Autoimmune endocrine disease induced by recombinant interferon-alpha therapy for chronic active type C hepatitis

To elucidate the role played by interferon-alpha (IFN alpha) in the pathogenesis of autoimmune endocrine disease, we determined the autoantibody status, thyroid function test results, hemoglobin-A1c levels, and clinical symptoms of 58 patients who received IFN alpha for treatment of chronic active type C hepatitis. Each patient was treated for 6 months with a total dose of 391 +/- 140 x 10(6) U (mean +/- SD). Thyroid microsomal and/or thyroglobulin antibodies newly appeared or were increased in titer in 6 patients, 2 of whom developed hypothyroidism during IFN alpha therapy. Neither islet cell antibodies nor insulin-dependent diabetes mellitus developed during IFN alpha therapy, although hemoglobin-A1c levels were increased in 2 patients. One patient became positive for antimitochondrial antibodies, and another patient with preexisting antimitochondrial antibodies also manifested deterioration in liver function test results. Parietal cell antibodies and smooth muscle cell antibodies were the most frequent newly developed antibodies in 7 patients. Adrenal medullary cell antibodies and nuclear antibodies newly developed in 2 and 1 patients, respectively. At least 1 of 8 autoantibodies newly appeared in 19 patients (32.8%) and hypothyroidism developed in 2 patients (3.4%) during IFN alpha therapy. On the other hand, in 19 age- and sex-matched patients who did not receive IFN alpha, no autoantibody appeared, and no autoimmune disease developed during a follow-up period of 3 months. These findings suggest that IFN alpha acts as an immunomodulatory agent, inducing autoantibody production and the development of autoimmune disease in susceptible patients. Special attention should be paid to the development of hypothyroidism during IFN alpha therapy.     

Thyroid autoantibodies and thyroid dysfunction during treatment with interferon-alpha for chronic hepatitis C

Previous studies have shown that polymerized [14C]arabinan can be synthesized from polyprenylphosphate-[14C]arabinose by the particulate enzymes of Mycobacterium smegmatis [R.E. Lee, K. Mikusová, P.J. Brennan and G.S Besra (1995) J. Am. Chem. Soc. 117, 11829-11832]. In the present investigation, the [14C]arabinan product was biochemically characterized. Sizing chromatography revealed a molecular weight consistent with that expected from mature arabinan. Digestion of the [14C]arabinan with a mixture of arabinases produced oligo[14C]arabinoside fragments including hexa[14C]arabinoside and tetra[14C]arabinoside which originated from the non-reducing terminal regions of the polymer, and di[14C]arabinoside from the internal regions of the polymer. These arabinoside fragments represent the major known structural motifs that comprise the arabinan segment of arabinogalactan and lipoarabinomannan. The presence of [14C]arabinose in both the internal and external regions of the [14C]arabinan suggests that polyprenylphosphate-arabinose is the major, and perhaps the only, donor of arabinosyl residues in mycobacteria.     

Long-term follow-up of patients with chronic hepatitis C after interferon-alpha treatment

In this study, 72 patients with chronic hepatitis C virus (HCV) were followed prospectively for a mean period of 27 months after interferon treatment. Fifty-seven percent (20/35) of the patients with complete response, 18/20 with HCV-RNA-negative serum, had a sustained biochemical remission. Reactivation was seen in 43% of these patients after a mean follow-up of 7.3 months. A late relapse after more than 12 months of follow-up occurred in only 2/15 patients. Patients with a long-term complete response had significantly lower pretreatment serum HCV RNA levels than complete responders with relapse (106,239 vs. 345,649 mEq/ml, p = 0.0213). A delayed sustained biochemical remission was seen in 3/37 patients with partial or no response. Thus, long-term response is achieved in 32% of the patients treated with interferon, clearly associated with a suppression of serum HCV RNA. Patients with normal ALT values and undetectable levels of HCV RNA for more than 12 months of follow-up may usually be considered as sustained responders. Thus, for the first time, the pretreatment HCV RNA level in serum was identified as predictive of long-term response.     

