Hepatitis C contributes to liver disease in children and adolescents with hemophilia.

Non-A non-B (NANB) hepatitis plays a major role in liver disease in hemophiliacs. HCV is known to be the predominant cause for blood-borne NANB hepatitis. A cross-sectional study for anti-HCV and anti-HIV-1 antibodies in sera, presence of HBsAg in sera and liver function tests was conducted in 116 male patients with hemophilia (mean age: 14.6 years) in order to study the impact of hepatitis C as well as the significance of concurrent hepatitis B and HIV infection on the liver disease in hemophilic children and adolescents. 56.9% of the patients tested seropositive for anti-HCV; the mean age of the anti-HCV positive group was higher than that of the anti-HCV seronegative group (15.9 versus 11.9 years). Seropositivity to anti-HCV was more often associated with abnormal liver function than it was found in the seronegative group (37.9% versus 17%). Eight of nine patients positive for anti-HCV and HBsAg showed abnormal liver function tests. 68.9% of the anti-HIV-1 positive patients were also anti-HCV positive compared to 44.8% of the anti-HIV-1 negative patients. The liver function tests revealed an abnormal result in 47% of the anti-HIV-1 positive patients compared to 20.7% in the anti-HIV-1 negative group. In conclusion, a high seroprevalence for anti-HCV is detected in young patients with hemophilia which is associated with liver disease in a considerable number of patients when assessed by liver function tests. The coinfection of HCV and HBV seems to increase the risk of liver as also does concurrent HIV-1 infection, which is assumed to contribute to liver disease in a yet unexplained way.

Autoantibodies against the human asialoglycoprotein receptor: effects of therapy in autoimmune and virus-induced chronic active hepatitis.

The hepatic asialoglycoprotein receptor (ASGPR) was recently identified as a target antigen for both humoral and cellular immune response in inflammatory liver diseases. Thereby anti-ASGPR autoantibodies directed against human substrate were closely associated with autoimmune chronic active hepatitis. The present study compares the occurrence, titer and immunoglobulin classification of anti-human(h-)-ASGPR antibodies in 23 patients with newly diagnosed autoimmune chronic hepatitis before and after initiation of immunosuppressive therapy to 22 patients with autoimmune hepatitis in remission. Additionally, 1-year follow-up examinations of 42 patients with HBsAg-positive chronic hepatitis and of 32 patients with chronic hepatitis C receiving recombinant interferon-alpha were included. Nineteen of 23 patients with newly diagnosed and 9/22 with autoimmune hepatitis in remission, 5/42 with untreated chronic hepatitis B and 5/32 patients with chronic hepatitis C exhibited anti-h-ASGPR at the beginning of the study. In autoimmune hepatitis anti-h-ASGPR were found in higher titers (median > 1:1000) than in viral hepatitis (maximum 1:400). After initiation of immunosuppressive therapy in autoimmune hepatitis anti-h-ASGPR decreased sharply. Eight of 19 patients eliminated anti-h-ASGPR within 18 months in contrast to 11 patients with persistent anti-h-ASGPR titer over 18 months and longer. Anti-h-ASGPR with maximum titer of 1:600 were detected in 5 patients with chronic hepatitis B (transiently in 4/5 patients) and in 2 patients with chronic hepatitis C during interferon-alpha. Anti-h-ASGPR were from immunoglobulin classes IgG and IgM in cases with untreated autoimmune hepatitis and chronic hepatitis B and C exhibiting mainly IgG2-subclass in autoimmune and IgG4 in viral hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation of hepatitis B virus, hepatitis D virus and human immunodeficiency virus type I infection markers in hepatitis B surface antigen positive haemophiliacs and patients without haemophilia with clinical and histopathological outcome of hepatitis.

