Portal pressure is of significant prognostic value in primary biliary cholangitis.

BACKGROUND AND AIMS: In other forms of chronic liver disease, measurement of portal pressure is of prognostic value, but this has not yet been established in primary biliary cholangitis (PBC). The aim of the study is to determine the prognostic value of hepatic venous pressure gradient (HVPG) in relation to liver-related survival outcomes, as well as to the development of hepatic decompensation, oesophageal varices and variceal bleeding. METHODS: Baseline HVPG and liver biopsies were obtained in 86 patients followed for 10 years in a controlled trial of colchicine treatment, and subsequently in a long-term observational cohort study for a further 30 years. RESULTS: There were 49 Hepatic deaths in addition to 10 Liver Transplants (Hepatic death/transplant; n = 59). Some of these were associated with a significant variceal bleed within 3 months of death or transplant (Portal hypertension-associated death or transplant; n = 19). There were 63 deaths from all causes. During follow-up, oesophageal varices developed in 26 patients, whilst 17 bled from varices and 32 developed hepatic decompensation over a median follow-up of 18.1 years (1.9-28.5). Baseline HVPG was highly predictive of all 6 clinical outcomes and contributed significant predictive information additional to that provided by Mayo score and Ludwig stage. CONCLUSION: Measurement of baseline portal pressure is of significant prognostic value in primary biliary cholangitis.

Portal hypertension in primary biliary cholangitis: prevalence, natural history and histological correlates.

OBJECTIVES: The histopathological mechanisms underlying portal hypertension in primary biliary cholangitis (PBC) are poorly understood, as is its natural history. We have therefore determined the prevalence, severity and progression of portal hypertension in PBC and investigated whether its presence is related to specific histological lesions. METHODS: Hepatic venous pressure gradient (HVPG) was measured in 86 patients, with 186 assessments over up to 7 years of follow-up and the results correlated with a semiquantitative grading of 8 histological features and nodular regenerative hyperplasia (NRH). RESULTS: Portal hypertension (HVPG >5 mmHg) was present in 88% of all assessments (86% at baseline), and in 45% of patients at baseline was >12 mmHg (high-risk portal hypertension). The rise in portal pressure occurs early in the disease, since 45% of patients with normal serum bilirubin had a raised HVPG, as did 72% of patients with early (Ludwig stages 1 and 2) disease. After baseline, there was a small increase in HVPG over the next 5 years in most patients. In patients with precirrhotic PBC, 82% had portal hypertension and in 34% this was >12 mmHg. Portal pressure correlated significantly with a semiquantitative grading of cholestasis, interface hepatitis and portal tract and sinusoidal fibrosis. NRH was present in only 20% of wedge biopsies. CONCLUSIONS: Portal hypertension commences in the early stages of PBC, long preceding both rises in serum bilirubin and the development of cirrhosis. Around 34% of precirrhotic PBC patients have 'high-risk' portal hypertension, which is associated with lesions in the portal tracts and sinusoids rather than with NRH.

Ursodeoxycholic acid in primary biliary cirrhosis improves glutathione status but fails to reduce lipid peroxidation.

BACKGROUND: Ursodeoxycholic acid (UDCA) may slow progression in primary biliary cirrhosis (PBC), but its effect on survival is controversial. We have previously demonstrated that oxidant stress, with severely depressed plasma glutathione, is a feature of untreated PBC; this study examines the effect of UDCA on lipid peroxidation, antioxidant status and associated processes. PATIENTS AND METHODS: Markers of lipid peroxidation, antioxidant status, hepatic fibrogenesis, inflammation, cholestasis and synthetic function were measured at 0, 3, 6, 9 and 12 months in blood and urine from 35 PBC patients receiving UDCA. RESULTS: Plasma glutathione, reflecting intrahepatic levels, climbed steadily on UDCA; although still subnormal, the median value at 12 months was 2.4-fold higher than the untreated level. Liver enzyme markers and C-reactive protein also improved, whilst PIIINP improved steadily, but the change did not attain statistical significance. Serum bilirubin remained unchanged and total antioxidant capacity, albumin and vitamin E decreased after 12 months' UDCA treatment. 8-Isoprostane increased and malondialdehyde was unchanged. CONCLUSIONS: UDCA treatment partially corrected plasma glutathione status and some other biomarkers greatly improved, but lipid peroxidation was not reduced. UDCA may, therefore, require supplementation with glutathione precursors and/or antioxidant cocktails to reduce oxidant stress and thus delay disease progression to cirrhosis.

