Immunosuppression induces regression of fibrosis in primary biliary cholangitis with moderate-to-severe interface hepatitis.

BACKGROUND: In patients with primary biliary cholangitis (PBC) treated with ursodeoxycholic acid (UDCA), the presence of moderate-to-severe interface hepatitis is associated with a higher risk of liver transplantation and death. This highlights the need for novel treatment approaches. In this study, we aimed to investigate whether combination therapy of UDCA and immunosuppressant (IS) was more effective than UDCA monotherapy. METHODS: We conducted a multicenter study involving PBC patients with moderate-to-severe interface hepatitis who underwent paired liver biopsies. Firstly, we compared the efficacy of the combination therapy with UDCA monotherapy on improving biochemistry, histology, survival rates, and prognosis. Subsequently we investigated the predictors of a beneficial response. RESULTS: This retrospective cohort study with prospectively collected data was conducted in China from January 2009 to April 2023. Of the 198 enrolled patients, 32 underwent UDCA monotherapy, while 166 received combination therapy, consisting of UDCA combined with prednisolone, prednisolone plus mycophenolate mofetil (MMF), or prednisolone plus azathioprine (AZA). The monotherapy group was treated for a median duration of 37.6 months (IQR 27.5-58.1), and the combination therapy group had a median treatment duration of 39.3 months (IQR 34.5-48.8). The combination therapy showed a significantly greater efficacy in reducing fibrosis compared to UDCA monotherapy, with an 8.3-fold increase in the regression rate (from 6.3% to 52.4%, P < 0.001). Other parameters, including biochemistry, survival rates, and prognosis, supported its effectiveness. Baseline IgG >1.3 × ULN and ALP <2.4 × ULN were identified as predictors of regression following the combination therapy. A predictive score named FRS, combining these variables, accurately identified individuals achieving fibrosis regression with a cut-off point of ≥ -0.163. The predictive value was validated internally and externally. CONCLUSION: Combination therapy with IS improves outcomes in PBC patients with moderate-to-severe interface hepatitis compared to UDCA monotherapy. Baseline IgG and ALP are the most significant predictors of fibrosis regression. The new predictive score, FRS, incorporating baseline IgG and ALP, can effectively identify individuals who would benefit from the combination therapy.

Update on ischemic hepatitis.

PURPOSE OF REVIEW: Ischemic hepatitis (IH) refers to diffuse liver injury secondary to hypoperfusion. The condition is usually seen in the critical care setting and is associated with significant mortality. IH typically occurs in the setting of systemic hypotension superimposed on some form of underlying cardiac dysfunction. This review aims to report what is known and what is new about the etiology, pathophysiology, and clinical features associated with IH. RECENT FINDINGS: In recent years, studies on IH have largely confirmed earlier reports regarding etiologies, comorbid conditions, and associated mortality. Recent study has also shed light on the potential treatment of IH with N -acetyl-cysteine (NAC). SUMMARY: IH is typically associated with underlying cardiac disease, and patients with IH have a very high mortality rate. Treatment remains largely supportive, although the utility of agents such as NAC are being explored.

Clinical characteristics of hepatitis-associated aplastic anemia in children.

To understand the current situation of hepatitis-related aplastic anemia (HAAA) in children, we analyzed the patients with HAAA admitted to our hospital in the past 5 years to understand the disease characteristics and prognosis. The clinical data of patients with HAAA admitted to our hospital from February 2017 to May 2022 were retrospectively analyzed. A total of 81 patients with HAAA, 56 males and 25 females. The median onset age was 5.9 years. The median time from hepatitis to occurrence of hemocytopenia was 30 days, and the median follow-up time was 2.77 years. There were 23 cases (28.5%) of severe aplastic anemia (SAA), 50 cases of very severe aplastic anemia (VSAA), and 8 cases of non-severe aplastic anemia (NSAA). At the beginning of the disease, cytotoxic T lymphocyte (CTL) was higher than normal in 60% of patients, and the median CD4/CD8 ratio was 0.2. As of follow-up, 72 children survived, 4 were lost, and 5 died. Thirty-four cases were treated with immunosuppressive therapy (IST), with a median follow-up time of 0.97 years. The total reaction rate was 73.5% (25/34), the complete reaction rate was 67.6% (23/34), and the nonreaction rate was 26.5% (9/34). Multivariate analysis suggested that co-infection was an independent risk factor affecting the efficacy of IST at 6 months, with an OR value of 16.76, 95% CI (1.23, 227.95), P=0.034. No independent influencing factors were found at the end of follow-up. The proportion of CTL cells in peripheral blood of children with HAAA is relatively increased, and IST is effective in 73.5% of children. Co-infection may prolongs the time to response to IST.

