Antimitochondrial antibody profiles in primary biliary cirrhosis distinguish at early stages between a benign and a progressive course: a prospective study on 200 patients followed for 10 years.

In recent retrospective studies, it was shown that subtypes of antimitochondrial antibodies (AMA) can help to discriminate between a benign [only anti-M9 and/or anti-M2 positive by enzyme-linked immunosorbent assay (ELISA)] and a rather progressive course (anti-M2, -M4 and/or -M8 positive). According to different constellations of these AMA subspecificities in ELISA and complement fixation test (CFT), four AMA profiles (A-D) were defined. In 1984 we started a prospective study based on 200 PBC patients with known AMA profiles in order to correlate the antibody pattern with the clinical outcome. Progression was defined primarily as the necessity of liver transplantation and death due to hepatic failure or variceal bleeding. At entry, 18 (9%) of the 200 patients had AMA profile A (only anti-M9), 57 (29%) profile B (only anti-M2 with or without anti-M9), 74 (37%) profile C (anti-M2 in association with anti-M4/-M8 by ELISA), and 51 (26%) profile D (anti-M2/-M4/-M8 by ELISA and CFT). At the beginning of the study, 177 patients had PBC stage I/II. During the observation period of ten years, ten patients died and in 18 orthotopic liver transplantation (OLT) was performed; all these patients belonged to profile C/D. Furthermore, 44% of the patients with profile C and 31% of the patients with profile D progressed to late stages, as defined by histology and clinical manifestations such as portal hypertension and increase of bilirubin, while only one of the patients with profile B and none of the profile A-patients developed late stage PBC. A significant increase of bilirubin was observed only in C/D-patients. AMA profiles did not change during the follow-up. In conclusion, AMA profiles discriminate between a benign and a progressive course of PBC already at early stages.

[The effect of alcohol on portal vein hemodynamics in nutritional-toxic liver cirrhosis]. / Einfluss von Alkohol auf die Hämodynamik der Pfortader bei nutritiv-toxischer Leberzirrhose.

The influence of alcohol on portal vein haemodynamics was assessed prospectively in 30 patients (20 men, 10 women; mean age 54.3 [34-70] years) with nutritional-toxic cirrhosis of the liver (Child-Pugh stages A-C) and portal vein hypertension. During the period of observation hepatic vein occlusion pressure as an indirect measure of portal vein pressure was repeatedly determined. In addition, the size of oesophageal varices and the Child-Pugh stage were monitored. After complete alcohol abstinence of one year, portal vein pressure fell from 23.11 to 12.43 mm Hg (-46%, P < 0.001), the Child-Pugh score from 8.08 to 7.2 (-10.9%, not significant), and the size of oesophageal varices was reduced from grade 1.33 to grade 0.79 (-40%, P < 0.02). On resuming alcohol abuse, portal vein pressure increased by an average of 10 mm Hg (+60%, P < 0.001) to its previous level of 25 mm Hg. The portal vein pressure has thus proved to be a sensitive gauge of alcohol abstinence or abuse. Lasting, absolute alcohol abstinence is essential in nutritional-toxic liver cirrhosis.

Long-term effectiveness of high-dosed ornithine-aspartate on urea synthesis rate and portal hypertension in human liver cirrhosis.

The effectiveness of ammonia reducing amino acids on hyperammonemia and hepatic encephalopathy is well known in patients suffering from liver cirrhosis. Data concerning long-term therapy on hepatic function and urea synthesis rate (UNSR) are still lacking. According to Vilstrup/Poulsen it is a good standard for functioning liver mass. Therefore, 25 patients with histologically proven liver cirrhosis and distinct portal hypertension were treated daily with 9 gr. ornithinasparte over 13 years (8-20 years). Shunt operations, esophageal varicosis sclerosis, or portal pressure reducing medication were not applied. Rigorous alcohol abstinence and 60 gr protein/day were prescribed. During the investigation, 3 laparoscopies and 4 liver biopsies were performed, on the average, on each individual. Significant improvements of clinical and biochemical results (Child-Pugh-Index; Composite Clinical and Laboratory Index) were obtained during the long-term therapy with ornithine-aspartate. Esophageal varicosis II-III was either reduced to 0-I or totally eliminated. Also significant was an increased urea synthesis rate and a decreased hyperammonemia.A plausible explanation for the long-term therapy effectiveness with ornithine-aspartate is the possible recovery of the functioning mass without hepatic size increase. Also important is the rigorous alcohol abstinence. It leads to a significant reduction of portal hypertension in patients suffering from alcohol induced liver cirrhosis (Reynolds, own observations).Additional favorable factors are intensive muscle training and absence of gastrointestinal bleeds.

