Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt insertion: a decade of experience.

BACKGROUND: Since its introduction, transjugular intrahepatic portosystemic shunt (TIPS) has been extensively used for treatment of portal hypertension. We report a decade of experience with particular emphasis on characterizing post-TIPS hepatic encephalopathy (HE). AIM: To determine the frequency of clinically evident or minimal HE post-TIPS, identify predisposing factors and determine the impact of minimal HE on quality of life. DESIGN: Prospective data collection and retrospective case notes analysis. METHODS: Of 197 patients referred for TIPS insertion, 136 patients who survived the procedure by more than 4 weeks were available for assessment. Data collected at TIPS insertion was supplemented by case note analysis. Psychometric testing was performed and health profile questionnaires administered on patients still attending. RESULTS: Most patients had alcoholic liver disease (62.4%) and bleeding varices unresponsive to endoscopic therapy (86%). Clinically evident post-TIPS HE developed in 34.5% of patients, was of similar frequency in the groups treated with polytetrafluoroethylene covered and uncovered stents, and the only significant predictor was pre-TIPS HE. Post-TIPS HE necessitating liver transplant or contributing to death occurred in only 14 (10.3%) patients. Minimal encephalopathy (abnormal psychometry) was present in 49% of patients at 26 (3-123) months after TIPS but this frequency was similar in a cohort of cirrhotics being assessed for liver transplant. However, patients with abnormal psychometry had significantly lower quality of life scores than those with normal psychometry. CONCLUSION: Although, HE is relatively common after TIPS insertion, with careful selection of patients it is usually short-lived and easily managed. Minimal HE is no more prevalent than expected in a cirrhotic population without TIPS.

Monitoring methotrexate-induced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified?

BACKGROUND: Reports that up to 26% of subjects with psoriasis develop cirrhosis have led to a recommendation of serial liver biopsies after each cumulative dose of 1500 mg of methotrexate. AIM: To evaluate the progression of liver injury in patients with psoriasis and the impact of monitoring by liver biopsy on their management. METHODS: One hundred and twenty-one liver biopsies from 66 subjects (aged 11-79 years) with psoriasis, receiving a median cumulative dose of 3206 mg of methotrexate over a period of 280.5 weeks, were evaluated. RESULTS: The assessment of advanced fibrosis according to the Ishak system (>or= 4) correlated perfectly with that of the Scheuer system (>or= 3) and poorly with that of the Roenigk scale (>or= 3b) (r2 = 1.0 and 0.31, respectively). Two of 24 pre-treatment biopsies showed advanced fibrosis and both subjects were heavy drinkers. The cumulative probabilities of advanced fibrosis (Ishak >or= 4) were 0%, 2.6%, 2.6%, 8.2% and 8.2% at cumulative doses of 1500, 3000, 4500, 5000 and 6000 mg, respectively. None of the subjects developed cirrhosis during follow-up or discontinued therapy on the basis of liver biopsy findings. CONCLUSIONS: Advanced hepatic fibrosis with low-dose methotrexate therapy is much less frequent than previously reported. Pre-treatment or monitoring liver biopsies in accordance with the current guidelines have little impact on patient management.

Quantitative assessment of fibrosis and steatosis in liver biopsies from patients with chronic hepatitis C.

