Acute liver failure caused by concurrent autoimmune hepatitis and hepatitis B in a 16-year old girl

Abstract

A 16 year-old girl was admitted to hospital because of fatigue and somnolence, nausea, epistaxis and jaundice. Physical examination revealed jaundice, an enlarged liver and tenderness of upper right abdomen. Laboratory tests revealed an increased level of acute liver failure, bilirubin, bile acids, GGTP and a decreased prothrombin ratio, with elevated gamma-globulin and IgG levels, and the presence of anti-mitochondrial M2 antibodies and HBV infection markers. The patient was diagnosed with liver failure resulting from chronic hepatitis B with an autoimmune component. The treatment consisted of steroids, azathioprine, vitamin K, low-protein diet and lactulose enemas. After undergoing a molecular test (HBV DNA 3.23 × 10⁵ IU/mL and mutations I 204 and I 80), the treatment was modified by adding entecavir. After one month the patient was discharged in good clinical condition, with the recommendation of continued entecavir, prednisone and azathioprine. In subsequent months, no clinical deterioration or abnormal biochemical liver function test results were found, despite the discontinuation of immunosuppressive therapy after 10 mo. The patient continues entecavir therapy.

Key Words: Acute liver failure; Chronic hepatitis B; Autoimmune hepatitis; Adolescent

INTRODUCTION

In Poland, the number of persons with chronic HBV infection is estimated at 400 000, and HBV or HCV infection is the most frequent cause of chronic hepatitis in children.

The natural history of HBV infection in children is different from that of adults. It commonly takes the form of asymptomatic chronic infection, most often diagnosed incidentally or as a result of epidemiological investigation. In children, the disease usually remains asymptomatic for many years, and children acquiring the infection in the early period of life are at high risk of clinical sequelae, which may present in adulthood. The infection in an early period of life is often associated with a high HBV DNA replication rate, presence of HBe antigen in serum with normal alanine aminotransferase (ALT) levels, and minor abnormalities of liver histology[1].

Autoimmune hepatitis (AIH) is the leading cause of chronic liver disease in the regions where HLA B8 DR3 haplotype is common, and the prevalence of chronic viral hepatitis is low. Based on the presence of certain types of antibodies, AIH is divided into 2 main types: type 1 with antinuclear antibodies (ANA) and/or anti-smooth muscle antibodies (ASMA), and type 2 with anti liver-kidney microsome antibodies (anti-LKM). Acute liver failure is more frequent in patients with type 2 AIH, and particularly young women or adolescent girls[2]. In autoimmune liver diseases, in addition to the most common overlap syndromes of AIH/primary biliary cirrhosis (AIH/PBC) and AIH/primary primary sclerosing cholangitis (AIH/PSC), an AIH/viral hepatitis (AIH/VH) variant is distinguished. When establishing the diagnosis of this syndrome it is important to differentiate between AIH with positive viral infection markers, and chronic viral hepatitis with positive autoimmune markers. In the majority of the latter cases, viral components are predominant, and the disease is successfully treated with antiviral drugs. Much less often, the autoimmune components are predominant, and viral infection markers coexist (AIH/VH); such cases respond well to steroid treatment[3].

Gergiadou et al have reported occult HBV infections with concurrent autoimmune liver disease. The occult HBV infections did not promote progression of AIH. Moreover, no patient had a reactivation of HBV infection during immunosuppressive treatment[4]. To date, no HBV infection with concurrent AIH has been reported in children.

We report a case of acute liver failure in the course of chronic hepatitis B with a component of autoimmune hepatitis.

CASE REPORT

A 16 year-old girl (initials P.P.; medical record No.689/2008) was admitted to hospital because of fatigue and somnolence, which increased over a week, nausea and loose stools lasting 3 d, epistaxis and jaundice.

Her past medical history included 2 hospitalizations in infancy, and surgery for a left forearm fracture at the age of 12. One year later she received the hepatitis B vaccine without prior HBs antigen testing.

Her general condition at admission was rated as quite good. Physical examination revealed jaundiced skin and sclerae, enlarged liver and tenderness of upper right abdomen. During hospitalization the patient complained of fatigue, skin pruritus, abdominal pain and headache. She also had epistaxis, somnolence and loss of appetite.

Laboratory test results revealed elevated aminotransferases (ALT: 1115 U/L, AST: 647 U/L), as well as elevated bilirubin, with predominant conjugate bilirubin, (respectively 9.41 mg/dL and 6.43 mg/dL), bile acids (216 mol/L), GGTP (60 U/L) and decreased prothrombin ratio (56%). Serum protein electrophoresis revealed elevated gamma-globulin (3.60 g/dL) and decreased albumin (3.82 g/dL) levels, and immunoglobulin tests revealed elevated IgG (34.7g/L) levels and the presence of anti-mitochondrial M2 (AMA M2) antibodies.

