Persistent hypercobalaminemia three months after successful gradual attenuation of extrahepatic shunts in dogs: a prospective cohort study

Background Deficiencies in vitamin A and D and disorders in the vitamin B complex are often present in people with chronic liver diseases. So far, the serum concentrations of these vitamins have not yet been studied in dogs with congenital extrahepatic portosystemic shunts (EHPSS), who also have some degree of liver dysfunction. The objective was to assess serum vitamin concentrations in dogs with EHPSS from diagnosis to complete closure. A prospective cohort study was performed using ten client-owned dogs with EHPSS, closed after gradual surgical attenuation. Serum concentrations of vitamin A, 25-hydroxyvitamin D, folic acid, cobalamin and methylmalonic acid (MMA) were measured at diagnosis prior to institution of medical therapy, prior to surgery, and three months after gradual attenuation and complete closure of the EHPSS. Results At diagnosis, median serum concentrations of vitamin A, 25-hydroxyvitamin D and folic acid were 18.2 μg/dL (8.8 - 79.5 μg/dL), 51.8 ng/mL (19.4 - 109.0 ng/mL), and 8.1 μg/L (5.2 - 14.5 μg/L), respectively, which increased significantly postoperatively (88.3 μg/dL (51.6 - 182.2 μg/dL, P=0.005), 89.6 ng/mL (49.3 - >150.0 ng/mL, P =0.005), and 14.8 μg/L (11.5 - 17.7 μg/L, P <0.001), respectively). Median serum cobalamin concentrations were 735.5 ng/L (470 - 1388 ng/L) at diagnosis and did not significantly decrease postoperatively (P =0.122). Both at diagnosis and three months postoperatively 7/10 dogs had hypercobalaminemia. Conclusions Serum concentrations of vitamin A, 25-hydroxyvitamin D and folic acid significantly increase after surgical attenuation. Nevertheless, persistent hypercobalaminemia is suggestive of ongoing liver dysfunction, despite successful surgery.

Hyaluronic Acid May Be a Predictive Biomarker for Thrombocytopenia and Liver Dysfunction After Oxaliplatin-based Chemotherapy

Background/Aim: Following oxaliplatin-based chemotherapy, approximately half of all colorectal cancer patients develop sinusoidal obstruction syndrome (SOS). SOS can be monitored by measuring splenic volume; however, obtaining this measurement is not a simple process. In this study, we evaluated changes in hyaluronic acid (HA) concentrations as a simpler marker of SOS. Patients and Methods: We measured splenic volume and laboratory data, including hyaluronic acid concentration, liver enzymes, and platelet counts, in 34 patients with colorectal cancer who underwent radical resection and who received capecitabine plus oxaliplatin (CapeOx) chemotherapy. Results: A strong correlation was identified between ≥30% increase in splenic volume and significantly elevated HA concentrations. Affected patients also had persistent thrombocytopenia and liver dysfunction compared to patients without elevated HA concentration. Conclusion: HA concentration may predict SOS in patients who receive CapeOx adjuvant chemotherapy.

Acute Liver Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference

CONTEXT Develop evidence-based criteria for individual organ dysfunction. OBJECTIVES Evaluate current evidence and develop contemporary consensus criteria for acute liver dysfunction with associated outcomes in critically ill children. DATA SOURCES Electronic searches of PubMed and Embase conducted from January 1992 to January 2020, used medical subject heading terms and text words to characterize acute liver dysfunction and outcomes. STUDY SELECTION Studies evaluating critically ill children with acute liver dysfunction, assessed screening tools, and outcomes were included. Studies evaluating adults, infants ≤36 weeks gestational age, or animals or were reviews/commentaries, case series with sample size ≤10, or non-English language studies were excluded. DATA EXTRACTION Data were abstracted from each eligible study into a data extraction form along with risk of bias assessment by a task force member. RESULTS The systematic review supports criteria for acute liver dysfunction, in the absence of known chronic liver disease, as having onset of symptoms &lt;8 weeks, combined with biochemical evidence of acute liver injury, and liver-based coagulopathy, with hepatic encephalopathy required for an international normalized ratio between 1.5 and 2.0. LIMITATIONS Unable to assess acute-on-chronic liver dysfunction, subjective nature of hepatic encephalopathy, relevant articles missed by reviewers. CONCLUSIONS Proposed criteria identify an infant, child, or adolescent who has reached a clinical threshold where any of the 3 outcomes (alive with native liver, death, or liver transplant) are possible and should prompt an urgent liaison with a recognized pediatric liver transplant center if liver failure is the principal driver of multiple organ dysfunction.

