Vitamin D deficiency in cirrhosis relates to liver dysfunction rather than aetiology

AIM: To examine the vitamin D status in patients with alcoholic cirrhosis compared to those with primary biliary cirrhosis. METHODS: Our retrospective case series comprised 89 patients with alcoholic cirrhosis and 34 patients with primary biliary cirrhosis who visited our outpatient clinic in 2005 and underwent a serum vitamin D status assessment. RESULTS: Among the patients with alcoholic cirrhosis, 85% had serum vitamin D levels below 50 nmol/L and 55% had levels below 25 nmol/L, as compared to 60% and 16% of the patients with primary biliary cirrhosis, respectively (P < 0.001). In both groups, serum vitamin D levels decreased with increasing liver disease severity, as determined by the Child-Pugh score. CONCLUSION: Vitamin D deficiency in cirrhosis relates to liver dysfunction rather than aetiology, with lower levels of vitamin D in alcoholic cirrhosis than in primary biliary cirrhosis.

Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease

The prevalence of obesity and related conditions like non-alcoholic fatty liver disease(NAFLD) is increasing worldwide and therapeutic options are limited.Alternative treatment options are therefore intensively sought after.An interesting candidate is the natural polyphenol resveratrol(RSV) that activates adenosinmonophosphate-activated protein kinase(AMPK) and silent information regulation-2 homolog 1(SIRT1).In addition,RSV has known anti-oxidant and anti-inflammatory effects.Here,we review the current evidence for RSVmediated effects on NAFLD and address the different aspects of NAFLD and non-alcoholic steatohepatitis(NASH) pathogenesis with respect to free fatty acid(FFA) flux from adipose tissue,hepatic de novo lipogenesis,inadequate FFA β-oxidation and additional intra- and extrahepatic inflammatory and oxidant hits.We review the in vivo evidence from animal studies and clinical trials.The abundance of animal studies reports a decrease in hepatic triglyceride accumulation,liver weight and a general improvement in histological fatty liver changes,along with a reduction in circulating insulin,glucose and lipid levels.Some studies document AMPK or SIRT1 activation,and modulation of relevant markers of hepatic lipogenesis,inflammation and oxidation status.However,AMPK/SIRT1-independent actions are also likely.Clinical trials are scarce and have primarily been performed with a focus on overweight/obese participants without a focus on NAFLD/NASH and histological liver changes.Future clinical studies with appropriate design are needed to clarify the true impact of RSV treatment in NAFLD/NASH patients.

Treatment of Budd-Chiari syndrome with a focus on transjugular intrahepatic portosystemic shunt

AIM:To evaluate long-term complications and survival in patients with Budd-Chiari syndrome (BCS) referred to a Danish transjugular intrahepatic portosystemic shunt (TIPS) centre.METHODS:Twenty-one consecutive patients from 1997-2008 were retrospectively included [15 women and 6 men,median age 40 years (range 17-66 years)].Eighteen Danish patients came from the 1.8 million catchment population of Aarhus University Hospital and three patients were referred from Scandinavian hospitals.Management consisted of tests for underlying haematological,endocrinological,or hypercoagulative disorders parallel to initiation of specific treatment of BCS.RESULTS:BCS was mainly caused by thrombophilic (33%) or myeloproliferative (19%) disorders.Fortythree percents had symptoms for less than one week with ascites as the most prevalent finding.Fourteen (67%) were treated with TIPS and 7 (33%) were manageable with treatment of the underlying condition and diuretics.The median follow-up time for the TIPS-treated patients was 50 mo (range 15-117 mo),and none required subsequent liver transplantation.Ascites control was achieved in all TIPS patients with a marked reduction in the dose of diuretics.A total of 14 TIPS revisions were needed,mostly of uncovered stents.Two died during follow-up:One non-TIPS patient worsened after 6 mo and died in relation to transplantation,and one TIPS patient died 4 years after the TIPS-procedure,unrelated to BCS.CONCLUSION:In our BCS cohort TIPS-treated patients have near-complete survival,reduced need for diuretics and compared to historical data a reduced need for liver transplantation.