Cytokine storm and severe hepatitis in pregnancy due to herpes simplex virus 2.

CASE PRESENTATION: A pregnant woman developed hepatitis due to a herpes simplex virus 2 primary infection with a severe systemic inflammatory response. Treatment with acyclovir and human immunoglobulin was given and both mother and baby survived. PURPOSE: We provide the first description of the inflammatory response associated with herpetic hepatitis in pregnancy.

The association between periodontitis and hepatitis virus infection: a cross-sectional study utilizing data from the NHANES database (2003-2018).

OBJECTIVES: Periodontitis and hepatitis virus infection significantly impact individuals' well-being and are prevalent public health concerns globally. Given the current scarcity of large-scale cross-sectional epidemiological studies, this study seeks to enrich the evidence base by examining the link between these two conditions. STUDY DESIGN AND METHODS: A cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2003-2018. A multivariate logistic regression analysis was performed to assess the association between periodontitis and hepatitis virus infection, adjusting for the potential confounding factors. Subsequently, a stratified analysis was conducted to explore the relationship between periodontitis and hepatitis virus infection based on age, gender, race, marital status, alcohol consumption, smoking status, and the presence of chronic diseases. RESULTS: In this study, which included 5755 participants, there was a positive association between hepatitis virus infection and periodontitis (odds ratio [OR]: 2.609 [95% confidence interval (CI): 1.513, 4.499]). Furthermore, a significant association was observed between moderate periodontitis and hepatitis virus infection (OR: 2.136 [95% CI: 1.194, 3.822]), and this association was even stronger for severe periodontitis (OR: 3.583 [95% CI: 1.779, 7.217]). Importantly, this positive association between hepatitis virus infection and periodontitis was consistent across different subgroups. CONCLUSIONS: This study presents evidence of a significant association between periodontitis and hepatitis virus infection. These findings highlight the crucial importance of integrating periodontal health and liver health considerations into public health interventions. Further research is necessary to elucidate the underlying mechanisms and develop targeted interventions for effectively managing periodontitis and hepatitis virus infection.

Acute hepatitis of unknown aetiology in children: a clinical update on the recent outbreak with mechanistic insights.

Since April 2022, over 1000 children across 35 countries have developed episodes of acute hepatitis of unknown origin. At King's College Hospital, a total of 65 children were referred with acute hepatitis of unknown etiology, with 10 of these children presenting with acute liver dysfunction leading to acute liver failure. Multiple hypotheses have been proposed and continue to be investigated worldwide. In this review, we explore the current understanding of potential aetiologies for this outbreak. We further characterize the proposed immunological mechanisms of liver injury in these cases.

Adenovirus is Not Detected in Liver Tissue From a Historical Multicenter Cohort of Children With Acute Liver Failure.

There has been a recent surge in cases of pediatric acute hepatitis and pediatric acute liver failure (PALF) of unknown cause. Several reports have described clusters of these children who were positive for adenovirus (AdV) DNA, primarily in peripheral blood but some in liver tissue. We tested archived liver tissue specimens from a historical cohort of 44 children with PALF who were enrolled in a multicenter biorepository between 2007 and 2014 for AdV 40/41 using quantitative polymerase chain reaction. Most children had final diagnosis indeterminate. All samples were negative. Our findings suggest that AdV was unlikely to be an unidentified cause of indeterminate PALF during this past era. The significance of AdV viremia in contemporary cohorts of children with PALF remains unknown and requires further study.

