Secondary Logo

Journal Logo

Original Articles: Hepatology and Nutrition

Ascitic Form of Sporadic Acute Viral Hepatitis in Children: A Distinct Entity for Recognition

Yachha, Surender K*; Goel, Amit; Khanna, Vikrant; Poddar, Ujjal*; Srivastava, Anshu*; Singh, Uttam

Author Information
Journal of Pediatric Gastroenterology and Nutrition: February 2010 - Volume 50 - Issue 2 - p 184-187
doi: 10.1097/MPG.0b013e3181aecb4c
  • Free

Abstract

Acute viral hepatitis (AVH), an inflammatory pathology of liver, is caused by infection with 1 of the several hepatotrophic viruses. It is a widespread disease in all parts of the world and a major public health problem in developing countries (1–3). AVH can have a varied presentation ranging from subclinical infection, anicteric hepatitis, and uncomplicated icteric sporadic AVH, to one complicated by liver failure (4). Hepatitis A virus (HAV), hepatitis E virus (HEV), and hepatitis B virus (HBV) as single infection or in combination have been responsible for most of the cases of sporadic AVH, fulminant hepatic failure, or subacute hepatic failure in children and adults (2,5–13). In uncomplicated sporadic AVH, the classical presentation is a prodrome followed by an icteric phase with or without cholestatic manifestations followed by a complete resolution of all symptoms and signs of liver disease (4). Ascites has been recently mentioned to occur in 10% to 22% cases of sporadic AVH in children (3,12). This ascitic variant of AVH may be expected to have a more severe clinical illness, differences in viral etiology, host factors, and outcome as compared with nonascitic AVH (NAVH). However, no data are available on this aspect both for children and adults. This study was conducted with the aim to find out the frequency of occurrence and to characterize the differences in presentation, laboratory parameters, and outcome between AAVH and NAVH forms of AVH in children.

METHODS

We prospectively evaluated consecutive children (2–17 years of age), presenting with AVH, between January 2000 and December 2006, at Paediatric Gastroenterology Services of the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India. Detailed history and clinical examination was recorded in all of the patients. Children with AVH were divided into 2 groups: AAVH and NAVH.

Diagnosis of AVH was based on clinical features, more than 3-fold elevation of alanine aminotransferase, positive serology for markers of AVH at presentation, absence of previous history of liver disease, subsequent normalization of clinical features, and liver functions within 6 months from the onset of symptoms along with sustained resolution of ascites in AAVH on follow-up. All of the patients underwent biochemical evaluation using standard automated techniques. Liver function tests, prothrombin time, and viral markers for hepatitis (IgM anti-HAV, IgM anti-HEV, hepatitis B surface antigen, and IgM antihepatitis B core antigen) were done in all of the cases. IgM anti-HEV was tested using commercially available enzyme immunoassay kits (Genelabs Diagnostics, Singapore); the assay detects antibodies against recombinant proteins corresponding to open reading frames 2 and 3 of HEV. Enzyme immunoassay kits (Organon Teknika, Boxtel, the Netherlands) were used for detection of other serological markers. Serum specimens that tested borderline values were retested and those repeatedly giving borderline values were considered as negative. Acute hepatitis B was diagnosed if there was hepatitis B surface antigen positivity together with IgM antihepatitis B core antigen positivity. Abdominal ultrasonography was done on all of the patients to evaluate liver characteristics, splenomegaly, gallbladder wall thickness, pericholecystic fluid collection, ascites, portal vein diameter, hepatic veins, and portosystemic collaterals. Ascites was diagnosed either by clinical examination or by ultrasonography or both.

Ascitic tap was done in children with clinically detectable ascites. Total and differential cell count as well as biochemical analysis and culture were done for ascitic fluid (14). Patients having ascites were investigated further: diagnostic upper gastrointestinal endoscopy for esophageal or gastric varices or portal hypertensive gastropathy, chest x-ray, and routine urine examination. We evaluated the nutritional parameters of height standard deviation z score (HSDS) in both groups of patients. HSDS was calculated as the difference between the value of observed height and median height of the reference population divided by the standard deviation value of reference population. We did not assess nutrition on the basis of weight or weight for height because the weight depiction could have been false because of presence of ascites.

Patients with fulminant hepatic failure and subacute hepatic failure as defined by O'Grady et al (15) and Tandon et al (16), respectively, were excluded. Patients presenting for the first time with ascites, underlying cirrhosis was excluded by clinical history and examination coupled with investigative support of either presence of nodular, irregular liver, portosystemic collaterals, and increased portal vein diameter on ultrasonography, or esophageal, or gastric varices at upper gastrointestinal endoscopy at any given point of study. Patients with history of hepatotoxic drug intake or any other systemic disease were also excluded.