BACKGROUND: Hepatic fibrosis is one of the main consequences of liver disease. Both fibrosis and steatosis may be seen in some patients with chronic hepatitis C and alcoholic liver disease (ALD). AIMS: To quantitate fibrosis and steatosis by stereological and morphometric techniques in patients with chronic hepatitis C and compare the results with a control group of patients with ALD. In addition, to correlate the quantitative features of fibrosis with the Ishak modified histological score. MATERIALS AND METHODS: Needle liver biopsies from 86 patients with chronic hepatitis C and from 32 patients with alcoholic liver disease (disease controls) were analysed by stereological and morphometric analyses using the Prodit 5.2 system. Haematoxylin and eosin and Picro-Mallory stained sections were used. The area fractions (A(A)) of fibrosis, steatosis, parenchyma, and other structures (bile duct and central vein areas) were assessed by stereological method. The mean diameters of fat globules were determined by morphometric analysis. RESULTS: Significant differences were found in the A(A) of fibrosis, including fibrosis within portal tract areas, between chronic hepatitis C patients and those with ALD (mean (SD): 19.14 (10.59) v 15.97 (12.51)). Portal and periportal (zone 1) fibrosis was significantly higher (p = 0.00004) in patients with chronic hepatitis C compared with the control group (mean (SD): 9.04 (6.37) v 3.59 (3.16)). Pericentral fibrosis (zone 3) occurred in both groups but was significantly more pronounced in patients with ALD. These results correlate well with the modified Ishak scoring system. However, in patients with cirrhosis (stage 6) with chronic hepatitis C the A(A) of fibrosis varied between 20% and 74%. The diameter of fat globules was significantly lower in patients with hepatitis C (p = 0.00002) than the ALD group (mean (SD): 14.44 (3.45) v 18.4 (3.32)). Microglobules were more frequent in patients with chronic hepatitis C than in patients with ALD. In patients with chronic hepatitis C, the fat globules had a zonal distribution in comparison with pan steatosis in ALD. CONCLUSION: Quantitative, stereological techniques are simple and reliable for evaluating hepatic fibrosis and steatosis in chronic hepatitis C. They are most useful for assessing the origin, location, and the stage of fibrosis. Stereology and morphometry are recommended for the quantitation of fibrosis and steatosis, particularly for the evaluation of new treatment strategies in patients with chronic hepatitis C.

Effect of L-ornithine-L-aspartate on patients with and without TIPS undergoing glutamine challenge: a double blind, placebo controlled trial.

BACKGROUND AND AIM: An oral glutamine load in cirrhotic patients awaiting liver transplantation was shown to cause a rise in blood ammonia and psychometric abnormalities which were reversed by hepatic transplantation. L-Ornithine-L-aspartate (LOLA) has been shown to reduce ammonia and improve psychometric function in patients with hepatic encephalopathy. The aim of the present study was to assess the effect of LOLA in healthy patients with cirrhosis and no evidence of clinical encephalopathy after challenging the central nervous system by administration of oral glutamine. PATIENTS AND METHODS: Eight cirrhotics (Child's B or C) without transjugular intrahepatic portosystemic shunts (TIPS) and seven with TIPS underwent two oral glutamine (20 g) challenges, receiving LOLA (5 g intravenously) on one occasion and placebo on the other in random order. Psychometric tests, including choice reaction time (CRT) and number connection test, were performed before and after glutamine, together with electroencephalography and blood ammonia. RESULTS: Mean basal ammonia was 27 (SEM 5) micromol/l in non-TIPS and 76 (10) micromol/l in TIPS patients (p<0.05). Basal CRT 2 was 0.643 (0.033) s in non-TIPS and 0.825 (0.076) s in TIPS patients (p<0.02). In non-TIPS patients, ammonia increased to 36 (10) micromol/l when LOLA was administered and to 62 (13) micromol/l with placebo (p<0.02). There was no alteration in psychometric function in non-TIPS patients after glutamine when LOLA was given but when placebo was given, glutamine caused prolongation of CRT (p=0.02). Glutamine did not affect psychometric function in TIPS patients with or without LOLA. CONCLUSION: This study showed that LOLA ameliorated the deleterious psychometric effects of glutamine in Child's grade B and C patients with cirrhosis without TIPS and supports its use in clinical practice in hepatic encephalopathy.

Do gastric and oesophageal varices bleed at different portal pressures and is TIPS an effective treatment?

