Dr Ehsan Assad, Dr Arshad Javaid Sh, Dr Mehboob Ashraf, Dr Shahid Pervaiz Sh, Dr Saleem A Rana.Choice of questions belonged to the panel.
Common Viruses affacting Liver.
A: Hepatitis Group: A to E, G and F viruses.
B: Infectitious mononucleosis (Epstain Barr virus)
Cytomegalovirus.
AIDS, HIV.
Herpes Simplex.
Yellow Fever.
All viruses producing other systemic illnesses do invade liver. These may elevate enzymes also. But this is of no significance usually. Viruses mentioned in-group B can present as acute viral hepatitis, although very rarely and not as predominant feature. Here clinical picture shall make the differential diagnosis. Level of suspision shall be high whenever above mentioned viruses come in the mind. Cytomegalovirus shall be considered only in immunocompromised patients such as HIV patients.
Infectitious Mononucleosis.
It is characterised as painful cervical lymphadenopathy and splenomegaly. Diagnosis is usually considered when ampicillin causes a rash. Monospot test and atypical lymphocytes confirm the diagnosis. It is common in children, 5-15 years of age. This is self-limiting disease, with usual period of 2-3 weeks. Whenever hepatitis is a feature, it is usually mild to moderate. It has no chronic phase.
AIDS.HIV Infection.
This is becoming sufficiently common to be included in the screening of all undiagnosed cases of Viral Hepatitis. Awareness about the possibility and then history of multiple sex partners or transfusions in the past shall increase the suspicision. Screening for HIV shall rule out it in all unexplained cases of viral hepatitis. It can also co-exist with Hepatitis B or C.
It is practically confined to 5 viruses. A to E.G virus, TT virus (Transfusion Transmitted Virus) has also been reported in Pakistan.It is responsible for 2 % cases of trasfusion transmitted hepatitis. All viruses are RNA viruses except Hep B and TT virus, which are DNA viruses. But RNA or DNA characteristic has no significance as for as features of acute or chronic hepatitis are concerned. All these viruses belong to different families. These do no not share any morphological feature. Just because of Liver being their primary host, these have been grouped together as hepatitis viruses.
HBsAg can be tested before starting vaccination. If it is positive then obviously there is no need for vaccination. Vaccination can be started without testing for HBsAg.Vaccination will not harm already positive persons.
Vaccination for hepatitis B is very effective. It shall become part of EPI.It shall be given as early as possible, prefereabley on 1st day of life. Three doses in different schedules are advised. It is easier for the patient to remember 0,1,2 months. If two doses have been given on time and third has been missed, and more than a year has passed than either whole schedule of 3 doses can be repeated or antibodies for HBsAg can be ordered to see whether adequate level has been achieved by previous two doses.
There is no established opinion for booster dose or duration of immunity this vaccination is inducing. It is long lasting. It can be 10 years. Booster dose can be given anytime if patient or doctor wish to do so. It is not harmful.
Opinion on dose is again divided.20 units after 20 years of age and 10 units under 20 years of age are the formula I follow. Every individual shall be vaccinated. Patients suffering from Hepatitis C shall be given vaccination for A & B.
90 % of our population is exposed to Hepatitis A.So there is no need for this vaccination. Only travellers to endemic areas or people at special risk have to be vaccinated.
Structure Of Hepatitis B Virus.
It consists of a core and a surrounding layer of cytoplasm, known commonly as outer coating. Core contains DNA, and two antigens. Core antigen and e antigen. Outer coating contains surface antigen.
So there are 3 antgens.
1) Core antigen. It never appears in the blood. It remains confined to cells.
2) E antigen tested as e antigen.
3) Surface antigen. Commonly tested as HBsAG.
There are 3 antibodies, which are manufactured by body immune system against these antigens.
These are
1) Ig M Anticore antibodies against core antigen. These appear in blood.
2) Anti e antibodies against e antigen
3) Anti surface antibodies against surface antigens. These are protective. These show immunity. These are tested to investigate the success of vaccination.
During infection these appear in one sequence. First antigen from outer layer becomes positive. That is surface antigen. Then it is inner layer that is e antigen, which appears after surface antigen. When infection resolves completely then order of disappearance from blood is in opposite direction. First antigen from inner core, e antigen disappears. And later on it is surface antigen, which becomes negative after e antigen.
SEROCONVERSION This term is used in Hepatits B infection. This denotes disappearance of e antigen and positivity for anti e antibodies. This means patient is no more a carrier.
Pre-Core Mutation. In some patients mutation occurs in pre-core gene. When these patients are tested for routine antigens, these will test as negative in spite of presence of these in altered chemical structures. Here PCR for HBV will decide the issue.
Virus A, C, D, & E.
These are simple structures. One strand RNA.Virus D needs outer covering from Hepatits B virus (as HBsAg) for its RNA to replicate. All these are detected as single antigens i.e as viral RNA by PCR amplification. Antibodies appear in blood against these RNA strands. These are Ig M in acute infections. These are known as anti HAV, antiHCV, antiHDV, and antiHEV.
Acute versus Chronic Hepatitis.
If infection persists in-patients after 6 months then it is termed as chronic infection. Before 6 months it is acute infection.
Figure of Six (6) is important to remember many durations defined for these hepatitis infections.
Incubation Periods.
