Endoscopic retrograde cholangio-pancreatogram showing diffuse bilateral intra- and extrahepatic cholangiopathy in a child with a form of hyper IgE syndrome (DOCK8 deficiency)
ERCP demonstrating diffuse CS-positive cholangiopathy in a 7-year-old immunodeficient patient with dedicator of cytokinesis 8 protein (DOCK8) deficiency (a form of hyper IgE syndrome)
Liver replacement will not work for the patients with PIDs until their immune defect is also rectified. There are many reports describing recurrence of cholangiopathy in the liver grafts within months after successful liver transplantation. Patients with less advanced liver disease can survive isolated non-myeloablative HSCT, but generally children with established cholangiopathies secondary to hyper-IgM syndrome or any other PIDs should be identified and screened for a matched donor for HSCT early . When the liver injury becomes clinically more severe, the children with PIDs are unlikely to tolerate conventional HSCT protocols, which often include potentially hepatotoxic medications. Thus, they should be transplanted while their liver involvement remains minimal, mild or absent if a good donor is available . A sequential approach with combined liver and non-myeloablative (“mini”) HSCT may be required for the ones with decompensated biliary cirrhosis and complications of advanced liver disease .
Effective HSCT not only prevents progression of established cholangiopathy but also could revert the histological abnormalities. We have observed four children with significant improvement of their histological features of cholangiopathy within couple of years after HSCT. However, there was no short-term change in the calibre of their bile ducts on ultrasonography .
Over the past decade, we have observed a reducing number of patients with PIDs and advanced chronic liver disease. There are two possible explanations for that: (1) these patients are referred earlier due to increased awareness of possible liver problems among immunologists and (2) they receive their HSCT earlier, before serious liver disease develops. It is hoped that this strategy will continue to work and that the hepatologists would only exceptionally be required to see the patients with PIDs.
Haemophagocytic lymphohistiocytosis (HLH) is a condition which probably still remains underdiagnosed due to specific diagnostic tools and the clinical features mimicking acute septicaemia of early infancy and relatively atypical diagnostic approach. Majority of primary or familial HLH cases could be regarded as a form of PID. Secondary or nonfamilial forms can be associated with any infectious pathogen or presence of malignancy. Some use the term macrophage activation syndrome to highlight ubiquitous nature of this systemic reaction . A subgroup of patients with primary perforin deficiency presents acutely, often in infancy, with acute liver failure , but also in respiratory distress, fever, pancytopenia, rash and renal impairment, all indicative of systemic involvement. Perforin is a 60 kDa polypeptide, produced by cytoplasmic granules of activated natural killer (NK) cells and cytotoxic lymphocytes. Perforin then assists in primary immune response by forming perforations/“pores” on membrane of the invading cells, facilitating entry of mediators such as granzyme, which lead to osmotic cell lysis and consequent cell death . There are at least five different loci where mutations for familial forms of HLH can be detected .
The liver involvement is frequently so severe to warrant consideration for liver transplantation. In addition to classical signs of acute liver failure such as hyperbilirubinemia, coagulopathy and hypoalbuminemia with ascites , those patients have hyperferritinaemia, hypertriglyceridaemia, hypofibrinogenaemia and signs of activated T lymphocytes, in particular interleukin (IL)-2R positive cells in circulation. Patients often exhibit fever, splenomegaly and pancytopenia. Bone marrow aspirate reveals haemophygocytosis—a phenomenon defined by macrophages engulfing other cells and cellular debris . This urgent situation requires prompt identification of immune defect if it underlies the clinical situation, as liver transplantation would only be a palliative measure; the underlying ongoing immune overactivity continues. Potential cure is control of the immune reaction by combination of steroids and chemotherapy (HLH protocol) . The mortality is high and surviving patients should be worked up for HSCT as each new exposure to an infectious agent could trigger another life-threatening episode of haemophagocytosis .
Therefore, any child who presents in acute liver failure with fever, splenomegaly and pancytopenia should, in addition to standard treatment of this condition, be urgently investigated for primary immunodeficiency by performing bone marrow aspirate and flow cytometry for expression of IL-2R and perforin on activated lymphocytes . Suggestion that the child could be immune deficient may indicate that consideration for emergency liver transplantation may not be justified .< div class='tao-gold-member'>