[Liver injury induced by immune checkpoint inhibitor-therapy : Example of an immune-mediated drug side effect]. / Leberschaden durch Therapie mit Immun-Checkpoint-Inhibitoren : Beispiel einer immunvermittelten Medikamentennebenwirkung.

BACKGROUND: Drug-induced liver injury is increasing, especially in elderly patients with polymedication and multimorbidity. OBJECTIVES: Clinicopathologic correlation of immune-mediated liver injury, specifically liver injury following therapy with immune checkpoint inhibitors against PD-1, PDL-1, and CTLA4. METHODS: Histologic assessment of liver biopsies of nine patients after therapy with immune checkpoint inhibitors and correlation with clinical parameters. RESULTS: In all nine patients, liver injury was apparent after variable administration of immune checkpoint inhibitors. Transaminase levels were increased up to a maximum of 3818 U/l. Liver histology showed liver injury resembling autoimmune hepatitis respective cholangitis. In two patients, veno-occlusive disease was seen. Corticosteroid therapy was initiated in eight patients, subsequently four patients showed decreasing transaminases and five patients died of tumor progress. In three patients, it remains unclear whether liver injury by immune checkpoint inhibitors may have ultimately contributed to the fatal course, especially in one patient with liver cirrhosis and hepatocellular carcinoma. CONCLUSIONS: Therapy with immune checkpoint inhibitors may lead to potentially fatal immune phenomena in susceptible patients, which may affect liver and/or other organs independently. Other causes of hepatopathy need to be ruled out clinically and/or histologically.

[Lipid droplet-associated proteins. Importance in steatosis, steatohepatitis and hepatocarcinogenesis]. / Lipidtropfen-assoziierte Proteine. Bedeutung für Steatose, Steatohepatitis und Hepatokarzinogenese.

Hepatocellular steatosis constitutes the most frequent liver disease in western countries and may progress to steatohepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). The lipid droplet (LD)-associated proteins perilipin, adipophilin, TIP47 ("tail interacting protein of 47 kDa"), S3-12 and myocardial LD protein (MLDP), so-called perilipins 1-5 (PAT family) govern formation, maintenance and degradation of LDs. A lack of perilipin in mice inhibits obesity and a lack of adipophilin or TIP47 inhibit the development of fatty liver disease. In long-term cell culture models as well as in liver biopsies of patients with different acute and chronic liver diseases, LD-associated proteins are sequentially recruited to LDs and regulated via peroxisome proliferator-activated receptor (PPAR) α and PPARγ as well as posttranscriptionally via alternative splicing, LD fusion and lipolysis. Whereas TIP47 and MLDP coat small newly formed LDs in acute microvesicular steatosis, adipophilin constitutes a robust general marker for LDs in many different cell types. Perilipin is important for the long-term storage of lipids in macrovesicular steatosis and controls lipolysis via hormone-dependent phosphorylation. During malignant transformation, increased formation of small LDs and overexpression of adipophilin, TIP47 and MLDP are detected, possibly as the expression of an altered tumor metabolism analogous to a Warburg effect. Adipophilin correlates positively with the proliferation rate of HCC cells. Cultured cells with downregulation of TIP47 or adipophilin via small interfering RNA (siRNA) or small hairpin RNA (shRNA) show less but larger LDs with reduced neutral fat content.

[Lipid droplet-associated proteins in steatosis. Effects of induction and siRNA-mediated downregulation of PAT proteins in cell culture models of hepatocyte steatosis]. / Lipidtropfen-assoziierte Proteine bei Steatose. Effekte einer Induktion und siRNA-vermittelten Herunterregulation von PAT-Proteinen in hepatozytären Zellkulturmodellen.

BACKGROUND: The accumulation of hepatocellular lipid droplets, referred to as steatosis, is the most frequent liver pathology in western industrial countries. The surface of lipid droplets is stabilized by amphiphilic proteins of the PAT family (perilipin, adipophilin, TIP47). We recently showed that PAT proteins are differentially expressed in liver. METHODS: The effects of lipid droplet induction with oleate and of siRNA-mediated downregulation of PAT proteins were evaluated using immunofluorescence microscopy, immunoblot and functional assays. RESULTS: Whereas perilipin, adipophilin and (in only minor amounts) also TIP47 coat lipid droplets in steatotic hepatocytes, adipophilin and TIP47, but not perilipin, are detectable in hepatocellular cell cultures. Likewise, perilipin is not induced after downregulation of adipophilin and TIP47. CONCLUSIONS: Common cell culture models show specific differences to human hepatocyte steatosis in vivo. Perilipin may play a role in the long-term storage of fat, which may be only partially reflected by cell culture models.

