Alfred Gangl

Wilson's disease in patients presenting with liver disease: A diagnostic challenge

BACKGROUND & AIMSnIn patients with Wilsons disease presenting with liver involvement, the correct diagnosis is often missed or delayed. The aim of this study was to find an algorithm for diagnosis of this difficult patient group.nnnMETHODSnClinical and laboratory findings of 55 patients with Wilsons disease were evaluated at diagnosis before treatment. Presenting symptom was chronic liver disease in 17 patients, fulminant hepatic failure in 5 patients, hemolysis in 3 patients, and neurological disease in 20 patients, and 10 patients were detected by family screening (siblings). Evaluation included neurological and ophthalmologic examination, routine laboratory tests, and parameters of copper metabolism including liver copper content in 43 liver biopsy specimens.nnnRESULTSnIn the whole group, serum ceruloplasmin level was <20 mg/dL in 73%, urinary copper excretion was increased in 88%, and liver copper content was elevated in 91% at diagnosis. Kayser-Fleischer rings were detected in 55%. In contrast to patients with neurological disease (90% Kayser-Fleischer rings, 85% low ceruloplasmin), only 65% of patients presenting with liver disease were diagnosed by these typical findings. Ceruloplasmin levels were lower in patients with Kayser-Fleischer rings or with neurological disturbances than in patients without these symptoms.nnnCONCLUSIONSnThe commonly used clinical and laboratory parameters are not sufficient to exclude the diagnosis of Wilsons disease in patients with liver disease of unknown origin.

Improvement of hepatic encephalopathy treated with flumazenil.

The effects of the benzodiazepine antagonist flumazenil were studied in 20 episodes of hepatic encephalopathy (HE) in 17 patients with acute (n = 9) or chronic (n = 8) liver failure who had not responded to conventional therapy. Patients with a history of benzodiazepine intake were excluded. Changes in HE stage, in Glasgow coma scale, and in somatosensory evoked potentials were measured. In 12 of 20 episodes HE stage improved. The response to treatment occurred rapidly (within 3-60 min). In 8 of these 12 episodes HE worsened 0.5-4 h after treatment. In 5 of the 8 episodes that did not respond to flumazenil patients had clinical evidence of brain oedema. Flumazenil may be valuable in the treatment of HE in acute and chronic liver failure.

Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver

BACKGROUND/AIMSnThrombocytopenia secondary to cirrhosis of the liver and portal hypertension is a well-known complication of advanced stage liver disease, but theories about the underlying pathogenetic mechanisms, mostly centering on splenic sequestration and destruction of platelets, have failed to solve the problem so far.nnnMETHODSnPeripheral platelet count and thrombopoietin levels in human plasma were measured in 28 patients with cirrhosis of the liver. Seven of those patients underwent orthotopic liver transplantation and five patients portal decompression by transjugular intrahepatic portosystemic shunt. Thrombopoietin plasma levels were followed for 14 days after the interventions.nnnRESULTSnNo measurable thrombopoietin was detectable in the plasma of 28 thrombocytopenic patients with cirrhosis of the liver, in contrast to thrombocytopenic patients without liver disease. Seven of these patients with cirrhosis underwent orthotopic liver transplantation, resulting in a rise of thrombopoietin levels within 2 days after transplantation. The rise in platelet number followed with a mean lag of 6 days, and shortly thereafter, thrombopoietin levels returned to levels below the limit of detection. Five patients with thrombocytopenia, who underwent only decompression of portal hypertension, showed no rise in either thrombopoietin levels or platelet count.nnnCONCLUSIONSnThrombocytopenia associated with liver disease may at least in part be attributable to inadequate thrombopoietin production in the failing liver.

Successful long-term treatment of portal-systemic encephalopathy by the benzodiazepine antagonist flumazenil

A patient with portal-systemic encephalopathy refractory to standard therapy (40-g protein diet, oral neomycin and lactulose, supplementation of diet with branched chain amino acids) following extensive liver resection and construction of a portacaval shunt was treated with 25 mg of flumazenil twice daily by mouth. Before treatment with flumazenil she was encephalopathic and experienced 12 attacks of coma within 2 yr. When treated with flumazenil all signs of encephalopathy abated in spite of an unrestricted dietary intake of protein. Two days after discontinuation of flumazenil treatment she became comatose again. She remained chronically encephalopathic and had four further episodes of coma during the subsequent 3 mo. Since reinstitution of flumazenil treatment she has been well for 14 mo during follow-up without any signs of encephalopathy while on an unrestricted protein diet. Furthermore, flumazenil therapy reversed abnormalities of recordings of multimodality evoked potentials that were associated with hepatic encephalopathy. The striking remission of encephalopathy by treatment with flumazenil suggests that this benzodiazepine antagonist may be valuable in the long-term management of portal-systemic encephalopathy.

