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Reddi, Y.R., M.D., M.A.M.S., Professor and Head of the Department of Paediatrics, Osmania Medical College, Director of Paediatric Services, Institute of Child Health and Superintendent, Niloufer Hospital, Hyderabad, India. Rohini, K., M.D., D.C.H., Research Scholar, Kusuma, G., M.D., D.C.H., Assistant Professor of Paediatrics and Sudhakar Rao, V., M.D. (Ped.), D.C.H. (Bom.), D.A.B.P. (U.S.A.), F.A.A.P. Assistant Professor of Paediatrics Research.
Abdominal pain was noticed in 30% which is in agreement with Sule et al26. Abdominal pain varied from mild discomfort to an acute episode suggesting a surgical problem. A single case was admitted for acute pain in the abdomen and conservative line of treatment was given. Two days later jaundice appeared. The abdominal pain could be attributed to perihepatitis, distension of Glisson’s capsule, phlegmonous enteritis causing diffuse pain or sudden shrinkage of the liver in acute hepatic necrosis12.
Mild respiratory tract infection was seen in 23.3% of the present series. Report of Lucke13 and Mallory14 give respiratory infections in 75% in the paediatric age group. Headache was encountered in 21.6% of the present series and 33% in Haven’s series. This is most probably a constitutional symptom. In one series certain neuropsychiatric symptoms were seen. One case which was in a precomatose state became boisterous and a day later became drowsy. Three per cent of the present series had excessive sleepiness and drowsiness.
Physical Signs
Jaundice, observed in all cases, is attributed to the lack of function of hepatic parenchymal cells, obstruction of biliary canaliculi by bile thrombi, increased permeability of the smaller bile ducts and canaliculi for bile, or shortened life span of RBC. As the jaundice was clearing serum bilirubin levels also came down. Only a few cases showed persistence of serum bilirubin levels even after the jaundice cleared clinically. Clearance of jaundice varied from case to case. Hepatomegaly was the next important physical sign observed in 98.3% of the present series, 100% according to Dave et al3, and 95% of Deshpande’s series4. Only one case did not have a palpable liver though the histologic lesion was suggestive of viral hepatitis. Tenderness could be elicited only in 54% of the cases. Though Rappaport20 concluded that the degree of hepatic tenderness varies inversely with the extent of liver enlargement, such relationship could not be elicited in the present series. Liver remained palpable for a variable time, it receded as early as 6 days in few; whereas it persisted for more than a year in 2 cases. Splenomegaly was noticed in 35% of the present series, and 20% according to Sherlock24. The size varied from 1-3 cm below the costal margin and it denotes a slight rise in portal pressure resulting in congestion of spleen. In most of the cases it disappeared within 1–4 weeks and occasionally persisted even after a year. Lymphadenopathy was observed in 35% of the cases. Wood29 and Barker1 reported a generalised lymphadenopathy in almost all of their cases. Posterior cervical lymphadenopathy on the right side was stressed by Sherlock24, as the lymphatics draining the diaphragm are connected to them. In the present series cervical and submandibular groups were palpable, discrete, firm and not tender. Bradycardia was observed only in one case. It is more frequent in adults due to the effect of bile salts on the vagal nerve endings. The infrequency of this sign in children is probably because of sympathetic ovetonus. Ascites was also observed in a single case which completely disappeared after prednisone therapy. Ascites when present denotes a rise in portal pressure but is a rare feature17. Skin manifestation appeared in none of the series. Fifteen per cent of the present series showed various manifestations of protein and vitamin deficiencies. Similar were the findings of Sheth et al4. Convalescence was quick and short in almost all cases.
Laboratory Tests
Urine examination was done on the day of admission for bile salts, bile pigments and urobilinogen. Colour of the urine varied from light yellow to dark red or port wine colour. The urine gave a positive test in almost all cases for bile pigments except in 6% where bilirubin levels were very low (less than 1.6 mg). Methylene blue test and Fouchet’s test (Harrison Spot) were done in all cases but methylene blue test was found to be unreliable. In 80% of the cases urobilinogen as tested by Ehrlich’s aldehyde reagent was present. Disappearance of urobilinogen signifies complete obstruction. In the present series disappearance of urobilinogen was not associated with high alkaline phosphatase levels and passing clay coloured stools in most of the cases.
Haematological Investigations
The blood counts were normal in 69%, leucopenia which is said to be characteristic was observed only in 11% of cases; leucocytosis in 20% and relative lymphocytosis in 10% of the present series. A high relative lymphocytes was recorded in 87% of cases by Finks and Blumberg.
