Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial.

BACKGROUND & AIMS: New treatments for primary biliary cirrhosis (PBC) need to be evaluated. We conducted a single-center double-blind, randomized trial of methotrexate, 7.5 mg/wk (n = 30), vs. placebo (n = 30) for up to 6 years in PBC. METHODS: Methods included three monthly symptom assessment and liver function tests and liver biopsy and gastroscopy at baseline, after 2 years, and after 4-6 years. RESULTS: Patients randomized to methotrexate had, compared with patients randomized to placebo, (1) significantly lower on-treatment serum alkaline phosphatase, gamma-glutamyltransferase, immunoglobulin (Ig) M, IgG, and (after 24 months) aspartate aminotransferase and alanine aminotransferase levels (P < 0.02-0.001 by analysis of covariance to adjust for baseline differences); (2) a nonsignificant trend toward lower on-treatment pruritus scores; (3) similar on-treatment Knodell inflammatory scores but nonsignificant trends toward lower Knodell fibrosis score and less ductopenia; (4) a trend toward greater increases in serum bilirubin level and Mayo score with time (both significant after 5 years of follow-up); and (5) a 2.9-fold (95% confidence interval, 0.85-10.25-fold) increase the rate of death or liver transplantation as a result of liver disease during or after the trial (P = 0.09) in a Cox multivariate regression analysis compared with patients randomized to placebo. CONCLUSIONS: These results do not support the clinical use of low-dose methotrexate in PBC.

The natural history of chronic hepatitis C in haemophiliacs.

Most haemophiliacs treated with non-virally-inactivated clotting factor concentrates have been infected with hepatitis C virus (HCV). We have studied the natural history of chronic HCV infection by following all 138 HCV-positive patients from our centre for periods of up to 28 years. As well as the clinical and biochemical characteristics, we studied 116 liver samples from 63 patients obtained at elective biopsy (n = 103) or autopsy (n = 13). 36 (26%) of the patients were HIV positive, and three were chronic carriers of hepatitis B. Evidence of previous exposure to hepatitis A and B was found in 37.2% and 48.1% respectively. Raised transaminase levels were found in 82.6% of patients. 11 of 15 patients with normal transaminases tested by PCR for HCV RNA were positive, indicating that most patients, even in this group, have chronic hepatitis C infection. Cirrhosis was diagnosed by liver histology in 19 patients, and nine patients developed liver failure. The incidence of cirrhosis rose rapidly 15 years after HCV infection to 15.6 per 1000 person-years. Multivariate analysis showed that HIV status, length of time since HCV infection and age at HCV infection were independently associated with both the development of cirrhosis and liver failure. Two patients developed hepatocellular carcinoma: one of these was exposed only to a single batch of FVIII concentrate 11 years earlier. Chronic hepatitis C is increasingly recognized as a major cause for morbidity and mortality in haemophiliacs, especially those who are HIV positive and who were infected at an older age.

How valid are our reference standards of nutrition?

The validity of anthropometric measurements in the assessment of nutritional status depends on the use of appropriate standards. The most commonly used standards for triceps skinfold thickness and mid-arm muscle circumferences are based on Jelliffe's and Frisancho's tables. In this study we compared these two standards in a population of healthy subjects and patients with a variety of pathological disorders. The study showed that the correlation between these two standards was poor. When Frisancho's standards were used as "gold standards," the positive predictive value of Jelliffe's standards for triceps skinfold thickness was only 22% and for mid-arm muscle circumference only 53%; the false positive results for triceps skinfold thickness and mid-arm muscle circumference were 28% and 27%, respectively. This study emphasizes the need to develop appropriate standards for the studied population. Until such standards are available, workers assessing nutritional status in population studies would be advised to interpret their findings with caution, and, on the basis of this study, we recommend the use of Frisancho's standard in preference to Jelliffe's standards.

Evaluation of nutritional status by using anthropometry in adults with alcoholic and nonalcoholic liver disease.

