Definition

Definition: Hepatitis means inflammation of the liver.

Causes: Hepatitis may be due to: 1- Infections: - Viral hepatitis. - CMV, herpes simplex, EB- V, yellow fever. 2- Drugs & toxins: Alcohol, isoniazide, Paracetamol. 3- Metabolic:- Wilson's disease. Here, we are going to discuss viral hepatitis. - At least 5 types of hepatitis viruses can cause the disease (HAV, HBV, HCV, HDV, HEV ). - other viruses as CMV,herpes simplex, Eb-V & yellow fever virus can also cause hepatitis.

Epidemiology:Hepatitis A virus: - Mode of infection:- Faecal - oral route & rarely parenteral transmission. It spreads into food & water (fresh & salty ones). Shillfishs are a good source of infection. - Incubation period: 2-6 weeks. - The disease occurs mainly in children (5-15 years ) & young adults.

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- The disease occurs as sporadic cases or in epidemics -Severity of acute stage usually mild. -Choronicity:- No chronicity & no relation to hepatocellular carcinoma. - IT occurs mainly in endemic areas, tropical & under developed countries due poor hygiene & crowdness. - Primary infection gives solid immunity & reinfection is rare. - The case is the source of infection.

Hepatitis B virus: - Mode of infection:1- Parenteral transmission:- Transfusion of blood & blood Products. Death rates may be from 10- 20% in this case, partly due to large dose of virus received & partly due to weakened condition of partient needing the transfusion. - Use of contaminated needles &syringes e.g. in I. v. drug abusers. 2- sexual transmission . 3- Transmission from the mother to her baby. - Incubation period: 1-6monthes. - The disease occures at any age. - The disease usually occures as sporadic cases & accidental outbreakes may occure on mass exposure to infected blood as in

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immunization for shistosomiasis & units for parenteral treatment of diabetes. - Severity of acute stage: Mild or severe - Chronicity:- May lead to chronic complications & hepatocellular carcinoma . In developing countries where HBV is widespread most adults have been infected. This infection usually occure in early childhood & many become carries of the virus. About one – third of these will develop chronic forms of hepatitis. - Recovery from primary attack or vaccination provides immunity for 10 years but secondary attack may occure. - The case & carriers are the source of infection.

Hepatitis C virus: - Mode of infection:1- Parenteral transmission . 2- Sexual transmission & transmission from mother to her baby are rare. - Incubation period :- 1 week -4 monthes. - The disease occures at any age but more common in adults. - The disease occures as sporadic cases. - Severity of acute stage: usually mild. - Chronicity: may lead to chronic complications & hepatocellular carcinoma.

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- The case & carriers including incubatory & chronic ones are the source of infection.

Hepatitis D virus or Delta agent:* - Its an incomplete virus depending on HBsAg, so it affect only those with hepatitis B infection. There are 2 forms of infection:1- Co-infection: Simultaneous infection with HBV & HDV 2- Super-infection of a hepatitis B carrier with HDV. - Mode of infection:- As in HBV. - Incubation period: 1-6 months - The disease occures at any age. - The disease occures as sporadic cases. - Severity of acute stage: Usually severe. - Chronicity: May lead to chronic complications.

Hepatitis E virus: - Mode of infection: Foecal-oral transmission. Incubation period: 2-9 weeks. - The disease occures mainly in children & young adults as sporadic cases or in epidemics. - Severity of acute stage: usually mild except in pregnant females. - Chronicity: no chronicity & no relation to hepatocellular carcinoma.

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Clinical Findings:Hepatitis A virus: Clinical picture:The clinical presentation is variable in severity & includes: 1- Asymptomatic cases. 2- Anicteric hepatitis. 3- Icteric hepatitis. 4- Fulminant hepatitis. 1- Anicteric hepatitis:These are mild cases without jaundice. - The condition presents by influenza-like or gastrointestinal symptoms. - It is usually missed in diagnosis. 2- Icteric hepatitis:- passes through 3 stages:A- Pre-icteric stage: (3day up to 2weeks) * Symptoms:- Acute onset of fever, headache & malaise. - Anorexia is marked. - There may be nausea, vomiting & abdominal distension. - Dull aching pain in right hypochondrium & epigastrium. *Signs:- Fever with relative bradycardia. 5

- The liver is enlarged, soft, smooth & tender. - non – specific rash & neck rigidity may occure especially in children. B- Icteric stage : (1-4 weeks ):-

*Symptoms:- Jaundice appears with drop of fever & improvement of general condition. Darkening of urine occures at first followed by lightening of stools & then scleral icterus. - Anorexia, nausea & vomiting usually diminish or disappear. - Pruritis may occure.

