Activated T-Cell Hepatitis in Pediatric Acute Liver Failure

Naseem Ravanbakhsh

3-year-old previously healthy female presented to the Emergency Department with a two-week history of intermittent fevers, abdominal distension, and scleral icterus. She was briefly admitted to an outside hospital for evaluation of an abnormal hepatic profile the prior week. At that time, her infectious workup was negative, and she was subsequently discharged home after two days. She then presented to her pediatrician three days after discharge, at which time her liver transaminases continued to be elevated. She was thus sent to the Emergency Department for further management. She was afebrile and hemodynamically stable upon arrival, mildly dehydrated, irritable, inconsolable, jaundiced, and with significant hepatomegaly; there was no notable splenomegaly or edema present and no focal neurologic abnormalities. 

Initial investigations were as follows: 

INR 1.7
ALT 1955 IU/L (5 - 45 IU/L)
AST 6355 IU/L (9 - 50 IU/L)
GGT 110 IU/L (8 - 55 IU/L)
Total bilirubin 12.5 mg/dL (0.2 - 1.0 mg/dL)
Direct bilirubin 8.5 mg/dL ( < 0.3 mg/dL)
Glucose 55 mg/dL (70 - 110 mg/dL)
Fibrinogen 426 mg/dL (180-410)
Ferritin 6500 ng/mL (11 - 320 ng/mL)
WBC 5.5 thous/uL ( 6 - 17.5) with neutrophilic predominance (80%)
Hemoglobin 9 g/dL (10.5 - 13.5)
Hematocrit 28% (33 - 39%)
Platelets 515 thous/uL (150 - 450 thous/uL)
Ammonia 88 umol/L (11 – 35 umol/L) 

Abdominal ultrasound with doppler was unremarkable. Notably, her aminotransferases have improved from one week ago. 

What is the next best step in management?

Correct Answer:

D. Fluid resuscitate as needed, give 5 mg of subcutaneous vitamin K, and admit to the pediatric intensive care unit for further management and evaluation/monitoring of hepatic encephalopathy

The correct answer is D. The patient’s presentation is consistent with pediatric acute liver failure as evidenced by coagulopathy with an INR > 1.5 and signs of hepatic encephalopathy (irritable and inconsolable). Vitamin K administration is an important step in determining whether the patient’s coagulopathy is from vitamin K deficiency or hepatic synthetic dysfunction. The patient’s behavioral changes are consistent with grade II hepatic encephalopathy (HE); therefore, one should also check an ammonia level and performed a detailed history and exam to elucidate if the patient has evidence of HE (fatigue, irritability, confusion, abnormal reflexes, tremor, ataxia, etc). Neurocritical care involvement for evaluation of hepatic encephalopathy can be invaluable for documenting these findings as well as performing EEG assessment on patients which can support the diagnosis of HE and be trended over time for changes. The Animal Naming Test is another option to assess HE in children and was found to correlate with various stages of HE.  Patients with acute liver failure should be admitted to the intensive care unit for further management and observation given high risk for rapid clinical deterioration due to hepatic encephalopathy.

Pediatric Acute Liver Failure 

As outlined in the Liver Fellow Network post, Pediatric Acute Liver Failure: from Prompt Recognition and Management to Liver Transplant Considerations, pediatric acute liver failure (PALF) is a medical emergency, characterized by the acute onset of hepatocellular damage in a child without pre-existing liver disease. Prompt recognition and management, including admission to the pediatric intensive care unit (PICU) for close monitoring, supportive care, and consideration for dialysis.

Back to the Case

Upon admission to the PICU, the patient became progressively somnolent. vEEG showed generalized slowing with moderate background abnormality. Urine output dropped coinciding with a rise in BUN/creatinine. The patient remained hemodynamically stable without need for vasopressor support. Repeat labs (about four hours after vitamin K administration) were as follows: 

INR 2.8
ALT 1000 IU/L (5 - 45 IU/L)
AST 2500 IU/L (9 - 50 IU/L)
GGT 200 IU/L (8 - 55 IU/L)
Total bilirubin 12.9 mg/dL (0.2 - 1.0 mg/dL)
Direct bilirubin 8.7 mg/dL ( < 0.3 mg/dL)
Ammonia 120 umol/L (11 – 35 umol/L)

Her clinical exam was consistent with HE grade III. Therefore,  decision was made to intubate the patient for airway protection and pursue continuous renal replacement therapy (CRRT) in the setting of acute kidney injury, hyperammonemia, and stage three hepatic encephalopathy (HE). Notably, various scoring criteria are utilized to diagnose HE among children. As shown in this position paper, reflexes and neurologic signs may be challenging to test in the assessment of HE. EEG testing may be a valuable tool for this pediatric patient.  