No systematic studies have examined the nutritional status of patients with alcoholic and nonalcoholic liver disease by using anthropometry. In this study the nutritional status of 132 patients with chronic liver disease was evaluated by using anthropometry, and results were compared with 56 control subjects and 46 patients with other diseases by using standards recommended by Frisancho. Nineteen percent of patients with liver disease were below the 5th percentile for arm fat area and 35% were below the 5th percentile for arm muscle area. Malnutrition was seen equally among patients with alcoholic and nonalcoholic liver disease. Nutritional status of patients with liver disease was similar to that of patients with carcinoma. Anthropometric measurements correlated significantly with measurements of albumin concentration but not with other liver-function tests or with the severity of liver disease as assessed by Child-Pugh score. These data suggest that malnutrition is common in patients with both alcoholic and nonalcoholic liver disease.

Vagal dysfunction and impaired urinary sodium and water excretion in cirrhosis.

OBJECTIVE: To evaluate the possible role of vagal impairment in the disturbances of urinary sodium and water excretion observed in cirrhosis. METHODS: Standard cardiovascular reflex tests were used to assess Autonomic function in 11 cirrhotic patients, and the response to an acute intravenous water load was determined. Changes in plasma noradrenaline, antidiuretic hormone, renin, and atrial natriuretic peptide also were evaluated. RESULTS: Patients with vagal dysfunction were shown to have significantly impaired urinary sodium and water excretion, compared with those whose cardiovascular tests were normal (5-h urinary sodium excretion, 32.3 +/- 9.0 vs. 69.4 +/- 12.7 mmol, p < 0.05; % water load excreted at 5 h, 67.8 +/- 10.5 vs. 109.2 +/- 3.67%, p < 0.008). This was associated with higher circulating noradrenaline, renin, and antidiuretic hormone levels after the water load in the vagal dysfunction group. Urinary sodium excretion correlated with the heart rate variation on deep breathing (r = 0.74, p < 0.013) and the heart rate response to atropine (r = 0.75, p < 0.020); the % water load excreted correlated with the number of abnormal cardiovascular tests in each patient (rS = 0.67, p < 0.02). Although patients with vagal abnormalities had worse liver function, urinary sodium and water excretion correlated better with parasympathetic tests than with standard parameters of hepatic function. CONCLUSIONS: The presence of vagal impairment in cirrhosis appears to be associated with impaired urinary sodium and water excretion, as well as disturbances in circulating vasoactive hormones. These findings could be due to an afferent defect resulting in diminished inhibitory input from intrathoracic volume and arterial baroreceptors, although a confounding effect of worse hepatic function in patients with vagal impairment cannot be excluded.

Autonomic and peripheral neuropathy in primary biliary cirrhosis.

Autonomic and peripheral nerve function was examined in a group of patients with primary biliary cirrhosis using standard cardiovascular reflex tests and peripheral nerve conduction studies. Sixty-three percent had cardiovascular autonomic dysfunction with predominantly parasympathetic abnormalities. Symptoms of peripheral neuropathy were rarely volunteered spontaneously but occurred frequently when specifically sought; 40.7% had definite peripheral neuropathy, with symptoms and/or signs plus peripheral neurophysiological abnormalities. A close association between autonomic and peripheral nerve function was found with correlation between the heart rate variation on deep breathing and both peroneal nerve conduction velocity (r = 0.67, P < 0.001) and sural nerve conduction velocity (r = 0.52, P < 0.008). Correlations were also noted between other autonomic tests and peripheral nerve function. Both autonomic and peripheral nerve function correlated with serum bilirubin and albumin; no significant association was noted with vitamin E deficiency or hyperlipidaemia. A generalised neuropathy with peripheral and autonomic abnormalities is common in primary biliary cirrhosis and could be related to hepatic damage. Although rarely clinically disabling, the autonomic impairment associated with this neuropathy may be of prognostic significance.

Multiple-dose pharmacokinetics of rufloxacin in patients with cirrhosis.