Serologic tests revealed the presence of HBV infection markers: HBsAg, HBeAg, total and IgM anti-HBc, and an anti-HBs level of 326 IU/L. The HAV, HCV, EBV, CMV, and Toxoplasma infections were excluded, as well as Wilson’s disease and alpha-1 antitripsin deficiency.

The patient was diagnosed with liver failure resulting from chronic hepatitis B with autoimmune component. The treatment consisted of steroids, azathioprine, vitamin K, low-protein diet and lactulose enemas.

In the first days of hospitalization, despite the above therapy, increasing levels of liver damage markers were observed. On d 7, after receiving molecular test results confirming high HBV replication (HBV DNA 3.23 × 10⁵ IU/mL) and presence of HBV polymerase gene mutations in codons I 204 and I 80, the treatment was modified by adding 1 mg entecavir daily. From the second week of therapy, a gradual clinical improvement was observed, with concomitant decrease of aminotransferase and bilirubin levels and increase of prothrombin ratio. On d 30, the HBV viral load had decreased to 6.05 × 10³, ALT levels had decreased to 48 U/L, prothrombin ratio had increased to 90% and gamma-globulin levels had decreased to 1.91g/dL. AMA M2 antibodies; HBe antigens were still detectable in serum.

The patient was discharged in good clinical condition with the recommendation of continued entecavir, prednisone and azathioprine, and systematic follow up in the Hepatology Clinic. After another month of treatment ALT levels normalized, and, after another three months the HBV viral load became negative. Steroid and azathioprine doses were reduced, with continued antiviral treatment.

Six mo from the onset of the disease, a liver biopsy was performed. The liver histology revealed altered architecture of the liver, with trabecular thickening, loss of continuity of the basal lamina at ¼ of its circumference due to inflammatory infiltrate, expanded portal spaces, features of balloon degeneration of hepatocytes and multiple focal necrosis of lobules with periportal necrosis. Histological diagnosis of chronic hepatitis B was established, with Grade 1 inflammatory activity, and Grade 2 fibrosis according to modified Scheuer’s scale.

In subsequent months, no clinical deterioration nor abnormal biochemical liver function test results were found, despite the discontinuation, after 10 mo, of immunosuppressive therapy. The patient continues entecavir therapy. The serologic tests still reveal the presence of HBsAg and HBeAg, with undetectable HBV replication, normal serum ALT and protein levels and negative AMA M2 antibodies.

DISCUSSION

We have described a patient with liver failure in the course of chronic hepatitis B with autoimmune component. To our knowledge, it is the first report of a pediatric patient with exacerbation of hepatitis B and concurrent AIH.

By definition, the diagnosis of autoimmune hepatitis is based on typical criteria and the exclusion of other causes of liver disease, including viral infection. In children, the use of the generally accepted AIH classification is virtually impossible in view of the criteria employed, such as alcohol intake, or the presence of viral infections (EBV, CMV, HHV-6), which may initiate autoimmune processes or autoantibody production[5,6]. Using this classification we would not have been able to diagnose AIH in our patient because of the presence of HBV infection and AMA M2 antibodies. ANA and ASMA are known to be present in 20% to 40% patients with HBV infection, but there are no reports of the positive AMA, particularly AMA M2 typical for PBC, in patients with HBV infection[7]. The diagnosis of PBC in our case is excluded by the histology of the liver and the minor increase of GGTP levels.

Viral infections may induce autoimmune processes. Tabak et al described AIH in the course of prolonged viral hepatitis A Michalska et al reported the emergence of autoimmune processes within 5 to 18 years from the diagnosis of chronic hepatitis B in 5 HBe-negative patients[8,9].

In our patient, the dominant role of HBV infection as a cause of both autoimmune processes and liver failure, was confirmed not only histologically, but also clinically - by rapid improvement after the HBV-specific antiviral treatment with entacavir was started, as well as by sustained normalization of liver function tests and immunological markers, despite the discontinuation of immunosuppressive therapy. The reason for the use of this specific nucleoside analogue was the patient's clinical characteristics - features of liver failure, presence of mutations associated with resistance to lamivudine and presence of autoimmune processes. It was also justified by a high genetic barrier of entecavir. Entecavir combined with immunosuppressive agents proved effective in the treatment of liver failure in the course of HBV infection with concurrent autoimmune process.

It is difficult to speculate whether HBV infection in our patient took place before the administration of the hepatitis B vaccine, or whether the vaccine failed to protect the patient from infection. Our patient was found to be infected with a mutant HBV strain. In the literature there are few reports on the effectiveness of the hepatits B vaccine against strains other than wild-type HBV[10,11].

It would also be very interesting to learn whether infection with a virus with altered genome nucleotide sequences predisposes the emergence of autoimmune abnormalities, including autoimmune processes. In the era of the increasing problem of HBV mutations, this might be of much importance for both the clinical aspects and the epidemiology of HBV infection.