Liver Function Tests (LFT)
Depth of jaundice could be well correlated with serum bilirubin level. In the present series 2 cases who had very low serum bilirubin levels of 1.4 and 1.7 mg% showed typical histologic lesion. One case having very high serum bilirubin level showed almost normal structure of the liver on needle biopsy of the liver therefore serum bilirubin level is not useful for prognostic purposes as it does not indicate the degree of hepatic damage19. Return of serum bilirubin to normal was slower when compared to SGOT and SGPT levels. Tables XI and XII illustrate the efficacy of Liv.52 and steroids in lowering hyper bilirubinemia to 2 mg% or less, within 15 days of treatment. The efficacy of Liv.52 was observed by Raju et al21 and Sule et al26, and that of steroids by Ducci, and Katz6. In the Van den Bergh reaction, a direct positive reaction was noted in most of the cases and a delayed positive was noted only in a few cases who had very low serum bilirubin levels. Thymol turbidity values ranged from 3.8 to 6 units/ml. Thymol turbidity values returned to normal at the time of discharge as illustrated in Table XIV for all cases. These tests depend on high beta and gamma globulins or a fall in albumin level. This test is considered valuable by Sherlock in detecting hepatic damage but such correlation could not be made in the present study. Serum alkaline phosphatase is a valuable test to differentiate obstructive and non-obstructive types of jaundice. Though the initial levels were normal, all the cases registered a fall in the levels 15 days after treatment (Table XIII). Ester component of total serum cholesterol may be very much reduced in hepatocellular damage. A rising cholesterolemia with declining bilirubinemia is definite evidence of convalescence. Since the method of estimating cholesterol esters is time consuming, they have a limited practical application. The values of serum proteins ranged from 3 g. to 6.4 g. in the present series. A definite rise in total serum proteins especially in those in whom the levels were low at the time of admission was observed as illustrated in Table XV at the time of discharge. Histopathological changes in liver biopsy studies varied from case to case depending upon the stage of the disease. The histopathological changes on serial liver biopsies which are reported are of different opinions25,2,22,23,6,5. In the present study vacuolation was noted in all cases. Portal tracts were infiltrated with mono-nuclear and segmented leucocytes. Cholestasis was appreciable only occasional. Lobular architecture was intact in all cases and the reticulin framework was not distorted.
Correlation between Clinical, Biochemical and Histopathological Changes
There was no correlation between clinical, biochemical and histopathological lesions as has been observed in the present study. In one case though the child had severe jaundice, histopathological changes were minimal and in another case the child had all clinical and biochemical features suggestive of acute viral hepatitis but histopathological examination was essentially negative. About 12% of the present series who had normal SGOT, SGPT values exhibited hepatic damage on histologic examination. Serum bilirubin levels also were not helpful in indicating the degree of hepatic damage. Presence of bile thrombi histologically may not always be associated with clinical and biochemical evidence of the obstructive phase. According to Shetana25 these bile thrombi indicate subsiding phase of viral hepatitis. Till recently treatment has had little effect in altering the course of an ordinary case of acute viral hepatitis. Till today various drugs have been tried as therapeutic measures and various authors have claimed beneficial results (Sherlock).
Liv.52 therapy: In the present series Liv.52 was tried on 31 cases (Group ‘A’). Improvement in symptomatology was observed in all cases, but earlier in the Liv.52 group. Patients experienced a subjective sense of well-being and improved as in Group B (Prednisone). Hyperbilirubinemia which is an index of severity of jaundice remarkably regressed as shown in Tables X and XI. Serial transaminase estimation also showed a considerable fall 15 days after Liv.52 therapy as illustrated in Table XI. This proved the efficacy of Liv.5226,3,21. Serial needle biopsy of the liver revealed a dramatic recovery of the histological lesion as also observed by Mukerjee et al15, 18, the earliest improvement being 6 weeks after treatment. This was not observed in group B (Prednisone) and group D (vitamins B-complex and C). None of the cases treated with Liv.52 showed any untoward toxic symptoms and in none did jaundice recur.
Corticosteroid therapy: The observations made in the present series were in agreement with some authors i.e. steroids showed a good clinical as well as biochemical improvement6,7,8. (Though a single case showed fluctuation of serum bilirubin level while it was being tapered off) but the histological lesion showed little alteration26,28. Almost all cases of groups B and C receiving prednisone developed puffiness of the face and oedema of the feet following steroid therapy as observed by Libov11.