Statistical Analysis

The values are expressed as median with range. The data were analyzed using the Mann-Whitney U test or the χ2 test. A P value of <0.05 was taken as significant.

RESULTS

A total of 139 (96 boys) consecutive children with ages ranging from 2 to 17 years were enrolled in the study after they had met the inclusion and exclusion criteria. Ascites was detected in 18 (12.9%) patients at the first evaluation. Of these cases with ascites 38.9% (7/18) had clinically detectable ascites, whereas the others had ascites detected by ultrasonography. None of the children with AAVH had varices or evidence of portal hypertensive gastropathy on upper gastrointestinal endoscopy. A comparison of clinical features between NAVH and AAVH is shown in Table 1. Significant differences between the 2 groups observed were those of median age of presentation NAVH 8 years (range 2–17 years) and AAVH 4 years (range 2–10 years), and frequency of symptoms of prodrome NAVH 51% and AAVH 22% (Table 1). No significant differences were found in symptoms of prodrome, sex, duration of symptoms, liver span, or consistency between the groups (Table 1). Nutritional profile of patients as assessed by HSDS in both groups was comparable. On comparison of laboratory parameters (Table 2), patients with AAVH had lower serum albumin (median 2.8 vs 3.7 g/dL) and lower total serum protein (median 6.5 vs 7.4 g/dL) in comparison with the NAVH and had a more prolonged prothrombin time (median 4.3 vs 1.05 seconds). Most of the children in the AAVH group (15/18, 83%) had hypoalbuminemia (<3.5 g%). There were no significant differences in the levels of serum transaminases, alkaline phosphatase, and total bilirubin at admission to our hospital (Table 2). None of the cases with AAVH had renal dysfunction or hyponatremia.

TABLE 1
TABLE 1:
Comparison of clinical parameters between NAVH and AAVH
TABLE 2
TABLE 2:
Comparison of laboratory parameters between NAVH and AAVH

Of the 121 patients with NAVH, 52% were because of HAV alone, 9% had isolated acute HBV infection, 4% had HEV alone, whereas 35% had dual infections (29% with HAV plus HEV, and 3% each had HBV along with either HAV or HEV, respectively). This etiological profile of the NAVH was not significantly different from that of AAVH in whom 67% (12/18) were because of HAV alone, 11% (2/18) HEV alone, whereas 22% (4/18) had dual infections of HAV with HEV. None of the patients with AAVH had acute HBV infection (Fig. 1).

FIGURE 1
FIGURE 1:
Relative frequencies of hepatitis A, E, and B in nonascitic acute viral hepatitis (NAVH) and ascitic acute viral hepatitis (AAVH) expressed as percentage of cases.

In the AAVH group, 6 patients (33%) also had pedal edema and 8 patients (44%) had pleural effusion (4 bilateral, 3 right sided, and 1 left sided). None of these patients had urinary protein losses. Diagnostic ascitic tap done on patients with clinically detectable ascites in the AAVH group (n = 8) showed a high serum ascites albumin gradient (median 1.7, range 1.0–3.4). Of these cases 1 patient had a borderline low value of 1. Two of these 8 patients (11%) had spontaneous bacterial peritonitis and recovered with appropriate antibiotic therapy. Patients with AAVH and clinically detectable ascites (n = 8) showed a good response to a short course of diuretics and restriction of salt and fluids.

Children with AAVH were followed up for a median duration of 60 months (range 7–160 months) from the time of presentation to our hospital. Ascites resolved in all of the cases by 8 weeks (94.4% cases in <4 weeks) and liver functions normalized in 17%, 50%, and 33% cases in <4, 4 to 8, and >8 weeks duration, respectively. Patients with AAVH at presentation had jaundice and in the subsequent course ascites resolved in all of the cases before they became jaundice free. Apart from ascites in AAVH, we did not find significant differences in recovery of the 2 groups. None of the cases of both groups on the last follow-up had any clinical or biochemical evidence of liver disease.

DISCUSSION

Serum proteins, especially albumin and prothrombin time, are known laboratory parameters of biosynthetic liver functions. Significant derangement of serum albumin and prothrombin time in our AAVH group are indicative of more severe hepatic injury as compared with NAVH. Serum albumin plays a critical role in modulating the distribution of fluid between the body compartments (14,17). A majority (15/18) of our patients with AAVH had hypoalbuminemia, and thus children with AVH who develop increasing hypoalbuminemia become more prone to develop ascites. However, ascites in the AAVH group as shown by us is transitory. In these patients liver functions start returning to normal with recovery. Synthesis of both serum albumin and protein start normalizing in parallel with recovery of liver functions. All of our cases of AAVH on follow-up had normalization of liver functions and complete resolution of ascites. None of our patients with AAVH had urinary protein losses; thus the low albumin was attributed to liver injury.

