Mucolipidosis type II (MLII) is a severe multi-systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock-in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency of numerous acid hydrolases results in accumulation of storage material in chondrocytes and osteoblasts, and impaired bone formation. In osteoclasts, no morphological or functional abnormalities are detected whereas osteoclastogenesis is dramatically increased in MLII mice. The high number of osteoclasts in MLII is associated with enhanced osteoblastic expression of the pro-osteoclastogenic cytokine interleukin-6, and pharmacological inhibition of bone resorption prevented the osteoporotic phenotype of MLII mice. Our findings show that progressive bone loss in MLII is due to the presence of dysfunctional osteoblasts combined with excessive osteoclastogenesis. They further underscore the importance of a deep skeletal phenotyping approach for other lysosomal diseases in which bone loss is a prominent feature.

In 2015, more than 13 000 people died due to the consequences of liver cirrhosis in Germany. Frequently, relevant liver fibrosis is diagnosed by non-invasive methods (e. g., ultrasound-based measurement of liver stiffness) already in the compensated stage. Following diagnosis of liver fibrosis, a thorough investigation of the underlying chronic liver disease and effective treatment are important to prevent progression to decompensated cirrhosis. Since morbidity and mortality dramatically increase in the decompensated stage (patients may present with jaundice, ascites, hepatic encephalopathy, gastrointestinal bleeding) with an upsurge in 1-year-mortality from 1 - 3.4 % to 20 - 57 %, prophylactic measures to prevent decompensation are indicated. Based on a risk stratification, these measures include propranolol or carvedilol as non-selective betablockers, as well as endoscopic band ligations as primary prophylaxis to prevent variceal bleeding. Because of the high risk for malignant transformation (2 - 8 % per year depending on the underlying etiology), surveillance by liver ultrasound every six months is essential to detect liver cancer in an early stage and to facilitate curative therapy. Currently under debate is the administration of antibiotics to prevent bacterial infections, which commonly trigger acute decompensation. To this regard, studies are not convincing and the risk to induce drug resistance has to be observed. However, health care providers should check the vaccination status and recommend missing vaccinations. The management of compensated liver cirrhosis also includes counseling and potentially also a drug therapy to prevent osteoporosis and muscle wasting. In this review, we will discuss specific prophylactic measures in the management of compensated liver cirrhosis based on the pathophysiological background and central clinical studies. If a patient decompensates despite these prophylactic measures (approximately 15 % of patients with liver cirrhosis per year), liver transplantation has to be discussed as definitive therapy (especially in patients with MELD > 15).

<b><i>Introduction:</i></b> The number of efficacious systemic agents for advanced hepatocellular carcinoma (HCC) has rapidly increased over the past 3 years. However, guidance for optimal sequential systemic treatment in patients with advanced disease and experience with outcome and safety profiles are lacking. <b><i>Objective:</i></b> We aimed to assess efficacy and tolerability of sequential systemic therapy of advanced HCC. <b><i>Methods:</i></b> Our single-center study prospectively followed 14 patients who received multiple, sequential systemic therapies after progression or intolerance to sorafenib. Endpoints were overall and progression-free survival (OS, PFS), objective response rate (ORR), and treatment-emergent adverse events (TEAE). <b><i>Results:</i></b> Patients had well-compensated liver function and good performance status at start of each systemic therapy. Agents included sorafenib (<i>n</i> = 14), regorafenib (<i>n</i> = 10), immunotherapy with nivolumab or pembrolizumab (<i>n</i> = 10), lenvatinib (<i>n</i> = 3), ramucirumab (<i>n</i> = 2), and others, with a median of 3 lines of systemic therapy per patient. Median OS was 37.4 months from initiation of first-line therapy with sorafenib. PFS and ORR for sorafenib, regorafenib, and immunotherapy were 6.6, 5.3, and 6.6 months, and 15.4, 11.1, and 22.2%, respectively. TEAE were frequent (46–80%), but mostly manageable during tyrosine kinase inhibitor therapy and without the need for termination in most patients. However, TEAE due to immunotherapy (60%) led to cessation of treatment in 40% of the patients. <b><i>Conclusions:</i></b> Sequential systemic therapy is able to prolong median OS in selected patients with advanced HCC to more than 3 years. TEAE are frequent, but manageable, and the quality of adverse events depends on the respective agent. Further investigation of potential predictive biomarkers for treatment allocation is needed.