Role of Liv.52 and Steroids in the Management of Viral Hepatitis in Children
Reddi, Y.R., M.D., M.A.M.S., Professor and Head of the Department of Paediatrics, Osmania Medical College, Director of Paediatric Services, Institute of Child Health and Superintendent, Niloufer Hospital, Hyderabad, India. Rohini, K., M.D., D.C.H., Research Scholar, Kusuma, G., M.D., D.C.H., Assistant Professor of Paediatrics and Sudhakar Rao, V., M.D. (Ped.), D.C.H. (Bom.), D.A.B.P. (U.S.A.), F.A.A.P. Assistant Professor of Paediatrics Research.
Abdominal pain was noticed in 30% which is in agreement with Sule et al26. Abdominal pain varied from mild discomfort to an acute episode suggesting a surgical problem. A single case was admitted for acute pain in the abdomen and conservative line of treatment was given. Two days later jaundice appeared. The abdominal pain could be attributed to perihepatitis, distension of Glisson’s capsule, phlegmonous enteritis causing diffuse pain or sudden shrinkage of the liver in acute hepatic necrosis12.
Mild respiratory tract infection was seen in 23.3% of the present series. Report of Lucke13 and Mallory14 give respiratory infections in 75% in the paediatric age group. Headache was encountered in 21.6% of the present series and 33% in Haven’s series. This is most probably a constitutional symptom. In one series certain neuropsychiatric symptoms were seen. One case which was in a precomatose state became boisterous and a day later became drowsy. Three per cent of the present series had excessive sleepiness and drowsiness.
Physical Signs
Jaundice, observed in all cases, is attributed to the lack of function of hepatic parenchymal cells, obstruction of biliary canaliculi by bile thrombi, increased permeability of the smaller bile ducts and canaliculi for bile, or shortened life span of RBC. As the jaundice was clearing serum bilirubin levels also came down. Only a few cases showed persistence of serum bilirubin levels even after the jaundice cleared clinically. Clearance of jaundice varied from case to case. Hepatomegaly was the next important physical sign observed in 98.3% of the present series, 100% according to Dave et al3, and 95% of Deshpande’s series4. Only one case did not have a palpable liver though the histologic lesion was suggestive of viral hepatitis. Tenderness could be elicited only in 54% of the cases. Though Rappaport20 concluded that the degree of hepatic tenderness varies inversely with the extent of liver enlargement, such relationship could not be elicited in the present series. Liver remained palpable for a variable time, it receded as early as 6 days in few; whereas it persisted for more than a year in 2 cases. Splenomegaly was noticed in 35% of the present series, and 20% according to Sherlock24. The size varied from 1-3 cm below the costal margin and it denotes a slight rise in portal pressure resulting in congestion of spleen. In most of the cases it disappeared within 1–4 weeks and occasionally persisted even after a year. Lymphadenopathy was observed in 35% of the cases. Wood29 and Barker1 reported a generalised lymphadenopathy in almost all of their cases. Posterior cervical lymphadenopathy on the right side was stressed by Sherlock24, as the lymphatics draining the diaphragm are connected to them. In the present series cervical and submandibular groups were palpable, discrete, firm and not tender. Bradycardia was observed only in one case. It is more frequent in adults due to the effect of bile salts on the vagal nerve endings. The infrequency of this sign in children is probably because of sympathetic ovetonus. Ascites was also observed in a single case which completely disappeared after prednisone therapy. Ascites when present denotes a rise in portal pressure but is a rare feature17. Skin manifestation appeared in none of the series. Fifteen per cent of the present series showed various manifestations of protein and vitamin deficiencies. Similar were the findings of Sheth et al4. Convalescence was quick and short in almost all cases.
Laboratory Tests
Urine examination was done on the day of admission for bile salts, bile pigments and urobilinogen. Colour of the urine varied from light yellow to dark red or port wine colour. The urine gave a positive test in almost all cases for bile pigments except in 6% where bilirubin levels were very low (less than 1.6 mg). Methylene blue test and Fouchet’s test (Harrison Spot) were done in all cases but methylene blue test was found to be unreliable. In 80% of the cases urobilinogen as tested by Ehrlich’s aldehyde reagent was present. Disappearance of urobilinogen signifies complete obstruction. In the present series disappearance of urobilinogen was not associated with high alkaline phosphatase levels and passing clay coloured stools in most of the cases.
Haematological Investigations
The blood counts were normal in 69%, leucopenia which is said to be characteristic was observed only in 11% of cases; leucocytosis in 20% and relative lymphocytosis in 10% of the present series. A high relative lymphocytes was recorded in 87% of cases by Finks and Blumberg.