Incidence of viral hepatitis after administration of factor IX concentrates

A high frequency of viral hepatitis has been reported after treatment with the human factor IX concentrate 'Konyne'. Clinical trials with 'Konyne' and a similar factor IX concentrate, called 'Preconativ', was started in Sweden 1969. During the first 2 years, 26 patients were treated with either one or both preparations. Nine patients developed viral hepatitis within 6 months after treatment. 'Preconativ' alone was introduced on the Swedish market in 1971. During the period 1971-1974, another 26 hemophiliacs were treated but only two cases of hepatitis have occurred. Selection of donors and screening for hepatitis B surface antigen in donor blood used for the manufacturing of 'Preconativ', might be contributing factors to this low hepatitis incidence.     

The risk factor for development of thyroid disease during interferon-alpha therapy for chronic hepatitis C

OBJECTIVES: To determine the risk factors for the development of thyroid diseases during interferon-alpha therapy, we analyzed the patients with chronic hepatitis C who were treated with interferon-alpha. METHODS: One hundred nine patients with chronic hepatitis C (77 men and 32 women, ages 20-72 yr) were treated with interferon-alpha (alpha, 48; alpha 2a, 38; alpha 2b, 23) for 14-40 wk. Thyroid function tests and seven autoantibodies were assessed at the beginning and end of interferon-alpha therapy, and every other month. A logistic multiple regression model was used in the statistical analysis of risk factors for development of thyroid diseases. RESULTS: Among the 106 patients with normal pretreatment thyroid function tests, nine patients (three men and six women, ages 33-62 yr) developed thyroid diseases. However, among three patients with abnormal thyroid function tests, exacerbation of thyroid disease was not observed during interferon-alpha therapy. Logistic multiple regression model revealed that positivity for microsome antibody was a significant risk factor for the development of thyroid disease (p < 0.0001, chi 2 = 20.18). Actually, compared to patients without microsome antibody at the beginning of therapy, the incidence of thyroid diseases in the patients with pretreatment microsome antibody was very high: 3.3% (3/99) versus 60% (6/10), respectively. Six patients developed hyperthyroidism and three patients developed hypothyroidism. The patients with hyperthyroidism had atypical clinical features. CONCLUSION: Our study revealed that positivity for microsome antibody at the beginning of interferon-alpha therapy is a risk factor for thyroid dysfunction.     

Dynamics of hepatitis C viremia following interferon-alpha administration

Knowledge of the dynamics of hepatitis C virus (HCV) in vivo is important for elucidation of its pathogenesis and the establishment of therapeutic guidelines. The aim of this study was to obtain kinetic information about virus load following interferon-alpha (IFN-alpha) administration. Serial serum HCV core protein and HCV RNA levels were measured. IFN-alpha exponentially reduced serum HCV levels. The mean (+/-SD) viral half-life was 7.0 +/- 2.6 h in HCV core protein assay and 7.2 +/- 3.1 h in HCV RNA assay on the first day of therapy. This initial rapid decrease was followed by a slower decrease in serum HCV levels thereafter. Thus, the biphasic reduction in virus load during IFN-alpha therapy was demonstrated.     

Changes of antipyrine pharmacokinetics during influenza and after administration of interferon-alpha and -beta

Muscle morphological alterations derived from protein malnutrition are subjected to debate, specially regarding the alteration of the proportion of the different fibre types. The aim of the present study was to analyse the morphologic changes of the different muscle fibre types in experimental protein malnutrition. Twelve male Wistar rats were fed on a 6% protein containing diet, and another 12 rats were fed on an isocaloric, 20% protein containing diet as control group. Right gastrocnemius muscle was removed. Fibre diameter and relative proportions of type I, IIa and IIb muscle fibre (by means of the myosin-ATPasa reactivity) were evaluated. Protein deprived rats showed a significant decrease in the mean diameter of type IIb fibres and also a decrease of the proportion of the type IIb fibres.     