The multiple-dose pharmacokinetics of rufloxacin were investigated in 13 patients with biopsy-proven cirrhosis and in 5 healthy controls. Rufloxacin was administered once a day for 5 consecutive days, starting with a loading dose of 400 mg on day 1 and 200 mg on the subsequent days. Plasma and urinary drug concentrations were determined by high-performance liquid chromatography and a microbiological assay. A one-compartment model applied to the high-performance liquid chromatography data was used to calculate the pharmacokinetic parameters of rufloxacin. In the controls rufloxacin had a low plasma clearance (41 +/- 4 ml/min, mean +/- S.E.M.), a long half-life (30.1 +/- 3.9 hr), a large area under the plasma concentration vs. time curve (171 +/- 18 micrograms.hr/ml) and a low renal clearance (18 +/- 2 ml/min). No appreciable differences were observed in the pharmacokinetic parameters between patients with various degrees of liver-function impairment (modified Child-Pugh score ranging from 5 to 13). In these patients plasma clearance was slightly reduced (-32%), but this decrease was caused by a marked reduction in renal clearance (-65%) rather than nonrenal clearance, which remained unchanged (22 ml/min in cirrhotic patients vs. 23 ml/min in controls). A significant (p < 0.01) correlation was found between creatinine clearance and both rufloxacin renal clearance (r = 0.769) and rufloxacin plasma clearance (r = 0.681). The elimination half-life and the area under the plasma concentration vs. time curve were moderately increased in cirrhotic patients (+33% and +26%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic dysfunction in chronic liver disease.

Chronic liver disease is accompanied by a number of circulatory changes including impairment of cardiovascular autonomic reflexes. This occurs irrespective of the aetiology of liver disease, increases in prevalence and severity with worsening hepatic function, and is related at least in part to an autonomic neuropathy. Parasympathetic abnormalities predominate and, although largely subclinical, they may play a role in the altered fluid homeostasis and neurohumoral disturbances associated with cirrhosis. On prospective follow up, the presence of autonomic impairment was associated with a five-fold increased mortality, largely from sepsis and variceal haemorrhage. Defective responses to such stressful events as a result of an afferent defect could possibly explain these findings. Further studies are required to evaluate the natural history of this complication, and determine if it is reversible with improvement in hepatic function or after liver transplantation.

Interferon alfa for chronic hepatitis C in haemophiliacs.

Chronic hepatitis C virus (HCV) associated liver disease is an important cause of morbidity and mortality in haemophilia. Recombinant interferon alfa-2b was used in a randomised controlled liver biopsy trial to treat haemophiliacs with chronic HCV. All 18 patients entered had antibodies to HCV. During the first year of the study, 10 patients were randomised on the basis of histology to receive interferon alfa-2b, 3 million units subcutaneously, thrice weekly and eight to receive no treatment (control group). After 12 months, all patients had a second liver biopsy and the control group patients were offered interferon at the same dosage but for only six months. The alanine aminotransferase (ALT) activity had returned to normal in four of 10 patients treated for one year and five of six patients treated for six months, compared with none of the eight patients in the control group (p < 0.01). Although the histological scores of the two groups were similar at entry into the study, after one year the biopsy specimens in the treated group showed significant improvement compared with controls (p < 0.01). It is concluded that interferon alfa-2b is effective in returning ALT values to normal and improving liver histology in at least 50% of patients treated.

A prospective trial of endoscopic sclerotherapy v oesophageal transection and gastric devascularisation in the long term management of bleeding oesophageal varices.

In a prospective three centre study oesophageal transection and gastric devascularisation have been compared with endoscopic sclerotherapy in the long term management of bleeding oesophageal varices. Cirrhotic patients (Child's A or B grade) with documented bleeding oesophageal varices were treated initially with emergency sclerotherapy, and after five days stability, were allocated to one of the two treatment regimes. The endoscopic sclerotherapy group underwent regular sclerotherapy until variceal obliteration while those undergoing surgery were not endoscoped unless bleeding recurred, when they were treated by sclerotherapy if appropriate. Ninety two patients were eligible for analysis (68% alcoholic cirrhosis; mean age 50.1 years) and follow up was achieved for a mean of 52.5 months (range 17-83). Mortality in the first three months was greater in the oesophageal transection and gastric devascularisation group (20% v 1%) but by two years the survival curves were the same and thereafter there was no difference in mortality. Rebleeding occurred in 13/41 (31%) patients, undergoing oesophageal transection and gastric devascularisation. The costs incurred during the first year of oesophageal transection and gastric devascularisation treatment were significantly greater than with endoscopic sclerotherapy (4369 pounds v 1067 pounds, p < 0.0001) and the high rate of rebleeding in the surgical group meant that no cost savings occurred in subsequent years. It is concluded that oesophageal transection and gastric devascularisation confers no benefit over endoscopic sclerotherapy in terms of long term survival and that it is not cost effective as judged by the current health care costs in the United Kingdom.