The hepatitis D virus (HDV) infection plays a major role in severe liver damage caused by hepatitis. To establish the prevalence of HDV infection in haemophilic patients and patients without haemophilia, 87 patients with chronic hepatitis B virus (HBV) infection were examined for serological evidence of delta hepatitis. In addition HBV, HDV and human immunodeficiency virus type 1 (HIV) infection markers were compared to clinical and histopathological outcome of hepatitis. Out of 46 haemophiliacs 30 (65%) were anti-HD-seropositive; 10 out of 30 anti-HD-positive patients (33%) had pathological liver function tests compared to 2 out of 16 anti-HD-negative haemophiliacs (13%). The rate of HIV infection did not differ between the HDV infected and the non-HDV infected individuals with haemophilia (17/27 anti-HD-positive patients versus 12/16 anti-HD-negative patients). Two haemophilic anti-HD-positive patients underwent liver biopsy, in both cases hepatitis D antigen (HDAg) was detected in the biopsies. Only 2 out of 41 patients without haemophilia were anti-HD-positive. Both had pathological liver function tests; chronic active hepatitis and cirrhosis, respectively, were diagnosed and HDAg was found in the liver biopsies. Out of 39 anti-HD-seronegative patients without haemophilia, 26 (67%) were hepatitis B e antigen positive; in the sera of 20 patients (51%) HBV-DNA was demonstrated, but only 6 patients (15%) had pathological liver function tests. In conclusion a high seroprevalence of HDV infection was found in haemophilic patients treated with non-pasteurized commercial clotting factor concentrates. An endemic spreading of HDV infection in patients without haemophilia with chronic HBV infection could not be detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Multipoint linkage mapping of the Emery-Dreifuss muscular dystrophy gene.

The clinical features to establish the diagnosis of X-linked Emery-Dreifuss muscular dystrophy (EMD) were recently redefined at the European EMD workshop in Baarn 1991. These criteria were used to select families from the literature and two new families for linkage analysis with the DNA markers F9, DX52, DXS15, F8C and DXS115. Recombinations are observed with the DNA markers F9, DXS52 and DXS15. No recombinations were found with F8C and DXS115. Multipoint linkage analysis indicates with a maximum location score of 73.9 that the EMD locus maps very close to F8C.

25 Hydroxyvitamin D and vitamin E absorption in healthy children and children with chronic intrahepatic cholestasis.

Patients with chronic cholestasis have reduced 25-hydroxyvitamin D (25OHD) and vitamin E levels. We determined serum concentrations of 25OHD, 1,25-dihydroxyvitamin D [1,25(OH)2D] and vitamin E before and after oral administration of 10 micrograms/kg body weight 25-hydroxyvitamin D3 (25OHD3) and 100 IU/kg body weight vitamin E, respectively, in 4 patients with intrahepatic cholestasis and 6 healthy children. Vitamin E increased in all controls but in only one of the four patients. In contrast, oral 25OHD3 induced a normal rise in circulating 25OHD and 1,25(OH)2D. The low serum levels of 25OHD in the patients before the oral bolus may have been due to inadequate parenteral vitamin D administration and/or to the simultaneous phenobarbital treatment. The latter possibility is supported by the increase of serum 25OHD into the normal range after withdrawal of phenobarbital in one of the four patients. We conclude that vitamin E has to be supplemented parenterally or in water-soluble oral form. Further studies are necessary to clarify whether high-dose long-term oral 25OHD3 supplementation is sufficient to prevent vitamin D deficiency in patients with chronic cholestasis.

A simple index relating clinical activity in Crohn's disease with T cell activation: hematocrit, frequency of liquid stools and urinary neopterin as parameters.

Crohn's disease is characterized by alternating acute and quiescent periods. Several indices for activity of the inflammatory process have been proposed to have criteria for prognosis of the clinical course and therapeutic efficacy. Neopterin is specifically released from human monocytes-macrophages after induction by interferon-gamma secreted from activated human T lymphocytes. Thus, urinary neopterin excretion is elevated in diseases involving activation of cellular immunity. Fifteen clinical and laboratory parameters, including urinary neopterin levels, collected from 35 visits of patients with Crohn's disease, were compared using multiple linear regression analysis with a simple clinical activity index as reference. Prediction of clinical activity was best with the combination of hematocrit, weekly number of liquid stools and neopterin. A simple triple-parametric Crohn's disease activity index was established on the basis of this result. Its quality was tested on independent data obtained from 25 repeat visits of 13 of these patients. A comparison with the well-known Crohn's Disease Activity Index (CDAI) was performed. The results obtained with the proposed activity index were slightly better than those with the eight-parametric CDAI for the data from the first as well as from the repeat visits. We conclude that our simple index is a reliable and easily accessible measure for clinical activity in patients with Crohn's disease.

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

Urinary neopterin excretion was measured in 34 patients with Crohn's 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 Crohn's Disease Activity Index (CDAI). Thus, neopterin determination may be introduced as an additional biochemical parameter in the assessment of disease activity.

Serum immunoreactive trypsin and pancreatic lipase in cystic fibrosis.

