PEDIATRICS Vol. 105 No. 1 January 2000, pp. 62-65

Clinical and Histologic Features of Chronic Hepatitis C Virus Infection After Blood Transfusion in Japanese Children

Atsuo Hoshiyama, MD^*, Akihiko Kimura, MD, PhD^*, Takuji Fujisawa, MD, PhD^*, Masayoshi Kage, MD, PhD, and Hirohisa Kato, MD, PhD^*

From the ^* Department of Pediatrics and Child Health, and the  First Department of Pathology, Kurume University School of Medicine. Kurume, Japan.

	ABSTRACT

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Objective.  To characterize the clinical and histologic features of chronic hepatitis C virus (HCV) infection after blood transfusion in Japanese children.

Study Design.  We studied 231 children with a history of blood product transfusion. Patients were divided into two groups: 116 patients with a history of malignant disease (group 1), 115 patients who had undergone open heart surgery (group 2). We examined changes in serum alanine aminotransferase (ALT) activity and HCV markers, and patients' clinical course. Moreover, in 38 patients in whom the time of HCV infection could be defined, we examined liver histology.

Results.  The proportions of patients in each group who were anti-HCV-positive were 35 out of 116 (30%) and 20 out of 115 (17%), respectively. Of the anti-HCV-positive patients, the proportions of HCV RNA-positive patients in each group were 30 out of 35 (86%) and 12 out of 20 (60%), respectively. Levels of ALT activity in patients with HCV infection varied widely for several years after blood transfusion; thereafter ALT activity fell to <100 IU/L in 2 groups. Serum ALT activity in patients who were HCV RNA-negative became normal. With regard to liver histology, there were no differences in the grade of necroinflammation or stage of fibrosis in patients with different durations of infection or when patients were analyzed according to the presence or absence of malignant disease. Patients mostly had grade 2-4 inflammation and stage 1-2 fibrosis. Thus, chronic hepatitis C was a morphologically mild disease in most children in this study.

Conclusions.  Sixty percent to 80% of children with HCV infection in this study developed chronic hepatitis C. However, examination of liver histology findings in children with chronic hepatitis C showed only mild changes.  Key words:  hepatitis C virus, children, natural course, blood transfusion.

Hepatitis C virus (HCV) was discovered in 1989^1,2 and has since been identified as the major cause of transfusion-associated non-A, non-B hepatitis.³ Numerous epidemiologic studies indicate that HCV is transmitted most efficiently through parenteral routes, such as blood product transfusion, intravenous drug abuse, accidental needlesticks, and perinatal infection.^4,5 Although more is known about HCV infection in adults than in children,^6-9 the natural history of HCV infection in adults from the beginning of infection is far from clear. Furthermore, we do not know whether the course of HCV infection in children is similar to that in adults. Therefore, it is important to understand the natural history of HCV infection in children.

In this study, we retrospectively reviewed high risk children who had previously been treated for malignant diseases, such as leukemia, or surgically correctable congenital heart disease, and evaluated liver function tests, serum HCV markers, liver histology, and clinical course, to elucidate the natural history of HCV infection as the result of blood transfusion in Japanese children.

	METHODS

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Patients

Study participants were identified between January 1995 and December 1996 at our hospital during screening of 231 patients who had received blood product transfusion before 1992, when nationwide screening of anti-HCV in donated blood was started. These patients were considered to be at high risk for HCV infection because of blood transfusion for malignant disease, including leukemia (116 patients, group 1), and blood transfusion for open heart surgery (115 patients, group 2). In these patients, hepatomegaly and/or splenomegaly, abnormal liver ultrasound findings, or jaundice were not found during the chronic phase of infection. In group 2, most of the patients with acute HCV infection had hepatomegaly and jaundice. For patients in whom serum anti-HCV antibodies were detected by a second generation passive hemagglutination method, serum HCV RNA concentrations were assayed by nested polymerase chain reaction.

Patterns of Alanine Aminotranferase (ALT) Activity

We examined the pattern of ALT activity of patients in each group with anti-HCV antibodies. ALT activity was examined once between 3 and 6 months and HCV RNA levels once between 6 and 12 months.

Liver Histology

We examined the histology and grade of necrosis, inflammation, and fibrosis according to the classifications of Deswet et al¹⁰ and Scheuer.¹¹ Inflammation in the portal/periportal and lobular areas was classified into 5 different grades, and the sum of the inflammatory grades in the two areas was considered the final grade. The stage of fibrosis was classified into 4 different grades.

	RESULTS

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Table 1 shows the results of screening for serum anti-HCV antibodies and HCV RNA in patients in two groups. Genotypes and HCV RNA titers of HCV RNA-positive patients in each group are shown in Table 2.

In group 1, the level of ALT activity in HCV RNA-positive, anti-HCV-positive patients (n = 30) varied widely, between 100 and 800 IU/L, for 5 to 6 years after blood product transfusion. Thereafter, levels of ALT activity were mildly elevated, usually being <100 IU/L (Fig 1). Levels of ALT activity of HCV RNA-negative, anti-HCV-positive patients in group 1 (n = 5) returned to the normal range within 5 years, with ALT activity thereafter becoming normal (Fig 1).

