Case Presentation: A 65-year-old healthy man presented with a 4 day history of fatigue and fevers. He denied any cough, chest pain, diarrhea or any recent sick contacts. He did complain of nausea and mild abdominal pain. He denied any significant family history, drug allergies, or medication use. He denied any recent travel outside of the United States. Physical exam revealed a temperature of 103°F, heart rate of 80/min, and blood pressure of 132/69mmHg. There was no evidence of scleral icterus and his abdomen was non-distended, not tender and with no hepatosplenomegaly. Neck was supple. He was alert and well oriented. No motor deficits noted. No skin rash was noted. Lab work revealed a normal white blood cell count and a mild transaminitis. He was placed on doxycycline for empiric tick-borne illness treatment. Right upper quadrant ultrasound was normal. He continued to spike fevers and on the fifth day he had evidence of worsening transaminitis and coagulopathy, with AST/ALT 1888/2078IU/L, Total bilirubin of 5.9mg/DL, and an INR of 2.0 Initial evaluation for Acute Viral Hepatitis, autoimmune hepatitis, and infectious workup all returned negative. Further workup included a ferritin level that returned elevated at 56,000ng/ml (22-232). An urgent bone marrow biopsy was performed . Testing for soluble IL-2 level returned significantly elevated. A diagnosis of Secondary Hemophagocytic Lymphohistiocytosis (HLH) was made and given his worsening liver function, was transferred to a liver transplant center. Interestingly, an acute IgM Hepatitis A and viral level both returned elevated (IgM level was negative on initial presentation). The patients conditioned worsened and he unfortunately passed away.
Discussion: Secondary Hemophagocytic lymphohistiocytosis is a rare disease entity that may present with liver involvement ranging from transaminitis to fulminant liver failure. It is hypothesized that a deficiency in perforin leads to an uncontrolled immune response releasing large amounts of cytokines causing a state of severe hyperinflammation. Despite prompt diagnosis and therapy, the mortality rate for severe cases of HLH remains elevated above 40%. Secondary triggers that have been associated with HLH range from malignancy to infections. The most common viral cause of HLH is Epstein-Barr virus. Proposed diagnostic criteria for HLH includes splenomegaly, cytopenias, hypertriglyceridemia, hemophagocytes in the bone marrow, and elevated ferritin/soluble IL-2 levels. Treatment of the disease encompasses immunosuppressive agents (steroids), chemotherapy, and ultimately Hematopoetic Stem Cell Transplant. The association between Hepatitis A and HLH is not well documented. Hepatitis A infection is usually self-limited without lasting consequences. Despite best-practiced interventions, secondary HLH carries a grave prognosis. Our case highlights how rapidly the disease progresses and the importance of including HLH in the differential for acute liver failure in order to afford early treatment intervention.
Conclusions: Hospitalists see a number of cases of transaminitis. Some cases progress and are associated with various forms of liver failure- fulminant, acute and subacute. The association of HLH with a number of infections, malignancy and connective tissue diseases requires a high index of suspicion for the right diagnosis to made to ensure pormpt therapeutic intervention. HLH is a fulminant syndrome of immune dysregulation and occurs after a variety of triggers.