The patient’s workup returned negative for evidence of metabolic disease, autoimmune hepatitis, toxin ingestion, and infection. She was ultimately listed as status 1A for liver transplant. As mentioned, the differential diagnoses for PALF are broad, ranging from infection, toxic exposure, autoimmune liver disease, and metabolic etiologies. The cause of PALF is not found in 30-50% of cases, dubbed “indeterminate PALF.”

Indeterminate PALF

Within the indeterminate group, a subset of patients have been found to have distinct liver histology, which includes a dense infiltrate of CD103+CD8+ T-cells. In recent years, studies have shed light on this entity known as ‘activated CD8 T-cell hepatitis’, an immune-mediated cause of liver injury. It has been shown that these patients are more likely to require liver transplant (LT) for survival compared with children with PALF from other causes. Some centers have treated these patients with immunosuppression given the suspected immune-mediated pathophysiology, though the therapeutic benefit has not been established and there is active enrollment in a multicenter randomized trial of immunosuppressive therapy for children with acute liver failure.

Liver pathology immunohistochemical staining patterns in active T-cell hepatitis are characterized by dense CD8 staining: 

Patients with indeterminate PALF often have features of immune activation including excessive production of inflammatory cytokines, elevated serum soluble interleukin-2 receptor (sIL-2R) levels, and peripheral blood cytopenias. It has been shown thathigh perforin and granzyme expression as well as elevated absolute CD8 lymphocyte count and serum sIL-2R levels help characterize this distinct pathology. 

Back to the Case

The patient remains intubated and sedated. Given her worsening HE, a head CT head performed and is without evidence of cerebral edema. On day two of hospitalization, she developed metabolic acidosis and hypotension prompting initiation of vasopressors. Blood cultures were drawn and antibiotics initiated. The patient’s workup had not yielded a diagnosis. 

Additional workup was as follows: 

Interleukin 2 Receptor (CD25), soluble: 30,240 pg/mL (reference range 175.3 – 858.2 pg/mL)

Flow cytometry: 

Transjugular liver biopsy is performed and liver histology was significant for predominant portal and lobular CD8+ T cell infiltration as well as dense CD103+ and perforin staining.

What is the next best step in management? 

A. Continue CRRT alone
B. Continue supportive care and consider plasma exchange 
C. Ongoing observation
D. De-listing the patient given her new vasopressor requirement 

Answer: B

The correct answer is B. Plasma exchange may be utilized as a bridge to LT, and possibly to recovery in PALF. Given that the patient continues to deteriorate while awaiting transplantation, now with evidence of multi-organ failure, therapeutic plasma exchange would allow for the removal of cytokines and other inflammatory drivers in the blood and potentially create an environment in which the liver may regenerate and heal. 

The patient continues to meet criteria for liver transplant status 1A. Contraindications for liver transplant typically include high ventilator requirement, the requirement of multiple, high dose vasoactive agents, and/or severe or irreversible neurological injury.

The constellation of biochemical data and liver biopsy findings are consistent with activated T-cell hepatitis. 

Notably, flow cytometry can be helpful to determine the functional status of T cells, particularly in activated T-cell hepatitis. In the results above, the patient has elevated CD3+DR% which would be consistent with this entity, and a low CD4/CD8 ratio, which has previously been associated with hepatitis-associated aplastic anemia. 

Case conclusion

A liver offer became available on the third day of PICU admission. Given that the patient showed minimal improvement in her clinical state despite CRRT and plasma exchange, the organ was accepted, and the patient underwent deceased donor LT. She recovered well from her surgery and hospitalization. 

Six months after liver transplant, the patient presented to the Emergency Department with fatigue and bruising, found to have pancytopenia on her CBC with an otherwise unremarkable workup. She was diagnosed with aplastic anemia (AA) and required a stem cell transplant. 

Unique complications in immune dysregulation 

Comorbidities including AA and transient bone marrow suppression have been seen in patients with activated CD8 T-cell hepatitis, even after LT, as seen in this patient. While the precise pathophysiology of AA in this patient cohort has not been established, it is thought to be similarly immune-mediated, related to hematopoietic stem cell injury from CD8+ T cells and high cytokine burden. It has been previously described that a low CD4:CD8 T-cell ratio, as noted in the patient in the question stem, is associated with the development of AA in T-cell mediated pediatric ALF. It may potentially be a biomarker of a risk for this complication. 

Take Home Points 

  • Pediatric acute liver failure is a rapidly evolving disease state and medical emergency that requires prompt management at a liver transplant center. The etiology of PALF is not uncovered in 30 to 50% cases and dubbed “indeterminate PALF.”
  • Within the indeterminate PALF category, a subset of patients has features of immune dysregulation or “activated T-cell hepatitis.” Studies to evaluate for this entity include sIL-2R, flow cytometry, perforin and granzyme expression, in addition to CD8 lymphocyte staining on liver biopsy.
  • Recent studies have shed light into the pathophysiology, biochemical and liver pathology findings for immune-mediated/activated T-cell hepatitis cases associated with PALF. 

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