BACKGROUND: It has been suggested that gastric varices bleed at lower portosystemic pressure gradients (PSPG) than oesophageal varices and that transjugular intrahepatic portosystemic shunt (TIPS) is a particularly effective treatment in these patients. AIMS: This study was undertaken to assess the difference in PSPG measured at the time of TIPS insertion between patients bleeding from gastric and those bleeding from oesophageal varices. Rebleeding and mortality rates between the two groups were also compared. PATIENTS AND METHODS: In a five year period, 64 patients (36 males and 28 females) undergoing TIPS for acute variceal bleeding had PSPG measured at the time of TIPS insertion. 12 patients underwent TIPS for gastric variceal haemorrhage (GVH) and 52 for oesophageal variceal haemorrhage (OVH). The median age was 53 years and 40/64 patients (63%) had alcoholic liver disease. The median Child's Pugh score was 8 for GVH and 9 for OVH patients. Median follow up was 75 weeks. RESULTS: There was no significant difference in median PSPG between patients with GVH, 21 mmHg (range 15-30 mmHg) and OVH, 22 mmHg (range 12-45 mmHg). Following TIPS, PSPG was 8.5 mmHg (range 3-11 mmHg) and 9 mmHg (range 4-20 mmHg) in GVH and OVH patients respectively. Rebleeding occurred in 2/12 (16%) GVH patients and 12/52 (23%) OVH patients (p= 1.0). Mortality during follow up was 25% (4/12) in the GVH and 25% (13/52) in the OVH patients. CONCLUSION: In this study, there was no difference between the pressures at which gastric and oesophageal varices bled. Rebleeding and mortality rates were similar in the two groups. TIPS is equally effective in the treatment of both oesophageal and gastric variceal haemorrhage.

Hepatitis C virus genotypes in a cohort of Middle Eastern patients.

BACKGROUND: The epidemiology of hepatitis C virus infection has been well characterized in Western Europe, North America and Japan. Less is known about it in other regions of the world. In order to fully understand the relationship between host and virus, it is important to study the effect of virus infection in all regions of the world. In this report, we have analyzed patients from the United Arab Emirates, Egypt and Jordan. DESIGN AND METHODS: Serum from 81 Middle Eastern HCV ELISA-2-positive patients was analyzed for the presence of HCV RNA by PCR. RNA-positive patients were genotyped by selective hybridization of amplicons to HCV genotype-specific oligonucleotides (InnoLipa2, Innogenetics, Belgium). Where possible, data was also obtained on racial origin, liver histology, serum ALT, prothrombin time, albumin, and risk factors for infection. RESULTS: Sixty-five of 81 patients were HCV RNA-positive. A higher proportion of Middle Eastern patients were genotype 4 compared to equivalent studies from Western Europe, USA and Japan. However, the most common genotype was 1a. No significant difference in genotype was found between patients with chronic hepatitis and patients with cirrhosis. CONCLUSIONS: Eight of 65 (12%) patients were genotype 4, but the most common genotype was 1a, a âWesternâ genotype (24/65, 37%). The mean age of cirrhotics was low compared to Western studies. This may be due to infection in early childhood or race-related host factors. Twelve of 65 patients (18%) were not classifiable for genotype using InnoLipa2. This may be due to multiple infecting genotypes in these patients, or unusual, non 13 HCV genotypes which cannot be classified by InnoLipa2.

Quantitative studies of testicular atrophy following portacaval shunt in rats.

To evaluate the differential effects of portacaval shunting (PCS) on the morphological changes that occur in humans with portal-systemic encephalopathy, male rats underwent either PCS (13) or sham operations (10). Normal adult rats (6) were used as controls. All animals were killed 5 to 7 weeks after the surgery. The wet weight of the testes was obtained. Hematoxylin-eosin (HE)-stained sections at 5-micrometers thickness were used for stereological analysis using an image analysis system. Apoptosis was assessed quantitatively in HE and in in situ end-labeling (ISEL)-stained slides, while mitotic activity and mast cell numbers were assessed in 20 high-power fields. There was a significant reduction in the testicular mass (664 mg) in PCS rats in comparison with sham (2,199 mg) and control (1,937 mg) rats (P <.00001). The thickness of germinal epithelium was significantly reduced in PCS rats (64 micrometers) compared with sham (126 micrometers) and control groups (108 micrometers). The number of tubules per square millimeter and the mean curvature were significantly increased in PCS rats (P <.00001). There was a 112-fold increase in apoptosis in PCS rats (112) in comparison with the control and sham-operation groups (1.2 and 0.7, respectively). Mitosis was significantly reduced in the PCS group (P =.0089), but mast cells were unchanged. The results suggest that PCS in the absence of liver dysfunction produces testicular atrophy by reduction in mitosis, maturation arrest, and increased apoptosis of the germinal epithelium. PCS may therefore be responsible for gonadal atrophy that occurs with advanced liver disease in humans.