Protein tolerance to standard and high protein meals in patients with liver cirrhosis

AIM To investigate the plasma amino acid response and tolerance to normal or high protein meals in patients with cirrhosis.METHODS The plasma amino acid response to a 20 g mixed protein meal was compared in 8 biopsy-proven compensated cirrhotic patients and 6 healthy subjects.In addition the response to a high protein meal(1 g/kg body weight) was studied in 6 decompensated biopsy-proven cirrhotics in order to evaluate their protein tolerance and the likelihood of developing hepatic encephalopathy(HE) following a porto-caval shunt procedure.To test for covert HE,the "number connection test"(NCT) was done on all patients,and an electroencephalogram was recorded in patients considered to be at Child-Pugh C stage.RESULTS The changes in plasma amino acids after a 20 g protein meal were similar in healthy subjects and in cirrhotics except for a significantly greater increase(P < 0.05) in isoleucine,leucine and tyrosine concentrations in the cirrhotics.The baseline branched chain amino acids/aromatic amino acids(BCAA/AAA) ratio was higher in the healthy persons and remained stable-but it decreased significantly after the meal in the cirrhotic group.After the high protein meal there was a marked increase in the levels of most amino acids,but only small changes occurred in the levels of taurine,citrulline,cysteine andhistidine.The BCAA/AAA ratio was significantly higher 180 and 240 min after the meal.Slightly elevated basal plasma ammonia levels showed no particular pattern.Overt HE was not observed in any patients.CONCLUSION Patients with stable liver disease tolerate natural mixed meals with a standard protein content.The response to a high protein meal in decompensated cirrhotics suggests accumulation of some amino acids but it did not precipitate HE.These results support current nutritional guidelines that recommend a protein intake of 1.2-1.5 g/kg body weight/day for patients with cirrhosis.

Body composition changes after transjugular intrahepatic portosystemic shunt in patients with cirrhosis

AIM:To investigate the effect of transjugular intra-hepatic porto-systemic shunt (TIPS) on malnutrition in portal hypertensive cirrhotic patients.METHODS: Twenty-one patients with liver cirrhosis and clinical indications for TIPS insertion were investigated before and 1, 4, 12, 52 wk after TIPS. For each patient we assayed body composition parameters [dry lean mass, fat mass, total body water (TBW)], routine liver and kidney function tests, and free fatty acids (FFA). Glucose and insulin were measured for the calculation of the homeostasis model assessment insulin resistance (HOMA-IR); liver function was measured by the galactose elimination capacity (GEC); the severity of liver disease was graded by model for end-stage liver disease (MELD).RESULTS: Porto-systemic gradient decreased after TIPS (6.0±2.1 mmHg vs 15.8±4.8 mmHg, P<0.001). Patients were divided in two groups according to initial body mass index. After TIPS, normal weight patients had an increase in dry lean mass (from 10.9±5.9 kg to 12.7±5.6 kg, P=0.031) and TBW (from 34.5±7.6 L to 40.2±10.8 L,P=0.007), as well as insulin (from 88.9±49.2 pmol/L to 164.7±107.0 pmol/L,P=0.009) and HOMA-IR (from 3.36%±2.18% to 6.18%±4.82%,P=0.023). In overweight patients only FFA increased significantly (from 0.59±0.24 mmol/L to 0.93±0.34 mmol/L, P=0.023).CONCLUSION: TIPS procedure is effective in lowering portal pressure in patients with portal hypertension and improves body composition without significant changes in metabolic parameters.