Non-invasive monitoring of oxidant stress in alcoholic liver disease.

OBJECTIVE: In alcoholic liver disease (ALD), progression from initial steatosis, through hepatitis to cirrhosis is well described, resulting in 20,000 deaths in the UK annually. However, pathological mechanisms are not well understood and drug trials have led to conflicting results. It has been established that alcohol consumption increases hepatic free radical production and oxidant stress has been implicated in the disease process. MATERIAL AND METHODS: Markers of lipid peroxidation, antioxidant status, hepatic fibrogenesis, inflammation and liver function were measured in blood and urine from 24 patients with established alcoholic cirrhosis and in 49 age- and sex-matched controls. RESULTS: In the ALD group, lipid peroxidation markers 8-isoprostane and malondialdehyde were significantly increased (p<0.001), as was the ratio of oxidized to reduced glutathione (p=0.027). The antioxidants selenium, glutathione (whole blood and plasma) and vitamins A, C and E were all significantly decreased (p<0.001); median plasma glutathione levels were only 19% of control levels. Type III procollagen peptide (PIIINP), a serum marker of hepatic fibrogenesis, and C-reactive protein (CRP) were both increased (p<0.001). Urinary 8-isoprostane correlated positively with PIIINP, CRP and markers of cholestasis (alkaline phosphatase and bilirubin) and negatively with glutathione (whole blood), vitamins A and E and albumin. CONCLUSIONS: Oxidant stress, as reflected in blood and urine by a wide range of pro- and antioxidant markers, is a significant feature of alcoholic cirrhosis, providing a mechanism by which alcohol intake may be linked to hepatic inflammation and fibrosis. Non-invasive markers could prove valuable in monitoring response to treatment during clinical trials.

Transjugular intrahepatic porto-systemic shunt and variceal embolisation in the management of bleeding stomal varices.

BACKGROUND AND AIMS: Bleeding from stomal varices is uncommon. Local measures to control the bleeding offer short-lived control. Our experience with transjugular intrahepatic porto-systemic shunt (TIPS) and variceal embolisation is presented and appraised. PATIENT AND METHODS: Three patients presented with bleeding from stomal varices (Child-Pugh class B, n=2 and class C, n=1) in association with primary sclerosing cholangitis, autoimmune hepatitis and alcoholic liver disease. Local treatment measures including suture ligation, sclerotherapy and re-siting of the stoma achieved short-lived control. TIPS were inserted in all 3 patients, with embolisation of the stomal varices in 2. RESULTS/FINDINGS: The radiological interventions were uncomplicated and resulted in cessation of the bleeding in all patients. One of the patients has had no further bleeding at 12 months' follow-up post-TIPS insertion. The other two patients re-bled at 5 and 6 months post-TIPS insertion and were successfully managed by insertion of a second TIPS in one patient and by balloon dilatation of the TIPS in another. The former patient has had no re-bleeding at a further 8 months' follow-up, while the latter had re-bleeding at 12 months post-TIPS insertion and underwent liver transplantation. INTERPRETATION/CONCLUSION: Transjugular intrahepatic porto-systemic shunt with variceal embolisation offers an effective, minimally invasive management option in patients with bleeding stomal varices, and may be used as the primary mode of intervention in conjunction with medical therapy, and as the definitive therapy in patients unfit for surgery. TIPS and variceal embolisation do not preclude subsequent liver transplantation, and may be used during the acute situation as a bridge to transplantation.

