EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Giant cell hepatitis is an important diagnostic consideration in early childhood, especially for patients who present with jaundice. Different diseases may play a role in their etiology. In this study, we presented pediatric patients in our center diagnosed with giant cell hepatitis.
Materials and Methods: Liver biopsies performed in our hospital between January 2010 and December 2023 were retrospectively evaluated, and biopsies with histological giant cell formation were included in the study. Demographic, clinical, and histopathological characteristics of the patients were obtained from the medical records.
Results: Our study included 31 cases of giant cell hepatitis. Twenty-four (90.3%) of the patients were male, and the median age was 4 months (range, 1-148 mo). The most common clinical findings were jaundice (93.5%). Among the 31 patients, idiopathic giant cell hepatitis was observed in 13 cases (41.9%), and etiology was elucidated in 18 patients. The most common diagnoses in these patients were progressive familial intrahepatic cholestasis, biliary atresia, and autoimmune hepatitis (22.6%, 19.4%, and 9.7%, respectively). The most common accompanying histopathologic findings were canalicular cholestasis (87.1%), lobular cholestasis (54.8%), and pericellular fibrosis (35.5%). Liver transplant was required in 10 patients (32.3%). Nine patients (29%) died from various reasons. Although follow-up of 13 patients (41.9%) are ongoing, 9 patients (29%) are no longer being followed.
Conclusions: Few studies in the pediatric age group on giant cell hepatitis have been conducted in the literature. Similar to our series, etiology could not be specified in most of the patients in these reports. Additional research is needed to improve our understanding of the disease process, uncover any other potential causes, and create specific treatment options.

Key words : Biopsy, Idiopathic, Liver transplantation, Pediatric

Giant cell hepatitis (GCH) is characterized by the formation of hepatitis with syncytial hepatocellular giant cells containing 4 or more nuclei histologically, along with lobular inflammation and Kupffer cell hypertrophy.^1,2 Giant cell hepatitis is predominantly seen in the neonatal period, especially in infants under age 2 years of age. The presence of giant cells in a liver biopsy of cases with suspected hepatitis and/or cholestasis is diagnostic.

The pathophysiology related to giant cell formation is still not clear, but 2 separate hypotheses have been proposed to explain the mechanism of their formation. The first hypothesis suggests that nuclear hyperproliferation occurs without accompanying cytoplasmic division due to rapid cell turnover in the cells.^1,3,4 This hypothesis also explains the aggressive nature of giant cell hepatitis. Another hypothesis is hepatocyte fusion resulting from microtubular disruption caused by cytokines related to underlying diseases or viral infections.^3,5-7

Congenital infections, viral hepatitis, biliary atresia, choledochal cyst, metabolic disorders (alpha-1 antitrypsin deficiency, galactosemia, Niemann Pick disease) and disorders in bile acid synthesis play a role in the transformation of hepatocytes into giant cells.⁸ The clinical course of GCH can vary significantly. Although some patients may experience spontaneous improvement or respond well to treatment, others may develop cirrhosis or even liver failure.^9,10 The underlying cause is the most important factor determining the prognosis.⁹ In the present study, we aimed to share our experience on pediatric patients diagnosed with GCH in a single center by retrospectively evaluating their demographic, clinical, and pathological data.

Materials and Methods

In this single-center, descriptive study, liver biopsies conducted at the Pediatric Gastroenterology Clinic of Gazi University Faculty of Medicine between January 2010 and December 2023 were retrospectively evaluated. Pediatric patients diagnosed with GCH based on pathological evaluation were included in the study. Demographic, clinical, and histopathological characteristics, as well as follow-up information of patients, were obtained from hospital medical records. Ethical approval was obtained from the Gazi University Ethics Committee.

We used SPSS version 20 for all statistical analyses. We assessed distribution of variables by using the Kolmogorov-Smirnov test. We presented descriptive statistics as means ±SD for normally distributed data and as median (minimum-maximum) for nonnormally distributed data. We used the Mann-Whitney U test to compare 2 groups with nonnormally distributed continuous variables. P < .05 was considered statistically significant.

Clinical and histological features

Our study included 31 patients with giant cells detected in liver biopsy; patient age ranged from 1 to 148 months, with median age of 4 months. The male-to-female ratio was 9.3:1 (90.3% male patients). Leading symptoms and signs were jaundice (93.5%). In 13 patients (41.9%), underlying etiological factor could not be identified, and the patients were diagnosed with idiopathic GCH. Among the patients diagnosed with idiopathic GCH, 3 patients (23%) had autoimmune hemolytic anemia (AHA), and all these patients underwent transplant during follow-up. In patients in whom an underlying etiological factor could be determined, biliary atresia was the most common (22.6%). Demographic data, symptoms, findings, and etiologies of patients are shown in Table 1, and information related to patients with idiopathic GCH are shown in Table 2.

When pathological findings were evaluated, giant cells were detected in all patients. Canalicular cholestasis, lobular cholestasis, and periseptal fibrosis were the most common accompanying features with giant cells (87.1%, 54.8%, and 35.5%, respectively). Extramedullary hematopoiesis was observed in 14 patients (45.2%). The histopathological findings accompanying giant cells in patients are shown in Table 3.

Liver transplant was performed in 10 patients (32.3%) during follow-up. We did not find any difference between the age of patients who underwent liver transplant (8.9 ±11.1 mo) and those who did not (11.5 ±31.5 mo). Patients who underwent liver transplant and their diagnoses are shown in Table 4.