HAV 6 days to 6 weeks.
HBV 6 weeks to 6 months.
HCV 6 weeks to 6 months
HBsAg is tested after 6 monts to label as chronic hepatitis if positive.
HBsAg disappears between 3 to 6 months after symptoms of acute hepatitis.
Liver Biopsy after 6 months in HBsAg positive patients.
Anti HCV positive after 6 weeks to 6 months of infection.
Acute Viral Hepatitis.
First other causes of hepatitis should be ruled out. Drugs, other infections, and other concurrent conditions like Diabetes Mellitus; CCF shall be properly assessed.
Routine investigations in the appropiate clinical background.
v Enzymes.
v T.Bilirubin.
v Viral Marker.
v Abdominal Ultrasound.
Acute hepatitis can not be labeled as acute viral hepatitis until an appropriate viral marker is identified. (Table for markers has been included in the section on management of Ac Hepatitis). These must be ordered.
Incidenc of different Viruses.
Overwhelming majority is A & E.In Children it is A which is common and in adults it is E which is common. So first these two shall be tested. If these are negative then HBsAG shall be tested. If HBsAg is negative along with IgM for HAV and HBV then anticore antibodies shall be ordered to rule out window period in Hepatitis B Acute infection.
Window Period.
Sometimes immune system of body is so aggressive that by the time jaundice appears due to damaged hepatocytes, virus has already been cleared from the body. So HBsAg will be negative.e antigen will also be negative. Antibodies against surface antigen and against e antigen appear late. So then acute phase can only be ascribed to HBV if anticore antibodies are positive.
Think of HCV or other viruses only when all above-mentioned markers are negative. AntiHCV antibodies will appear late. PCR for HCV becomes positive withen one week of infection. So this can be ordered to confirm that acute Hepatitis is due to HCV.Acute phase in C is very rare. D virus can be suspected under circumstances where acute on chronic situation in Hepatitis B is suspected. Ig M for D virus can be ordered.
Monitoring of Acute Hepatits against Acute Liver Failure.
Enzyme levels and colour of sclera are not good indicators for prognosis. It is only the Prothrombin Time, which co-relates best with the progress of liver damage. It is affacted at the earliest even before the enzymes are raised. It progresses with the damage. If it keeps on increasing then this is a very poor prognostic indicator inspite of apparently good clinical presentation. To combat the differences in figures of different laboratories, a new parameter or let us say a new way of calculating prothrombin time is now in use. This is the term of
INR = International Normalised Ratio = Actual time divided by the control time of the same Laboratory.
Intervals for repeating investigations.
Enzymes and prothrombin time should be repeated at 1 week, 2 weeks, and 4 weeks and then at 3-6 months.
Vomiting in Acute Hepatitis.
Bilirubin is a very strong stimulant for vomiting centre. So vomiting is always central in origin. As such there is no role of antiacid treatment. Only if some gasteritis is suspected due to some other cause, then these can be uses. Antiemetics can be used. Dextrose 5% infusion can be used.
Chronic Hepatitis.
Symtoms originate from disturbed liver function, obstruction in portal circulation and immune disturbances due to chronic infection. These have been covered in previous interview and journal. Extrahepatic manifestations are more frequent in hepatitis B.This may be due to 3 antigens body is dealing with rather than one as in all other viral infections.
Specific Treatment of Chronic Viral hepatitis.
It is combination therapy of antivirals and Interferon.
Contraindications of Interferon.
Age: 18-60 years in westren world is the limit. It is always relative contraindication. It is being used in children to prevent chronic phase. Older people are also using it, with established Cirrhosis of liver, just to prevent hepatocellular carcinoma.
Diseases.
v Assess life expectancy based upon any concurrent disease.
v Diabetes Mellitus is a relative contraindication.
v Autoimmune diseases like thyroiditis are absolute contraindications. TSH, T3 and T4 must be ordered before initiating interferon. ANA, ANF and other relevant immunological investigation can be done.
v Depression is another absolute contraindication. As this is a frequent side effect. Suicides are on record after use of interferon.
v Neutropenia and thrombocytopenia are also absolute contraindications, unless treated completely.
v Compensation level of Cirrhosis.This must be considered. How much damage has been already done? This can not be reversed. Although it can be used to prevent hepatocellular carcinoma.
Following 3 parameters assesses liver Compensation.
1. Albumin level
2. Platelet counts.
3. Total Bilirubin
Higher the load, greater is going to be the response.
Usually interferon is started at 3.5 million copies.
Genotyping.
Type 2 and 3 respond better than other types. In Pakistan majority of infections fall withen these two types. Other types are not contraindicated. But these require higher doses and for longer duration of period.
Higher the levels, better is the response. Patients with normal ALT levels respond very poorly to interferon.
Moderate to severe changes in biopsy are a poor prognostic sign. Still it can be used to prevent further damage and to prevent carcinoma.
Monitoring of Interferon Therapy.
Mainly 3 parameters are checked to see the efficacy and to rule out threatening side effects.
v Platelet counts.
v Neutrophil count
v Enzymes.
These shall be repeated at week 1,week 2 and week 4 initially. PCR shall be repeated after 4 weeks. After 4th week these can be repeated after 3 months.
If platelet and neutrophil count falls rapidly then stop interferon temporarily. Give some rest. Then start after 2 weeks in lower doses.