C virus (HCV) is a major public health problem and a leading cause of chronic liver disease
• Hepatitis C virus, a member of the Flaviviridae family, was discovered as a new viral agent of non-A, non-B hepatitis virus by Choo and co-workers in 1989 [77].


DEFINITION
Hepatitis C is an inflammation of liver caused by hepatitis C virus, a virus of Flaviviridae family causing usually chronic hepatitis [78]

DIAGNOSTIC CONSIDERATIONS [79]
• Infection with the hepatitis C virus (HCV) can result in both acute and chronic hepatitis.
• Acute HCV:
Clinical Description -
An acute illness with
• Discrete onset of symptoms consistent with acute viral hepatitis, and
• Jaundice or elevated serum aminotransferase levels (ALT)
Laboratory criteria -
• Serum aminotransferase levels >7 times the upper limit of normal, and
• IgM anti-HAV negative, and
• IgM anti-HBc negative (if done) or HBsAg negative and
• Hepatitis C Virus Antibody (Anti-HCV) positive (repeat reactive)by an enzyme immunoassay
(EIA) with a signal to cut-off (s/c) ratio of > 3.8
Or
Anti-HCV positive (repeat reactive) by EIA, verified by an additional more specific assay (e.g.
recombinant immunoblot strip assay [RIBA]* for anti-HCV or RT-PCR for HCV RNA [Test to
detect HCV RNA by amplification of viral genetic sequences]
Or
• Anti-HCV positive by RIBA alone
Or
• HCV RNA positive
Chronic HCV:
Clinical Description -
The course of chronic liver disease is usually insidious, progressing at a slow rate without
symptoms or physical signs in the majority of individuals during the first two or more decades
after infection.
Laboratory criteria -
• Hepatitis C Virus Antibody (Anti-HCV) positive (repeat reactive)by an enzyme immunoassay
(EIA) with a signal to cut-off ratio of > 3.8
Or
• Anti-HCV positive (repeat reactive) by EIA, verified by an additional more specific assay (e.g.
RIBA for anti-HCV or RT-PCR for HCV RNA)
Or
• Anti-HCV positive by RIBA alone
Or
• HCV RNA positive

EPIDEMIOLOGY

• It is difficult to estimate the real prevalence of HCV accurately in the world, as it is mainly asymptomatic [80]
• On the basis of published reports, it is estimated that HCV prevalence is approximately 3% equating 170 million patients all over the world [80].
• Prevalence ranges from 0.08% to >10% in different regions of the world. It has also been reported that approximately 21% community acquired viral hepatitis is due to HCV.[81]
• Asia and Pacific region in recent years. Hepatitis C is a rapidly emerging health problem in Pakistan as in other Asian countries. Several published reports from different regions of Pakistan have indicated that approximately 10 million (6%) people with HCV are living in the country.[82,83]
• Recent studies showed seroprevalence rate from 0.1% to 15.9% in different regions of India and 1.5% in Saudi Arabia [84, 85, 86]
• The HCV distribution in China, Japan and Taiwan is 1 to 2%, 2% and 3.2% respectively.[87, 88]
• It was estimated that the seroprevalence rate in Malaysian blood donors was between 1.5 to 3%.[89]
• The estimated distribution of HCV infection in the United States ranges from 1.4% to 1.8%, affecting 4 million people.[90]
• In Europe, HCV infection prevalence is from 0.08% to 0.72% and 8.4% to 12.6% in UK and Italy respectively. [91]
• Between 20-30% patients with chronic HCV infection succumb to cirrhosis, further developing hepatocellular carcinoma (HCC).
• Prevalence of anti-HCV positivity in HCC patients was 3.2 %, 13.5%, and 7% in Italy, Pakistan and US respectively.[92, 93, 94]
• In Pakistan, anti-HCV has been present in nearly 80% of the patients, with alpha fetoprotein elevation in 75%, in patients with HCC.[95]


TRANSMISSION [79]
• Unsafe blood supply
• Current or past IVDU
• Reuse of glass syringes and needle
• Unsterilised medical equipments
• Organ transplant
• Ear piercing
• Tattooing
• Reuse of blades at barber’s community shop
• Unsafe sexual practices
• Vertical transmission
• Sharing tooth brush with HCV patients
• Occupational needle stick injury

CLINICAL FEATURES
Acute hepatitis
• Hepatitis C virus infection is rarely diagnosed during the acute phase of illness due to its asymptomatic nature. It is not astonishing that HCV infection has largely been ignored in the world.
• Average incubation period ranges from 3 to 12 weeks although HCV RNA can be detected in patients’ serum within 1 to 2 weeks.

• The serum level of HCV viremia rises rapidly during the first few weeks then slows down to maintaining levels between 105 to 107 IU/ml; followed by an increase in the serum level of ALT.

• A recent study has described that acute symptomatic resolution has been confirmed in 50% cases, whereas the absolute recovery from primary HCV infection does not appear in more than 15% cases.

