Hepatitis A virus infection is usually a self-limited disease during childhood. Autoimmune manifestations are rarely reported among patients. We describe two children with acute hepatitis A infection who developed immune thrombocytopenia and hepatic venous thrombosis during the course of acute infection. Antiphospholipid antibodies were increased in both of them during the thrombocytopenic and thrombotic complications and decreased during the resolution of these events.
Hepatitis A virus (HAV) infection is usually a self-limited disease, and full recovery is the rule in 85% of cases. 1 Although many viral infections such as hepatitis B, parvovirus and Epstein-Barr virus are associated with extrahepatic autoimmune phenomena, such manifestations are rare during the course of acute HAV infection. 2–4 Autoimmune manifestations such as idiopathic thrombocytopenic purpura (ITP), aplastic anemia and hemophagocytic syndrome have been rarely reported during the course of acute HAV infection, although transient hematologic complications may be seen during the course of acute HAV infection. 2–5
Hepatic venous outflow block, Budd-Chiari syndrome (BCS), results in ascites, hepatomegaly and abdominal pain. BCS is frequently associated with an underlying etiology in adults. On the other hand it is difficult to find a definitive cause in children. 6 In recent years studies of adults have shown an association between Budd-Chiari syndrome and antiphospholipid antibody syndrome (APS), a condition characterized by recurrent arterial or venous thrombosis and the presence of antiphospholipid (aPL) antibodies. 7–9 Several risk factors have also been suggested for the development of aPL antibodies such as exogenous estrogen use, infections (HIV, parvovirus B19, HAV) and some drugs (procainamide, phenytoin, valproic acid). 10, 11
Although Budd-Chiari syndrome and antiphospholipid syndrome are rare among infants and young children, we describe two cases with acute HAV infection, developing ITP and hepatic vein thrombosis during the course of illness. We propose that the cause of thrombocytopenia and thrombosis in these cases was the high titer of serum aPL antibodies induced during the course of acute HAV infection.
A 24-month-old girl developed hepatic vein thrombosis during acute HAV infection. The patient experienced signs and symptoms of hepatitis infection 4 weeks before admission to the hospital. The diagnosis of HAV infection was based on a positive assay for anti-HAV IgM, and she was treated conservatively. Four weeks after the initial illness she developed the second attack of jaundice. On her admission to the hospital physical examination revealed an ill appearing child with jaundice. She had prominent abdominal distension without tenderness. Her liver and spleen were both enlarged. Physical examination of the other systems was normal. Laboratory investigation revealed elevated liver function tests [aspartate aminotransferase 993 units/l, alanine aminotransferase 714 units/l, alkaline phosphatase 609 units/l] with normal serum protein and albumin values. Total serum bilirubin concentration was 13.9 g/dl with a direct fraction of 7.69 g/dl. Prothrombin time and partial thromboplastin time were prolonged. The serologic investigation for viral agents (hepatitis B virus, hepatitis C virus, Epstein-Barr virus, cytomegalovirus, rubella) were negative except for the presence of anti-HAV IgM.
An ultrasonographic (US) examination of the liver showed an enlarged liver with an increased echogenicity of the liver parenchyma and a narrowing of the right hepatic vein. A Doppler US was performed to visualize the hepatic blood flow. The right hepatic vein was totally and the middle hepatic vein was partially obstructed by thrombi (Fig. 1). Blood circulation within the left hepatic vein and portal system was normal. Magnetic resonance angiography of the hepatic vasculature confirmed the Doppler US findings, and BCS was diagnosed.
Investigation of factors predisposing to the thrombus formation revealed a serum antithrombin III level of 329 mg/dl (N, 200 to 400 mg/dl), protein C and protein S activities of 50 and 63%, respectively (N, 70 to 140%). Antinuclear, anti-double stranded DNA, anti-smooth muscle and anti-liver-kidney microsomal antibodies were negative. Lupus anticoagulant was negative, IgG anticardiolipin antibody was 5.6 IgG phospholipid units (GPLU)/ml (N <13.3), but IgM anticardiolipin antibody (MPLU) was >60/ml (N <9.8).
She was given orally 3 mg/kg/day acetylsalicylic acid and bed rest. Twelve weeks after admission, the jaundice disappeared and the liver function tests became almost normal. Serum anti-HAV IgM disappeared, and she developed anti-HAV IgG. At the 12th week of follow-up the serum anticardiolipin (aCL) antibodies of IgM and IgG were decreased to 20 MPLU/ml and 5.3 GPLU/ml, respectively. Meanwhile the Doppler US showed that the right hepatic vein was recanalized and the partial obstruction of the middle hepatic had disappeared (Fig. 2).