Nanomedicine in Hepatocellular Carcinoma: A New Frontier in Targeted Cancer Treatment

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and is associated with a dismal median survival of 2–9 months. The fundamental limitations and ineffectiveness of current HCC treatments have led to the development of a vast range of nanotechnologies with the goal of improving the safety and efficacy of treatment for HCC. Although remarkable success has been achieved in nanomedicine research, there are unique considerations such as molecular heterogeneity and concomitant liver dysfunction that complicate the translation of nanotheranostics in HCC. This review highlights the progress, challenges, and targeting opportunities in HCC nanomedicine based on the growing literature in recent years.

Formimidoyltransferase cyclodeaminase prevents the starvation-induced liver hepatomegaly and dysfunction through downregulating mTORC1

The liver is a crucial center in the regulation of energy homeostasis under starvation. Although downregulation of mammalian target of rapamycin complex 1 (mTORC1) has been reported to play pivotal roles in the starvation responses, the underpinning mechanisms in particular upstream factors that downregulate mTORC1 remain largely unknown. To identify genetic variants that cause liver energy disorders during starvation, we conduct a zebrafish forward genetic screen. We identify a liver hulk (lvh) mutant with normal liver under feeding, but exhibiting liver hypertrophy under fasting. The hepatomegaly in lvh is caused by enlarged hepatocyte size and leads to liver dysfunction as well as limited tolerance to starvation. Positional cloning reveals that lvh phenotypes are caused by mutation in the ftcd gene, which encodes the formimidoyltransferase cyclodeaminase (FTCD). Further studies show that in response to starvation, the phosphorylated ribosomal S6 protein (p-RS6), a downstream effector of mTORC1, becomes downregulated in the wild-type liver, but remains at high level in lvh. Inhibition of mTORC1 by rapamycin rescues the hepatomegaly and liver dysfunction of lvh. Thus, we characterize the roles of FTCD in starvation response, which acts as an important upstream factor to downregulate mTORC1, thus preventing liver hypertrophy and dysfunction.

Technical Note: Novel Use of CytoSorb™ Haemadsorption to Provide Wound Healing Support in Case of Severe Burn Trauma via Reduction of Hyperbilirubinaemia

Hyperbilirubinaemia has been shown to compromise wound healing in severely burned patients. The therapy options for patients with impairment of wound healing and subsequent severe liver dysfunction are limited. A novel extracorporeal treatment, CytoSorb® (CytoSorbents Corp, USA), is a whole blood adsorber composed of highly biocompatible and porous polystyrene divinylbenzene copolymer beads covered in a polyvinylpyrrolidone coating. It is capable of extracting mainly hydrophobic middle-sized (up to 55 kDa) molecules from blood via size exclusion, including cytokines and bilirubin. We performed therapy with CytoSorb® on a severely burned (48% Total Body Surface Area-TBSA) patient with secondary sclerosing cholangitis (SCC) to promote the wound healing process by reducing bilirubin concentrations and to bridge the time to spontaneous liver regeneration or eventually to liver transplantation after two skin transplantations had failed to provide wound closure. In the first 6 days the cartridge was changed on a daily basis and later after every 2–4 days. The therapy with six adsorbers decreased a total bilirubin concentration from 14.02 to 4.29 mg/dl. By maintaining a stable bilirubin concentration under 5 mg/dl, debridement of abdomen and upper extremities with autologous skin grafting and, 4 weeks later, autologous skin grafting of the back from scrotum and lower extremities were performed successfully. After wound healing had been achieved, the CytoSorb therapy was discontinued after 57 days and 27 adsorber changes. CytoSorb therapy can be a promising support of wound and skin graft healing in patients with severe burns and liver dysfunction due to a significant reduction of total bilirubin concentration.