BMSC cells alleviate liver injury induced by ulcerative colitis via repairing the intestinal-liver barrier and activating hepatocyte growth factor.

Ulcerative colitis (UC), which belongs to inflammatory bowel diseases (IBD), frequently induces liver inflammation and injury. Previous studies have proved that bone marrow-derived mesenchymal stem cells (BMSCs) can suppress inflammation and improve intestinal mucosal injury in colitis, however, the effects of BMSCs on colitis-induced liver injury and the underlying molecular mechanisms remain unclear. Here, we investigated the effects and mechanisms of BMSCs in acute ulcerative colitis BALB/c mice, which were induced by 4 % dextran sodium sulphate (DSS). In this study, BMSCs derived from BALB/c mice were administrated by single intravenous injection with a dose of 5*10^7 cells/kg. And then, the effects and underlying molecular mechanisms were investigated. Firstly, the degree of liver injury in colitis mice was evaluated by hepatic ALT, AST, ALP and TBIL levels, which were measured by specific determination kits, the levels of TNF-α, IL-6, IFNγ and LPS were examined by ELISA. Secondly, as the indicator of intestinal-liver barrier disorder, tight junction proteins were analyzed by western blot. Thirdly, the pathological changes in the colon and liver were detected by H&E staining. At last, homing of BMSCs to lesion tissues was investigated by Immunofluorescence. The results indicated that histopathological changes in model mice had been greatly alleviated, BMSCs infusion remarkably decreased the serum ALT, AST, ALP and TBIL levels, and meanwhile reduced pro-inflammatory cytokines in liver tissues. Furthermore, homing of BMSCs was observed in the colon and liver, and the disorder of the intestinal-liver barrier declined significantly. In conclusion, BMSCs alleviate liver injury induced by ulcerative colitis via repairing the intestinal-liver barrier and activating hepatocyte growth factor, it has potential application prospects in the treatment of liver injury induced by ulcerative colitis.

Treatment of Superficial Necrolytic Dermatitis with Copper Chelationina Dog with Copper-Associated Hepatitis.

A 7 yr old castrated male Cavalier King Charles spaniel presented for evaluation of liver enzyme elevations. Abdominal ultrasound revealed a small liver with mixed echogenicity, small hypoechoic nodules, and an irregular surface. Histologic examination and copper quantification of the liver obtained by laparoscopy diagnosed copper-associated hepatitis. One month later the dog developed hyperkeratosis of all four foot pads and ulcerations of feet, legs, and rectum. Punch biopsies confirmed superficial necrolytic dermatitis. After a total of 2 mo of chelation with no changes to medications, skin lesions began to improve, continuing over the following 6 wk to almost complete resolution. At this point the skin lesions returned and had minimal response to four amino acids infusions. The dog was switched from penicillamine to trientine. Zinc acetate was initiated 6 wk after the switch to trientine, and skin improvement was noted soon thereafter. At the time of death, skin lesions were improving and the dog was clinically comfortable. Copper-associated hepatitis should be considered as a possible etiology for superficial necrolytic dermatitis. Treatment of superficial necrolytic dermatitis is often unrewarding, and copper chelation, when copper-associated hepatitis has been confirmed, represents another therapeutic option.

SPECIFICITIES OF THE COURSE OF SUBCLINICAL HEPATITIS AMONG YOUNG ADULTS WITH ACUIE GLOMERULONEPHRITIS.