*Signs:- The liver is enlarged, soft, smooth & tender. - The spleen is mildly enlarged in 20% of cases. -Lymph nodes in the posterior triangle of neck may be enlarged. C- convalescence stage :- There is gradual improvement of symptoms & signs.

Sequelae of hepatitis:(A) complete recovery:Occurs in the great majority of cases.

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(B) complications:1) Hepatic complications:1- fulminant hepatitis:- It’s a rare condition occurring in 1-2% of patients & presenting with manifestations of acute liver failure. - The disease may develope so rapidly that jaundice is not apparent. - It has a high mortality percent. 2- cholestatic hepatitis :- It presents with prolonged course of cholestatic features e.g. pruritis, dark urine, light stools & elevation of alkaline phosphatase. - Jaundice persists for 8-28 weeks & recovery is almost complete. 2) Extra-hepatic complications :- (due to CMI) . - Arthritis & arthralgia. - Urticaria & skin rash.

Hepatitis B virus: Clinical picture:The clinical picture of hepatitis B is somewhat similar to hepatitis A except the incubation period is longer. (6 weeks to 6monthes ) & the disease is more severe.

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Sequelae of hepatitis:(A) complete recovery: Most patients recover completely after several monthes. (B) complications :1) hepatic complications :1- Fulminant hepatitis:- Death rate is about 1% due to liver fulminant. 2- chronic sequelae: * chronic hepatitis: - chronic active hepatitis: - chronic persistant hepatitis; - chronic lobular hepatitis: *Post – hepatitis cirrhosis. *Hepatocellular carcinoma. * carrier state. 2) Extra –hepatic complications:- Arthritis & arthralgia. - Vasculitis & glomerulonephritis. Hepatitis c virus: * The clinical finings are similar to that of other viral hepatitis. Incidence of liver fulminant with HCV is high compared to that of

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HBV.More than 40% of the infected cases become chronic, out of them 20% develop cirrhosis & liver cancer.

*Hepatitis D virus: - Delta agent causes infection at the same time of HBV infection (co- infection). This induces the severity of acute sings of VBH & the prevelance of liver fulminant. - When it infects the chronic VBH patient (super infection) chronic delta infects occurs with increasing of complications.

N.B. * clinical picture of chonic hepatitis:Symptoms:- may be asymptomatic. - Non – specific symptoms: as fatigue, food intolerance anorexia, abdominal discomfort. - Hepatic manifestations: as pain in right hypochondrium jaundice & features of liver failure which appear lately. Signs:- The liver is enlarged, firm & tender but later may be shrunken. -The spleen is usually enlarged. -Signs of liver failure (e. g. jaundice, ascitis, oedema, & encephalopathy )are late features. -signs of portal hypertension are also late.

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Diagnosis:Hepatitis A virus 1-liver function tests:- The enzyme levels in crease in the blood with hepatitis. Serum bilirubin is increased. – - Transaminases (S G O T & S G P T ) are markedly increased. - Alkaline phosphatase is moderately increased. - Gamma globulins are increased. 2-Hepatitis A markers:- The IgM appears early in the disease &lasts for up to 4 monthes. Thus, it indicates recent infection. - The IgG appears later & persists for years or life long. Thus, its valuable in survey study rather than diagnosis.

Hepatitis B virus 1-liver function tests:There is increase in liver enzymes in the blood. 2- Hepatitis B markers:* HBsAg (hepatitis B surface antigen):Appears in blood about 6 weeks after infection & disappears After 3monthes. Persistence for more than 6monthes indicates a carrier or chronic state.

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* Anti – HBs:Appears after 3monthes & persists. It accounts for recovery & immunity. * HBcAg (Hepatitis B core antigen):It's not detected in blood but in liver biopsy. * Anti – HBc (IgM & IgG):-* They are present in all acute & chronic cases & in carriers. IgM indicates active viral replication. * HBeAg:It indicates infectivity: * HBV DNA by PCR:It’s the most sensitive indicator of viral replication. 3-Liver imaging: e.g. Abdominal ultrasonography shows diffuse hepatomegaly. 4- Blood picture:Leucopenia with relative lymphocytosis. 5- Urine analysis :- Bilirubin & bile salts are present. - Urobilinogen is variable. - There may be slight protheinuria.