Hepatocellular fat accumulation and low serum cholesterol in patients infected with HCV-3a

OBJECTIVE:The aim of this study was to prospectively investigate the prevalence of hepatic steatosis in chronic hepatitis C patients with respect to viral genotype, hepatic iron concentration, total body iron, body mass index, and serum lipid parameters. Furthermore, the effect of hepatitis C virus (HCV) eradication by antiviral therapy on serum cholesterol levels was studied.METHODS:Hepatocellular fat and hepatic iron were determined in liver biopsies obtained from 137 interferon-naïve patients with chronic hepatitis C (100 men, 37 women, mean age 40.8 ± 10.7 yr) enrolled in two prospective clinical trials of interferon/ribavirin therapy. Body mass index and fasting cholesterol levels were determined at baseline, during, and after therapy.RESULTS:Marked steatosis (>20% of fat-containing hepatocytes) was found in 74.5% of patients infected with HCV-3a compared with 17.9% in HCV-1 and 21.7% in HCV-4-infected patients (p < 0.01). Steatosis in HCV-3a-infected patients did not correlate with the body mass index, hepatic iron content, ferritin, or transferrin saturation. At baseline, serum cholesterol was lower in patients infected with HCV-3a (147 ± 42 mg/dl; p < 0.01) compared with HCV-1 (188 ± 36) or HCV-4 (172 ± 35). In contrast to HCV-1- or HCV-4-infected patients, serum cholesterol increased in HCV-3a virological responders at the end of treatment and 6 months after therapy (baseline 146 ± 38, end of treatment 166 ± 29, p < 0.05, sustained virological response 200 ± 34, p < 0.01). However, serum cholesterol remained unchanged in HCV-3a nonresponders.CONCLUSIONS:Our data suggest that, in addition to inducing steatosis, HCV-3a lowers serum cholesterol. This metabolic effect is fully reversible after successful HCV-3a eradication. This unique property is not shared by other HCV genotypes.

ANEMIA IN CROHN'S DISEASE : IMPORTANCE OF INADEQUATE ERYTHROPOIETIN PRODUCTION AND IRON DEFICIENCY

Intestinal blood loss as well as chronic inflammation are regarded as the most important mechanisms in the pathogenesis of anemia in Crohns disease. In addition, cytokines such as interleukin-6 can suppress erythropoietin production. This study was performed to investigate the importance of iron status, inflammatory activity, and endogenous erythropoietin concentrations for the development of anemia in Crohns disease. In 49 consecutive patients with Crohns disease, hemoglobin, inflammatory activity (Crohns disease activity index, C-reactive protein, α1-acid glycoprotein), iron status (serum iron, transferrin, transferrin saturation, ferritin), and serum erythropoietin levels were studied. Anemic (Hb<12.0 g/dl;N=16) vs nonanemic patients (Hb≥12 g/dl;N=33) showed reduced iron compartments (eg, ferritin 28.7±12.9 µg/liter vs 63.2±15.0 µg/liter, transferrin saturation 6.2±1.4% vs 11.5±1.3%,P<0.01) but no differences in inflammatory activity. An inverse correlation between erythropoietin and hemoglobin concentrations was found (r=-0.62;P<0.001), but the increase in erythropoietin levels was inadequate to the degree of anemia. There was no correlation between erythropoietin and interleukin-6 serum levels. Four of five anemic patients with hemoglobin below 10.5 g/dl and erythropoietin levels within the normal range were treated with parenteral iron (200 mg iron saccharate in 250 ml NaCl, weekly, intravenously). Two of them additionally received recombinant human erythropoietin (150 units/kg, 3× weekly, subcutaneously). After five weeks all patients had a marked increase in hemoglobin. However, the mean increase in erythropoietin-treated patients was 5.0 g/dl compared to 2.0 g/dl in the patients with iron therapy only. No side effects were seen. Our data demonstrate that inadequate erythropoietin production and iron deficiency are pathogenetic factors of anemia in Crohns disease. The therapeutic management using recombinant human erythropoietin and parenteral iron is reasonable and effective.