Portal hypertensive gastropathy.

There is now substantial clinical evidence to suggest that portal hypertensive gastropathy is an important source of gastrointestinal bleeding in patients with portal hypertension. Although a relatively uncommon presenting feature in such patients, it appears to become progressively more frequent and important the longer such patients with bleeding oesophageal varices survive after treatment by endoscopic sclerotherapy. It is now being increasingly recognized as the most important cause of haemorrhage after oesophageal varices in such patients. The endoscopic and histological characteristics of the condition are now well established but from a clinical point of view it is important to distinguish it from a number of other disorders. The pathogenesis of portal hypertensive gastropathy is poorly understood; venous congestion secondary to portal hypertension undoubtedly plays an important role but this is not thought to account entirely for the condition since abnormalities in the arterial blood supply are also observed. Many abnormalities in gastric mucosal function have been reported but it is unclear whether these are secondary disturbances or whether they play an important primary role in the development of the condition. Animal studies to date have not been helpful due to the lack of a satisfactory experimental model. Portocaval shunt surgery cures portal hypertensive gastropathy but propranolol has been shown to be highly effective in controlling haemorrhage from this condition and should now be considered the treatment of choice. The mechanism of action is unclear, and it remains to be shown whether other beta-blockers, or indeed any other drugs, are useful in treating this disorder.

Peripheral and cardiovascular autonomic impairment in chronic liver disease: prevalence and relation to hepatic function.

We have evaluated autonomic function using standard cardiovascular tests and a test of peripheral autonomic denervation, the acetylcholine sweatspot test, in 104 patients with biopsy proven chronic liver disease and 35 age- and sex-matched controls. Cardiovascular autonomic dysfunction was significantly more frequent in advanced liver disease compared with early liver disease (71.8% Child B or C vs. 39.7% Child A; p < 0.0006), and a strong correlation between the number of abnormal tests and Child-Pugh score could be demonstrated (Rs = 0.5; p < 0.0001). On multiple logistic regression analysis, cardiovascular autonomic dysfunction was related to age and to Child-Pugh score and occurred independently of the aetiology of liver disease. Peripheral autonomic denervation was found in 39% of patients, was significantly associated with cardiovascular abnormalities (p < 0.009) and correlated with the number of abnormal cardiovascular tests in each patient (Rs = 0.48; p < 0.0001). In chronic liver disease, the prevalence and severity of cardiovascular autonomic dysfunction is related to the severity of hepatic dysfunction and is independent of aetiology, suggesting a common pathogenetic basis related to hepatic damage; the association with peripheral autonomic denervation indicates that at least some of the abnormalities may be due to a true autonomic neuropathy. The possible significance of these findings to the complications of cirrhosis is discussed.

Natural history of autonomic neuropathy in chronic liver disease.

To determine the natural history of autonomic neuropathy in chronic liver disease we used standard cardiovascular autonomic tests to evaluate prospectively 60 patients (33 male, 27 female) with initially well-preserved hepatic function. On initial testing, 27 patients (45%; median [range] age 56 [32-67] years) had vagal neuropathy. Autonomic dysfunction was equally common in patients with alcohol-related and nonalcoholic-related liver disease. The cumulative 4-year mortality rate in patients with vagal neuropathy was 30% compared with 6% in those with normal autonomic function. Multiple logistic regression analysis showed that presence of vagal neuropathy and severity of hepatic damage were independent predictors of mortality. Serial testing showed that whereas disease progression occurred in some patients, in others mild abnormalities in autonomic function were reversible. Vagal dysfunction is common in well-compensated chronic liver disease and its presence identifies a subgroup of patients with a substantially worse outlook.

A study of the penetration of meropenem into bile using endoscopic retrograde cholangiography.

