Natural history and etiology of liver disease in patients with previous community-acquired acute non-A, non-B hepatitis. A follow-up study of 178 Danish patients consecutively enrolled in The Copenhagen Hepatitis Acuta Programme in the period 1969-1987.

BACKGROUND/AIMS: Consecutive patients originally diagnosed with acute non-A, non-B hepatitis were followed up to assess the long-term morbidity and mortality and to re-evaluate the etiology in surviving patients. METHODS: Follow-up was performed in 178 patients with acute non-A, non-B hepatitis enrolled in the Copenhagen Hepatitis Acuta Programme in the period 1969-1987. Mortality and morbidity were assessed using: i) death certificates and ii) diagnoses at discharge following all somatic admissions. All patients who were alive were offered a re-examination encompassing clinical, biochemical and virological evaluation. RESULTS: After a median of 23 years, 71 (40%) had died and seven (4%) were untraceable. Overall mortality and mortality due to cirrhosis and accidents, mainly intoxication with drugs, were significantly higher compared to those of an age- and sex-matched Danish population. Chronic hepatitis had been diagnosed in 19 (11%) and cirrhosis in 16 (9%). Of 100 patients who were alive, 57 accepted a re-examination. Anti-HCV was detected in 24 (42%) and 19 (33%) were HCV-RNA positive. Of the viremic patients, 11 (58%) had elevated P-ALT, but only three (16%) had already been diagnosed with HCV infection. A history of intravenous drug use was tantamount to anti-HCV positivity. CONCLUSIONS: Danish patients with community-acquired acute non-A, non-B hepatitis had an increased mortality due to liver cirrhosis during the first years after the acute infection. Alcohol was the etiological agent in several cases, but HCV infection may also have been present. However, the long-term HCV-related morbidity and mortality were low.

Biochemical, virological and histopathological changes in Danish blood donors with antibodies to hepatitis C virus.

BACKGROUND: Previous studies have indicated that the presence of antibodies to Hepatitis C virus (HCV) is indicative of current HCV infection irrespective of S-alanine aminotransferase (S-ALT) values. STUDY DESIGN AND METHODS: Over three years, all confirmed anti-HCV-positive blood donors form the Blood Banks of Copenhagen County were consecutively evaluated. Seven women and 14 men with a median age of 34 years were included. Serum HCV-RNA was measured with an in-house developed single PCR. Liver biopsies were classified according to standard criteria. RESULTS: All were asymptomatic at presentation with no history of liver disease. Previous intravenous drug abuse and/or tattooing were identified in 16. Seventeen blood donors were evaluated biochemically and histologically. Serum HCV-RNA was detectable in 14, all of whom had histopathological changes in their liver biopsy including chronic active hepatitis and active cirrhosis. Twelve of the 14 HCV-RNA-positive donors had elevated S-ALT. In the three HCV-RNA-negative donors, S-ALT was normal. Two of these had normal liver biopsies, whereas the third had minimal changes. CONCLUSION: To diagnose and evaluate the activity of chronic HCV infection, liver biopsy and HCV-RNA assessment are essential in confirmed anti-HCV-positive individuals irrespective of symptoms and S-ALT levels.

[Temporal arteritis without histological changes]. / Arteritis temporalis uden histologiske forandringer.

A patient with severe giant cell arteritis with involvement of both eyes is presented. The symptoms were partly reversible by treatment with high doses of prednison. Three months previously (having symptoms of polymyalgia rheumatica) she had started treatment with a low dosage of prednison. Biopsies of both temporal arteries showed no signs of giant cell arteritis at that time, and the results of eye examinations were normal. The importance of follow-up on patients with symptoms of polymyalgia rheumatica, even if biopsies of the temporal arteries show no histological changes, is emphasised.

Prevalence of hepatitis B virus infection in out-patient alcoholics.

Sera from 192 out-patient alcoholics attending a clinic for the treatment of alcoholism were tested for hepatitis B surface antigen (HBsAg) and for antibodies to HBsAg and to hepatitis B core antigen (HBcAg). Three sera (1.5%) were positive for HBsAg. Of the remaining 189 alcoholics, 29 (15%) were positive for one or both antibodies. This prevalence is not significantly different from that found in 137 hospitalized HBsAg-negative patients with alcoholic liver disease (35/137 [26%] were positive for one or both antibodies). However, the prevalence of hepatitis B antibodies in out-patient alcoholics is significantly (p less than 0.01) higher when compared with the prevalence in healthy volunteer blood donors (5/114 [4%] were positive for one or both antibodies). A comparison of out-patient alcoholics positive for one or both antibodies (n = 29) with patients negative for both antibodies (n = 160) revealed that the median age in the former group (46 years) was significantly (p less than 0.05) higher than that in the latter group (40 years).