• However, non-alcoholic groups had tremendous chances to clear virus.
Common symptoms includes

• Jaundice – appears in 25% of patients
• Fever
• Myalgia
• Fatigue
• Lethargy
• Increased ALT
• Anorexia
• Fulminant hepatic failure


Chronic hepatitis
HCV infection becomes chronic in most cases and there are usually no symptoms, however possible features include


• Fatigue
• Steatosis
• Cirrhosis - 20-30% patients with HCV develop cirrhosis in 20-30 years.
• 15-20% patients with HCV infection have only mild to moderate chronic hepatitis infection and may not develop cirrhosis
• HCC
• Varicael bleeding
• Ascites
• Hepatic encephalopathy


Extrahepatic features:
• Non-Hodgkin’s lymphoma
• Membranoproliferative glomerulonephritis
• Arthritis
• Sjogren’s syndrome
• Lichen planus
• Porphyria cutanea tarda
• Vasculitis
• Cryoglobulinaemia
Cryoglobulins (IgM, IgG or both) can be found in more than 50% HCV infected patients that can lead to severe vasculitis and renal failure
• Peripheral neuropathy
• Patients with HCV had a higher prevalence of DM as compared to general population and advance HCV infection was linked with higher prevalence of impaired fasting glucose in DM

INVESTIGATIONS
Who should be tested for HCV [79]:

● Persons who have injected illicit drugs in the recent and remote past, including those who injected only once and do not consider themselves to be drug users
● Persons with conditions associated with a high prevalence of HCV infection, including:
– Persons with HIV infection
– Persons with hemophilia who received clotting factor concentrates before
1987
– Persons who were ever on hemodialysis
– Persons with unexplained abnormal aminotransferase levels
● Prior recipients of transfusions or organ transplants, including:
– Persons who were notified that they had received blood from a donor who later tested positive for HCV infection
– Persons who received a transfusion of blood or blood products before July
1992
- Person who had a tattoo or acupuncture with unsterlized needle
– Persons who received an organ transplant before July 1992
● Children born to HCV-infected mothers
● Health care, emergency medical and public safety workers after a needle stick injury or mucosal exposure to HCV-positive blood
● Current sexual partners of HCV-infected persons*
Tests for HCV patients [79]:
• All patients suspected of having infection with HCV should be tested for antibody to HCV (anti-HCV) using an EIA (enzyme immunoassay) screening test.
• In low-risk patients with a positive EIA test, confirmatory testing with the recombinant immunoblot assay (RIBA) should be performed.
• For patients at low risk with a positive EIA and RIBA, confirmatory testing with a qualitative PCR test for detection of HCV RNA should be performed.
• For patients at moderate or high risk and/or unexplained elevated serum alanine aminotransferase (ALT) value, a positive EIA should be followed by a qualitative test for HCV RNA in the blood.
• For immunocompromised patients at high risk with unexplained elevated ALT value and a negative screening EIA, a qualitative test for detection of HCV RNA should be performed to diagnose HCV infection.

• Antibodies can be detected only after 4 to 6 months from exposure, and after 2 to 4 months from the onset of symptoms. This test will be positive in 97% of patients by 6 months after infection, and probably will persist for life.
• HCV RNA is usually positive from at symptom onset.
• HCV RNA testing should be performed in
(a) Patients with a positive anti-HCV test
(b) Patients for whom antiviral treatment is being considered, using a quantitative assay
(c) Patients with unexplained liver disease whose anti-HCV test is negative and who are immunocompromised or suspected of having acute HCV infection
• Patients with low-level viraemia may require HCV-RNA levels testing on two or more occasions to confirm infection
• HCV genotype should be determined in all HCV-infected persons prior to treatment in order to determine the duration of therapy and likelihood of response
• Regardless of the level of ALT, a liver biopsy should be done when the results will influence whether treatment is recommended, but a biopsy is not mandatory in order to initiate therapy.
• A liver biopsy may be obtained to provide information on prognosis
• Patients with HCV infections should be tested for HIV, Hepatitis A Virus (HAV) and HBV infections due to similar risk factors.
• If a patient is hepatitis C positive other tests which should be done include [80]:

1. ALT
2. Bilirubin
3. Albumin
4. Prothrombin time
• Prior to treatment, patients should have a baseline complete blood count (CBC), chemistry evaluations, serum creatinine, thyroid function tests and pregnancy tests in women

TREATMENT

• Early clearance of HCV, to prevent the risk of developing cirrhosis and HCC and to decrease mortality has been the aim of antiviral treatment in patients with HCV infection [96].
• Treatment should be considered for all patients with detectable HCV RNA and an abnormal liver biopsy, regardless of the presence or absence of liver enzyme elevation [96].
• Prior to making a decision regarding treatment, patients should be evaluated with HCV RNA, HCV genotype, liver enzymes (ALT), and liver biopsy, unless contraindicated.
• The decision to initiate antiviral therapy should be made based upon the willingness of the patient to undergo therapy, ability to regularly attend appointments, and agreement to use contraception to prevent pregnancy.
• The decision to initiate antiviral therapy should be made on an individualized basis that considers severity of liver disease, co-morbid conditions, the potential for serious side effects and the likelihood of response [96].
• Patients with HCV infection on methadone maintenance therapy should not be considered ineligible for treatment.
• The treatment of the actively using injection drug user is not contraindicated and may be appropriate under some circumstances.
• Patients with a history of well-controlled psychiatric disorders may be excellent candidates for antiviral therapy and should be under the care of a qualified mental health professional [96].


NON PHARMACOLOGICAL TREATMENT
• Alcohol and drug abuse should be treated before the initiation of antiviral therapy for HCV infection, as these may worsen the course of disease and outcome
• Persons found to be HCV-infected need to be counseled regarding prevention of spread of the virus to others.
• Environmental support is an important part of patient assessment because treatment may be given for up to one year, and the adverse effects of treatment may incapacitate patients [96]
• Family meetings can be helpful to prepare family members for side effects of treatment. Neuro-psychiatric side effects such as irritability and hostility can strain relationships if unexpected. These issues can be assessed with the collaboration of social services [96].
• Counsel those who are overweight (defined by a raised body mass index of >25 kg/m2) to attempt to lose weight.