In spite of the progress in medical science in our country during recent years, the investigation of some problems of development and course of acute glomerulonephritis (AG) particularly in young adults remains topical. In this paper we discuss classical types of AG in young adults, when the intake of paracetamol and diclofenac led to a dysfunctional and organic liver injury, at the same time it negatively affected the course of AG. Goal - assessment of cause-and-effect relations of renal and liver injuries in young adults with acute glomerulonephritis. To achieve the goals of the research we examined 150 male patients with AG, aged 18-25. According to clinical presentations all the patients were divided into two groups. In the first group (102 patients) the disease manifested with acute nephritic syndrome; in the second group of patients (48 patients) - with isolated urinary syndrome. Out of 150 patients examined for AG 66 had subclinical liver injury, which resulted from the effect of antipyretic hepatotoxic drugs taken in the initial stage of the disease. Due to the toxic and immunological liver injury, levels of transaminases increase, and albumin levels decrease. These changes occur along with the development of AG and are correlated with some laboratory values (ASLO, CRP, ESR, hematuria), the injury is more evident when etiological factor is the streptococcal infection. In AG liver injury has a toxic allergic character and is more expressed in post streptococcal glomerulonephritis. Frequency of liver injury depends on specific features of a particular organism; it does not depend on the dose of the taken drug. In case of any type of AG it is necessary to assess the functional state of liver and after the treatment of the main disease hepatologist follow-up of patients is recommended.

A link between severe hepatitis in children and adenovirus 41 and adeno-associated virus 2 infections.

Over the past few months there have been reports of severe acute hepatitis in several hundred, otherwise healthy, immunocompetent young children. Several deaths have been recorded and a relatively large proportion of the patients have needed liver transplants. Most of the cases, so far, have been seen in the UK and in North America, but it has also been reported in many other European countries, the Middle East and Asia. Most common viruses have been ruled out as a causative agent; hepatitis A virus (HAV), hepatitis B virus (HBV) and hepatitis C virus (HCV) were not detected, nor were Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) in many cases. A small proportion of the children had been infected with SARS-CoV-2 but these seem to be in a minority; similarly, almost none of the children had been vaccinated against COVID-19. Significantly, many of the patients were infected with adenovirus 41 (HAdV-F41). Previously, HAdV-41 had not been linked to hepatitis and is usually considered to cause gastroenteritis in both immunocompetent and immunocompromised patients. In two most recent studies, adeno-associated virus 2 (AAV2) was detected in almost all patients, together with species C and F HAdVs and human herpesvirus 6B (HHV6B). Here, I discuss the possibility that a change in tropism of HAdV-41 and changes in AAV2 may be responsible for their links to acute hepatitis.

Comparable clinical outcomes of haploidentical hematopoietic stem cell transplantation in patients with hepatitis-associated aplastic anemia and non-hepatitis-associated aplastic anemia.

Hepatitis-associated aplastic anemia (HAAA), a rare subtype of aplastic anemia (AA), is defined as bone marrow failure occurring after acute hepatitis. Severe HAAA requires immunosuppressive therapy (IST) or hematopoietic stem cell transplantation (HSCT) as lifesaving treatment. The outcomes of HAAA patients who underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT) have not been systematically evaluated. We retrospectively compared the characteristics of 15 patients with HAAA and 60 non-hepatitis-associated aplastic anemia (non-HAAA) patients, all 75 of whom underwent haplo-HSCT in our hospital between January 2006 and October 2021. The median ages of the patients were 18 years old (range, 3-36) for HAAA patients and 13 years (range, 2-45) for non-HAAA patients (p = 0.693). The median time for neutrophil engraftment was 14 days (range, 11-22) in the HAAA group and 12 days (range, 10-21) in the non-HAAA group (p = 0.363). At the time of analysis, 15 HAAA patients and 58 non-HAAA patients were alive, and their median follow-up times were 37 (range, 3-87) months and 31 (range, 2-110) months (p = 0.347), respectively. There were no significant differences in the three-year overall survival (OS) rates (100% vs. 96.7 ± 0.33%, P = 0.638) or liver event-free survival (LEFS) (80.0 ± 0.17% vs. 76.7 ± 0.19%, P = 0.747) between the two groups. Despite the small number of HAAA patients due to the rarity of the disease, these results, such as the similar incidence rates of 3-year OS and fewer liver events than expected, suggest that haplo-HSCT is a feasible treatment for HAAA a when there are no human leukocyte antigen (HLA)-matched donors available and has a low risk of transplant-related mortality and complications.