Serum immunoreactive trypsin (IRT) and pancreatic lipase have been measured in 59 patients with cystic fibrosis (age 1 month-27 years). Follow-up values were obtained from 49 patients. Their serum enzyme levels were compared to those of 120 healthy children of all age groups. Faecal fat excretion was determined in selected patients (n = 23) to elucidate the relationship between serum enzyme levels and pancreatic exocrine function. In cystic fibrosis IRT and lipase showed a very similar age-correlated pattern: in infancy levels were markedly elevated. During the following years the concentrations of both enzymes decreased rapidly and were found to be far below the normal range after the 10th year of life. Elevated enzyme levels in infancy as well as low levels in all age groups coincided with steatorrhea. Older patients (11-27 years) without severe pancreatic insufficiency however, had IRT and lipase levels in or above the normal range. In healthy children there was no age dependency of IRT levels, whereas in the first 12 months of life lipase levels were significantly lower than in later childhood.

[Acute-phase proteins and beta 2 microglobulin in the follow-up of Crohn disease and ulcerative colitis]. / Akut-Phase-Proteine und Beta-2-Mikroglobulin bei der Verlaufskontrolle von Morbus Crohn und Colitis ulcerosa.

The concentrations of orosomucoid, CRP, prealbumin and beta-2-microglobulin were measured in 109 serum samples taken from 19 children with M. Crohn and in 62 samples from 7 children with colitis ulcerosa. The levels were correlated with an activity index calculated on the basis of clinical observations and routine laboratory tests. The orosomucoid and CRP levels rose significantly with increasing severity of both diseases, while neither prealbumin nor beta-2-microglobulin revealed a sufficiently close correlation with the clinical activity. The measurement of CRP and orosomucoid, which is simple to carry out (radial immunodiffusion), enables a fairly exact estimate of the severity of inflammation. Both acute-phase-proteins proved to be of valuable assistance not only in difficult decisions regarding therapy but also for follow-up examinations in randomized studies.

Biliary lipid metabolism in children with chronic intrahepatic cholestasis.

Biliary lipid composition, standard liver function tests, serum lipids and faecal fat excretion were studied in 15 children with chronic intrahepatic cholestasis (severe intrahepatic cholestasis, n = 6; paucity of intralobular bile ducts, n = 4; benign recurrent cholestasis, n = 5) and compared to 15 children without gastrointestinal diseases. Severe and benign intrahepatic cholestasis were associated with normal or moderately elevated serum lipids. Biliary lipid concentrations were extremely reduced, bile acid concentrations were below the critical micellar concentration. This may account for the high incidence of gallstone formation in these patients. Remission periods in patients with benign recurrent cholestasis were not followed by complete normalisation of biliary lipid concentrations, indicating a primary defect in hepatic excretory function. Children with paucity of intralobular bile ducts showed markedly increased serum lipids, but only a two-fold reduction in biliary lipid concentrations. Cholic acid was the predominant bile acid in bile of all cholestatic children even during remission. Neither increased levels of monohydroxy bile acids nor unusual bile acids could be identified in notable amounts.

Effects of phenobarbital on biliary lipid metabolism in children with chronic intrahepatic cholestasis.

The effects of phenobarbital (5.4-7.5 mg/kg body weight) for 14 days were studied in four children with severe intrahepatic cholestasis (group I) and in four with a syndromatic type of paucity of intralobular bile ducts (group II). Phenobarbital administration resulted in a moderate improvement of pruritus in all patients. There was a significant decrease of bilirubin in serum (group I: from 4.8 to 2.7 mg/dl; group II: from 6.1 to 2.1 mg/dl); total bile acids (group I: from 416 to 337 mumol/l; group II: from 156 to 123 mumol/l) and cholesterol (group I: from 248 to 207 mg/dl; group II: from 351 to 292 mg/dl). Alkaline phosphatase activity increased from 929 to 1126 U/l in group I and from 1751 to 2360 U/l in group II. SGOT and SGPT activities remained unchanged in both groups. In group I total biliary lipid concentration and bile acid output increased from 0.09 to 0.17 g/dl and from 3.9 to 7.2 mumol/kg per 30 min, respectively. Molar percentages of cholesterol, phospholipids and bile acids in bile remained unchanged. In group II total lipid concentrations and bile acid output increased from 1.62 to 2.0 g/dl and from 27.8 to 39.1 mumol/kg per 30 min, respectively. The molar percentage of cholesterol decreased from 5.6 to 3.5 mol%. The present results indicate that short term administration of phenobarbital has only minimal effects on biliary lipid metabolism in children with chronic intrahepatic cholestasis.

