Rapid development of pseudo‐ground‐glass bodies in liver transplants

Pseudo-ground-glass inclusions (PGG) in hepatocytes represent a distinctive, eye-catching morphological phenomenon due to a variety of underlying pathologies.1-6 Hadziyannis et al. first described similar inclusions in 1973 in patients with hepatitis B virus infection using the eponymous designation “ground-glass hepatocytes”.7 The term “pseudo-ground-glass” inclusion characterizes all other similar homogeneous hepatocellular inclusions. Two causative groups of PGG can be grossly distinguished: (1) inborn storage diseases of pathologic glycogen metabolism: Lafora's disease, Anderson's disease (type IV glycogenosis), Adult Polyglucosan Body Disease, and glycogenin deficiency, and (2) metabolic/pharmaco-toxic diseases esp. in context with posttransplantation state under immunosuppressive treatment. We report on the rapid development of PGG in close-meshed follow-up biopsies of liver transplants in correlation with liver function under immunosuppressive treatment including mycophenolate-mofetil, tacrolimus, everolimus, and prednisolone. Beginning with time zero, follow-up liver transplant biopsies from a 3-year-old girl (Case 1) and a man in his mid-60's (Case 2) were analysed. In each case, variable amounts of hepatocytes contained round, well-circumscribed homogeneous pale eosinophilic cytoplasmatic inclusions of 5–20 μm, separated from the cytoplasmic membrane. The nuclei were not deformed or displaced by the inclusions. PGG stained strongly positive in the periodic shiff acid reaction and were mostly sensitive to predigestion by diastase (Figure 1). The depositions were negative or discretely positive for HepPar1 and ubiquitin and negative for HBsAg, as well as for fibrinogen and the c-reactive protein (CRP) antibody. According to previous descriptions, PGG were ultrastructurally composed of polyglucosan rosettes and residual fragmented cell organelles. In the first positive biopsies, periportal hepatocytes were especially affected by PGG. The follow-up biopsies showed a substantial increase of PGG-containing hepatocytes covering complete liver acini. In the case of the little girl, PGGs were not present in the biopsy 2 weeks after transplantation but occurred 4 months after transplantation in overall 8% of hepatocytes, restricted to the periportal areas. Nine months after transplantation, 80% of hepatocytes were affected by PGG in a panacinar distribution. In the adult patient (Case 2), the same phenomenon was observed, with moderate amounts of PGG-containing hepatocytes (40%) in the first biopsy 4 years after the third transplantation and a strong panacinar extension (80%) in the follow-up biopsy after 10 months (Figure 1). Remarkably, Case 2 did not develop PGG in the first and second liver transplant in the time range of 5 years. Neither significant inflammatory infiltration, steatosis, fibrosis, nor rejection were seen. Mild punctual elevations of transaminases and cholestatic parameters, above all γGT, were observed but did not correlate with the steady PGG increase. In conclusion, PGG in liver transplants are a rare and quickly developing manifestation of medically induced secondary glycogen storage. The glycosyltransferase glycogenin plays a major role in the early steps of glycogen synthesis. Docking experiments have shown a high binding affinity of special drugs, e.g. tacrolimus and mycophenolate-mofetil to the active region of glycogenin.3 This interference might inactivate glycogenin and its interaction with glycogen synthase, resulting in dysregulated glycogen synthesis and degradation. Occurrence of PGG in only a very small proportion of liver transplants and not even in every retransplant furthermore suggests a preexisting alteration of glycogen synthesis, which makes certain donor livers more susceptible to drug-induced development of PGG. Even large amounts of affected hepatocytes do not have a significant pathogenic effect in terms of inflammation, fibrosis, and steatosis in the observed time range. Open Access funding enabled and organized by Projekt DEAL. AK Fischer designed, wrote, and edited the article. AK Fischer, M Müller, and U Zens performed (immuno)histochemical and electron microscopic examinations. H-P Fischer and H Baba made the final diagnoses. E Lainka and J Kälsch treated the patients and provided clinical data. AK Fischer, H-P Fischer, H Baba, and R Büttner discussed the results and contributed to the final article. The authors do not have any disclosures to report. Informed consent was obtained from the patients for the publication of their information and imaging. The data used to support the findings of this study are available from the corresponding author upon request.