Prevalence, clinical characteristics and outcomes of hypoxic hepatitis in critically ill patients.

BACKGROUND: Hypoxic hepatitis (HH) is an important clinical entity in patients in the intensive care unit (ICU). The aims of the study were to assess the etiology, clinical characteristics and outcomes of HH in the ICU of a tertiary hospital. Secondary aim was to analyze the effects of concomitant ischemia in other organs than the liver. METHODS: All patients with HH, 2011-2018, in a university hospital ICU were included. Data were collected on etiology, relevant clinical data and outcome. HH was defined by an increase in aminotransferases ≥10 times the upper limit of normal within 48 h from a clinical event of cardiac, circulatory or respiratory failure. Other causes of liver cell necrosis were excluded. RESULTS: Of 9,931 patients hospitalized in the ICU, 159 (1.6%) fulfilled criteria for HH. In-hospital mortality occurred in 85 (53%) and 60 (38%) survived one year. Median ICU stay was five days (interquartile range (IQR) 3-10) and median hospital stay 16 days (IQR 7-32). Shock (48%), cardiac arrest (25%) and hypoxia (13%) were the most common causes of HH. Acute kidney injury (81%), rhabdomyolysis (50%), intestinal ischemia (6%) and ischemic pancreatitis (3%) occurred concomitantly. Age (odds ratio (OR) 1.05 (95% CI 1.02-1.09)), serum lactate (OR 2.61 (95% CI 1.23-5.50)) and lactate dehydrogenase (OR 1.14 (95% CI 1.02-1.27)) were predictors of mortality. CONCLUSIONS: Hypoxic hepatitis was related to shock in approximately 50% of cases and associated with high in-hospital mortality. HH was commonly associated with ischemia in other organs. In-hospital mortality was associated with age, lactate and LD.

Hepatitis-Associated Aplastic Anemia: Etiology, Clinical Characteristics and Outcome.

Hepatitis-associated aplastic anemia (HAA) is a form of acquired aplastic anemia (AA) in which bone marrow failure develops after an acute attack of hepatitis. Bone marrow failure leading to AA is generally severe in cases of HAA and fatal if left untreated. This retrospective multicenter study investigated clinical and laboratory characteristics, possible causes, treatment, and outcome of HAA in children. Twenty patients from 8 centers were included in the study. Aspartate aminotransferase and alanine aminotransferase were <3 to 5×upper limit of normal (ULN) in 2 patients, <5 to 10×ULN in 2 patients, and >10×ULN in 16 patients. Acute liver failure developed in 5 (29%) patients. Pancytopenia was simultaneously present in 6 of 20 (30%) patients. Eleven of the 20 patients (55%) were alive, in remission and transfusion free. Those who were alive either had undergone hematopoietic stem cell transplantation and/or immunosuppressive treatment, except 1 patient who had received no treatment. Patients with the diagnosis of acute hepatitis should be evaluated and followed up carefully for presence of cytopenia, so that definitive treatment of AA can be initiated in a timely and appropriate manner when needed.

Crosstalk between Oxidative Stress and Inflammatory Liver Injury in the Pathogenesis of Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is characterized by the injury, inflammation, and scarring in the liver owing to excessive alcohol consumption. Currently, ALD is a leading cause for liver transplantation. Therefore, extensive studies (in vitro, in experimental ALD models and in humans) are needed to elucidate pathological features and pathogenic mechanisms underlying ALD. Notably, oxidative changes in the liver have been recognized as a signature trait of ALD. Progression of ALD is linked to the generation of highly reactive free radicals by reactions involving ethanol and its metabolites. Furthermore, hepatic oxidative stress promotes tissue injury and, in turn, stimulates inflammatory responses in the liver, forming a pathological loop that promotes the progression of ALD. Accordingly, accumulating further knowledge on the relationship between oxidative stress and inflammation may help establish a viable therapeutic approach for treating ALD.

