Hartman, Corina*; Berkowitz, Drora*; Brik, Riva†; Arad, Ayala‡; Elhasid, Ronit§; Shamir, Raanan*
Giant cell hepatitis (GCH) is a common histopathologic finding in infants with neonatal cholestasis and is regarded as a reaction of the neonatal liver to various insults. In contrast, GCH in association with autoimmune hemolytic anemia (AHA) is a rare disease of early childhood with unknown pathogenesis and poor prognosis. Although an initial response to immunosuppressive therapy has been reported, most patients progress to liver failure and die (1–8). Orthotopic liver transplantation in these patients results in disease recurrence in the transplanted liver within weeks after transplantation (4).
An autoimmune etiology has been suggested for GCH with AHA because of the association with Coombs-positive hemolytic anemia and the response to immunosuppressive therapy. However, in contrast to classic autoimmune hepatitis, liver biopsies show diffuse giant cell transformation and do not meet the histologic criteria accepted for the diagnosis of autoimmune hepatitis (1–5,8).
We report a patient with GCH with AHA with associated multiple autoimmune phenomena who responded briefly to steroids, azathioprine and FK 506 (Tacrolimus), but ultimately died 14 months after disease onset with hepatic failure and encephalopathy. Evidence of hemophagocytosis was present on postmortem examination within bone marrow, spleen, and lymph nodes.
Our patient was the third child of healthy, unrelated Jewish parents of Ashkenazi and Sephardim descent. The mother is a Gaucher carrier and the maternal uncle has mild Gaucher disease. The patient's two sisters, 8 and 10 years old, are healthy. The patient was born after an uncomplicated pregnancy and labor by spontaneous delivery with a birth weight of 3,400 g. He had a normal perinatal course, and developed well until 6 months of age, when pallor was noted by his mother. The initial physical examination disclosed a pale but alert and active child with no cardiorespiratory distress. His weight and length were in the 10th percentile. The liver was not enlarged and the spleen was palpable 3 cm below the left costal margin. The rest of his physical examination was normal. A blood count showed a hemoglobin level of 6.1 g/dL with a reticulocyte count of 16%. Evaluation of anemia showed a strongly positive direct Coombs test with warm antibodies (immunoglobulin G and complement). White blood cell and platelet counts were within normal limits, as were liver enzymes and prothrombin time. AHA was diagnosed, and the patient was treated with intravenous immunoglobulin infusion, packed red blood cell transfusion, and high-dose steroids. His general status was good and he was discharged 2 days later on steroids, with a hemoglobin level of 10.1 g/dL.
Because his hemoglobin values were stable for 2 months, steroid dosage tapering was attempted. Within days his mother noted reoccurrence of pallor. On physical examination, tender hepatosplenomegaly (liver span, 8 cm) and jaundice were found. Laboratory studies revealed alanine aminotransferase, 2,456 IU/L; aspartate aminotransferase, 1,947 IU/L; total bilirubin, 3.4 mg/dL (direct fraction, 2 mg/dL); alkaline phosphatase, 312 IU/L; hemoglobin, 11 g/dL; reticulocyte count, 13%; and erythrocyte sedimentation rate, 30 mm/hour. Levels of ammonia, lactate, blood gases, blood urea nitrogen, creatinine, albumin, and glucose were normal. Platelet count, white blood cell count, prothrombin time, and partial thromboplastin time were also normal. Evaluation of liver disease included negative serology for hepatitis viruses A, B, and C (and negative hepatitis C virus ribonucleic acid); Epstein–Barr virus, cytomegalovirus, human immunodeficiency virus, adenovirus, influenza, parainfluenza, measles, mumps, rubella, Coxsackie, herpes virus, mycoplasma, and several echovirus types. Immunoglobulin levels and lymphocyte subtypes were normal. Plasma amino acids and urinary organic acids were normal, and the patient had normal glucocerebrosidase activity. Antinuclear antibodies were positive (titer, 1:64), with positive anti-ribonuclear protein, anti-SS-A, and anti-SS-B autoantibodies. Antimitochondrial, antismooth muscle, and antiliver–kidney microsomal antibodies were negative. The mother of the patient was tested for the same autoantibodies, with negative results. Liver needle biopsy disclosed preserved hepatic lobular architecture and no cholestasis. Giant cell and pseudoglandular transformation was present. The portal spaces were enlarged by inflammatory infiltrate composed mainly of mononuclear cells and less polymorphonuclear cells and eosinophils. The inflammatory infiltrate occasionally penetrated the hepatic parenchyma, which showed clusters of mononuclear cells and few acidophilic bodies (Fig. 1). Electron microscopy showed nonspecific changes. No viruslike particles were detected.