Limited hepatic resection for selected cirrhotic patients with hepatocellular or cholangiocellular carcinoma: a prospective study.

From 1 January 1983 to 1 January 1989 123 cirrhotic patients with hepatocellular cancer (n = 122) or cholangiocarcinoma (n = 1) were screened using liver function tests, alpha-fetoprotein determination, ultrasonography with biopsy (and in selected cases computed tomography or nuclear magnetic resonance), laparoscopy and angiography, Child-Pugh classification and urea-nitrogen synthesis rate. Twenty-three patients were selected for surgical resection because the tumour was smaller than 5 cm, not centrally located and at least 1 cm away from main structures; there was no evidence of multicentricity or metastatic disease; and the Child-Pugh classification was A or B and the urea-nitrogen synthesis rate at least 6 g/day. Upper gastrointestinal endoscopy was used routinely to identify oesophageal varices which were present in 17 cases; ten patients with a history of variceal haemorrhage (43 per cent) had preoperative endoscopic sclerotherapy. In cases with recurrent haemorrhage, surgery was used to prevent intraoperative and postoperative bleeding. Tumour resection was carried out using controlled hypotension and hepatoduodenal ligament clamping. Twelve bisegmentectomies, ten segmentectomies and one atypical resection were performed. The operative mortality rate was 13 per cent with liver failure and sepsis as the causes of death. The 'recurrence rate' was 26 per cent and the late mortality rate for the whole group up to 1 January 1990 was 30 per cent; 13 patients were still alive. The 12-month survival rate was 77 per cent and after 5 years it was 49 per cent. Thus, surgical resection of small liver tumours is the treatment of choice in this selected group of patients.

Conservative and semi-invasive modalities for treating bleeding esophageal varices.

Although controversial, pharmacological therapy aimed at controlling acute variceal bleeding is widely used. A combination of intravenous vasopressin and nitroglycerin or glypressin alone with the aim of lowering portal pressure is currently recommended. Immediate endoscopy is mandatory to confirm that the patient is bleeding from varices. When variceal bleeding is detected, the patient should be immediately submitted to sclerotherapy, if expert treatment is available, or have the bleeding controlled by balloon tamponade or by pharmacological means, with subsequent performance of sclerotherapy with the use of a flexible endoscope within 6 to 24 hours, or transportation of the patient to a special center during this time. If bleeding has stopped, sclerotherapy can be performed immediately, or the patient can be observed while appropriate long-term management is planned. Patients who do not respond to immediate or delayed emergency sclerotherapy should be identified early and their suitability for a shunt or devascularisation procedure assessed. There is no question that at least after one or two early or even late recurrences of variceal hemorrhage, surgery should be planned and initiated. Although sclerotherapy is the favored form of emergency treatment, a nonshunting procedure or a portosystemic shunt operation should be recommended and thoroughly evaluated in order to determine whether this may be a preferable therapeutic option in a minority of patients, representing about 20% of all patients bleeding from esophageal varices referred to our institution.

Spontaneous regression of oesophageal varices after long-term conservative treatment. Retrospective study in 20 patients with alcoholic liver cirrhosis, posthepatitic cirrhosis and haemochromatosis with cirrhosis.

Spontaneous regression of oesophageal varices in liver cirrhotics without sclerotherapy or shunt operation has only been known in alcoholic cirrhosis after alcohol abstinence. Therefore, 20 liver cirrhotics of different aetiologies were controlled over 13 years (six alcohol, nine hepatitis, five haemochromatosis). Under strict alcohol abstinence, all underwent treatment with lactulose and ammonia-reducing amino acids to improve the urea synthesis in the liver. Since gastrointestinal bleeding was not observed, neither sclerotherapy nor shunt operation were performed. Initially, all patients had oesophageal varices (nine stage III, three stage II-III, eight stage II). Following conservative therapy, eight cirrhotics showed total regression and twelve showed stage I-II. Their Child-Pugh index, and urea synthesis rate improved significantly. Possible causes for the spontaneous regression of oesophageal varices are strict abstinence from alcohol, spontaneous seroconversion in six posthepatic B-cirrhoses and consequent phlebotomy in haemochromatosis.