Of 31 patients included in our study, 13 patients (41.8%) are still under follow-up, 9 patients (29.1%) were lost to follow-up, and 9 patients (29.1%) died. Survival status according to etiology is shown in Table 5.

Giant cell hepatitis is a type of hepatitis characterized by hepatocytes with large and ≥4 to 5 nuclei, accompanied by Kupffer cell hypertrophy, necrosis, and fibrosis.^11,12 Giant cell hepatitis is usually observed in the first year of life, mainly in childhood. The transformation of hepatocytes into giant cells is thought to occur as a result of exposure to harmful agents such as viruses or impairment/dysfunction of the regenerative response.^7,12,13 The diagnosis is made based on the presence of giant cells in the liver biopsy.¹¹ The clinical course can vary from improvement of hepatic histology to cirrhosis depending on the underlying cause.^9,10 This retrospective single-center descriptive study is important in terms of the clinical and histopathological information it provides about GCH.

Pathological findings in GCH can be quite variable. Giant cell hepatocytes have been shown to be most frequently accompanied by lobular cholestasis, ductopenia, and portal-pericellular fibrosis (84%, 32%, and 30%, respectively).¹¹ In our research, we found that giant cell hepatocytes were commonly associated with canalicular and lobular cholestasis. Most of our patients also showed signs of fibrosis. Furthermore, extramedullary hematopoiesis was found in 45.2% of the cases. These concomitant features seen alongside giant cell hepatocytes, particularly the presence of extramedullary hematopoiesis, may indicate a high rate of cell turnover, contributing to the nature of GCH. In contrast to expectations, this rapid cycle of destruction and regeneration may be present not only in hepatocytes but also in other cells of the liver.

The most important factor determining the prognosis in GCH is the underlying triggering disease.^9,14 A previous study showed that 49% of newborns diagnosed with GCH were diagnosed as idiopathic, 25% as hypopituitarism, 8% as biliary atresia, and 6% as Alagille syndrome. Other cases were reported to be associated with viral infections and metabolic disorders.¹¹ Biliary atresia was the most common among the identifiable causes; nevertheless, similar to our study, most cases were diagnosed with idiopathic neonatal hepatitis. Because our patient group did not include only newborns, progressive familial intrahepatic cholestasis may be found to be the most common identifiable cause. None of our patients was diagnosed with pan-hypopituitarism. In addition, similar to our study, the condition has been more commonly observed in males.

Idiopathic GCH is one of the causes of neonatal intrahepatic cholestasis.¹⁵ Diagnosis of idiopathic GCH is made when giant cells are seen on liver biopsy, but the etiological factor cannot be determined through physical examination, laboratory tests, imaging, and histopathological findings. In our study, there were 13 patients diagnosed with idiopathic GCH, and 10 of these patients (76.9%) were managed with supportive care. However, the other 3 patients had coexisting AHA with idiopathic GCH. Bernard and colleagues published a first report on 4 children diagnosed with chronic AHA accompanied by giant cells and severe hepatitis.¹⁶ Infantile idiopathic GCH with AHA is a clinical condition commonly seen in children under the age of 2 years,¹⁷ which has a high mortality rate.¹⁸ Immunosuppressive treatment is typically the initial approach because of the hematological involvement associated with idiopathic GCH.¹⁹ The preferred initial immunosuppressive treatment consists of a combination of steroids and azathioprine. In cases where steroids are not effective, other immunosuppressive options such as 6-mercaptopurine, cyclosporine, tacrolimus, mycophenolate, and vincristine may be considered.¹⁸ Despite treatment, patients with GCH and AHA may have severe clinical progression and may require liver transplant during follow-up. However, the success rate of transplant in these cases appears to be low based on existing literature.²⁰ In our study, all patients diagnosed with idiopathic GCH received initial treatment with steroids along with supportive care. One patient required a switch to mycophenolate from azathioprine because of adverse effects. Despite these treatments, all 3 patients had severe acute liver injury initially and did not respond to immunosuppressive therapy. As a result, all 3 patients underwent liver transplant; unfortunately, the patients did not survive posttransplant. These outcomes may have been influenced by the fact that our center is a tertiary transplant facility, which may introduce a bias in patient selection.

In line with the poor prognosis expectation of GCH, approximately one-third of our patients underwent liver transplant during follow-up. Among our patients, final survival status of only 22 patients could be determined, and 9 of these patients (40.9%) died. Although the underlying cause is effective in determining the prognosis of GCH, the presence of giant cells may serve as a sign of the poor course of the disease.

Our study had several limitations. Because of our retrospective design, some patient data could not be accessed. In addition, patients referred to a tertiary level transplant center may be followed with a prognosis that is poorer than expected. This may create bias in terms of clinical follow-up. Transplant patients could also not be evaluated for the need for retransplant during follow-up.

Giant cell hepatitis is a rare clinical condition with a highly variable etiology and prognosis. Although the most important factor determining the prognosis of GCH is the underlying cause, the presence of giant cell hepatocytes can also be a determinant of poor disease course. Further studies are necessary to enhance our comprehension of the disease mechanism, identify any additional etiological factors, and develop targeted therapies.

Volume: 22 Issue: 10 October 2024 - Supplement - 5

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