Oxidant stress in type I autoimmune hepatitis: the link between necroinflammation and fibrogenesis?

Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology characterized by circulating autoantibodies, hyperglobulinaemia and interface hepatitis. The mechanisms of progression from initial autoimmune attack to fibrosis and cirrhosis are unclear but oxidant stress may be involved. Markers of lipid peroxidation, antioxidant status, hepatic fibrogenesis and liver function were measured in blood and urine in 35 controls and in 33 patients with type-1 AIH; histology was assessed in 18 patients. In AIH, markers of lipid peroxidation were significantly elevated (8-isoprostane in both plasma and urine P < 0.001; plasma malondialdehyde P = 0.017). Total antioxidant capacity in protein-free serum and total glutathione in both whole blood and plasma were significantly reduced (P = 0.007, P = 0.037, P < 0.001, respectively). The antioxidants selenium, vitamin A and vitamin E were significantly decreased (P = 0.007, P < 0.001, P = 0.025, respectively); vitamin C was unchanged. Urinary 8-isoprostane correlated positively with interface hepatitis and necroinflammatory score and with hepatic fibrogenesis (type III procollagen peptide). Interface hepatitis correlated negatively with vitamin A and whole blood total glutathione. Oxidant stress, as reflected in blood and urine by a wide range of pro- and antioxidant markers, is a significant feature of AIH and provides a probable mechanism linking hepatic necroinflammation to fibrogenesis and disease progression.

Oxidant stress is a significant feature of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic cholestatic disorder characterised by an immunological, and often granulomatous, attack on bile ducts leading to fibrosis, cirrhosis, liver failure and death. Animal and human studies suggest that oxidant stress plays a key role in progression of other liver diseases, but no comprehensive investigation has been performed previously in PBC. A wide range of lipid peroxidation and antioxidant markers were measured in the blood and urine of 41 patients with histologically confirmed PBC. Lipid peroxidation markers were significantly elevated [plasma and urinary 8-isoprostane, P<0.001; plasma malondialdehyde (MDA), P=0.007] compared to age- and sex-matched controls. The most striking antioxidant depletion occurred with plasma total glutathione where levels were significantly reduced (30% of controls). Total serum antioxidant levels were decreased (P=0.013) and serum selenium and vitamin A were also lower (both P<0.001); vitamins C and E were normal. Most patients had early disease biochemically and were Child-Pugh grade A. Urinary 8-isoprostane correlated positively with Ludwig stage and markers of hepatic injury and cholestasis. This study clearly demonstrates that oxidant stress, as reflected in a comprehensive spectrum of lipid peroxidation and antioxidant markers, is a significant feature of early-stage PBC.

Oxidative stress in chronic hepatitis C: not just a feature of late stage disease.

BACKGROUND/AIMS: Chronic hepatitis C infection is a major world-wide problem, frequently progressing to cirrhosis, liver failure or hepatoma. The pathological mechanisms of disease progression are unclear but oxidant stress may play a role. METHODS: Markers of lipid peroxidation, antioxidant status, hepatic fibrogenesis and liver function were measured in blood or urine from 42 chronic hepatitis C patients. Fibrosis was graded histologically in a subgroup of 33 patients. RESULTS: The lipid peroxidation marker 8-isoprostane and the ratio of oxidized to reduced glutathione were significantly elevated (P<0.001, P=0.006). The antioxidants glutathione, selenium and vitamins A, C and E were significantly decreased (all P<0.001) compared to age and sex matched controls. Abnormal values were more marked in cirrhotics, but significant changes were also observed in the non-cirrhotic group. The fibrosis score correlated positively with urinary 8-isoprostane and type III procollagen peptide and negatively with vitamin A. CONCLUSIONS: Oxidant stress, as reflected in blood and urine by a wide range of pro- and antioxidant markers, is a significant feature of hepatitis C infection. Although more severe in the cirrhotic group, there was clear evidence of oxidant stress in non-cirrhotic patients. Antioxidant therapy may therefore have a role in slowing disease progression to cirrhosis.