Sinusoidal collapse because of liver cell dropout is a major factor in the pathogenesis of portal hypertension in severe acute hepatitis or liver failure (10,18). Increase in hepatic venous pressure gradient is related to the severity of acute hepatitis, and it is higher in patients with ascites than in patients without ascites (18). Valla et al (18) in their study showed that no ascites was clinically detectable in patients with acute hepatitis in whom the hepatic venous pressure gradient was below 6 mmHg. In our AAVH group a low serum albumin resulted in a decrease in oncotic pressure, thereby promoting ascites formation. A simultaneous prolongation of prothrombin time reflected severe liver injury among patients with AAVH. In our patients with AAVH we found a high serum ascites albumin gradient that correlated with the presence of portal hypertension, having an accuracy of approximately 97% (19,20), which points to development of transient portal hypertension in some patients with AVH with full recovery on follow-up. HSDS is a valid parameter of assessing chronic nutritional status. We did not find any significant differences in HSDS between NAVH versus AAVH groups (Table 1), suggesting no role of nutritional compromise in AAVH to explain predisposition to ascites formation. We also observed pleural effusion and pedal edema in 44% and 33% cases of AAVH, respectively, that could be explained on the basis of systemic manifestations of hypoalbuminemia. Pleural effusion and pedal edema both normalized on recovery of liver injury.

There was a predominance of male patients (69%) with AVH in our series. Hepatitis A and E are known to be transmitted by the fecal–oral route. Boys in comparison with girls in our country have more freedom for outings and thus exposure to outside consumption of contaminated drinks or foods. There is another factor of relative gender bias in our society that causes families to seek the best medical attention for boys. We found dual infection in 33% of cases of AVH, and no significant differences were observed in viral etiology between NAVH and AAVH. Multiple viruses are known to be the cause in 24.6% of cases of acute sporadic viral hepatitis, most commonly because of HAV and HEV together (12) due to their similar mode of transmission. We have also shown previously that the mortality rates are similar in single versus multiple viral infections in acute sporadic viral hepatitis. (12).

In our study patients with AAVH were younger (Table 1). We did not find any significant differences in transaminases, serum bilirubin, and viral agents between NAVH and AAVH. The structural and functional development of liver beginning from fetal to adolescent phases in the pediatric population are known and sensitivity to toxins, drugs, and common infectious agents contributes to the varied responses (21). We diagnosed spontaneous bacterial peritonitis in 11% of cases of AAVH and all of them responded to antibacterial therapy. Spontaneous bacterial peritonitis is a known complication of liver-related ascites that has a prevalence of 10% to 30% (22,23).

The present definition of acute liver failure (ALF) in children also includes coagulopathy uncorrected by vitamin K administration with an international normalized ratio (INR) >1.5 with encephalopathy or INR >2.0 without encephalopathy (24). Based on revised criteria of ALF we found 3.3% (4/121) cases of NAVH and 27.7% (5/18) cases of AAVH to fulfill this definition (INR >2 without encephalopathy) at presentation to our hospital. Thus, 13 of 18 of AAVH and 117 of 121 of NAVH cases were outside the revised definition of ALF. Overall, 130 patients with AVH were outside the definition of revised ALF (90% patients with NAVH and 10% with AAVH). Risk of ALF in patients with AVH is low. The risk is 0.1% in hepatitis A, 0.1% to 1.0% in hepatitis B, and 1% to 2% in hepatitis E as per the unrevised definition of ALF (25).

Acute sporadic viral hepatitis usually requires supportive management; however, the same does not hold true for AAVH. Recognition of the subset of AAVH is important because it entails specific management to treat ascites along with the complication of spontaneous bacterial peritonitis, vigilant monitoring of prothrombin time, and follow-up to ensure complete resolution of liver function and disappearance of ascites. Identification of AAVH has also the clinical implication of not unnecessarily investigating this group for etiology of chronic liver disease.

To summarize, we have contributed to a better knowledge of AVH presenting with ascites. This subgroup of AVH, mostly affecting younger children, has compromised biosynthetic liver functions irrespective of viral etiology and the recovery is complete. Identification of such a subset of AVH will be of importance particularly in countries with a high prevalence of the disease.