Bone disease in vitamin D-deficient patients with Crohn's disease

Vitamin D deficiency is frequently observed in patients with Crohns disease and may be associated with an increased risk of development of metabolic bone disease. To estimate the incidence of metabolic bone disease by noninvasive methods, 31 patients (17–75 years old) with Crohns disease and low 25-hydroxy vitamin D (25-OHD) levels in winter were investigated in the following summer by measuring the bone mineral content (BMC) of the distal radius by single photon absorptiometry and the cortical area ratio (CAR) calculated from radiographs of the right hand and by x-ray of the lumbar spine. Forty-five percent of the patients showed signs of metabolic bone disease. BMC and CAR correlated with 25-OHD serum levels (P<0.05), especially in men. Furthermore, the amount of sun exposure has an influence not only on 25-OHD serum levels both in summer and in winter (P=0.0006), but also on the BMC (P=0.07). Consequently, vitamin D deficiency is of major importance for the development of metabolic bone disease in patients with Crohns disease. Vitamin D deficiency can be prevented by increasing sun exposure and long-term vitamin D supplementation.

RELATIONSHIP BETWEEN THE USE OF UNCONVENTIONAL THERAPIES AND DISEASE-RELATED CONCERNS: A STUDY OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE

We studied the use of unconventional therapies of a well-defined population of 105 patients with inflammatory bowel disease (IBD; 72 with Crohns disease and 33 with ulcerative colitis) who were attending a university out-patient clinic. The following items were used to compare those patients who used unconventional therapies with those who did not. We compared disease-related data, sociodemographic variables, patients disease-related concerns, and their perceived level of information about IBD. Concerns were measured with the Rating Form of IBD Patient Concerns (RFIPC), inflammatory disease activity was assessed by physicians with the Crohns disease activity index (CDAI) and the clinical activity index (CAI). Of the 97 (92.4%) patients who answered all questions, 33 (34%) reported using unconventional therapies in addition to conventional therapy. In their level of information about IBD and in their clinical and sociodemographic data, they were not different from the IBD patients who were not using alternative treatments. In their duration of disease, there was a significant difference (p < 0.0002). The longer the disease duration, the more often patients used unconventional therapies. The most important differences between users and nonusers were the following: patients who used unconventional therapies were more concerned about having surgery (p < 0.001), being treated as different (p < 0.04), and feeling out of control (p < 0.05). We conclude that there is a relationship between the use of unconventional therapies and some disease-related concerns, which should be considered in clinical practice. This may help these patients avoid using unproven and expensive alternative therapies.

Primary interferon resistance and treatment response in chronic hepatitis C infection: a pilot study

Summary Only 30% of patients with chronic hepatitis C virus genotype 1 (HCV-1) infection achieve a sustained virological response to interferon and ribavirin combination therapy. We prospectively assessed decline in viral load 24 h after one dose of interferon alfa as a predictor of non-response to 6 months of treatment with interferon and ribavirin. Interferon sensitivity was measured before initiation of combination therapy. We measured viral load in 29 consecutive patients, who had not previously been treated with interferon and who were chronically infected with HCV-1 within 24 h after one dose of 5 MU or 10 MU interferon alfa-2b, and 14 days of daily 5 MU interferon alfa-2b. A 24 h viral load decline by less than 70% of baseline after 5 MU interferon was the best pretreatment measure to identify non-responders (specificity 100%, n=10, 95% CI 74–100], sensitivity 83% [15/18], 59–96]).

Which patients with IBD need psychological interventions? A controlled study.

Background: Psychological distress is frequent in inflammatory bowel disease (IBD). Whether there is a need for psychological interventions is unknown. This study investigated the quantity and quality of the need for psychological interventions in IBD as compared to rheumatoid arthritis (RA). Methods: In all, 302 patients with IBD and 109 patients with RA answered the ADAPT questionnaire, assessing the need for psychosomatic support (physicians support) and for psychotherapy, the hospital anxiety and depression scale, the SF‐36, a questionnaire on social support (SOZU‐K22), and the Rating Form of IBD Patient Concerns (IBD patients only). Detailed biomedical data were also assessed. Results: Ninety‐three patients with IBD (31%) expressed a need for psychological intervention compared to 14 patients with RA (13%; P < 0.001). Stepwise logistic regression analysis revealed that anxiety (odds ratio [OR] 3.6; 95% confidence interval [CI] 2.2‐6.0; P < 0.001), age ≤44 years (OR 2.6; 95% CI 1.5‐4.3; P < 0.001) and impaired social support (SOZU‐K22 <4.20) (OR 2.0; 95% CI 1.2‐3.3; P = 0.009) accounted for this difference. In IBD the need for psychosomatic (physicians) support was associated with worries and concerns about IBD and the need for psychotherapy was associated with worries and concerns about IBD, anxiety, impaired “social functioning” (SF‐36), and short disease duration. Conclusions: Patients with IBD express a higher need for psychological interventions than patients with RA due to greater psychosocial restrictions inherent in IBD. The need for psychological interventions was characterized by psychological factors, mainly worries about the disease and anxiety, rather than by medical variables.