Gert Judmaier

Prognosis and life expectancy in chronic liver disease

The aim of the present study was to define prognosis and life expectancy in patients with chronic liver disease of different etiologies and to relate them to an age- and sex-matched normal population. After a follow-up of 15 years, life expectancy of 620 patients with chronic liver disease was retrospectively calculated and compared with an age- and sex-matched normal population. Among patients with cirrhosis, prognosis was dependent upon the Child classification (P=0.001). Patients with alcoholic cirrhosis and fatty liver disease were younger (P=0.01) and had a lower life expectancy than patients with other causes of chronic liver disease (P=0.004). Patients with hepatitis B and hepatitis C cirrhosis showed a comparable prognosis and a significantly lower life expectancy than the age- and sex-matched population. Cryptogenic and autoimmune liver diseases showed a comparable life expectancy but a significantly shorter life expectancy than the normal population. In patients withα1-antitrypsin deficiency-associated cirrhosis, a high viral coinfection rate was found (P=0.01). For patients with noncirrhotic hemochromatosis, prognosis was poorer than that for the age- and sex-matched population. In patients with asymptomatic primary biliary cirrhosis, chronic persistent hepatitis B, andα1-antitrypsin deficiency without cirrhosis, life expectancy was equal to that of the normal population. Prognosis and life expectancy in chronic liver disease depend on stage, cause, and symptoms of chronic liver disease; age; and possibilities of treatment. In patients with hereditary liver disease, additional viral infection or alcohol abuse lead to a significant deterioration of life expectancy. Patients with alcoholic chronic liver disease have the poorest prognosis.

High Prevalence of Viral Infection in Adults with Homozygous and Heterozygous Alpha1-Antitrypsin Deficiency and Chronic Liver Disease

OBJECTIVE To determine the prevalence of chronic liver disease in adults with homozygous (Pi ZZ) and heterozygous (Pi Z) alpha 1-antitrypsin deficiency and to assess the presence of other possible risk factors for the development of chronic active hepatitis and cirrhosis of the liver in these patients. DESIGN Cross-sectional study. SETTING A referral-based university hospital. PATIENTS Consecutive patients (164) with the Pi ZZ and Pi Z phenotype with and without chronic liver disease. MEASUREMENTS The presence of antibody to hepatitis C virus (anti-HCV) was determined using an assay incorporating synthetic peptide antigen from capsid protein (United Biomedical [UBI] assay) and a second-generation enzyme immunoassay (Abbott test); the presence of antibody to hepatitis B virus (anti-HBV) was determined using radioimmunoassays incorporating hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg); assays for antinuclear antibody and antimitochondrial antibody (M2 subtype) were also done, and alcohol abuse was assessed by history. RESULTS Among patients with cirrhosis (32%), 62% were anti-HCV positive by the Abbott test (P = 0.006), and 41% were anti-HCV positive by the UBI assay (P = 0.007). Thirty-three percent of patients with cirrhosis had hepatitis B virus (HBV) infection (P = 0.01); 41% had a history of alcoholism; and 12% had features of autoimmune liver disease. Only five patients (9%) with cirrhosis had no other risk factor for chronic liver disease. Among patients with chronic active hepatitis (7%), 80% were anti-HCV positive by the Abbott test (P = 0.002), and 75% were anti-HCV positive by the UBI assay (P less than 0.001). Thirty percent of patients with chronic active hepatitis had HBV infection (P = 0.023); 18% had autoimmune hepatitis; and 8% abused alcohol. Only two patients (17%) had no additional risk factor for the development of chronic active hepatitis. Among patients with steatosis of the liver (48%), 5% were anti-HCV positive by the Abbott test, and none were anti-HCV positive by the UBI assay; 18% had serologic evidence of past HBV infection, and 28% abused alcohol. Among patients without chronic liver disease (13%), no viral infection could be found; 9% were alcoholics. CONCLUSIONS Chronic liver disease in patients with alpha 1-antitrypsin deficiency is associated with a high prevalence of viral infection; this infection, rather than alpha 1-antitrypsin deficiency alone, may be the cause of the liver disease in such patients.