[Primary intrastromal iris cysts]. / Primäre stromale Iriszysten.

BACKGROUND: Cysts of the iris are uncommon and most of them occur secondarily after surgery or penetrating injury. The minority of the iris cysts is primary without a reasonable cause. They are classified into the more common pigment epithelial cysts and the rare cysts of iris stroma ("intrastromal cysts"). These intrastromal iris cysts are generally diagnosed in children and often cause symptoms such as a decrease of visual acuity because of ingrowth into the optical axis. A diagnosis of stromal cysts in adults is very rare. Most of these patients remain without any symptoms and do not need treatment. The cellular origin is so far unknown. Mesoderm, neuroectoderm and surface ectoderm have been discussed in this context. CASE REPORTS: Two patients with primary intrastromal iris cysts are presented, a 5-year-old boy and a 65-year-old woman. In both cases, the cyst affected the optical axis and was removed by sector iridectomy. In histological and electron-microscopic examinations both cysts presented a typical epithelial structure. Immunohistochemical examination revealed positivity for epithelial markers and negativity for mesenchymal and neuroectodermal markers. CONCLUSION: Primary intrastromal iris cysts can occur in advanced age and may cause symptoms due to progressive growth. The cellular origin of primary intrastromal iris cysts is controversially discussed in the literature. On electron microscopy and immunohistochemistry, the iris cysts presented here showed characteristic features of surface ectodermal origin.

Renal Tubular Dysgenesis in a Case of Fetus Acardius Amorphus.

Fetus acardius amorphus is a rare congenital malformation characterized by the lack of a functional heart, the presence of a bivascular umbilical cord, as well as a developed and organized skeletal system and partially organized inner organs. Fetus acardii mostly occur in multiple gestations. The pathogenesis of this entity is not clarified yet. It has been hypothesized that, although formation of anastomosing vessels between the co-twin and the anomalous embryo as well as reverse directed blood flow within the umbilical arteries of the weaker twin may allow sufficient blood flow to form rudimentary internal organs, it is insufficient to develop a fully functional heart. We had a case of fetus acardius amorphus, where we performed autopsy as well as routine histology assessment to identify different types of tissues. We showed that our fetus acardius amorphus demonstrated histomorphological features of renal tubular dysgenesis, confirmed by lack of proximal tubules, extramedullary hematopoiesis and increased number of smooth muscle actin positive vessels. This is a novel finding and has not been reported previously.

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout.

Hepatocellular carcinoma (HCC) usually develops in the context of chronic hepatitis triggered by viruses or toxic substances causing hepatocyte death, inflammation and compensatory proliferation of liver cells. Death receptors of the TNFR superfamily regulate cell death and inflammation and are implicated in liver disease and cancer. Liver parenchymal cell-specific ablation of NEMO/IKKγ, a subunit of the IκB kinase (IKK) complex that is essential for the activation of canonical NF-κB signalling, sensitized hepatocytes to apoptosis and caused the spontaneous development of chronic hepatitis and HCC in mice. Here we show that hepatitis and HCC development in NEMO(LPC-KO) mice is triggered by death receptor-independent FADD-mediated hepatocyte apoptosis. TNF deficiency in all cells or conditional LPC-specific ablation of TNFR1, Fas or TRAIL-R did not prevent hepatocyte apoptosis, hepatitis and HCC development in NEMO(LPC-KO) mice. To address potential functional redundancies between death receptors we generated and analysed NEMO(LPC-KO) mice with combined LPC-specific deficiency of TNFR1, Fas and TRAIL-R and found that also simultaneous lack of all three death receptors did not prevent hepatocyte apoptosis, chronic hepatitis and HCC development. However, LPC-specific combined deficiency in TNFR1, Fas and TRAIL-R protected the NEMO-deficient liver from LPS-induced liver failure, showing that different mechanisms trigger spontaneous and LPS-induced hepatocyte apoptosis in NEMO(LPC-KO) mice. In addition, NK cell depletion did not prevent liver damage and hepatitis. Moreover, NEMO(LPC-KO) mice crossed into a RAG-1-deficient genetic background-developed hepatitis and HCC. Collectively, these results show that the spontaneous development of hepatocyte apoptosis, chronic hepatitis and HCC in NEMO(LPC-KO) mice occurs independently of death receptor signalling, NK cells and B and T lymphocytes, arguing against an immunological trigger as the critical stimulus driving hepatocarcinogenesis in this model.