PHARMACOLOGICAL TREATMENT
• If acetaminophen is to be given, the dose should not exceed 2 g per 24 hours [97].
• If patient has Hepatitis C, should be vaccinated against hepatitis A if they lack hepatitis A antibody [98].
• If patients lack antibodies to hepatitis B virus should be vaccinated against hepatitis B [98].
• If patient has Hepatitis C, pneumococcal vaccine and yearly influenza vaccination should be considered in patients who have developed cirrhosis

Characteristics of Persons for Whom Therapy Is Widely Accepted [79]
• Abnormal ALT values
• Liver biopsy showing chronic hepatitis with significant fibrosis (more-than-portal fibrosis: Metavir score >= 2; Ishak score >= 3)
• Compensated liver disease (total serum bilirubin < 1.5 g/dL; INR < 1.5; albumin > 3.4 g/dL; platelet count > 75,000 k/mm3; and no evidence of hepatic encephalopathy or ascites)
• Acceptable hematological and biochemical indices (hemoglobin > 13 g/dL for men and >12 g/dL for women; neutrophil count > 1.5 k/mm3; creatinine > 1.5 mg/dL)
• Treated previously for HCV infection
• History of depression but the condition is well controlled
• Willing to be treated and to conform to treatment requirements
• The presence of symptomatic cryoglobulinemia is an indication for HCV antiviral therapy, regardless of the stage of liver disease.

Characteristics of Persons for Whom Therapy Is Currently Contraindicated [79]
• Major, uncontrolled depressive illness
• Renal, heart, or lung transplantation recipient
• Autoimmune hepatitis or other condition known to be exacerbated by interferon and ribavirin
• Untreated hyperthyroidism
• Pregnant or unwilling/unable to comply with adequate contraception
• Severe concurrent disease such as severe hypertension, heart failure, significant coronary artery disease, poorly controlled diabetes, obstructive pulmonary disease
• Under 3 years of age
• Known hypersensitivity to drugs used to treat HCV


Characteristics of persons for whom therapy should be individualized

• Persistently normal ALT values
• Failed prior treatment (nonresponders and relapsers) consisting of either interferon given alone or in combination with ribavirin, or consisting of peginterferon given alone
• Current users of illicit drugs or alcohol, but willing to participate in a substance abuse program (such as a methadone program) or alcohol support program
• Liver biopsy evidence of either no or only mild fibrosis (portal fibrosis: Metavir score <2; Ishak score <3)
• Acute hepatitis C
• Coinfected with HIV
• Under 18 years of age
• Chronic renal disease (on or not on hemodialysis)
• Decompensated cirrhosis
• Liver transplantation recipient

Treatment objectives and outcomes
The goal of treatment is to prevent complications of HCV infection; this is principally achieved by eradication of infection. Accordingly, treatment responses are frequently characterized by the results of HCV RNA testing.

• Infection is considered eradicated when there is a sustained virologic response (SVR), defined as the absence of HCV RNA in serum by a sensitive test at the end of treatment and 6 months later.
• Persons who achieve an SVR almost always have a dramatic earlier reduction in the HCV RNA level defined in some studies as a 2-log drop or loss of HCV RNA 12 weeks into therapy, referred to as an early virologic response (EVR).
• Continued absence of detectable virus at termination of treatment is referred to as end of treatment response (ETR).
• A patient is considered to have relapsed when HCV RNA becomes undetectable on treatment but is detected again after discontinuation of treatment.
• Persons in whom HCV RNA levels remain stable on treatment are considered nonresponders.
• Those whose HCV RNA levels decline (eg, by >2 logs), but never become undetectable, are referred to as partial responders.






Initiating Treatment [96]
• Prior to treatment, patients should have a baseline complete blood count (CBC), chemistry evaluations, serum creatinine, thyroid function tests, pregnancy tests in women, HIV testing, contraceptive counseling for men and women, and screening for depression.
• Prior to initiating treatment, patients should be informed of the possible side effects of therapy to allow them to anticipate and manage with these side effects.
• The treatment of choice for patients with chronic hepatitis C infection is combination pegylated interferon and ribavirin.
• Patients infected with genotype 1 or 4 should be treated for 48 weeks with combination pegylated interferon and ribavirin. The ribavirin dose should be 1000 mg a day in patients < 75 kg and 1200 mg a day in patients > 75 kg.
• Patients infected with genotype 2 or 3 should be treated for 24 weeks with combination pegylated interferon and ribavirin. The ribavirin dose should be 800 mg a day.