Liver Function Tests (LFT)
Depth of jaundice could be well correlated with serum bilirubin level. In the present series 2 cases who had very low serum bilirubin levels of 1.4 and 1.7 mg% showed typical histologic lesion. One case having very high serum bilirubin level showed almost normal structure of the liver on needle biopsy of the liver therefore serum bilirubin level is not useful for prognostic purposes as it does not indicate the degree of hepatic damage19. Return of serum bilirubin to normal was slower when compared to SGOT and SGPT levels. Tables XI and XII illustrate the efficacy of Liv.52 and steroids in lowering hyper bilirubinemia to 2 mg% or less, within 15 days of treatment. The efficacy of Liv.52 was observed by Raju et al21 and Sule et al26, and that of steroids by Ducci, and Katz6. In the Van den Bergh reaction, a direct positive reaction was noted in most of the cases and a delayed positive was noted only in a few cases who had very low serum bilirubin levels. Thymol turbidity values ranged from 3.8 to 6 units/ml. Thymol turbidity values returned to normal at the time of discharge as illustrated in Table XIV for all cases. These tests depend on high beta and gamma globulins or a fall in albumin level. This test is considered valuable by Sherlock in detecting hepatic damage but such correlation could not be made in the present study. Serum alkaline phosphatase is a valuable test to differentiate obstructive and non-obstructive types of jaundice. Though the initial levels were normal, all the cases registered a fall in the levels 15 days after treatment (Table XIII). Ester component of total serum cholesterol may be very much reduced in hepatocellular damage. A rising cholesterolemia with declining bilirubinemia is definite evidence of convalescence. Since the method of estimating cholesterol esters is time consuming, they have a limited practical application. The values of serum proteins ranged from 3 g. to 6.4 g. in the present series. A definite rise in total serum proteins especially in those in whom the levels were low at the time of admission was observed as illustrated in Table XV at the time of discharge. Histopathological changes in liver biopsy studies varied from case to case depending upon the stage of the disease. The histopathological changes on serial liver biopsies which are reported are of different opinions25,2,22,23,6,5. In the present study vacuolation was noted in all cases. Portal tracts were infiltrated with mono-nuclear and segmented leucocytes. Cholestasis was appreciable only occasional. Lobular architecture was intact in all cases and the reticulin framework was not distorted.
Correlation between Clinical, Biochemical and Histopathological Changes
There was no correlation between clinical, biochemical and histopathological lesions as has been observed in the present study. In one case though the child had severe jaundice, histopathological changes were minimal and in another case the child had all clinical and biochemical features suggestive of acute viral hepatitis but histopathological examination was essentially negative. About 12% of the present series who had normal SGOT, SGPT values exhibited hepatic damage on histologic examination. Serum bilirubin levels also were not helpful in indicating the degree of hepatic damage. Presence of bile thrombi histologically may not always be associated with clinical and biochemical evidence of the obstructive phase. According to Shetana25 these bile thrombi indicate subsiding phase of viral hepatitis. Till recently treatment has had little effect in altering the course of an ordinary case of acute viral hepatitis. Till today various drugs have been tried as therapeutic measures and various authors have claimed beneficial results (Sherlock).
Liv.52 therapy: In the present series Liv.52 was tried on 31 cases (Group ‘A’). Improvement in symptomatology was observed in all cases, but earlier in the Liv.52 group. Patients experienced a subjective sense of well-being and improved as in Group B (Prednisone). Hyperbilirubinemia which is an index of severity of jaundice remarkably regressed as shown in Tables X and XI. Serial transaminase estimation also showed a considerable fall 15 days after Liv.52 therapy as illustrated in Table XI. This proved the efficacy of Liv.5226,3,21. Serial needle biopsy of the liver revealed a dramatic recovery of the histological lesion as also observed by Mukerjee et al15, 18, the earliest improvement being 6 weeks after treatment. This was not observed in group B (Prednisone) and group D (vitamins B-complex and C). None of the cases treated with Liv.52 showed any untoward toxic symptoms and in none did jaundice recur.
Corticosteroid therapy: The observations made in the present series were in agreement with some authors i.e. steroids showed a good clinical as well as biochemical improvement6,7,8. (Though a single case showed fluctuation of serum bilirubin level while it was being tapered off) but the histological lesion showed little alteration26,28. Almost all cases of groups B and C receiving prednisone developed puffiness of the face and oedema of the feet following steroid therapy as observed by Libov11.
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