Quantitative assessment of gastric atrophy using the syntactic structure analysis.

AIM: To assess the topographical relation between gastric glands, using the minimum spanning tree (MST), to derive both a model of neighbourhood and quantitative representation of the tissue's architecture, to assess the characteristic features of gastric atrophy, and to assess the grades of gastric atrophy. METHODS: Haematoxylin and eosin stained sections from corporal and antral biopsy specimens (n = 139) from normal patients and from patients with nonatrophic gastritis and atrophic gastritis of grades 1, 2, and 3 (Sydney system) were assessed by image analysis system (Prodit 5.2) and 11 syntactic structure features were derived. These included both line and connectivity features. RESULTS: Syntactic structure analysis was correlated with the semiquantitative grading system of gastric atrophy. The study showed significant reductions in the number of points and the length of MST in both body and antrum. The standard deviation of the length of MST was significantly increased in all grades of atrophy. The connectivity to two glands was the highest and most affected by the increased grade of atrophy. The reciprocal values of the Wiener, Randic, and Balaban indices showed significant changes in the volume of gland, abnormality in the shape of glands, and changes in irregularity and branching of the glands in both types of gastric mucosa. There was a complete separation in the MST, connectivity, and index values between low grade and high grade gastric atrophy. CONCLUSIONS: (1) Gastric atrophy was characterised by loss of the gland, variation in the volume, reduction in the neighbourhood, irregularity in spacing, and abnormality in the shape of the glands. (2) Syntactic structure analysis significantly differentiated minor changes in gastric gland (low grade atrophy) from high grade atrophy of clinical significance. (3) Syntactic structure analysis is a simple, fast, and highly reproducible technique and appears a promising method for quantitative assessment of atrophy.

Transjugular intrahepatic portosystemic shunt: a limited role in refractory ascites.

OBJECTIVE: To evaluate the role of the transjugular intrahepatic portosystemic shunt (TIPS) in the management of patients with refractory ascites. DESIGN: A retrospective study of 25 consecutive patients for whom refractory ascites was the primary indication for TIPS insertion. SETTING: Regional liver unit at Freeman Hospital, Newcastle upon Tyne, UK. PARTICIPANTS AND INTERVENTIONS: Twelve male and 13 female patients with a mean age of 58 years and mean Child-Pugh score of 10, treated with TIPS for refractory ascites between July 1992 and September 1995. MAIN OUTCOME MEASURES: Effect of TIPS on mortality, ascites and hospital admission rate. RESULTS: TIPS was successfully placed in all patients with a 59% mean reduction in portosystemic pressure gradient. Response rate was 68%, 48% and 33% at 1, 3 and 12 months, respectively. Mortality was 48% at 3 months and 67% at 12 months, being higher in those patients older than 60, those with renal impairment and those with higher Child-Pugh score. Amongst nine patients surviving long term (> 12 months) the mean time spent in hospital in the 3 months before TIPS was 35 days and in the year following TIPS 30 days. Patients who died (16 in total) spent a mean of 19 days in hospital before TIPS, 10 never leaving hospital, and 6 who were discharged spent a mean of 19 days post procedure in hospital (mean survival 84 days). CONCLUSION: TIPS has a limited role in the management of patients with refractory ascites. It is not an appropriate treatment where patients are older than 60, have renal impairment (creatinine > 200 mumol/l) or have a Child-Pugh score greater than 10.