Predictors of Response to PEG-IFN Plus Ribavirin Therapy in Previously Untreated, Immunocompetent Patients with Compensated Chronic Hepatitis C [79]

• Non-genotype 1
• Low HCV RNA levels (<2 million RNA copies/mL)
• Absence of cirrhosis/bridging fibrosis
• Duration of therapy (for genotype 1)
• Age 40 years or younger
• Lighter body weight
• Non-black ethnicity
• Adherence
• Absence of steatosis on liver biopsy
• Women
• No alcohol consumption

Interferon:

• If patient has chronic hepatitis C, the treatment of choice is peg interferon plus ribavirin
• Other interferons can be used
Types of Interferon
• Alpha Interferon
It has 4 types
1. Interferon alpha 2a
2. Interferon alpha 2b
3. Interferon alfacon-1 or consensus interferon --- dose is 9 µg SQ thrice a week.; 15 µg thrice a week in nonresponders
4. Interferon alfa-n1---- this is not approved in US but approved by European Union at a dose of 5 MU subcutaneously or intramuscularly three times weekly for 48 weeks.
Alpha interferon 2a and b can be attached to polyethylene glycol tale to make peg interferon which can be given once daily.
• Peg interferon alfa-2b is dosed by weight (1.5 µg/kg) and coupled with 800 mg of ribavirin;
• Peg interferon alfa-2a is given as a fixed dose of 180 µg along with a weight-adjusted, higher dose of ribavirin (1,000 mg if <75 kg and 1,200 mg if >75 kg).
SIDE EFFECTS

• If patient is put on therapy for chronic hepatitis C, "Flu-like" symptoms, such as headache, fatigue, myalgia, and fever are common and are mostly due to interferon. These symptoms improve spontaneously after two to three weeks. Administration of interferon at night and the prophylactic use of acetaminophen (1000 mg) prior to injection may be beneficial. We also advise patients to consume 12 to 16 glasses of water or juice daily.
• hematologic changes during therapy are common. The neutrophil count falls by an average of 1300 to 1600/µL, and usually returns to pretreatment levels within four weeks of cessation of therapy. The relative neutropenia is not generally associated with an increased risk of serious bacterial infections
• Mean platelet values may also decline, but generally stay within the normal range during therapy. Platelet counts below 100,000/µL develop in less than 10 percent of patients, and may in part be due to a blunted thrombopoietin response, which occurs more commonly in patients with cirrhosis
• Psychiatric changes occur in approximately 50 percent of patients including insomnia, irritability, depression, emotional lability, difficulty concentrating, and nervousness. Suicidal ideation and attempts occur in less than 1 percent of patients.
• Nausea occurs in up to one-half of patients, and anorexia in approximately 20 percent.Reversible hair loss occurs in approximately 20 percent of patients probably due to telogen effluvium, as a result of interferon
• Thyroid abnormalities requiring therapy develop in approximately 1 to 7 percent of patients treated with interferon alfa.
• Painless thyroiditis is most common but other thyroid abnormalities can occur, including Graves' disease, permanent hypothyroidism, and increased serum antithyroid antibody concentrations without thyroid dysfunction.
• Thyroid dysfunction is more likely if patients have preexisting antithyroid antibodies, suggesting that interferon alfa in some way exacerbates underlying thyroid autoimmune disease
• Interferon therapy usually can be continued while hypothyroidism is being treated. On the other hand, we have usually stopped interferon in patients who develop clinically apparent hyperthyroidism.
• Hyperglycemia is an uncommon side effect of interferon that is usually not clinically significant. However, it is recommended increasing monitoring of blood glucose in patients with known diabetes.
• Minor side effects can be pruritis, migranous headache, pulmonary disorders, including interstitial pneumonia and bronchiolitis obliterans, Ophthalmologic disorders (retinal hemorrhages, cotton wool spots, loss of color vision, and rarely retinal artery or vein obstruction) and hearing loss can occur

Ribavirin
• If patient has chronic Hepatitis C the addition of ribavirin (1000-1200 mg/day) will increase the response rate to 35-50%
• If patient is taking ribavarin, coadministration of antacids containing magnesium, aluminum, and simethicone may decrease the absorption of ribavirin, although the clinical significance of this effect is unknown. No clinically significant food interactions have been reported.
• If patient is taking ribavarin,it is contraindicated in the following groups of patients: Women who are or can become pregnant — Ribavirin is teratogenic and/or embryocidal, accumulates in gonadal tissues, and can be present for six months after therapy is discontinued. Patients with a known hypersensitivity to ribavirin should also not get the drug
• Ribavirin is not recommended for patients with a creatinine clearance below 50 mL/min.
• If patient is taking ribavarin, because anemia is a potential side effect of ribavarin, patients with cardiovascular disease that may be worsened by drug-induced anemia should not be treated.
• A reduction in hemoglobin levels to less than 10 g/dL is observed in approximately 10 percent of patients, and is largely due to hemolysis induced by ribavirin. Hemolysis correlates with the concentration of ribavirin and its metabolites in red blood cells; levels reach a steady-state after three to four weeks of therapy
• If patient has hemoglobinopathies such as thalassemia and sickle-cell anemia may be exacerbated by the hemolysis induced by ribavarin.
• Psychiatric disease, including depression and suicidal behavior can occur
• If patients have a history of stable cardiovascular disease, therapy should be discontinued if the hemoglobin concentration decreases by more than 2 g/dL during any four-week period or if the hemoglobin concentration remains below 12 g/dL after four weeks on a reduced dose.
• If reduction in the dose of ribavirin is done, it associated with a decreased sustained virologic response rate. As a result, there has been increasing experience with using recombinant human erythropoietin to help support the hemoglobin concentration and thereby permit continued use of higher doses of ribavirin



Genotype-1 HCV infection
• Treatment with peginterferon plus ribavirin should be planned for 48 weeks, using ribavirin doses of 1,000 mg for those <75 kg in weight and 1,200 mg for those more than 75 kg.
• Quantitative serum HCV RNA should be performed at the initiation of, or shortly before, treatment and at week 12 of therapy.
• Treatment may be discontinued in patients who do not achieve an EVR at 12 weeks, although the decision should be individualized according to the tolerability of therapy, severity of underlying liver disease, and demonstration of some degree of biochemical and/or virologic response
• Persons whose treatment continues through 48 weeks, and whose qualitative measurement of HCV RNA at that time is negative, should be retested for HCV RNA 24 weeks later to document an SVR.