Sarcoidosis associated with interferon-alpha therapy for chronic hepatitis C

PURPOSE: To compare the changes in visually guided performance as a function of age between Royal College of Surgeons (RCS) dystrophic and congenic rats and to correlate photoreceptor cell number with visually guided performance in age-matched populations of RCS dystrophic rats. METHODS: The visually guided performances of RCS dystrophic (n=6) and congenic (n=7) rats were studied from 0.75 to 12 months of age using a water escape paradigm that tested their ability to find a submersed, randomly placed platform that used a light source as a clue. The time to find the platform (latency) was recorded. In age-matched dystrophic RCS rats, histopathologic changes were described and the number of photoreceptor cell nuclear profiles per midsagittal retinal section was counted. Changes with age in visually guided behavior and photoreceptor cell populations of RCS dystrophic rats then were compared. RESULTS: The latency of RCS dystrophic rats increased significantly beyond that of congenic rats after 6 months of age. Photoreceptor cell number in dystrophic rats precipitously decreased through 6 months of age, stabilized at 9 months, and decreased further at 12 months. Two unexpected results were seen in the dystrophic animals: At 6 months of age, as few as 22+/-3 photoreceptor cell nuclei per midsagittal section provided similar latencies as at 2 months when there were as many as 400. Although the number of photoreceptor cells remained stable from 6 to 9 months of age, functional vision significantly deteriorated. CONCLUSIONS: Two important phenomena were observed. First, the RCS rats performed very well in the water escape test even while their photoreceptor cell population was being decimated. Second, once a low threshold was reached, a dramatic deterioration of visually guided behavior occurred without a further reduction in photoreceptor cell numbers.     

Treatment of chronic viral hepatitis

Recent advances have been made in the treatment of chronic viral hepatitis, mainly with recombinant interferon (IFN) alpha. However, the present treatment of chronic viral hepatitis is not entirely satisfactory because the efficacy is inconstant and/or incomplete. In chronic hepatitis B IFN-alpha induces a sustained interruption of hepatitis B virus (HBV) replication, with a HBeAg to anti-HBe seroconversion in about 30% of patients. Patients most likely to respond are those with no immunosuppression, HBV infection acquired during adulthood or active liver disease with low HBV replication. Responders usually show a significant decrease in serum HBV DNA levels during the first 2 months of therapy, followed by a significant increase in the level of aminotransferases. New nucleoside analogues might be useful in combination with IFN-alpha in the treatment of those who do not respond to IFN therapy. In chronic hepatitis B-D, the rate of sustained response to IFN-alpha therapy is low. To be effective, IFN-alpha must be used at a high dosage (9-10 mega units) with a long duration (1 year). In chronic hepatitis C, IFN-alpha at a dosage of 3 mega units over 6 months, induces a sustained response in about 20% of patients. A higher dosage of IFN (5-10 mega units) and a longer duration of treatment increases the rate of sustained response but is associated with poor tolerance. Non-responders to a first course of IFN do not respond to a second course of treatment. In patients who respond but relapse after treatment, the rate of sustained response after a second course of IFN needs to be assessed. Ribavirin, which has a significant antiviral effect on hepatitis C virus, might be useful in combination with IFN-alpha. At the dosage (3-6 mega units) usually used, IFN-alpha is relatively well tolerated. In about 10% of the patients therapy is interrupted, mainly because of severe fatigue, thyroid dysfunction or depression.     

Management of chronic viral hepatitis

Chronic viral hepatitis is a leading cause of death worldwide. Four of the six identifiable hepatitis viruses are associated with chronic disease. Until recently, the only accepted treatment has been injected interferon alfa. New antiviral medications currently hold promise in the treatment of hepatitis B. Hepatitis C remains more difficult to treat than hepatitis B, but involving the patient in selecting the treatment and identifying patients with better responses to interferon may help the physician direct the management of such patients more successfully.     