Hypothalamic-pituitary-gonadal function in relation to liver function in men with alcoholic cirrhosis.

Serum concentrations of oestrone, oestradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormone-binding globulin (SHBG) were significantly (P less than 0.01) raised in men with alcoholic liver cirrhosis (no. = 42) compared with age-matched controls (no. = 20). No significant difference was observed when comparing serum testosterone concentrations. Patients were divided into three groups in accordance with the severity of liver cirrhosis, using biochemical and clinical criteria. Patients with the best-preserved liver function (no. = 11) and patients with moderately affected liver function (no. = 18) had significantly (P less than 0.05) raised serum concentrations of testosterone, FSH, and LH when compared with both controls and patients with severely affected liver function (no. = 13). Serum concentrations of testosterone, FSH, and LH in the latter group showed no significant differences from the controls. Serum concentrations of oestrone and oestradiol were significantly (P less than 0.05) increased in all patient groups, and serum oestrone increased with decreasing liver function. No significant differences were observed concerning SHBG concentrations in the three groups of patients. Dexamethasone suppression did not change the concentration of testosterone significantly, but oestrone and oestradiol concentrations decreased significantly (P less than 0.01) in controls and patients. In patients, but not in controls, a significant (P less than 0.01) increase in FSH and LH concentrations was observed after dexamethasone suppression. The mean percentage increase of FSH and LH was higher the greater the severity of liver cirrhosis.

The accuracy of the clinical diagnosis in acute hepatitis and alcoholic liver disease. Clinical versus morphological diagnosis.

Microfilms were prepared from the case histories of 357 consecutive patients submitted to liver biopsy for the first time so that all information after the time of the liver biopsy was erased. The microfilms were assessed by four clinicians, and the pre-biopsy diagnostic proposals were graded according to the degree of certainty and were compared with the results of the liver biopsies. Out of 357 patients, 200 had a history of alcoholism, of whom 172 had alcohol-induced changes in the liver biopsies: 80 cases of alcoholic cirrhosis, 84 cases of steatosis, and 8 cases of alcoholic hepatitis without cirrhosis. In 65 of the 80 patients with biopsy-verified alcoholic cirrhosis the clinical pre-biopsy diagnosis was in agreement with the histological findings. In 51 cases in which the clinical diagnosis of alcoholic cirrhosis was given as moderately certain or very certain, 4 clinically incorrect diagnoses occurred. No incorrect diagnoses occurred in the 35 cases in which the clinicians claimed the greatest diagnostic accuracy. In the 84 patients with steatosis in the liver biopsies the clinicians felt uncertain or moderately certain about all but 2 patients, and 14 incorrect diagnoses occurred. In none of the 8 patients with histological alcoholic hepatitis without cirrhosis was a correct clinical diagnosis made. The clinical pre-biopsy diagnosis of acute hepatitis was in agreement with the results of the liver biopsies in 52 out of 57 patients. In 51 cases in which the clinical diagnosis of acute hepatitis was given as moderately certain or very certain, 1 clinically incorrect diagnosis occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Peritoneovenous shunt in treatment of ascites in patients with cirrhosis. A preliminary report with special reference to pathophysiology.

Peritoneovenous shunts (LeVeen type) were implanted in seven patients with cirrhosis complicated by ascites refractory to diuretic treatment. Three patients died of gastrointestinal bleeding and hepatic coma 1 to 7 weeks after the shunt implantation. The patients who died were those with the most severely impaired liver and kidney function. In two of the four surviving patients (observation time, 5-24 months) the shunt was patent during the observation time, and ascites disappeared. In the other two the shunt closed, in one patient repeatedly following several re-implantations. Enhanced urinary sodium excretion was observed in patients with patent shunts. After disappearance of ascites, the splanchnic venous pressures became less deranged. Long-term change in plasma volume or circulating albumin mass could not be detected. A patent shunt increases the drainage from the peritoneal cavity, but detectable increment in the overall lymph drainage was only found in a patient with a very low pre-shunt value. The findings do not support the 'overflow' theory of ascites formation but rather the 'lymph imbalance' theory. For clinical evaluation of peritoneovenous shunting in the treatment of ascites a controlled clinical trial is essential.

Oral testosterone load related to liver function in men with alcoholic liver cirrhosis.