One gram of meropenem was administered as prophylaxis to patients undergoing endoscopic retrograde cholangiography (ERC) in a study of the bile pharmacokinetics of this agent. Twenty-four patients were evaluated and a single bile sample was collected from each one during ERC at different time intervals following intravenous infusion. Bile concentrations after the dose ranged from 0.7 to 25.7 mg/L (mean 11.1) and exceeded the MIC90s for the pathogens most commonly associated with biliary tract infections for up to 203 mins. The bile concentrations of 13 patients with biliary tree obstruction were compared with those of 11 patients without obstruction. Bile concentrations in excess of the MIC90s for the predominant pathogens were achieved in both groups; a positive correlation between meropenem bile concentration and the time of dose administration was demonstrable only for the obstructed group. ERC may be a useful technique for biliary pharmacokinetic studies.

Selenium in chronic liver disease.

In order to assess the role of selenium (Se) in chronic liver disease, we have measured serum, urinary and hepatic selenium in a range of liver diseases and correlated them with nutritional status and conventional liver biochemistry. Serum Se levels (microgram/l +/- S.D.) were significantly lower in both alcoholic (63.6 +/- 18.2, p less than 0.0001) and non-alcoholic liver disease (NALD) (60.6 +/- 13.6, p less than 0.0001) compared to healthy controls (87.8 +/- 21.2) and non-malignant 'disease controls' (80.3 +/- 19.1). Hepatic Se levels (microgram/g of dry weight) were also reduced in both ALD (0.568 +/- 0.647, p less than 0.005) and NALD (0.863 +/- 0.308, p less than 0.005) compared to controls (1.227 +/- 0.296), 24-h urinary Se excretion (microgram) in ALD (24.6 +/- 10.7) and NALD (29.0 +/- 14.3) was similar to controls (30.3 +/- 8.7). Serum Se showed a highly significant positive correlation with albumin (p less than 0.001) in both ALD and NALD. Serum levels were also significantly correlated with anthropometric measurements. Dietary assessment of patients with primary biliary cirrhosis and low serum Se levels did not show a reduced dietary intake. Our data show that Se levels are low in liver disease irrespective of aetiology and suggest that these low levels are more likely to be related to overall nutritional status than to dietary intake.

Liver blood flow: non-invasive estimation using a gamma camera.

A non-invasive radioisotope technique for the measurement of total liver blood flow (TBF) is described. The method requires the use of two intravenously administered tracers, 99mTc (technetium 99m) human serum albumin (HSA) and 99mTc colloid. Computer analysis of first-pass time activity curves for HSA for liver and lung tissues yields values for the arterial and portal contributions to liver blood flow, from which TBF can be determined. These values are then corrected for attenuation using the images of the colloid distribution. The use of the method is illustrated in 17 subjects. Assumptions, limitations and possible applications of the technique are discussed.

A randomized controlled trial of recombinant interferon-alpha in chronic hepatitis C in hemophiliacs.

Chronic liver disease associated with hepatitis C virus (HCV) is an important cause of morbidity and mortality in hemophilia. We have used recombinant interferon alpha-2b (IFN alpha-2b) in a randomized controlled liver biopsy trial to treat hemophiliacs with chronic hepatitis. Eighteen patients entered the study, 16 of whom were subsequently shown to have antibodies to the HCV. All underwent liver biopsy at entry and were randomized to either treatment with self-administered IFN alpha-2b, 3 million units subcutaneously thrice weekly (n = 10) or no treatment (control group) (n = 8). Nine subjects had chronic active hepatitis, seven had chronic persistent hepatitis, and two had cirrhosis. Twelve months after entry into the study 17 patients underwent a second liver biopsy. All biopsies were coded, assessed, and scored according to the histologic severity of the liver disease. Ten patients were administered IFN for 1 year, and in four patients normalization of alanine aminotransferase (ALT) occurred compared with none in the untreated group. After the second liver biopsy, six of the eight initial no-treatment patients were treated with interferon 3 million units thrice weekly for 6 months, and normalization of ALT was seen in five patients. Biochemical relapse within 4 months of stopping IFN occurred in one of four patients treated for 1 year and in four of five patients treated for 6 months. IFN treatment was well tolerated. Although the histologic scores of the two groups were similar at entry into the study, after 12 months the biopsy appearances in the treated group were significantly improved compared with the controls (P less than .01). Histologic improvement was noted in the three interferon-treated human immunodeficiency virus antibody-positive patients and also in other patients who had no biochemical response. We conclude that low-dose recombinant IFN alpha is effective in normalizing transaminases and improving the histologic appearances in at least 50% of hemophiliacs with chronic hepatitis C.