Prevalence of hepatocellular carcinoma in alpha-1-antitrypsin deficiency

The aim of the present study was to determine the prevalence of hepatocellular carcinoma in adults with heterozygous alpha 1-antitrypsin deficiency and to assess the presence of possible co-risk factors for the development of hepatocellular carcinoma. Two hundred and forty patients with cirrhosis of different aetiologies and 130 patients with alpha 1-antitrypsin deficiency without evidence of chronic liver disease were investigated. Out of the 240 patients with cirrhosis, 61 patients (25%) were found to have alpha 1-antitrypsin deficiency, 36 patients (15%) had chronic hepatitis C infection, 50 (21%) had chronic hepatitis B and 24 (10%) had hepatitis C and hepatitis B infection. Thirty patients (12%) had cryptogenic cirrhosis and 39 (16%) alcoholic cirrhosis. The prevalence of hepatocellular carcinoma in patients with alpha 1-antitrypsin deficiency-associated cirrhosis was comparable to that of hepatocellular carcinoma in patients with cirrhosis of other aetiologies. Positive viral markers were found in 67% of the patients with alpha 1-antitrypsin deficiency-associated cirrhosis with hepatocellular carcinoma. In contrast, in the group of 130 patients with alpha 1-antitrypsin deficiency but without clinical and laboratory signs of chronic liver disease, none was found to have hepatocellular carcinoma (p = 0.001). Our results indicate that heterozygous alpha 1-antitrypsin deficiency-associated cirrhosis is a risk factor for hepatocellular carcinoma, but this is due to chronic liver disease and not due to the metabolic disorder itself.

Spontaneous bacterial peritonitis is associated with high levels of interleukin-6 and its secondary mediators in ascitic fluid

Abstract. We investigated 37 patients with ascites and liver cirrhosis in order to examine whether on the basis of correlation of cytokines and acute phase proteins of the ascitic fluid, prognosis of spontaneous bacterial peritonitis can be made. Significantly enhanced levels of interleukin‐6, as well as acute phase reactants a‐l‐antitrypsin and C‐reactive protein were found in the ascitic fluid of patients with spontaneous bacterial peritonitis. The levels of tumour necrosis factor alpha (TNF‐α), neopterin, interleukin 2–receptor and granu‐locyte‐macrophage colony stimulating factor were higher in patients with spontaneous bacterial peritonitis, but without statistical significance, whereas no differences were found between the interferon gamma, interleukin‐2 and interleukin‐1 levels. In addition, interleukin‐6, TNF‐α and neopterin levels were found to correlate significantly with the outcome of the disease. These findings show that acute phase reaction occurs in the ascitic compartment in correlation with the development of spontaneous bacterial peritonitis.

Urinary neopterin, a marker of clinical activity in patients with Crohn's disease

Urinary neopterin excretion was measured in 34 patients with Crohns disease. Neopterin excretion showed a significant correlation with disease activity using a clinical activity score. An interacting effect of previous medical or surgical therapy on neopterin excretion could be ruled out. Disease localization and extent did not exert any influence on neopterin excretion. Neopterin values were significantly correlated with disease duration, body weight and the presence of a palpable abdominal mass. Multiple stepwise regression analyses identified the combination of neopterin, hematocrit, weekly stool frequency, palpable abdominal mass and related symptoms as predicting clinical activity better than Crohns Disease Activity Index (CDAI). Thus, neopterin determination may be introduced as an additional biochemical parameter in the assessment of disease activity.

Neopterin as a New Biochemical Marker in the Clinical Assessment of Ulcerative Colitis

In previous publications we showed that neopterin, a pyrazino-pyrimidin compound, represents a biochemical marker for the assessment of cellular immune responses. We thought that the evaluation of this marker molecule might enable insight into the activity of cellular immune responses underlying ulcerative colitis (UC). Evaluation of urinary neopterin excretion in 25 consecutive untreated UC patients revealed striking correlations between neopterin levels and the severity of disease: elevated levels were observed in 9 out of 9 patients with moderately severe to severe, in 3 of 4 with mild and in none of 12 patients with quiescent disease. Further evidence for a correlation between disease activity and neopterin excretion was obtained on the basis of long-term follow-up studies performed in 4 cases. These studies indicated normalization of neopterin levels when clinical remission was achieved. Thereafter, the relative significance of neopterin excretion for determination of clinical stage was assessed by linear correlation analyses and was compared with conventional clinical parameters such as anemia, number of motions per day, raised temperature, ESR and extent of bowel involvement. The logarithm of neopterin excretion and the extent of bowel involvement were the two single parameters most closely related to the clinical stage of ulcerative colitis. We, therefore, conclude that evaluation of neopterin excretion in ulcerative colitis patients represents a new and useful tool for the clinical monitoring of disease activity.