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6- Stool analysis:- pale stools & may be features of steatorrhea - Decreased strcobilinogen.

Hepatitis c virus 1- Liver function tests:There is elevation of liver enzymes in blood. 2- Hepatitis C Markers:*Anti- HCV antibodies:- by ELISA or RIA detected After 5-6 week of infection. *HCV RNA: by PCR detected after 2weeks of infection. 3- Other investigations : as HBV.

Hepatitis D virus Hepatitis D Markers:*HDV RNA : by PCR *Anti – HDV antibodies: - Igm denotes recent infection. - IgG denotes previous infection. * HBS Ag is positive.

Hepatitis E virus Anti – HEV antibodies:IgM denotes recent infection. IgG denotes previous infection. 12

Treatment:Hepatitis A virus 1- Rest in bed: is advised until the patient becomes symptom free, the liver is no longer tender & serum bilirubin is less than 1.5 mg/dl. 2- Diet:- High carbohydrate & protein diet is given for regeneration to occure. - Proteins should be restricted if manifestations of liver failure appear. -Low fat diet is usually preferred if nausea is marked -Vitamins especially A, C, E, Antioxidant effect. 3- Symptomatic treatment:- Antiemetics e.g. domperidone for nausea & vomiting. - Cholestyramine for pruritis. 4- Treatment of complications:e.g. steroids may be used in cholestatic hepatitis.

Hepatitis B virus Treatment in general is made as described for hepatitis A. interferon, adenine arabinoside, cortcosteroids & azathioprine alone & in combinations may have a role to improve the chronic active carriers.

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The response occure in about 50% of patients. When the drug is stopped, 50% of responding patients experience a relapse.

Hepatitis C virus Only the general measures like that of VBH must be followed. Immunoglobuline is not effective as immunotherapy. Interferone may be useful in chronic active carriers.

Hepatitis D virus No specific treatment for delta hepatitis.

Prevention & control:Hepatitis A virus 1- Maintenance of good sanitary conditions. 2-Passive immunization with pooled human gamma globulin gives some protection for several monthes. Its recommended for military persons or persons going into areas where poor sanitation exists.

Hepatitis B virus A) General measures:1- Avoidance of contaminated instruments when cutting tissues or injecting medications. 2- Avoid transfusing blood that may contain HBV. Detect the prescence of HBV in the blood of donors using RIA or ELISA tests.

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B) Specific measures:1- seroprophylaxis using hepatitis B immunoglobulin that gives protection for 6-8 monthes. This immunoglobulin is applied for: *prevention of post – transfusion jaundice, in high risk individuals. *personel who have accidentaly handeled infected blood. *Neonates of HBS Ag – positive mothers: given 0.5 Ml, IM, within 24 hours of birth, & at 3& 6 monthes, to reduce the incidence of carriers & hepatoma later in life. N.B. Immuno globulins must be virus – free or sterilized by ultraviolet radiation. 2- Active immunization:Hepatitis B vaccine is highly immunological, giving effective neutralizing Abs in 96% of cases. The vaccine is given to special high risk groups:* personnel exposed to the risk of professional infection on providing laboratory, surgical, dental or other medical sevices. *Medical & paramedical students on starting hospital training. *Cases of lowered body resistance & immune response, when in

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Need of repeated blood transfusion. N. B. vaccination is achieved in Egypt at 2nd , 4th & 6th monthes after birth. This, according to the international role, gives protection for 10 years.

Hepatitis C virus Only the general measures like that of VBH must be followed. No available vaccine. Immunoglobulin is not effective either as immunotherapy or immunoprophylaxis, however its given to workers of high risk.

Hepatitis D virus General measures & vaccination against HBV protect against delta virus infection.

Hepatitis E virus - Improving sanitation is the most important measure which consists of proper treatment & disposal of human waste, higher standards for public water supplies, improved personal hygiene procedures & Sanitary food preparation. - A vaccine based on recombinant viral protein has been developed & recently tested in a high risk population (military personnel of a developing country). The vaccine appeared to de effective & safe but further studies are needed to assess the long term protection of this vaccine.