Analysis of a prospective series of 100 mesocaval interposition shunts for bleeding portal hypertension.

The results of a prospective series using the mesocaval interposition shunt (MIS) over a period of 13 years is reviewed. One hundred patients were selected for the operation using strict criteria, and in 98 cases the operation was performed electively. Selection criteria included a liver volume of between 1,000 and 2,500 ml, portal perfusion of between 15-30%, no active liver disease and no stenosis of hepatic artery or celiac axis, as well as a good functional Child-Pugh classification (A-B). In all the cases preoperative sclerotherapy was performed as many times as needed with the aim of controlling the active bleeding at admission and of diminishing the pre- and postoperative bleeding probability. Intra-operative postshunt measurements showed residual portal perfusion in all patients studied. Early mortality was 10% and the follow-up mortality 38.8%. The main causes of death were liver failure and hepatocellular carcinoma. The five- and ten-year survival rates were 65% and 35%, respectively. The total encephalopathy rate was 12.2%. Rebleeding was observed in 5.5% of the cases, and the long term-shunt patency rate was 90%. Anigography and sequential scintigraphy showed residual portal perfusion in 75% of the cases soon after operation, in 60% after 6 months, and in 38% after 2 years, showing the tendency of the diversion to diminish the portal perfusion rate in the late postoperative period. The results show that MIS still has a place in the treatment of portal hypertension and that it is an excellent alternative choice to the selective shunts and the devasculariaztion procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

100 meso-caval interposition-shunts for recurrent variceal hemorrhage in portal hypertension. A prospective study.

The results of a prospective series using the mesocaval interposition shunt (MIS) over a period of 13 years is reviewed: 100 patients were selected for the operation using strict criteria and in 98 cases the operation was performed electively. Selection criteria included liver volume between 1000-2500 mL, portal perfusion between 15-30%, no active liver disease and no stenosis of hepatic artery or coeliac axis as well as a good functional CHILD-PUGH classification (A-B). In all the cases preoperative sclerotherapy was performed so many times as needed by each individual patient with the goal of controlling the active bleeding episodes at admission and of diminishing the pre and postoperative bleeding probability. Intraoperative postshunt measurements showed residual portal perfusion in all studied patients. Early mortality was 10% and the follow up mortality 38.8%. Main causes of death were liver failure and hepatocellular carcinoma. Five and ten years survival rates were 63.9% and 35.1% respectively. The total encephalopathy rate was 12.2%. Rebleeding was observed in 5.5% of the cases and long term shunt patency rate among survivors was 90%. Angiography and sequential scintigraphy showed residual portal perfusion in 75% of cases soon after operation, in 60% after 6 months and 38% after 2 years, showing the tendency of the derivation to diminish the portal perfusion rate in the late postoperative period. The results show that MIS still has a place in the treatment of portal hypertension and that it is an excellent alternative choice to the selective shunts and the devascularization procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

The antimitochondrial antibody anti-M9. A marker for the diagnosis of early primary biliary cirrhosis.

The clinical relevance of a new antimitochondrial antibody, anti-M9, reacting with an outer membrane-associated antigen on liver mitochondria is described. Sera from 22 anti-M2-negative patients with histologically proven primary biliary cirrhosis (PBC) who had been followed for 5-15 years were tested for anti-M9 in the ELISA using a purified M9-fraction. 18 (82%) were anti-M9-positive, and 17 of them (94%) were in stage I/II. None of the 17 anti-M9-positive/anti-M2-negative patients with early PBC progressed to stage III/IV during the observation period of 5-15 years, and in all instances anti-M9 remained of the IgM-type. In one anti-M9-positive patient anti-M2 of the IgM type appeared 2 years after the first demonstration of anti-M9. Among 156 patients with anti-M2-positive PBC, 58 (37%) had anti-M9, and 39 of them (67%) were in stage I/II. 19 of these 39 stage I/II patients (49%) had anti-M9 exclusively of the IgM-type in contrast to none of the 19 stage III/IV patients. Using the purified M9-fraction in ELISA and Western blotting, anti-M9 antibodies were confined only to patients with PBC or overlap syndromes between PBC and autoimmune chronic active hepatitis (10% of 133 patients) and were not found in patients with other hepatic and non-hepatic disorders. We conclude that the determination of anti-M9 may be helpful for the diagnosis of early and asymptomatic PBC. From follow-up studies of anti-M9-positive but anti-M2-negative patients it emerges that this antibody type may be associated with a benign course of PBC.