A 5-year-old girl admitted to the hospital because of the presence of several bruises and purpuric lesions over the entire body. Her physical examination revealed several ecchymoses on the trunk and extremities and bruises on the frontal head region. She was not jaundiced. Her liver and spleen were enlarged. Laboratory investigations revealed elevated liver function tests (aspartate aminotransferase 1053 units/l, alanine aminotransferase 923 units/l, alkaline phosphatase 765 units/l) with normal serum protein and albumin values. Total serum bilirubin concentration was not elevated, but prothrombin time and partial thromboplastin time were prolonged. The serologic investigation for viral agents (hepatitis B virus, hepatitis C virus, Epstein-Barr virus, cytomegalovirus, rubella) were all negative except for the presence of anti-HAV IgM. There was severe thrombocytopenia (2 × 103/mm 3) but antiplatelet antibodies were negative. Antinuclear, anti-double stranded DNA, anti-smooth muscle and anti-liver-kidney microsomal antibodies were negative.
A Doppler US of the liver showed enlargement of the liver without any vascular abnormality. A bone marrow aspiration revealed normocellular marrow with trilineage hematopoiesis and increased megakaryocytes. Anticardiolipin antibodies of the IgG and IgM types were studied before the administration of intravenous immunoglobulin to the patient. The IgG aCL was 8 GPLU/ml (N<13.3), but IgM aCL was >60 MPLU/ml (N<9.8). She had been given 1gm/kg IVIG and her thrombocyte count increased to 89 × 10. 3 /mm 3 Within a week, it decreased to 18 × 10 3 /mm 3, and a second dose of intravenous immunoglobulin was administered. Thrombocyte count was 25 × 10 3, and serum anti-HAV IgM was still positive at the end of the fourth week of follow-up. She developed anti-HAV IgG at the end of the 14th week at which time the anti-HAV IgM became negative. The thrombocyte count returned to normal (257 × 103/mm 3) and the serum aCL IgM and IgG antibodies were negative by the time of HAV seroconversion.
Autoimmune manifestations are rare during the course of acute HAV infection. A few cases of immune-mediated thrombocytopenic purpura has been reported in the English language literature, mostly of adults. 2–4 Because the aPL antibodies are associated with acquired hypercoagulability and thrombocytopenia, we thought that the increased aPL antibodies developing during the course of acute HAV infection might be associated with the complications in our patients.
Antiphospholipid antibodies are a recently described class of proteins that have been linked to coagulation disorders in humans. 12 In general a rise of aPL antibodies, usually IgM and low in titer, occurs during uncomplicated viral infections. It has been suggested that these aPL antibodies are not involved in the development of thromboembolic complications. 12 Antiphospholipid antibodies of IgG type and high in titer are usually found secondary to autoimmune diseases such as systemic lupus erythematosus. It is possible that they play a role in the development of thromboembolic complications. High titers of aPL antibodies are closely correlated with severe arterial or venous thrombosis, thrombocytopenia and fetal loss. The presence of these proteins in association with vascular thromboses or thrombocytopenia constitutes criteria for the diagnosis of APS.
Several risk factors have been found for the development of aPL antibodies including exogenous estrogen use, infections (HIV, parvovirus B19) and some drugs (procainamide, quinidine, phenytoin, valproic acid, etc). 10 Colaço et al. 11 demonstrated an increase in aPL antibodies in viral infections such as those caused by parvovirus and Epstein-Barr, rubella and hepatitis A viruses. They suggested that the binding of these antibodies to platelet membranes might result in thrombocytopenia sometimes observed in these viral infections.
Yende et al. 4 described an adolescent who developed thrombocytopenia during the course of acute HAV infection. The authors suggested that a causal relationship between HAV infection and immune-mediated thrombocytopenia might be present, but they did not study aPL antibodies in their patient. In our 5-year-old patient with HAV-associated ITP, we demonstrated an increased titer of IgM type aPL antibodies.
Saca et al. 13 reported a 6-year-old girl who developed a thrombus in the inferior vena cava. They postulated that BCS was a manifestation of primary APS in their case and thought that the increased IgM aPL antibodies during acute viral infections did not play a role in development of BCS. In our younger child with hepatic vein occlusion, the only predisposing factor to thrombosis was the development IgM aPL antibodies during the course of HAV infection. To our knowledge she represents the youngest case of BCS with well-documented development of aPL antibodies. Because the aPL antibodies developed and regressed coincident with the onset of and recovery from HAV infection, we suggest that the two conditions were causally related.
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