REFERENCES

1. Aggarwal R. Hepatitis E and pregnancy. Indian J Gastroenterol 2007; 26:3–5.
2. Arora NK, Nanda SK, Gulati S, et al. Acute viral hepatitis types E, A, and B singly and in combination in acute liver failure in children in North India. J Med Virol 1996; 48:215–221.
3. Poddar U, Thapa BR, Prasad A, et al. Changing spectrum of sporadic acute viral hepatitis in Indian children. J Trop Pediatr 2002; 48:210–213.
4. Regev A, Schiff ER. Clinical features of hepatitis. In: Thomas HC, Lemon S, Zuckerman J, eds. Viral Hepatitis. 3rd ed. Malden, MA: Blackwell Publishing; 2005:32–49.
5. Malathi S, Mohanavalli B, Menon T, et al. Clinical and viral marker pattern of acute sporadic hepatitis in children in Madras, South India. J Trop Pediatr 1998; 44:275–278.
6. Kumar S, Ratho RK, Chawla YK, et al. The incidence of sporadic viral hepatitis in North India: a preliminary study. Hepatobiliary Pancreat Dis Int 2007; 6:596–599.
7. Mohapatra MK, Samal MM, Padhiary KN, et al. Clinicopathological profile of subacute hepatic failure. J Assoc Phys India 1996; 44:375–377.
8. Jaiswal SB, Chitnis DS, Asolkar MV, et al. Etiology and prognostic factors in hepatic failure in central India. Trop Gastroenterol 1996; 17:217–220.
9. Tandon BN, Joshi YK, Krishnamurthy L, et al. Subacute hepatic failure: is it a distinct entity? J Clin Gastroenterol 1982; 4:362–364.
10. Dhiman RK, Makharia GK, Jain S, et al. Ascites and spontaneous bacterial peritonitis in fulminant hepatic failure. Am J Gastroenterol 2000; 95:233–238.
11. Poddar U, Thapa BR, Prasad A, et al. Natural history and risk factors in fulminant hepatic failure. Arch Dis Child 2002; 87:54–56.
12. Kumar A, Yachha SK, Poddar U, et al. Does co-infection with multiple viruses adversely influence the course and outcome of sporadic acute viral hepatitis in children? J Gastroenterol Hepatol 2006; 21:1533–1537.
13. Kar P. Viral hepatitis—is it still a challenge in the Indian subcontinent? Indian J Med Res 2007; 125:608–611.
14. Evan TW. Albumin as a drug—biological effects of albumin unrelated to oncotic pressure. Aliment Pharmacol Ther 2002; 16:6–11.
15. O'Grady JG, Schalm SW, William R. Acute liver failure: redefining the syndromes. Lancet 1993; 342:273–275.
16. Tandon BN, Bernauau J, O'Grady J, et al. Recommendations of the International Association for the Study of the Liver Subcommittee on nomenclature of acute and subacute liver failure. J Gastroenterol Hepatol 1999; 14:403–404.
17. Kuiper JJ, Deman RA, Van Buuren HR. Management of ascites and associated complications in patients with cirrhosis. Aliment Pharmacol and Ther 2007; 26:183–193.
18. Valla D, Flejou JF, Lebrec D, et al. Portal hypertension and ascites in acute hepatitis: clinical, hemodynamic and histological correlations. Hepatology 1989; 10:482–487.
19. Yachha SK, Khanna V. Ascites in childhood liver disease. Indian J Pediatr 2006; 73:819–824.
20. Runyon BA, Montano AA, Akriviadis EA, et al. The serum-ascites albumin gradient is superior to the exudates-transudate concept in the differential diagnosis of ascites. Ann Intern Med 1992; 117:215–220.
21. Pineiro-Carrero VM, Pineiro EO. Liver. Pediatrics 2004; 113:1097–1106.
22. Rimola A, Garcia-Tsao G, Navasa M, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. J Hepatol 2000; 32:142–153.
23. Larcher VF, Manolaki N, Vegnent A, et al. Spontaneous bacterial peritonitis with chronic liver disease: clinical features and etiologic factors. J Pediatr 1985; 106:907–912.
24. Bucuvalas J, Yazigi N, Squires RH. Acute liver failure in children. Clin Liver Dis 2006; 10:149–168.
25. Dienstag JL. Acute viral hepatitis. In: Thomas HC, Lemon S, Zuckerman J, editors. Harrison's Principles of Internal Medicine. 17th ed. New York: McGraw Hill Medical; 2008. pp. 1932–1949.
Keywords:

acute; ascites; hepatitis; liver; viral

© 2010 Lippincott Williams & Wilkins, Inc.