Multiple biochemical effects in the pathogenesis of alcoholic fatty liver.

The pathogenesis of alcoholic fatty liver is unknown, but several causes have been proposed based on biochemical findings. These include the metabolism of alcohol leading to a shift in the cytosolic [NAD+]/ [NADH] ratio to reduction, which in turn causes a direct inhibition of beta-oxidation and enhanced triacylglycerol formation via the [glycerol-3-phosphate]/[dihydroxyacetone phosphate] ratio. There are also chronic effects of ethanol on hepatic enzyme activities. Thus, increased activity of phosphatidate phosphohydrolase, an increased amount of fatty acid binding protein, decreased secretion of very low-density lipoprotein and impairment of the respiratory chain as a result of decreased protein synthesis or decreased amounts of ubiquinone could all lead to fat accumulation and steatosis. The interplay of each of these with nutritional and genetic factors would then lead to the heterogeneity of the severity and characteristics of the steatosis observed in human alcoholics.

Oral glutamine challenge in cirrhotics pre- and post-liver transplantation: a psychometric and analyzed EEG study.

Latent or sub-clinical hepatic encephalopathy is a recognized complication of cirrhosis and is thought to represent one end of the spectrum of neuropsychiatric impairment, which occurrs as a result of portal-systemic shunting. We studied the psychometric, analyzed electroencephalography (EEG), and venous blood ammonia responses to an oral glutamine challenge in 17 patients with cirrhosis and in 4 normal controls. The cirrhotics were attending for liver transplant assessment and had no clinical evidence of hepatic encephalopathy. The oral glutamine challenge was repeated following liver transplantation. Five of sixteen patients (31%) showed impaired performance on at least one of the baseline psychometric tests. There was a correlation between fasting venous ammonia and choice reaction time (r = .7, P < .01). Following glutamine challenge there was a significant increase in blood ammonia from a mean fasting value ranging between 58 micromol/L to 120 micromol/L (P < .01), between significant prolongation of reaction times of 387 ms to 428 ms (P < .01), and an increase in mean EEG amplitude between 68.5 microV to 78.6 microV (P < .001). Four normal controls who were challenged with glutamine and 6 cirrhotic patients who were challenged with water showed no change in any of these parameters. Following orthotopic liver transplantation (OLT) the eight patients studied had normal baseline psychomotor performance with significant improvements in digit symbol, digit span, information processing, number connection tests (P < .05), and reaction time (P < .005). Posttransplantation, there were no significant changes in blood ammonia, analyzed EEG, or choice reaction time in response to oral glutamine challenge (six patients). We conclude that short lived changes in blood ammonia (in cirrhotics) can cause significant impairment of sensitive tests of brain function and that psychometric performance is improved following OLT.

Therapeutic modalities in portal hypertension.

Optimal medical management is with octreotide or terlipressin (Glypressin) for acute variceal bleeding and combined beta-blocker and nitrate prophylaxis for prevention of rebleeding. Injection sclerotherapy is necessary to arrest acute bleeding, with variceal banding preferred for the obliteration of large varices. Transjugular intrahepatic portosystemic shunts (TIPS) are best used for uncontrolled or recurrent bleeding episodes which fail to respond to endoscopic or drug therapy. They can also rarely be used to treat refractory ascites. Surgical portosystemic shunting and devascularization techniques have now been superseded. Hepatic transplantation should be considered where overall hepatic function is poor.

High insulin-like growth factor binding protein 1 levels in cirrhosis: link with insulin resistance.