Ubiquitously specific protease 4 inhibitor-Vialinin A attenuates inflammation and fibrosis in S100-induced hepatitis mice through Rheb/mTOR signalling.

Inflammation and fibrosis are major consequences of autoimmune hepatitis, however, the therapeutic mechanism remains to be investigated. USP4 is a deubiquitinating enzyme and plays an important role in tissue fibrosis and immune disease. Vialinin A is an extract from mushroom and is a specific USP4 inhibitor. However, there is lack of evidences that Vialinin A plays a role in autoimmune hepatitis. By employing S100-induced autoimmune hepatitis in mice and AML12 cell line, therapeutic mechanism of Vialinin A was examined. Inflammation was documented by liver histological staining and inflammatory cytokines. Fibrosis was demonstrated by Masson, Sirius red staining and fibrotic cytokines with western blot and real-time RT-PCR. In experimental animal, there were increases in inflammation and fibrosis as well as USP4, and which were reduced after treatment of Vialinin A. Vialinin A also reduced Rheb and phosphorylated mTOR. Moreover, in LPS-treated AML12 cells, LPS-induced USP4, inflammatory and fibrotic cytokines, phosphorylated mTOR and Rheb. Specific inhibitory siRNA of USP4 reduced USP4 level and the parameters mentioned above. In conclusion, USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver. The mechanism may be related to regulation of Rheb/mTOR signalling.

ALPPS Versus Portal Vein Embolization for Hepatitis-related Hepatocellular Carcinoma: A Changing Paradigm in Modulation of Future Liver Remnant Before Major Hepatectomy.

OBJECTIVE: The aim of this study was to evaluate the short- and long-term outcome of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) for hepatitis-related hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: ALPPS has been advocated for future liver remnant (FLR) augmentation in liver metastasis or noncirrhotic liver tumors in recent years. Data on the effect of ALPPS in chronic hepatitis or cirrhosis-related HCC remained scarce. METHODS: Data for clinicopathological details, portal hemodynamics, and oncological outcome were reviewed for ALPPS and compared with portal vein embolization (PVE). Tumor immunohistochemistry for PD-1, VEGF, and AFP was evaluated in ALPPS and compared with PVE and upfront hepatectomy (UH). RESULTS: From 2002 to 2018, 148 patients with HCC (hepatitis B: n = 136, 92.0%) underwent FLR modulation (ALPPS, n = 46; PVE: n = 102). One patient with ALPPS and 33 patients with PVE failed to proceed to resection (resection rate: 97.8% vs 67.7%, P < 0.001). Among those who had resections, 65 patients (56.5%) had cirrhosis. ALPPS induced absolute FLR volume increment by 48.8%, or FLR estimated total liver volume ratio by 12.8% over 6 days. No difference in morbidity (20.7% vs 30.4%, P = 0.159) and mortality (6.5% vs 5.8%, P = 1.000) with PVE was observed. Chronic hepatitis and intraoperative indocyanine green clearance rate ≤39.5% favored adequate FLR hypertrophy in ALPPS. Five-year overall survival for ALPPS and PVE was 46.8% and 64.1% (P = 0.234). Tumor immunohistochemical staining showed no difference in expression of PD-1, V-EGF, and AFP between ALPPS, PVE, and UH. CONCLUSIONS: ALPPS conferred a higher resection rate in hepatitis-related HCC with comparable short- and long-term oncological outcome with PVE.

Time and residual hematopoiesis are crucial for PNH clones escape in hepatitis-associated aplastic anemia.