Interleukin-1 receptor antagonist in differential diagnosis of inflammatory bowel diseases

Background: Immunoregulatory properties of cytokines may mediate disordered inflammatory events in inflammatory bowel diseases (IBDs). On the basis of data obtained in experimental colitis, the hypothesis has been advanced that in IBD the balance between interleukin-1 (IL-1) and the naturally occurring IL-1 receptor antagonist (IL-1 ra) might influence disease expression. Objective: We studied the profiles of IL-1 ra and acute phase proteins produced by activated macrophages to determine whether the level of IL-1 ra in peripheral blood is a marker of disease activity in IBD and a possible differential diagnostic marker. Patients and methods: Levels of IL-l ra, serum neopterin, urinary neopterin, α1,-glycoprotein and C-reactive protein (CRP) were measured in 80 patients with ulcerative colitis, Crohns disease or infectious colitis. Results: Levels of IL-1 ra were markedly increased in patients with active ulcerative colitis or active Crohns disease compared with those in patients with infectious colitis. Patients with active Crohns disease had significantly higher serum IL-1 ra levels than patients with active ulcerative colitis. Moreover, a positive correlation was found between levels of C-reactive protein, α1-glycoprotein, and serum neopterin and the level of IL-1 ra in active Crohns disease but not in active ulcerative colitis, strongly suggesting that the pathogenesis of the two conditions differs. Conclusion: Levels of IL-1 ra in the peripheral blood of patients with IBD are of clinical relevance, representing a potent marker of disease activity and and a possible differential diagnostic marker.

POTENTIAL OF URINARY NEOPTERIN EXCRETION IN DIFFERENTIATING CHRONIC NON-A, NON-B HEPATITIS FROM FATTY LIVER

Urinary neopterin excretion was measured in 26 patients with histologically proven chronic non-A, non-B hepatitis (16 chronic persistent hepatitis, 10 chronic active hepatitis) and in 16 patients with steatosis. The potential of neopterin levels to discriminate between the two patient groups was compared with that of standard laboratory variables. Neopterin levels and triglycerides were shown to be the best variables for discriminating between the hepatitis and fatty liver patients, neopterin being the more specific of the two. Neopterin excretion in chronic persistent hepatitis was not statistically different from that in chronic active hepatitis. In the absence of specific tests, increased neopterin excretion seems to be a useful marker for diagnosing chronic non-A, non-B hepatitis and particularly in differentiating it from fatty liver.

One-year treatment of chronic non-A, non-B hepatitis with interferon alfa-2b

Thirty patients with chronic non-A, non-B hepatitis (24 male, six female; median age 38 years, range: 15-68 years) were treated with recombinant interferon alfa-2b for 1 year. Treatment was started with 5 million units interferon alfa-2b daily for 2 weeks followed by 2 million units daily for another 2 weeks. Further doses were titrated according to alanine aminotransferase values. After 1 year, treatment was stopped and a follow-up biopsy was obtained. Thereafter, patients were followed for 6 months. Of the 24 patients who completed the 1-year treatment period, 14 (58%) had normal alanine aminotransferase values at the end of the study, eight of whom showed transient increases while on treatment. In another seven (29%), alanine aminotransferase levels decreased by more than 50% of pre-treatment values but remained above the normal range. Biopsies at the end of treatment showed a complete disappearance of inflammatory activity in four and a marked improvement in eleven other patients. The results of this study indicate that a 1-year treatment with recombinant interferon alfa-2b of patients with non-A, non-B hepatitis was very effective at normalizing or improving serum transaminases and liver histology. However, the overall relapse rate was 57%, with relapse occurring in a greater proportion of patients with temporary breakthroughs during therapy (requiring dosage increase), and particularly of patients with only a partial response to treatment (serum transaminases decreased by greater than or equal to 50%). Thus, further studies are needed to establish the optimal dose and duration of treatment to induce a complete resolution of the disease.

DETERIORATION OF PRIMARY BILIARY CIRRHOSIS DURING TREATMENT WITH URSODEOXYCHOLIC ACID

now ongoing in Europe and overseas (Dr Falk, Falk Foundation, personal communication). UDCA was introduced for the dissolution of radiolucent gallstones in the 1970s and is available on prescription in many European countries. As no treatment for PBC has so far been found to be effective, an increasing number of physicians are prescribing UDCA for desperate cases of PBC because of the drug’s supposedly low toxicity.! To add a word of caution when using UDCA in PBC, we would report the following