Genotype-2 or Genotype-3 HCV infection
• Treatment with peg interferon plus ribavirin should be administered for 24 weeks, using a ribavirin dose of 800 mg.
• Persons whose treatment continues for the full 24 weeks, and whose qualitative measurement of HCV RNA at that time is negative, should be retested for HCV RNA 24 weeks later to document an SVR


Management of side effects of antiviral therapy
• Flu-like side effects of IFN can be managed with acetaminophen or nonsteroidal anti-inflammatory drugs and giving interferon injection at night
• Sleep promoting agents can be used for insomnia
• Antidepressants can be used for depression.
• For management of neutropenia, dose reduction suffices, and the addition of granulocyte colony-stimulating factor is generally not recommended, although it may be considered in individual cases of severe neutropenia.
• Ribavirin is contraindicated in pregnancy, necessitating strict precautions and contraception in women of childbearing age and their sexual partners and in HCV-infected men with female partners of childbearing age.
• Treatment with ribavirin should be avoided in patients with ischemic cardiovascular and cerebrovascular disease and in patients with renal insufficiency.
• If anemia occurs, options include ribavirin dose reduction or the addition of erythropoietin

RETREATMENT OF PERSONS WHO FAILED TO RESPOND TO PREVIOUS TREATMENT
1. Nonresponders and partial responders
• Overall, an SVR can be achieved by retreatment with peginterferon alfa and ribavirin in 25 to 40 percent of persons who failed to respond to interferon alfa monotherapy and in about 10 percent who failed to respond to interferon alfa and ribavirin
• Retreatment with peg interferon plus ribavirin with the aim of eradicating HCV is not indicated in patients who have failed to respond to a prior course of peg interferon plus ribavirin, even if a different type of peginterferon is administered
2. Relapsers
Persons who relapse after an initial response will generally achieve another on-treatment response


3. Maintenance therapy
• While eradication of HCV RNA is the primary goal for treatment of persons with chronic hepatitis C, there is accumulating evidence that treatment may have a secondary benefit of reducing progression of fibrosis - thereby delaying evolution to cirrhosis - or possibly reversing early cirrhosis.
• studies have also shown that in treated patients who fail to clear virus, the rate of progression to cirrhosis may be decreased or reversed [99], and there may be a lower frequency of development of HCC [100, 101].

SPECIAL PATIENT GROUPS FOR HEPATITIS C TREATMENT

1. Treatment of persons with normal serum aminotransferase values [79]
• Management of persons with normal serum aminotransferase values is important because up to 60 percent of HCV-infected first-time blood donors and injection drug users have been reported to have normal values
• A person is considered to have normal ALT levels when there have been two or more determinations identified to be in the normal range of a licensed laboratory over 6 or more months.
• Regardless of the serum aminotransferase levels, the decision to initiate therapy with interferon and ribavirin should be individualized based on the severity of liver disease by liver biopsy, the potential of serious side effects, the likelihood of response, and the presence of co morbid conditions


Treatment of persons with renal disease [79]

• In patients on dialysis, HCV infection is associated with a modest increase in risk of death.
• There is an additional concern that hepatitis C has an adverse effect on long-term patient and graft survival after renal transplantation.
• As a result, current treatment efforts focus on eliminating the virus in dialysis patients who may be candidates for renal transplantation.
• There are several circumstances in which treatment of HCV infection in patients with renal disease might be considered. These include
• Persons with HCV-induced glomerulonephritis not on dialysis (most of whom have associated cryoglobulinemia);
• Persons on hemodialysis who are HCV-infected
• Persons with milder degrees of renal disease who develop superimposed HCV infection
• Persons who are infected peri- or post-renal transplantation.

• Although treatment of persons with cyroglobulinemia-related glomerulonephritis has led to improvement in the renal disease as defined by decreased levels of cryoglobulin, rheumatoid factor, and creatinine
• Relapse is common, even with the use of combination therapy
• Other therapeutic approaches have included the use of corticosteroids, cyclophosphamide, plasmapheresis, and the use of monoclonal antibody to B cells (rituximab)
• Individuals on hemodialysis with significant fibrosis on liver biopsy are less likely to have abnormal ALT values than HCV-infected persons with similar histologic findings who do not have renal disease
• There is a theoretical increased risk of bleeding in patients on hemodialysis who undergo liver biopsy, but studies involving liver biopsy in such patients have rarely reported severe side effects from the procedure
• Accordingly, a liver biopsy may be performed in persons with renal insufficiency for whom treatment is believed to be a high priority.
• Ribavirin is contraindicated in this patient population because the drug is not removed during conventional dialysis and its accumulation causes a dose-dependent hemolytic anemia
• Ribavirin is contraindicated in patients with renal failure, and, if treatment is undertaken, therapy should be with interferon alpha monotherapy.
• Treatment of patients with mild to moderate impairment in renal function (ie, not on dialysis) must be individualized. The closer the renal function to normal, the safer it is to use ribavirin.
• With regard to the use of peg interferon, a dose recommendation for persons on dialysis (135 µg SQ/wk) is available only for peg interferon alfa-2a
Treatment of persons with decompensated cirrhosis [79]
• Patients with clinically decompensated cirrhosis should be referred for consideration of liver transplantation.
• Antiviral therapy may be initiated at a low dose in patients with mild degrees of hepatic compromise, as long as treatment is administered by experienced clinicians, with vigilant monitoring for adverse events, preferably in patients who have already been accepted as candidates for liver transplantation as post transplantation hepitits C infection in infected patients is the rule
• Growth factors can be used for treatment-associated anemia (epoetin) and leukopenia (G-CSF, GM-CSF) and may limit the need for antiviral dose reductions in patients with decompensated cirrhosis
Treatment of patients after solid organ transplantation [79]
• Treatment of HCV-related disease following liver transplantation should be undertaken with caution because of the increased risk of adverse events and should be performed under the supervision of a physician experienced in transplantation
• Antiviral therapy is generally contraindicated in recipients of heart, lung, and kidney grafts
Treatment of active injection drug users [79]