GCH with AHA was diagnosed and the steroid dosage was increased to 2 mg/kg per day, with slow biochemical response. One month later, persistence of elevated liver aminotransferases (alanine aminotransferase, 551 IU/L) led to the introduction of azathioprine 1.5 mg/kg per day with no improvement of liver aminotransferases. Within 2 months alanine aminotransferase levels increased again to 2,277 IU/L, and at the age of 11 months Tacrolimus was added, starting with 0.1mg/kg per day and increasing further to 0.2 mg/kg per day while maintaining a blood level of 7 to 10 ng/mL. After the initiation of Tacrolimus, liver aminotransferase levels declined gradually to 230 IU/L. Because of the development of severe steroid-related side effects (Cushingoid changes, hypertension, osteoporosis with teeth shedding, and arrest of growth) 7 months after the disease onset, an attempt to reduce the prednisone dose resulted in a surge of liver aminotransferases up to 5,000 IU/L, which declined gradually after the return to full-dose steroids.
During the months of combined therapy with prednisone 2 mg/kg per day, azathioprine 1.5 mg/kg per day, and FK 506 0.2 mg/kg per day, there was a relative stabilization of liver aminotransferases at 500 to 600 IU/L and hemoglobin values at 11 to 12 g/dL.
At the age of 16 months, after an episode of acute gastroenteritis, a fall in hemoglobin level to 6.1 g/dL occurred. The anemia was treated with two courses of intravenous immunoglobulin and red packed cell transfusions with only a transient rise in hemoglobin level. In an attempt to stop the hemolysis, plasmapheresis was performed, twice with resulting stabilization of the hemoglobin value and improvement of liver enzymes. Two months thereafter, another hemolytic episode occurred in association with a febrile disease for which no etiologic agent was identified, and repeated blood transfusions were required during the next months to maintain the hemoglobin level around 9 to 10 g/dL.
In his last month of life there was unabated hemolysis. Plasmapheresis, which was again performed with the hope of arresting the hemolytic process, was ineffective. Fever and leukocyte counts as high as 49,000 leukocytes/mm3 were recorded several times, and empiric antibiotic treatment was administered despite sterile blood, urine, pleural fluid, and bronchial lavage cultures. Pleural effusion and a pulmonary infiltrate associated with mild respiratory distress developed within the last month. In addition to sterile blood and urine cultures, stool cultures were negative for bacteria, viruses, ova, and parasites. Serology and polymerase chain reaction for Epstein–Barr virus and cytomegalovirus were negative as well.
During this period, there was a steady deterioration of the liver function tests despite the immunosuppressive therapy, plasmapheresis, and supportive therapy. An additional 2 -week trial of mycophenolate mofetil 40 mg/kg per day, which replaced azathioprine, made no difference. While liver aminotransferases remained only mildly abnormal (alanine aminotransferase, 247 IU/L), the bilirubin level rose to 65.9 mg/dL (direct bilirubin, 52.1 mg/dL), the albumin level fell to 2.6 g/dL, and the coagulation studies deteriorated progressively. At that time, mild thrombocytopenia occurred (platelets at 100,000/mm3), and hemoglobin levels never rose above 9 g/dL despite almost daily blood transfusions. The child died 14 months after disease onset at the age of 20 months of liver failure and encephalopathy.
Postmortem liver examination showed complete distortion of the lobular architecture. Fibrosis extended from the portal tracts into the lobule, with bridges linking portal tracts to each other and to the central vein. Most of the liver cells were giant and multinucleated. Normal hepatocytes were very rare. Portal inflammatory infiltrate was minimal, consisting of mononuclear and polymorphonuclear cells (Fig. 2). Cholestasis was marked both in the giant cells and the bile ductlike structures (Fig. 3). Lung examination showed bronchopneumonia. The spleen was enlarged with extramedullary hematopoiesis. Hemophagocytosis was seen in the spleen, mediastinal lymph nodes, and bone marrow (Fig. 4). Massive lymphoid depletion was present in the lymph nodes in the mesenterium.
Hepatic giant cell transformation is distinctly uncommon after the neonatal period. In older children and adults, GCH has been described in association with autoimmune disorders (9,10), drug reactions (10), and viral infections such as human immunodeficiency virus (11), hepatitis B virus (12), and paramyxovirus (13). In view of the multiple etiologies associated with postinfantile GCH, it is felt that this is a descriptive diagnosis of a unique pattern of reaction to several different insults.
The association of GCH with Coombs-positive hemolytic anemia seems to be a distinct entity (1–8). The cases reported in the literature are quite uniform in their clinical presentation, clinical course, biochemical and histologic findings, response to therapy, and poor prognosis.
All patients had disease onset between 6 months and 2 years of age, with manifestations of acute hemolysis (fever, pallor, and hepatosplenomegaly) and Coombs-positive hemolytic anemia at presentation. Hepatitis occurred within 1 week to 15 months (usually 1–2 months) after the diagnosis of AHA (1–7). In addition, recurrent bacterial infections, uncontrollable seizures, and encephalopathy not related to liver failure were reported in half the patients (1–4). The hepatitis is thought to be autoimmune mediated because of the associated AHA, hypergammaglobulinemia, and response to immunosuppressive therapy. However, only in one patient were other autoimmune markers present (5). In our patient, multiple autoimmune phenomena were present (antinuclear antibodies, anti-RNP, anti-SS-A, and anti-SS-B autoantibodies). The reported liver histology was strikingly similar in all patients and was characterized by a distorted lobular architecture because of diffuse giant cell transformation and a variable degree of parenchymal collapse. Periportal and pericellular fibrosis was present in variable amounts, whereas portal inflammatory cell infiltrate remained mild (1–5,8).