Hyperinsulinemic euglycemic clamps were performed on six patients with compensated alcoholic cirrhosis and on six normal comparison subjects. As in previous studies, glucose uptake in the cirrhotic patients was only 21% of the comparison value. The cirrhotic patients had high growth hormone (GH) and low insulin-like growth factor-I (IGF-I) levels, with low insulin-like growth factor-binding protein (IGFBP)-3 levels, but surprisingly high IGFBP-I levels (26.8 +/- 8.4 microgH vs. 3.2 +/- 0.2 microm/L, P < .001). The log IGFBP-1 level was inversely correlated with the log insulin sensitivity (r = -.95). The clamps were repeated with a somatostatin infusion to suppress GH secretion. IGFBP-1 increased in both groups, especially in the cirrhotic subjects. Insulin sensitivity increased in the normal subjects but was unchanged in the cirrhotic patients. Following GH treatment (0.13 U/kg/d for 5 days), the clamps were repeated. GH, IGF-1, and IGFBP-3 levels were now similar in the two groups; IGFBP-1 levels decreased in the cirrhotic patients but remained fivefold higher than the comparison value (10.6 +/- 3.7 vs. 2.1 +/- 0.4, P < .05). Glucose uptake in the cirrhotic patients remained only 29% of the comparison value, but the change in their insulin sensitivity was inversely correlated with the change in their IGFB-1 levels (r = -.84). These results suggests an important role for IGFBP-1 in modulating insulin sensitivity in cirrhosis.

Combination of laser treatment and intraluminal radiotherapy for malignant dysphagia.

BACKGROUND: Laser treatment for malignant dysphagia is limited by recurrent intraluminal tumour requiring repeated treatment at four to eight week intervals. AIMS: To reduce the need for follow up treatment and to improve survival, patients successfully palliated by laser were treated with intraluminal radiotherapy. PATIENTS: 32 patients with inoperable oesophageal carcinoma (18 adeno and 14 squamous cell carcinoma). METHODS: The patients were initially palliated by a median of three laser treatments. They were then treated with intraluminal radiotherapy, receiving 10-15 Gy at 1 cm from the source as a single treatment with the Selectron system. Patients with squamous cell carcinoma also received external radiotherapy (30 to 50 Gy). RESULTS: After the radiotherapy nine patients survived a median of 22 (range 4-40) weeks without requiring any further endoscopic treatment. The remaining patients survived a median of 40 (range 4-102) weeks and required a median of three follow up endoscopic treatments over that time. Eleven patients developed fibrous strictures with no intraluminal tumour and were treated by dilatation. Twelve patients required dilatation and repeat laser therapy for a combination of fibrous stricture and recurrent intraluminal tumour. Six patients eventually required Atkinson tubes. CONCLUSIONS: The combination of laser treatment with intraluminal radiotherapy provides good palliation and may reduce the need for repeated endoscopic treatment. Fibrous stricture formation is a common complication.

beta-Oxidation in human alcoholic and non-alcoholic hepatic steatosis.

1. The CoA and carnitine ester intermediates of mitochondrial beta-oxidation have not previously been quantified in liver disease, although there is some evidence that beta-oxidation is inhibited in alcoholic fatty liver. Mitochondria were isolated from needle liver biopsies from normal subjects, from patients with alcoholic fatty liver and patients with fatty liver of other aetiologies, incubated with 60 mumol/l [U-14C]hexadecanoate and the resultant CoA and carnitine esters were measured. 2. Although there was no significant difference in beta-oxidation flux between the patient groups, there was a significant rise in the proportion of 3-hydroxyacyl-CoA and 2-enoyl-CoA esters in patients with alcoholic fatty liver compared with normal subjects, and in patients with non-alcoholic fatty liver, suggesting an inhibition at the level of 3-hydroxyacyl-CoA dehydrogenase activity. 3. In alcoholic patients this difference could not be accounted for on the basis of the measured activity of short and long-chain 3-hydroxyacyl-CoA dehydrogenases, and it is suggested that either an inhibition of complex I activity or diminished amounts of ubiquinone are likely to be responsible for the observed accumulation of CoA and carnitine esters, which may contribute to the accumulation of triacylglycerols in alcoholic steatosis. In fatty liver of other aetiologies, short- and long-chain 3-hydroxyacyl-CoA dehydrogenase activities were decreased.