• Treatment of HCV infection should not be withheld from persons who currently use illicit drugs or who are on a methadone maintenance program, provided they wish to take HCV treatment and are able and willing to maintain close monitoring and practice contraception
• The decision of whether to treat should be made considering the anticipated risks and benefits for the individual.
• Continued support from drug abuse and psychiatric counseling services is an important adjunct to treatment of HCV infection in persons who use illicit drugs
Acute Hepatitis C [79]
• If patient has acute icteric hepatitis C there is some evidence that high dose alpha and/or beta interferon given during the acute phase will reduce the rate of chronicity to only 10%
• If patient has mild to moderate acute Hepatitis C, specially emphesise on rest and oral hydration
• If patient of Hepatitis C develops severe disease characterized by vomiting, dehydration, or signs of hepatic decompensation (change in conscious level or personality); they should be hospitalized
• Recommending treatment of acute HCV infection, the use of pegylated interferon monotherapy may prevent the development of CHC infection, although the duration of therapy in still unknown.
• Based on available data, most authorities would initiate treatment no later than two to four months after presentation with acute hepatitis and would extend therapy for at least 24 weeks.

• There are insufficient data to recommend the use of ribavirin in the acute setting.
• Therapy should be deferred until 12 weeks after exposure, to allow for spontaneous clearance to occur, thus avoiding therapy.


Patients with Unstable Psychiatric Illness [79]
• Refer patients to a mental health provider for treatment and stabilization. Collaborate with mental health provider to reassess for antiviral treatment eligibility.
• Assessment for antiviral treatment readiness should include an assessment of the patient’s supportive networks, both formal and informal. Family meetings may help clarify expectations for the initiation of antiviral treatment, and promote family support to the patient.
• Patients with unstable psychiatric illness who refuse to engage in psychiatric treatment are not candidates for antiviral treatment.
• Assess stability of psychiatric illness and eligibility for antiviral treatment at periodic intervals.
• Patients not currently undergoing antiviral therapy should be reassessed periodically for eligibility and interest. Providers and patients should actively address substance abuse, psychiatric, and medical co-morbidities in order to prepare for antiviral treatment.
• Ideally, patients should have 3 to 6 months of symptom reduction to a socially stable level for anxiety, depression, and psychotic symptoms.
HCV infection in children [79]

• An estimated 240,000 children in the United States have antibodies to hepatitis C [10]. The seroprevalence is 0.2 percent for children under 12 years of age and 0.4 percent for those 12 to 19 years of age
• Diagnosis and testing (including liver biopsy) of children suspected of having chronic HCV should proceed as with adults (Grade, II-2).
• Because of the high rate of clearance of the HCV virus within the first year of life, and the level of anxiety that may be caused by an early positive test, routine testing for HCV RNA in infants born to HCV-infected mothers is not recommended.
• Testing with anti-HCV may be performed at 18 months or later.
• If an earlier diagnosis is desired, PCR for HCV RNA may be performed at or after the infant's first well-child visit at 1 to 2 months
• Children aged 3 to 17 who are infected with hepatitis C and are considered appropriate candidates for treatment may receive therapy with interferon alfa-2b and ribavirin, administered by those experienced in treating children
• Treatment of children under the age of 3 years is contraindicated

HCV/HIV Co infection [79

• Approximately 25 percent of HIV-infected persons in the Western world have chronic hepatitis C. In the United States, up to 10 percent of those with chronic hepatitis C may be HIV-co infected, an estimate based on the assumptions that there are 2.7 million persons infected with HCV and that approximately 250,000 of those with HIV infection are also infected with HCV
• All HIV-infected persons should be tested for HCV, and all HCV-infected persons with HIV risk factors should be tested for HIV.
• HCV RNA testing should be performed to confirm HCV infection in HIV-infected persons who are positive for anti-HCV, as well as in those who are negative and have evidence of unexplained liver disease.
• Hepatitis C should be treated in the HIV/HCV-coinfected person in whom the likelihood of serious liver disease and a treatment response are judged to outweigh the risk of morbidity from the adverse effects of therapy
• Initial treatment of hepatitis C in most HIV-infected persons is peginterferon alfa plus ribavirin for 48 weeks
• Given the high likelihood of adverse events, HIV/HCV-coinfected patients on HCV treatment should be monitored closely.
• Ribavirin should be used with caution in persons with limited myeloid reserves and in those taking zidovudine and stavudine. When possible, patients receiving ddI should be switched to an equivalent antiretroviral before beginning therapy with ribavirin
• HIV-infected patients with decompensated liver disease may be candidates for orthotopic liver transplantation

