Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis

Hepatorenal syndrome (HRS) is a serious complication of end-stage liver disease, occurring mainly in patients with advanced cirrhosis and ascites, who have marked circulatory dysfunction,1 as well as in patients with acute liver failure.2 In spite of its functional nature, HRS is associated with a poor prognosis,3 4 and the only effective treatment is liver transplantation. During the 56th Meeting of the American Association for the Study of Liver Diseases, the International Ascites Club held a Focused Study Group (FSG) on HRS for the purpose of reporting the results of an international workshop and to reach a consensus on a new definition, criteria for diagnosis and recommendations on HRS treatment. A similar workshop was held in Chicago in 1994 in which standardised nomenclature and diagnostic criteria for refractory ascites and HRS were established.5 The introduction of innovative treatments and improvements in our understanding of the pathogenesis of HRS during the previous decade led to an increasing need to undertake a new consensus meeting. This paper reports the scientific rationale behind the new definitions and recommendations. The international workshop included four issues debated by four panels of experts (see Acknowledgements). The issues were: (1) evidence-based HRS pathogenesis; (2) treatment of HRS using vasoconstrictors; (3) other HRS treatments using transjugular intrahepatic portosystemic stent-shunt (TIPS) and extracorporeal albumin dialysis (ECAD); and (4) new definitions and diagnostic criteria for HRS and recommendations for its treatment.

Altered thymic selection by overexpressing cellular FLICE inhibitory protein in T cells causes lupus-like syndrome in a BALB/c but not C57BL/6 strain.

The cellular FLICE inhibitory protein (c-FLIP) is an endogenous inhibitor of the caspase-8 proapoptotic signaling pathway downstream of death receptors. Recent evidence indicates that the long form of c-FLIP (c-FLIP(L)) is required for proliferation and effector T-cell development. However, the role of c-FLIP(L) in triggering autoimmunity has not been carefully analyzed. We now report that c-FLIP(L) transgenic (Tg) mice develop splenomegaly, lymphadenopathy, multiorgan infiltration, high titers of auto-antibodies, and proliferative glomerulonephritis with immune complex deposition in a strain-dependent manner. The development of autoimmunity requires CD4(+) T cells and may result from impaired thymic selection. At the molecular level, c-FLIP(L) overexpression inhibits the zeta chain-associated protein tyrosine kinase of 70 kDa (ZAP-70) activation, thus impairing the signaling pathway derived from ZAP-70 required for thymic selection. Therefore, we have identified c-FLIP(L) as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity.

Reversible cerebral vasoconstriction syndrome identification of prognostic factors.

OBJECT: Reversible cerebral vasoconstriction syndrome (RCVS) is described as a clinical and radiological entity characterized by thunderclap headaches, a reversible segmental or multifocal vasoconstriction of cerebral arteries with or without focal neurological deficits or seizures. The purpose of this study is to determine risk factors of poor outcome in patients presented a RCVS. METHODS: A retrospective multi-center review of invasive and non-invasive neurovascular imaging between January 2006 and January 2011 has identified 10 patients with criterion of reversible segmental vasoconstriction syndrome. Demographics data, vascular risks and evolution of each of these patients were analyzed. RESULTS: Seven of the ten patients were females with a mean age of 46 years. In four patients, we did not found any causative factors. Two cases presented RCVS in post-partum period between their first and their third week after delivery. The other three cases were drug-induced RCVS, mainly vaso-active drugs. Cannabis was found as the causative factor in two patient, Sumatriptan identified in one patient while cyclosporine was the causative agent in also one patient. The mean duration of clinical follow-up was 10.2 months (range: 0-28 months). Two patients had neurological sequelae: one patient kept a dysphasia and the other had a homonymous lateral hemianopia. We could not find any significant difference of the evolution between secondary RCVS and idiopathic RCVS. The only two factors, which could be correlated to the clinical outcome were the neurological status at admission and the presence of intraparenchymal abnormalities (ischemic stroke, hematoma) in brain imaging. CONCLUSIONS: Fulminant vasoconstriction resulting in progressive symptoms or death has been reported in exceptional frequency. Physicians had to remember that such evolution could happen and predict them by identifying all factors of poor prognosis (neurological status at admission, the presence of intraparenchymal abnormalities).

Phenytoin-associated severe hypocalcemia with seizures in a patient with a TSC2-PKD1 contiguous gene syndrome.

We report the case of an inaugural episode of generalized seizures in a 40-year-old male with a history of chronic kidney disease associated with TSC2-PKD1 contiguous gene syndrome. This patient was under prophylactic treatment of phenytoin since 2 years because of a subarachnoid hemorrhage due to a ruptured cerebral aneurysm. Laboratory results revealed therapeutic range of phenytoin levels, but severe hypocalcemia associated with profound vitamin D deficiency that could not be explained by secondary hyperparathyroidism alone. The interaction of phenytoin on the P-450 cytochromes activity has been demonstrated to accelerate the rate of 25-hydroxivitamin D3 and 1α,25-dihydroxivitamin D3 catabolism into inactive metabolites, leading to hypocalcemia. Physicians should be aware of significant phenytoin interactions on vitamin D metabolism which may lead to symptomatic hypocalcemia in patients with chronic kidney disease.

Long-term follow-up of patients with congenital myasthenic syndrome caused by COLQ mutations.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COlQ) cause recessive forms of synaptic CMS with end plate AChE deficiency. We present data on 15 COLQ -mutant CMS carrying 16 different mutations (9 novel ones identified) followed-up for an average period of 10 ears. The mean age at the first examination was 19 ears old (range from 3 to 48). We report relapses during short or long-term periods characterized by worsening of muscle weakness sometimes associated with respiratory crises. All the relapses ended spontaneously or with 3-4 DAP or ephedrine with no residual impairment. The triggering factors identified were esterase inhibitors, effort, puberty or pregnancy highlighting the importance of hormonal factors. There was no genotype-phenotype correlation. At the end of the follow-up, 80% of patients were ambulant and 87% of patients had no respiratory trouble in spite of severe relapses.