The clinical course of GCH with AHA is aggressive. In most patients there is an initial response to immunosuppressive therapy, but relapses occur commonly, and immunosuppression with steroids and azathioprine is needed for maintaining remission. Other immunosuppressants tried for the treatment of liver disease (cyclosporine A, penicillamine, Tacrolimus, and mycophenolate mofetil) are usually of no sustained benefit (4,8).
Usually, the hemolytic anemia is controlled readily after the initial episode. In a few children with persistent hemolysis, plasmapheresis and splenectomy have been reported to be beneficial (6,7).
Regarding prognosis, it seems that there were two subsets of patients in the literature. Approximately half of the reported patients had a mild disease, controlled readily by immunosuppressive therapy (prednisone and azathioprine) that could be withdrawn in isolated patients (5,7). Others had a severe, rapid fatal course, which is unresponsive to immunosuppression (1–4,8). Liver failure, severe seizure disorder, unexplained encephalopathy, and severe infections are usually the causes of death.
The outcome of the four reported children who underwent orthotopic liver transplantation for GCH with AHA was also poor. Three of the four died and all had recurrence of GCH in the transplanted liver within 4 weeks after transplantation (4).
The pathogenesis of GCH with AHA is not well understood. The origin and mechanisms of formation of giant cells have not been clearly established. Fusion of rosette-forming hepatocytes, or nuclear proliferation not followed by cell division, are possible mechanisms in their formation (14). A persistent host immune dysfunction, with cytokine elaboration by stimulated T lymphocytes and Kupffer cells is thought to be involved in the process of giant cell transformation (15). Whatever the cell of origin or the responsible mechanism, the giant cell is active and functional, and may potentially contribute to the progression of liver disease by releasing factors involved in inflammation and fibrosis (15).
Few investigators reported the extrahepatic postmortem findings in children with GCH with AHA, and none mentioned hemophagocytosis (2,3). We are the first to report the presence of hemophagocytosis within spleen, lymph nodes, and bone marrow in a child with GCH with AHA.
The hemophagocytic syndrome is considered to be a clinicopathologic reflection of poorly controlled activation of the cellular immune system (16). It is characterized clinically by fever, hepatosplenomegaly, peripheral blood cytopenia, hypertriglyceridemia, hypofibrinogenemia, and a high mortality rate (17). The pathology is dominated by infiltration of bone marrow, spleen, lymph nodes, meninges, liver, and to a lesser extent, other tissues, by ordinary but activated histiocytes, lymphocytes, and transformed lymphocytes. Hemophagocytosis, the hallmark of the syndrome, is widespread in these organs (18). Infection-associated hemophagocytic syndrome has been reported in association with a variety of infections including viral, bacterial, fungal, and parasitic infections (19,20). This hemophagocytic syndrome usually occurs in a setting of immunodeficiency that can be congenital or acquired.
In the last stages of his disease our patient manifested symptoms and laboratory abnormalities, which in retrospect could at least partially be ascribed to hemophagocytosis: fever, severe anemia with increase requirement for blood transfusion, thrombocytopenia, and hypertriglyceridemia. Because the diagnosis of hemophagocytosis was made postmortem, the microbiologic investigations did not cover all the viral agents known to be associated with hemophagocytic syndrome.
The central nervous system involvement by hemophagocytosis could be an additional explanation, besides the liver failure, for our patient's encephalopathy. Dramatic changes have been reported in the brain of children dying from hemophagocytosis: meningeal lymphohistiocytic infiltration, demyelination, gliosis, and focal leukomalacia (21,22). We have no data from our patient because the family denied central nervous system examination.
Considering GCH with AHA a disease of generalized immune dysregulation, the presence of hemophagocytosis may be part of the disease clinical spectrum, being another manifestation reflecting an inappropriate host immune response. Conversely, hemophagocytosis may be a secondary phenomenon in a severely immunocompromised patient, or it may be a reactive process to an unidentified infectious agent. Whatever the pathogenesis of hemophagocytosis, this is by itself a dramatic illness, frequently with fatal outcome, and death is usually caused by septicemia, coagulopathy, and multiorgan failure.
In summary, GCH with AHA is a rare entity limited to young children, probably representing a generalized immune dysregulation disorder. In approximately half of these children, the clinical course is complicated and the outcome is poor. In these children no consistent response was seen with various forms of treatment used. In some children successful results have been reported with early steroid and azathioprine treatment. Hemophagocytosis may be part of the disease clinical spectrum, a late complication of disease itself, or a complication of the massive immunosuppressive therapy. The treatment of these patients is many times unsuccessful in controlling the disease, which is frequently fatal.
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