OTHER MEDICAL THERAPIES
• Amantadine, which has been studied as monotherapy and in combination with IFN and with IFN and ribavirin. Although amantadine appeared to provide benefit in a few trials in naïve [102] and nonresponder [103] patient cohorts, most RCTs showed no benefit associated with amantadine therapy [104-108]. Therefore, amantadine cannot be recommended as a component of antiviral therapy for chronic hepatitis C.
• IFN beta has properties similar to IFN and therefore has been studied as therapy for HCV infection. Studies of treatment with IFN beta, however, show no advantage over treatment with IFN alfa [109-112]; IFN beta has not been approved for treatment of hepatitis C and cannot be recommended.
• IFN gamma, which has potential antifibrotic effects resulting from inhibition of stellate cell activation and proliferation, has also been evaluated in patients with chronic hepatitis C. Preliminary, promising data notwithstanding [113,114], a recent multicenter RCT failed to confirm an antifibrotic effect of IFN gamma in patients with chronic hepatitis C.
• Similarly, interleukin-10, evaluated in a preliminary, three-month trial, was found to have no antiviral effect [115,116] but possibly an antifibrotic effect [116].
Pregnancy and Hepatitis C
• Women chronically infected with hepatitis C may have an uneventful pregnancy without worsening of liver disease or increased risk of fetal malformations
• Elevated serum alanine aminotransferase level decreased from 56 percent at the beginning of pregnancy to 7 percent by the third trimester, returning to 55 percent six months after delivery
• Vertical transmission of the virus occurs, but appears to be much less efficient than for hepatitis B, occurring in about 5 to 10 percent of infants born to anti-HCV positive women [117].
• The risk of infection is approximately threefold higher in infants born to women co-infected with HCV and HIV [118,119].
• Transmission only occurs from mothers who are HCV-RNA positive (as opposed to those who are anti-HCV positive but HCV-RNA negative); the risk of transmission may, like HIV, be in part related to the level of viremia at the time of birth.
• There is no evidence that breastfeeding is a risk for infection among infants born to HCV-infected women [119]





FOLLOW UP
Follow up for acute Hepatitis C
• See at 1 or 2 weekly intervals until aminotransferase levels are normal (usually 4-12 weeks)
• Follow up after six months for development of chronic hepatitis C
Follow up during treatment
• If patient is on interferon, it is advised that complete blood counts (CBC) be obtained pretreatment and monitored routinely during therapy. Alpha interferon therapy should be discontinued in patients who develop severe decreases in neutrophil (<0.5 × 10 9 /L) or platelet counts (<25 × 10 9 /L).Routine monitoring for adverse effects includes a CBC weekly for the first month then CBC monthly
• Recommend HCV RNA at 12 weeks of therapy.Patients who do not achieve virologic suppression or a 2- log decrease in HCV RNA at 12 weeks may have therapy discontinued, although factors such as degree of fibrosis and tolerability of therapy should be considered.
• Patients should have blood chemistry evaluations 2 weeks after initiation of treatment to assess for potential toxicities.
• Chemistry evaluations and pregnancy tests in women should be done routinely at each follow-up visit and not less often then every 4-6 weeks during treatment.
•
Follow up after treatment
• If persons whose treatment continues through 48 weeks, and whose qualitative measurement of HCV RNA at that time is negative, should be retested for HCV RNA 24 weeks later to document an SVR
• If patient has Hepatitis C genotype 2 or 3, the virologic response should be assessed at 24 weeks (end of treatment) and at 48 weeks to determine whether patients have achieved a sustained virologic response.
Patients not receiving treatment
• Serial HCV viral loads should not be routinely performed for patients who are not receiving antiviral treatment.
• Liver biopsies every 4-5 years may be considered for those patients in whom treatment is deferred because of mild fibrosis (Metavir score <2 or Ishak score <3) if progression of disease affects the decision to treat
Peri natal period

• Infants born to infected mothers should be screened for HCV. Because of the presence of maternal antibodies, children younger than twelve (12) months should only be tested by HCV RNA methods, but children over twelve months can be tested using the anti-HCV EIA test.
• Children positive for either anti-HCV or HCV RNA should be evaluated for the presence or development of liver disease, and children with persistently abnormal ALT’s should be referred to a specialist for medical management.

Hepatitis C Post-exposure Management

The risk of transmission of HCV after a needle stick exposure from a hepatitis C-positive source is estimated at between 2-10%

At time of exposure:
• Determine the type of exposure and assess the associated risk.
• Wash wounds with soap and water; flush mucous membranes with water.
• No post-exposure prophylaxis (immune globulin or antiviral medications) is recommended.
• Counsel the exposed person regarding hepatitis C transmission risk.
• Test source and exposed individual for hepatitis C virus antibody and liver enzymes for exposed individual. If source is not available or refuses testing, treat exposed person as if source has active hepatitis C infection.
• If source is hepatitis C virus antibody positive, or is antibody negative and is immunocompromised, test source for qualitative HCV RNA.
• If source is negative for hepatitis C antibody (and HCV RNA, if indicated), no further testing is necessary and no further action beyond initial HCV testing, is necessary for the exposed person.
After exposure
• If source is positive for hepatitis C antibody and HCV RNA , and exposed person is negative, follow up of exposed person should be done after one month for qualitative HCV RNA and retest liver enzymes
• If positive consider treatment with pegylated interferon +/- ribavirin.
• If negative retest exposed after three Months for anti-HCV, qualitative HCV RNA and liver enzymes
• If still negative reassure the patient and no further testing is required