The relation between liver function and an oral testosterone load was examined in 42 consecutive patients with alcoholic liver cirrhosis. Administration of an oral load of 400 mg micronized free testosterone increased the serum concentration of testosterone (range, 31.9-694.4 nmol/l; median, 140.8 nmol/l) in male patients with alcoholic liver cirrhosis to significantly (P less than 0.01) higher levels than in male subjects without liver disease (range, 25.4-106.6 nmol/l; median, 61.5 nmol/l). The increase of testosterone after the load (log delta testosterone) in patients correlated inversely with galactose elimination capacity (r = 0.54; P less than 0.001), serum albumin (r = -0.53; P less than 0.001), plasma factor II + VII + X (r = 0.62; P less than 0.001), indocyanine green clearance (r = -0.71; P less than 0.001), and hepatic blood flow (r = -0.61; P less than 0.01) and correlated directly with wedged-to-free hepatic vein pressure (r = +0.54; P less than 0.01). The increase of testosterone after the load did not correlate significantly with sex hormone-binding globulin (r = +0.35; P greater than 0.05). It is concluded that the hepatic extraction of testosterone is significantly decreased in patients with alcoholic cirrhosis. This decrease seems to be due to decreased liver function, decreasing hepatic blood flow, and increased portosystemic shunting. Oral testosterone loading may therefore be of prognostic significance in patients with alcoholic liver cirrhosis.

Azathioprine versus prednisone in non-alcoholic chronic liver disease (CLD). Relation to a serological classification.

One hundred and forty-eight patients with non-alcoholic cirrhosis or chronic aggressive hepatitis entered a prospective, unblinded, randomized trial on the effect of azathioprine versus prednisone. For all 148 patients, there were no differences in survival related to the two drugs. In 99 patients the disease was classified as autoimmune, in 23 as posthepatitic, and in 26 as cryptogenic. No significant differences were seen in survival between these three groups of patients and no differences in survival related to the two drugs were registered within any of the groups. The autoimmune group included the patients with the biochemically most active disease, and a statistically significant reduction in activity was obtained with prednisone as well as azathioprine. Most remarkably, the frequencies of the autoantibodies were reduced parallel to the biochemical improvement in these patients. Immunosuppressive treatment was found to be rather ineffective in posthepatic chronic liver disease of type B; however, no signs of activation of the hepatitis B virus were seen.

Chronic persistent hepatitis: serological classification and meaning of the hepatitis B e system.

In order to evaluate the prognostic implications of the hepatitis B e system in patients with chronic persistent hepatitis (CPH), 53 consecutive patients were studied. Fourteen of 16 patients with HBsAg and HBeAg were followed from 12 to 120 months (mean, 38 months). Eleven of the 14 patients were persistently HBeAg positive and five of these developed chronic active hepatitis (CAH) or cirrhosis. A further nine patients were HBsAg positive but HBeAg negative at time of CPH diagnosis (mean follow-up, 47 months). One of these nine patients developed CAH during follow-up. The remaining 28 patients were all HBsAg negative, and only 2 or the 28 patients progressed to CAH or cirrhosis during the time of follow-up (mean, 43 months). It is concluded that the persistence of HBeAg in patients with CPH indicates a serious prognosis with a frequent transition to CAH or cirrhosis.

Pituitary-testicular function in patients with alcoholic cirrhosis of the liver.

In forty-two patients with alcoholic liver cirrhosis and without recent alcohol ingestion the pituitary-testicular function was studied in an effort to relate the endocrine abnormalities with the degree of liver cell dysfunction, evaluated on a quantitative basis. Compared with values in twenty-one healthy controls, we found significantly elevated serum oestrone, oestradiol, follicle-stimulating hormone, luteinizing hormone and prolactin (P less than 0.01). Serum dehydro-epiandrosterone and dehydroepiandrosterone sulphate were significantly reduced in the cirrhotics (P less than 0.01), whereas serum testosterone was not significantly different from that in the controls. Raised levels of sex-hormone binding globulin were found in 71% (22/31) of the patients (median 8 x 10(-18) mol/l, range 3-17 x 10(-8) mol/l). The incidence of gynaecomastia (38%), cutaneous spiders (67%), testicular atrophy (24%) and reduced axillary hair (71%) was without significant relation to raised levels of sex-hormone binding globulin or progressively reduced liver function. In the presence of clinical or hormonal hypo-gonadism we found evidence of a state of primary hypogonadism together with an inadequate secretion of gonadotropins. The state of hyperoestrogenaemia and the concentration of gonadotropins were significantly correlated to the hepatic synthesis of coagulation factors.