Hepatic detoxification and hepatic function in chronic active hepatitis with and without cirrhosis.

The detoxification capacity of the liver in chronic active hepatitis (CAH) without liver cirrhosis (LC) is not sufficiently known. Therefore, we examined, in 156 patients with morphologically proven CAH of different stages, plasma ammonia, free phenols, indican, glucuronic acid and urea synthesis rate as parameters for liver detoxification. We found a significant increase of ammonia, phenols, and indican and a significant decrease of glucuronic acid and urea synthesis rate parallel to the stage of CAH without LC. In 34 CAH patients with complete recovery, a retrospective 10-year follow-up was possible. Parallel to the normalization of liver morphology and general liver tests, detoxification parameters also normalized. However, the detoxification disorders in CAH without LC are mild in nature and do not produce hepatic encephalopathy. Probably, they are caused by a reduced synthesis of the urea-cycle enzymes and of glucuronyltransferase in the liver.

The role of protein metabolism in 204 liver cirrhotics with and without hepatic encephalopathy. I. Clinical and general biochemical findings.

Alcohol, hepatitis B, and Non A Non B hepatitis were the main aetiologies of 124 patients with hepatic encephalopathy (HE) due to histologically proven liver cirrhosis. All had severe portal hypertension (PH) and usually increased inflammatory activity of the liver. In stage I (n = 27) 7.4% died, in stage II (n = 28) 14.3%, in stage III (n = 32) 50% and in stage IV (n = 37) 94.6%. Even in cirrhotics without PH, serum albumin, cholinesterase activity and prothrombin time (PT) were significantly decreased. But only in the case of PT did the magnitude of the decrease parallel the stage of HE. Hyperammonaemia and serum creatinine were increased in parallel with the stage of HE. Therefore, in liver cirrhosis a quotient derived from decreased PT and increased serum creatinine has a good prognostic value. Early diagnosis of HE is possible on the basis of writing tests and the determination of free or toxic ammonia.

The role of protein metabolism in 204 liver cirrhotics with and without hepatic encephalopathy. II. Amino acids, free phenols and indoles.

Toxic protein metabolites are assumed to play an important role in the multifactorial pathogenesis of hepatic encephalopathy (HE). To investigate this, we examined the serum levels of free amino acids, free phenols and indoles in 100 healthy adults, and in 124 liver cirrhotics with HE and 80 without HE. We found a significant increase in free serum phenols and indican already in liver cirrhosis without portal hypertension (PH) and HE. In stage III and IV HE large amounts of p-hydroxy-phenyl lactic acid were detected, which was not the case in cirrhotics without HE. In HE the increase in free serum phenols and indican was much higher than that of the mother substances tyrosine and tryptophan. The quotient BCAA/AAA was decreased significantly already in PH without HE. In addition to the increased formation by intestinal bacteria, a diminished oxidative capacity of the cirrhotic liver seems to be one of the main causes of the increased serum levels of toxic protein metabolites in HE.

Treatment of chronic active hepatitis--present state.

Nowadays, both Anglo-Saxon and Middle European pathologists define chronic active hepatitis as synonymous with chronic aggressive hepatitis (CAH) without cirrhotic transformation. For its treatment, an accurate determination of the histological stage is necessary. CAH with slight to moderate activity (type 2a) requires merely general treatment, while corticosteroids and/or immunosuppressives are contraindicated. The latter drugs are indicated only for HBs- and HBeAG-negative CAH of type 2b with marked inflammatory activity. Every case should, however, be carefully assessed to determine whether these drugs might not be contraindicated. Our own experience with more than 600 patients with CAH shows that the prognosis is most favourable in HBs- and HBeAg-negative patients, in whom pre-existing chronic infections have been quickly recognized and eradicated, and in whom corticosteroids and/or immunosuppressives were not required. In the meantime, 13% of the CAH patients without cirrhotic transformation have been cured, and 42.5% improved. In contrast, CAH treatment with interferon, Virazol, arabinoside and immunostimulation remain disappointing.