Anti-CD163-dexamethasone conjugate inhibits the acute phase response to lipopolysaccharide in rats

AIM: To study the effect of a new anti-CD163-dexamethasone conjugate targeting activated macrophages on the hepatic acute phase response in rats. METHODS: Wistar rats were injected intravenous with either the CD163 targeted dexamethasone-conjugate(0.02 mg/kg) or free dexamethasone(0.02 or 1 mg/kg) 24 h prior to lipopolysaccharide(LPS)(2.5 mg/kg intraperitoneal). We measured plasma concentrations of tumour necrosis factor-a(TNF-a) and interleukin 6(IL-6) 2 h post-LPS and liver m RNAs and serum concentrations of the rat acute phase protein a-2-macroglobulin(a-2-M) 24 h after LPS. Also, plasma concentrations of alanine aminotransferase and bilirubin were measured at termination of the study. Spleen weight served as an indicator of systemic steroid effects.RESULTS: The conjugate halved the a-2-M liver m RNA(3.3 ± 0.6 vs 6.8 ± 1.1, P < 0.01) and serum protein(201 ± 48 μg/mL vs 389 ± 67 μg/mL, P = 0.04) after LPS compared to low dose dexamethasone treated animals, while none of the free dexamethasone doses had an effect on liver m RNA or serum levels of a-2-M. Also, the conjugate reduced TNF-a(7208 ± 1977 pg/mL vs 21583 ± 7117 pg/mL, P = 0.03) and IL-6(15685 ± 3779 pg/mL vs 25715 ± 4036 pg/mL, P = 0.03) compared to the low dose dexamethasone. The high dose dexamethasone dose decreased the spleen weight(421 ± 11 mg vs 465 ± 12 mg, P < 0.05) compared to controls, an effect not seen in any other group.CONCLUSION: Low-dose anti-CD163-dexamethasone conjugate effectively decreased the hepatic acute phase response to LPS. This indicates an anti-inflammatory potential of the conjugate in vivo.

Soluble membrane attack complex in ascites in patients with liver cirrhosis without infections

AIM: To study complement activation in 46 patients with alcoholic cirrhosis and ascites but no spontaneous bacterial peritonitis (SBP) and 10 healthy controls. METHODS: Complement activation was determined by the measurement of soluble membrane attack complex (sMAC) concentrations in ascites and plasma. In patients, metabolic liver function was determined by the galactose elimination capacity and the clinical status assessed by the Model of End-Stage Liver Disease and Child-Pugh scores. RESULTS: Ascites sMAC levels were markedly higherthan in the corresponding plasma sample (median (range): 596 (170 - 1519) vs 160 (77 - 848) μg/L; P < 0.01). Ascites sMAC levels correlated positively with liver status. There was no relationship between ascites sMAC and leukocyte count. No relationship between ascites sMAC and blood C-reactive protein, albumin or neutrophile count was found. Plasma sMAC concentrations were slightly higher in patients than in controls [130 μg/L (70 - 204); P = 0.04]. Neither sMAC in ascites nor plasma was related to mortality. CONCLUSION: The increased sMAC concentration in ascites and plasma indicate an activation of the complement system in cirrhosis even in the absence of SBP. This was particularly evident in the peritoneal fluid and most marked in patients with preserved liver status. The high ascites sMAC levels may reflect transudation of membrane attack complexes from the liver. Whether this complement activation has any clinical implications remains to be clarified.

Deep hyperammonemic hepatic encephalopathy precipitated by fecal microbiota transplantation for fulminant Clostridioides difficile infection

Introduction Fecal microbiota transplantation(FMT)is highly effective and potentially life-saving for recurrent Clostridioides difficile infection(CDI)[1].Recent pilot trials also reported the use of FMT to revert hepatic encephalopathy(HE)in patients with decompensated liver cirrhosis without infectious colitis[2,3].Intestinal microbiota-driven hyperammonemia is central to HE development and most treatments aim to reduce ammonia levels by modulating the intestinal microbiota.However,FMT might lead to increased intestinal ammonia production,as we describe here.