View larger version (27K): [in this window] [in a new window]   Fig. 1.   Pattern of alanine aminotransferase activity in anti-HCV positive patients. Group 1, malignant disease; group 2, open heart surgery.

In group 2, ALT activity in HCV RNA-positive, anti-HCV-positive patients (n = 12) varied widely, between 100 and 1000 IU/L, for 1 to 2 years after blood transfusion. Thereafter, levels of ALT activity fell to <100 IU/L (Fig 1). ALT activity levels in HCV RNA-negative, anti-HCV-positive patients (n = 8) varied widely between 100 and 800 IU/L, for only 1 year after transfusion; thereafter, ALT activity normalized (Fig 1).

There were 42 anti-HCV-positive patients (mean age, 14.2 ± 4.9 years) positive for HCV RNA, with 30 in group 1 (history of malignant disease) and 12 in group 2 (history of open heart surgery) in whom the time of onset of infection and date of blood transfusion were clearly defined. We examined ALT activity levels starting at 6 years after infection, since anti-cancer therapy for all patients in group 1 had been completed by 6 years after HCV infection.

We divided the 38 patients in whom the time of infection was defined into two groups according to duration of infection <10 years (n = 23) or >10 years (n = 15)). Liver histologic changes in these 38 patients are shown in Table 3. Liver histologic changes, grade of necrosis and inflammation, and stage of fibrosis did not differ according to duration of infection. Moreover, we also did not find a difference in histologic changes between patients with malignant (n = 26) and nonmalignant (open heart surgery patients, n = 12) diseases in the same 38 patients (Table 4). Almost all these patients had grade 2-4 inflammation and stage 1-2 fibrosis (Tables 3, 4), suggesting that chronic hepatitis C is a morphologically mild disease in most affected children.

	DISCUSSION

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In this study, the percentages of anti-HCV-positive and HCV RNA-positive patients in group 1 (patients with malignant disease who had blood product transfusion) were higher than among patients in group 2 with open heart surgery patients. This result may be because of an increased risk of HCV infection associated with multiple transfusions, and immunosuppression because of prolonged cancer chemotherapy. ALT activity in these patients was elevated for a prolonged period. The period of elevated ALT activity coincided with the timing of cancer chemotherapy. The drug therapy administered to patients in group 1 primarily differed from that given to patients in another group. Therefore, the outcomes of patients with chronic hepatitis C in group 1 may have been affected by hepatotoxicity and fluctuations in the level of viremia chemotherapy.^12,13 Approximately 85% of anti-HCV-positive patients in group 1 showed evidence of persistent HCV infection (Table 1).

Eight HCV RNA-negative patients in group 2, may have spontaneously converted from positive to negative, anti-HCV serologic status; these patients may represent one possible outcome after HCV infection. However, the timing of seroconversion from anti-HCV-positive to anti-HCV-negative in these patients is not clear. Anti-HCV-negative patients who are also HCV RNA-negative were originally anti-HCV-positive. It is generally thought that normalization of ALT activity occurs early, within 1 year, after HCV infection (Fig 1). Levels of ALT activity in HCV RNA-positive patients in group 2 fell to <100 IU/L, after varying widely between 100 and 1000 IU/L. In this study, 60% of anti-HCV-positive patients in group 2 showed evidence of persistent HCV infection (Table 1). Therefore, HCV infection in children may follow a generally mild course.

Histologic examination of liver specimens from our hepatitis C patients showed mild changes, low-grade portal and lobular necrosis and inflammatory lesions, and low-level fibrosis (Tables 3, 4), similar to other reports.^14,15 Histologic changes in pediatric patients seem to be generally milder than those in adult patients when compared with the results of Lefkowitch et al.¹⁶ Moreover, histologic changes in chronic hepatitis C have also been reported to be milder than those because of chronic hepatitis B in children.¹⁷ It is not known why histologic changes and degree of liver fibrosis were milder in pediatric patients with chronic hepatitis in this study, but this may be because of the short period between the onset of hepatitis and liver biopsy.¹⁸

Our results suggest the following natural history for chronic hepatitis C in children. The infectious rate of HCV infection in malignant disease is high (30%), moreover, abnormal ALT activity may occur for ~5 years after HCV infection including the period of cancer chemotherapy. Approximately 15% of HCV RNA-positive patients with malignant disease become HCV RNA-negative and have inactive hepatitis. Therefore, 85% of patients with HCV infection associated with malignant disease develop chronic hepatitis C (Table 1, Fig 1). The infection rate of patients with blood transfusion at surgery, such as open heart surgery, is lower (20%) than that of patients with malignant disease such as leukemia. Abnormal ALT activity lasted <2 years after HCV infection in these patients. Of HCV RNA patients who had surgery, 40% become HCV RNA-negative and have inactive hepatitis. Thus, 60% of these patients develop chronic hepatitis C (Table 1, Fig 1).¹³ Fortunately, ~25% of pediatric patients with chronic hepatitis C may be asymptomatic carriers. Moreover, it is very rare that histologic changes progress to cirrhosis or hepatocellular carcinoma in these patients, at least until the age of 20.