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Recent approaches in treatment & prevention of hepatitis Treatment of hepatitis B:- Current treatments for hepatitis B are very effective at controlling or suppressing the HBV. However HB treatment only rarely leads to (cure). - There are 5 drugs approved by FDA for use against HBV, these are:1- Interferon alfa (Intron A) 2- Lamivudine (EPIVIR) 3- Adefovir (HEPSERA) 4- Entecavir (BARACLUDE) 5- Pegylated interferone alfa - 2a . - Interferon works by helping the body's immune system fight infection. Antivirals work by stopping the virus from replication. - Interferons are given by injection. The other antiviral drugs are given by mouth in pills or liquid form. - Not every one with hepatitis B needs treatment. Treatment should be only considered in those with active liver disease (liver enzymes, HBV detected in blood & damage shown on liver biopsy).

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- Chances of responding to treatment:* Almost all patients can achieve an initial lowering of blood levels of HBV DNA & Liver enzymes. * Treatment with oral therapy can keep viral levels low & liver enzymes normal over prolonged periods. * Treatment with Interferone can lead to loss of HBeAg in about one third of patients. -Duration of treatment:* Interferone is given for 6-12 months. * Oral drugs may need to be given beyond one year depending on response. - Treatment of decompensated cirrhosis:* Interferone is contraindicated in these patients. Lamivudine is the 1st choice in patient with active viral replication. Lamivudine may reduce or delay the need for liver transplantation. In contrast, the benefit of Lamivudine in patients with advanced cirrhosis & inactive viral replication is doubtful & shouldn’t be used in these circumstances. * Treatment of cirrhosis is mainly symptomatic:- Ascitis:- Furosemide (lasix) - Spironolactone (Aldactone)

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- Encephalopathy:- Lactulose - Rifaximin. - Portal hypertension & varices:- Propranolol (indral) - Nadolol - Spontaneous bacterial peritonitis (SBP) prophylaxis & treatment:- Trimethoprim – sulfamethoxazole. - Fluroquinolones. * Treatment of HB in pregnant women:Some recommended the use of lamivudine in pregnant women with HBV DNA levels to reduce the risk of neonatal transmission. To date, there are no reports of fetal injuries due to Lamivudine. A single study has shown that if the HBV DNA levels are very high, the rate of maternal- fetal transmission is approximately 30% despite neonatal vaccination.

* Treatment of hepatitis C:-

Hepatitis C is very much a treatable condition .

- Treatment is with interferone (shots) & ribavirine (capsules)

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Not every one with hepatitis C needs treatment. Only

patient with active liver disease or with scarring to liver should be treated as long as they don’t have conditions that prevent them from being treated successfully. - In patient with confirmed HCV infection, genotype testing is generally recommended. HCV genotype testing is used to determine the required length & potential response to interferone - based therapy. -

Chances of responding to treatment:About one half of treated patients clear HCV if they take a complete course of treatment.

- Duration of treament:- depend on genotype:* For genotype 1→ A full year is needed. * For genotype 2 & 3 → six months are sufficient. -

Some new studies has shown higher success rates when

the antiviral drug "Amantadine" is added to interferone & ribavirine. This is called

(Triple therapy). This may be

especially helpful for non - responding patients to interferone & ribavirine only. * New additions used in treatment of both HB & HC:-Bile acids:* Bile acids may improve liver biochemistry of patients with HB or HC but there is insufficient evidence about long term beneficial effects.

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* Bile acids may decrease serum transaminase activities in patients with acute hepatitis B, chronic hepatitis B or chronic hepatitis C. However, bile acids have no effects in eradicating viral markers. There is insufficient evidence either to support or to refute effects on long term outcomes e.g. heapatocellular carcinoma, decompensated cirrhosis & / or liver related mortality. * Transfer factor (TF):* The results obtained from adult patients receiving TF along with conventional therapy attests to a high effectiveness of cellular cytokines use in this kind of pathology. Along with normalization of biochemical values & the decrease of viral load, all patients registered a marked improvement of general state, were more efficient & didn’t experience excessive fatigue & there was no discomfort in Right hypochondrium. * What is Transfer factor? The colostrum is the milk produced in the 1st few days after child birth. Colostrum contains a potent array of immune factors which can be passed from mother to child & is available in supplement form in health food stores from bovine sources. The principle immune factor in colostrum is a group of

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molecules called TF. It can also be derived from eggyolk protein & human WBCs. * Post - exposure prophylaxis against HB & HC:- Needle stick injuries &wounds should be washed with soap & water & shouldn’t be squeezed. Mucous membranes should be flushed with water. - For HB:- Initiation of HB vaccine series within 12-24h of an exposure has been demonstrated to be 70 - 90 % effective in preventing HBV infection. - For HC:- People who have HC can get into another infection of one of other genotypes which can make the person sicker so they should follow general guidelines for protection.

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