SURVEILLANCE
Patient with cirrhosis due to HCV should be screened for hepatocellular carcinoma (HCC) with alpha-fetoprotein (AFP) testing and hepatic ultrasound imaging at least once or twice yearly [96].
PROGNOSIS
• If patient has chronic hepatitis C, it is an indolent, often subclinical disease that may lead to cirrhosis and hepatocellular carcinoma after decades. Indeed, the mortality rate from transfusion-associated hepatitis C may be no different from that of an age-matched control population
[120].
• Acute HCV typically leads to chronic infection; 60 to 80 percent of cases develop chronic hepatitis (abnormal liver enzymes).
• Chronic HCV infection is usually slowly progressive; it may not result in clinically apparent liver disease in many patients if the infection is acquired later in life. Approximately 20 to 30 percent of chronically infected individuals develop cirrhosis over a 20- to 30-year period of time
• If patient has chronic hepatitis C,mortality rates clearly rise once cirrhosis develops, and mortality from cirrhosis and hepatocellular carcinoma due to hepatitis C is expected to triple in the next 10–20 years.


COUNCELLING
• Patients with chronic HCV infection should be counseled regarding lifestyle modifications and prevention of transmission.
• There are no specific dietary measures that have been shown to have any effect on the progression of chronic hepatitis C. However, heavy use of alcohol (>50 g/day) has been associated with higher ALT levels and development of cirrhosis. In addition, the development of cirrhosis and HCC occurs at a younger age in heavy drinkers with chronic hepatitis C.
• Persons who are HCV-positive should

7. Use barrier protection during sexual intercourse
8. Not share toothbrushes or razors
9. Cover open cuts and scratches
10. Clean blood spills with detergent or bleach
11. Not donate blood, organs or sperms
• Children and adults who are HCV-positive:
4. Can participate in all activities including contact sports
5. Should not be excluded from daycare or school participation and should not be isolated from other children
6. Can share food, utensils or kiss others
• Patients should be aware that over-the-counter medications can be hepatotoxic and that they should discuss medication use with a medical provider.
• Patients should be made aware that no herbal products have yet been shown to delay progression of hepatitis C and that some herbs are hepatotoxic.
• Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, have been have been associated with hepatitis C flares
HEPATITIS E
DEFINITION
Hepatitis E virus (HEV) is a self-limited, enterically-transmitted acute viral hepatitis caused by nonenveloped single stranded RNA virus [121].

DIAGNOSTIC CONSIDERATIONS [122]
• 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 E virus or by ingestion of food or water that has been contaminated with the virus or travel to endemic area.
• Mortality specially high in pregnant females
• Hepatitis E IgM is positive
• Hepatitis never goes into chronic stage.
• The incubation period following exposure to HEV ranges from 3 to 8 weeks, with a mean of 40 days

EPIDEMIOLOGY


• The highest prevalence of infection occurs in regions where low standards of sanitation promote the transmission of the virus [123]
• The prevalence of antibody to HEV in suspected or documented endemic regions has been much lower than expected (3 - 26%) [124]
• Screening of blood donors in central Europe and North America has shown a prevalence of anti-HEV antibodies of 1.4 - 2.5%, in South Africa of 1.4%, in Thailand of 2.8%, in Saudi Arabia of 9.5%, and in Egypt of 24.0%.
• The prevalence of antibody to HEV in non endemic regions (like the US) has been much higher than anticipated (1 - 3%) [124, 125]
• HEV infections account for >50% of acute sporadic hepatitis in some high endemic areas.
Race:
• Infection has no apparent racial predilection.
Sex:
• Although predilection is unknown, pregnant women are prone to complications.
Age:
• It predominantly affects those aged 15-40 years.
• It may affect younger age groups but generally is not recognized and may be subclinical.
• No chronic cases have been described.
TRANSMISSION

• HEV is spread by the oral-faecal route. This enterically transmitted virus has been implicated in several food and waterborne outbreaks [126]
• Consumption of faecally contaminated drinking water has given rise to epidemic cases, and the ingestion of raw or uncooked shellfish has been the source of sporadic cases in endemic areas [124]
• The low amount of intact HEV particles present in patient stools accounts for the generally lower rate of person-to-person transmission of hepatitis E when compared with that of hepatitis A [127]
• Naturally acquired HEV antibodies have been detected in primates, rodents and swine [124,128]. Swine HEV cross-reacts with antibodies to the human HEV capsid antigen.
• Person-to-person transmission is uncommon, ranging from 0.7 to 2.2 percent
• HEV can be transmitted by blood transfusion, particularly in endemic areas [129]
• HEV infection can be transmitted from mother to newborn with substantial perinatal morbidity and mortality [130,131]
CLINICAL FEATURES

Risk groups
Here is a list of groups of people who are at risk of contracting HEV:
• persons residing in areas where extended community outbreaks exist
• international travellers to regions of the world where HEV is endemic
• refugees residing in overcrowded temporary camps following catastrophies, especially in Sudan, Somalia, Kenya and Ethiopia
• persons who have chronic liver disease
• possibly persons working with non-human primates, pigs, cows, sheep and goats

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].