	CONCLUSION

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In summary, children with chronic hepatitis C may spontaneously convert from HCV RNA positive to negative to a greater degree than do adults.^19,20 Moreover, in pediatric patients with chronic hepatitis C who are HCV RNA-positive, liver histologic changes may not progress to cirrhosis or hepatocellular carcinoma, at least during childhood and adolescence. Finally, our results show that 60% to 80% of children with HCV infection may develop chronic hepatitis C before adulthood. Therefore, pediatricians should promptly institute therapy for chronic hepatitis C, such as interferon, and in pediatric patients with chronic hepatitis C, because of the risk for hepatocellular carcinoma as adults.

	FOOTNOTES

Received for publication Mar 8, 1999; accepted Aug 20, 1999.

Address correspondence to Akihiko Kimura, MD, Department of Pediatrics and Child Health, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. E-mail: hirof{at}med.kurume-u.ac.jp

	ABBREVIATIONS

HCV, hepatitis C virus; ALT, alanine aminotransferase.

	REFERENCES

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1. Choo QL, Kuo G, Weiner AJ, Bradley DW, Houghton M Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989; 244:359-362 [Abstract/Free Full Text]
2. Kuo G, Choo QL, Alter HJ, An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science. 1989; 244:362-364 [Abstract/Free Full Text]
3. Weiner AJ, Kuo G, Bradley DW, Detection of hepatitis C viral sequences in non-A, non-B hepatitis. Lancet. 1990; 335:1-3 [CrossRef][Medline]
4. Genesca J, Esteban J, Alter H Blood-borne non-A, non-B hepatitis: hepatitis C. Semin Liver Dis. 1991; 11:147-164 [Medline]
5. Palomba E, Manzini P, Fiammengo P, Maderni P, Saracco G, Tovo P-A Natural history of perinatal hepatitis C virus infection. Clin Infect Dis. 1996; 23:47-50 [Medline]
6. Hagiwara H, Hayashi N, Mita E, Quantitation of hepatitis C virus RNA in serum of asymptomatic blood donors and patients with type C chronic liver disease. Hepatology. 1993; 17:545-550 [Medline]
7. Di Bisceglie AM, Goodman ZD, Ishak KG, Hoofnagle JH, Melpolder JJ, Alter HJ Long-term clinical and histological follow-up of chronic posttransfusion hepatitis. Hepatology. 1991; 14:969-974 [CrossRef][Medline]
8. Botarelli P, Brunetto MR, Minutello MA, T-lymphocyte response to hepatitis C virus in deferent clinical course of infection. Gastroenterology. 1993; 104:580-587 [Medline]
9. Farci P, Alter HJ, Wang D, A long-term study of hepatitis C virus replication in non-A, non-B hepatitis. N Engl J Med. 1991; 325:98-104 [Abstract]
10. Deswet VJ, Gerber M, Hoofnagl JH, Manns M, Scheuer PJ Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994; 19:1513-1520 [CrossRef][Medline]
11. Scheuer PJ Classification of chronic viral hepatitis: a need for reassessment. J Hepatol. 1991; 13:372-374 [CrossRef][Medline]
12. Bortolotti F, Vajro P, Balli F, Non-organ specific autoantibodies in children with chronic hepatitis C. J Hepatol. 1996; 25:614-620 [CrossRef][Medline]
13. Bortolotti F, Faggion S, Con P Natural history of chronic viral hepatitis in childhood. Acta Gastroenterol Belg. 1998; 61:198-201 [Medline]
14. Kage M, Fujisawa T, Shiraki K, Pathology of chronic hepatitis C in children. Hepatology. 1997; 26:771-775 [CrossRef][Medline]
15. Gudo M, Rugge M, Jara P, Chronic hepatitis C in children: the pathological and clinical spectrum. Gastroenterology. 1998; 115:1525-1529 [CrossRef][Medline]
16. Lefkowitch JH, Schiff ER, Davis GL, Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. Gastroenterology. 1993; 104:595-603 [Medline]
17. Bortolotti F, Calzia R, Cadrobbi P, Liver cirrhosis associated with chronic hepatitis B virus infection in childhood. J Pediatr. 1986; 108:224-227 [CrossRef][Medline]
18. Iorio R, Guida S, Porzio S, Fariello I, Vegente A Chronic non-A, non-B hepatitis; role of hepatitis C virus. Arch Dis Child. 1993; 68:219-222 [Abstract]
19. Yousuf M, Nakano Y, Tanaka E, Sodeyama T, Kiyosawa K Persistence of viremia in patients with type-C chronic hepatitis during long-term follow-up. Scand J Gastroenterol. 1992; 27:812-816 [Medline]
20. Fujisawa T, Komatsu H, Inui A, Spontaneous remission of chronic hepatitis C in children. Eur J Pediatr. 1997; 156:773-776 [CrossRef][Medline]