The presence of paroxysmal nocturnal hemoglobinuria (PNH) clones in aplastic anemia (AA) suggests immunopathogenesis, but when and how PNH clones emerge and proliferate are unclear. Hepatitis-associated aplastic anemia (HAAA) is a special variant of AA, contrarily to idiopathic AA, in HAAA the trigger for immune activation is clearer and represented by the hepatitis and thus serves as a good model for studying PNH clones. Ninety HAAA patients were enrolled, including 61 males and 29 females (median age 21 years). Four hundred three of idiopathic AA have been included as controls. The median time from hepatitis to cytopenia was 50 days (range 0-180 days) and from cytopenia to AA diagnosis was 26 days (range 2-370 days). PNH clones were detected in 8 HAAA patients (8.9%) at diagnosis and in 73 patients with idiopathic AA (IAA) (18.1%). PNH cells accounted for 4.2% (1.09-12.33%) of red cells and/or granulocytes and were more likely to be detected in patients with longer disease history and less severe disease. During follow-up, the cumulative incidence of PNH clones in HAAA increased to 18.9% (17/90). Nine HAAA patients newly developed PNH clones, including six immunosuppressive therapy (IST) nonresponders. The clone size was mostly stable during follow-up, and only 2 of 14 patients showed increased clone size without proof of hemolysis. In conclusion, PNH clones were infrequent in newly diagnosed HAAA, but their frequency increased to one that was similar to the IAA frequency during follow-up. These results suggest that the PNH clone selection/expansion process is dynamic and takes time to establish, confirming that retesting for PNH clones during follow-up is crucial.

Outcomes of Severe Seronegative Hepatitis-associated Aplastic Anemia: A Pediatric Case Series.

OBJECTIVES: Hepatitis-associated aplastic anemia (HAAA) is a potentially life-threatening diagnosis without clear treatment guidelines. The goal of the study was to characterize the presentation, evaluation, histopathology, and outcomes of therapy in children with HAAA to guide future research and to develop standardized care guidelines for this rare disease. METHODS: Retrospective chart review of 4 patients with HAAA who presented to Children's Hospital Colorado between 2016 and 2019 was conducted. Patient presentation, evaluation, bone marrow and liver pathology, interventions, and clinical course were collected. Immunohistochemistry of liver biopsies was performed. RESULTS: We treated 4 patients with HAAA without liver failure. All had evidence of systemic hyperinflammation and CD8+ T cell predominant liver tissue infiltration. One had a genetic mutation predisposing him to immune-mediated disease, but all other genetic testing was negative. In 3 of the 4 patients, hepatitis was poorly responsive to standard therapy with steroids, azathioprine, or tacrolimus; however, sustained biochemical remission of hepatitis was induced after more aggressive immunosuppressive therapies including Anti-Thymocyte Globulin (ATG) at standard immunosuppressive therapy (IST) dosing for severe Aplastic Anemia (sAA). Two patients underwent hematopoietic stem cell transplant (HSCT); 1 as first line therapy and 1 for refractory sAA. CONCLUSIONS: We found that ATG-based IST induced remission of hepatitis in patients with steroid-refractory HAAA. This is also an appropriate initial treatment for severe Aplastic Anemia, though may not prevent the need for HSCT. We propose that equine ATG based IST at standard dosing regimen for sAA is a therapy that in select cases can be considered early on in the treatment course and could lead to a sustained remission of both hepatitis and sAA. This should be considered in collaboration with a pediatric hematologist.

Atypical Outcomes for Hepatitis-associated Acquired Aplastic Anemia: 2 Case Studies and Review of the Literature.

There is little data specifically dedicated to the long-term outcomes of the hepatitis-associated variant of aplastic anemia (HAAA). A majority of patients with nonsevere (moderate) aplastic anemia progress to severe aplastic anemia, and severe aplastic anemia typically results in death if left untreated. We present 2 unique cases of HAAA that contribute to our knowledge of the natural history of this disease variant. One patient had moderate HAAA that never progressed to severe disease. The second patient had severe HAAA that spontaneously resolved without treatment. The rare possibility of moderate HAAA failing to progress to fulfill severe criteria, or of severe HAAA spontaneously improving, may complicate early treatment decisions for some patients.