[Non A, non B-hepatitis in children]. / Nicht-A, Nicht-B-Hepatitis im Kindesalter.

Between 1975 and 1980, 10 children with acute and 8 children with chronic hepatitis type Non A, NON B (NANB) were seen in our hospital. Parenteral inoculation was probable in 10 cases. Hepatitis NANB was diagnosed in about 11% of all children with acute viral hepatitis who were admitted over this period. Children with parenterally acquired disease were more frequently anicteric and had less pronounced transaminase elevation than "sporadic" cases. An uncomplicated outcome was observed in only three of the ten children. Two patients died from acute liver failure, chronic hepatitis developed in three other children. The 9 children with chronic hepatitis NANB are representing 17% of all patients with chronic hepatitis who were seen in our clinic between 1975 and 1980. In six children with CPH a benign course was observed whereas three children with CAH were severely ill including portal hypertension. Immunosuppressive therapy was tried in two cases without success. In children as well as in adult patients, acute hepatitis NANB apparently has more frequently a prolonged course or progression to chronic liver disease than acute hepatitis of other etiology. It seems that CPH NANB shows a similarly benign course as chronic persistent hepatitis B. CAH NANB in our patients, however, had a poorer prognosis than CAH type B.

[Spontaneous bacterial peritonitis in cirrhosis of the liver caused by alpha-1-antitrypsin deficiency (author's transl)]. / Spontane bakterielle Peritonitis bei Leberzirrhose aufgrund eines Alpha-1-antitrypsinmangels.

A three year old child with cirrhosis of the liver and ascites caused by alpha-1-antitrypsin deficiency, developed severe abdominal pain with diarrhea and fever. Spontaneous bacterial peritonitis was diagnosed by demonstrating a purulent ascitic fluid with gram-positive cocci in the smear which were identified as pneumococci in the bacterial culture. The peritonitis subsided under antibiotic treatment without complications. Spontaneous bacterial peritonitis in children with cirrhosis of the liver is mentioned in the literature, but up to now, however, only three cases were reported in detail. In order to establish the diagnosis, abdominal tap should be tried rather than explorative laparotomy, the demonstration of gram-positive cocci is diagnostic of spontaneous bacterial peritonitis. With early antibiotic therapy, prognosis of the disease is favourable. Newborns and children with nephrotic syndrome, however, are particularly at risk.

[Infantile Campylobacter enteritis (author's transl)]. / Campylobacter-Enteritis bei Kleinkindern.

9 children with campylobacter enteritis aging from 3 days to 4 years were seen over a 8-month period. In 2 cases prompt recovery was achieved by erythromycin therapy. In the remaining 7 cases, the course was most often very mild, and symptomatic therapy was sufficient. Epidemiologically, the incidence of campylobacter enteritis is comparable to that of salmonella enteritis. Obviously, birds and poultry, but also dogs, cats, sheep and other domestic and farm animals are important sources of infection. Spread among human beings has also been made probable. The most frequent clinical features are fever, abdominal pain and bloody diarrhoea. Complications are most often associated with subspecies intestinalis whereas infections with subspecies jejuni almost exclusively cause enteritis. C. fetus is usually sensitive to erythromycin, tetracycline and aminoglycosides. The advantage of antibiotic therapy, however, has not yet been established.

Chronic viral hepatitis B in childhood. I. Clinical , Biochemical and histological results.

The results of clinical, biochemical and histological studies in 26 children with chronic hepatitis B are reported. Most cases were detected when diagnostic procedures were arranged because of non specific abdominal complaints, by routing tests after acute hepatitis or multiple transfusions, and by examination of family members. Hepatomegaly was found in half of the cases, splenomegaly in a quarter. Other clinical signs were rarely seen. Among the biochemical findings, elevated serum transaminase activities were the most reliable indicators of chronic hepatitis. There was a significant difference of the mean transaminase activities between patients with CPH and CAH. In 15 children CPH was diagnosed histologically. 9 children had CAH, 2 children showed signs of MinH.

Complement studies in children with treated coeliac disease after gluten challenge.

Changes of the complement components in the sera of 13 children with treated coeliac disease were studied after gluten challenge. The levels of C 1 and C3-activator (factor B) were significantly decreased at 4 h after the challenge, as were the levels of total complement (CH 50) and the components C 1, C 4 and C 1-inactivator at 8 h. After 24 h most values returned to normal but there was another significant decrease in serum C 4 after 24 h, and for CH 50, C 1, C 2 and C 4 after 48 h.