Gamma-glutamyltransferase, aspartate aminotransferase and alkaline phosphatase as markers of alcohol consumption in out-patient alcoholics.

Serum activity of gamma-glutamyltransferase, aspartate aminotransferase and alkaline phosphatase were determined in 316 patients attending an out-patients clinic for treatment of alcoholism. The activity of gamma-glutamyltransferase was raised in 34% and that of aspartate aminotransferase and alkaline phosphatase in 18% and 7%. Neither the activity of gamma-glutamyltransferase, aspartate aminotransferase nor alkaline phosphatase showed any significant (P greater than 0.05) correlation with the history of alcohol consumption. The activities of gamma-glutamyltransferase and aspartate aminotransferase were raised significantly more often in patients with recent alcohol consumption than in patients who had abstained for more than 9 days. The concentration of alkaline phosphatase was not significantly (P greater than 0.05) different in these groups. The predictive value of raised and normal activities of gamma-glutamyltransferase, in deciding whether a patient had had recent alcohol consumption or not, was not superior to the predictive value of raised and normal activities of aspartate aminotransferase.

Autoantibodies, histocompatibility antigens and testosterone in males with alcoholic liver cirrhosis.

Titres and immunoglobulin classes of autoantibodies were examined in 69 male patients with alcoholic liver cirrhosis and the findings were related to particular human leucocyte antigens and serum concentration of testosterone. Both anti-nuclear antibodies (ANA) and smooth muscle antibodies (SMA) were significantly more prevalent in patients with cirrhosis than in sex- and age-matched controls. Antimitochondrial antibodies and liver cell membrane antibody were found in 4% of the patients, and in none of the controls, but this difference was not significant. Patients with HLA-B8 and/or HLA-B12 had higher titres of ANA (n.s.) and SMA (P less than 0.05) than patients without these HLA antigens. Serum concentrations of testosterone were significantly lower in ANA-positive patients than in those negative (P less than 0.05), and a similar tendency was found in SMA-positive patients. With increasing titres of ANA the concentration of testosterone fell. Serum concentration of testosterone correlated inversely (P less than 0.05) with plasma immunoglobulin G and A. It is concluded that both genetic and hormonal factors may influence the humoral immune response in these patients.

Short-term parenteral and peroral testosterone administration in men with alcoholic cirrhosis.

Serum concentrations of testosterone were measured in 24 male patients with alcoholic cirrhosis during testosterone administration. The purpose was to compare serum concentrations of testosterone during peroral with those during parenteral testosterone administration in these patients. Patients who were injected intramuscularly with a combination of short- and long-acting testosterone (Triolandren, 348 mg testosterone) had median peak values of serum testosterone of about 40 ng/ml, which fell to basal levels after a fortnight. During testosterone propionate injections (84 mg testosterone) every other day, rather constant serum concentrations with median values of about 30 ng/ml were reached after 4 days. Peroral testosterone administration (800 mg micronized free testosterone) each day also resulted in fairly constant serum concentrations after 4 days, and the median values were about 50 ng/ml. No side effects were observed.

Human leucocyte antigens in patients with alcoholic liver cirrhosis.

No significant differences in the frequencies of HLA-B8, -B40, and other HLA-A, -B, and -C phenotypes were found among patients with histologically verified alcoholic cirrhosis compared with normal controls when the p values were multiplied by the number of comparisons. This was found both in the present study of 45 patients and in the combined data of this and three other similar studies. However, these findings do not rule out that alcoholic cirrhosis might be associated with HLA factors (for example. HLA-D/DR antigens) controlling immune responses.

The role of acute hepatitis type A, B, and non-A non-B in the development of chronic active liver disease.

In 19 patients followed from biopsy-verified acute viral hepatitis to chronic active liver disease and 74 patients followed to complete resolution verified by a normal liver biopsy, sera from the acute phase were studied for serologic evidence of hepatitis type A and B. Eleven of the 19 patients who developed chronic active liver disease progressed from acute hepatitis type B and 7 from acute hepatitis type non-A non-B. One patient could not be classified because the sera were exhausted. None had serological markers of actual hepatitis type A infection. Of the 74 patients with a histologically complete resolution, the acute episode could be classified as type B hepatitis in 47 and type A hepatitis in 13 patients. The remaining 14 patients were classified as having acute viral hepatitis type non-A non-B. Our findings confirm that type B and non-A non-B hepatitis may give rise to chronic liver disease, whereas type A hepatitis so far has not been demonstrated to initiate a chronic liver disease.