Treatment of chronic viral hepatitis

The initial appearance of tyrosine hydroxylase (TH)-, serotonin (5-HT)-, gamma-aminobutyric acid (GABA)-, calcitonin gene-related peptide- (CGRP), substance P-, and synaptophysin-immunoreactivity in the rat pituitary gland, and in the related brain regions was investigated. Several groups of TH-immunoreactive neurons were first detected in the brain stem on day E17, and in the hypothalamus on day E18, followed by TH-immunoreactivity in the median eminence and infundibulum on E19-E20. TH-positive fibers appeared in the posterior lobe on day E20 and in the intermediate lobe on day P0. 5-HT-immunoreactivity was first detected on day E17 in neurons and nerve fibers in the brain stem and in the median eminence, respectively. On day E18, a few 5-HT-immunoreactive fibers were detected in the posterior lobe of the pituitary, although they were consistently seen in the infundibulum from day E19. In newborn rats, some 5-HT-immunoreactive fibers, but no neurons, were seen in the hypothalamus. GABA immunoreactivity appeared on day E17 in several nerve fibers of the infundibulum and the posterior lobe. Some neurons in the cortex and ventral hypothalamus transiently expressed GABA-immunoreactivity on day E17. In newborn rats, a plexus of GABA-immunoreactive fibers was detected for the first time in the intermediate lobe. No CGRP-immunoreactive fibers could be detected in the prenatal pituitary. On day P10, CGRP-immunoreactive fibers were first observed in the anterior lobe. Later their number considerably increased, while only sporadic fibers could be found in the intermediate or posterior lobes. No substance P-immunoreactivity could be detected in any of the lobes in the embryonic or developing postnatal rat pituitary, instead the adult anterior lobe occasionally showed some substance P-immunoreactive fibers. Synaptophysin-immunoreactivity was first detected in the posterior lobe on day E20, followed shortly by its expression in the intermediate lobe in newborn rats. The time course of GABA and 5-HT expression revealed in the present study suggests that these transmitters, which are initially expressed in the developing pituitary clearly before synaptic maturation, may act as trophic molecules during the prenatal period.     

A prospective evaluation of dermatological side-effects during alpha-interferon therapy for chronic viral hepatitis

OBJECTIVE: Alpha-interferon therapy may occasionally account for immune-mediated phenomena. This study was conducted in an attempt to investigate the incidence of the development of immune-mediated dermatological diseases during alpha-interferon therapy in patients with chronic viral hepatitis. The latter has not been evaluated prospectively, whereas most of the previous studies examined small numbers of interferon treated patients or consisted of case reports. DESIGN: A prospective case-control study. SETTING: A tertiary referral centre. PARTICIPANTS: One hundred and twenty consecutive patients with chronic viral hepatitis (67 with hepatitis B, 45 with hepatitis C, six with both hepatitis viruses, and two with delta hepatitis) were evaluated during a course of alpha-interferon therapy. In addition, 120 consecutive patients with chronic liver diseases (disease control group), who had never received alpha-interferon therapy, were evaluated during the period of the study (at least for 12 months). INTERVENTIONS: Recombinant alpha-interferon at a dose of 4.5 or 5 million units subcutaneously (s.c.) three times per week for 6 to 12 months was administered to patients with hepatitis B. The patients with chronic hepatitis C were treated with 3 million units s.c. three times per week for 12 to 18 months. The patients with chronic hepatitis B and C infections received 4.5 million units for 6 months, and then 3 million units for an additional 6 to 12 months. Finally, the patients with chronic delta hepatitis received 5 million units for 1 year or more. MAIN OUTCOME MEASURES: To assess prospectively the incidence of these dermatological disorders during alpha-interferon therapy and to estimate if there is any relationship between their development and the clinical, laboratory or other characteristics of the patients with chronic hepatitis. RESULTS: Three to 6 months after the initiation of alpha-interferon three patients with chronic viral hepatitis (two with hepatitis C and one with hepatitis B) developed lichen planus, whereas one patient with hepatitis C developed relapsing aphthous stomatitis. The development of these disorders was significantly associated only with the presence of antinuclear antibodies before the initiation of alpha-interferon (P=0.000000). None of the patients from the disease control group had such a manifestation during the follow-up. Lichen planus resolved after the end of therapy in all of them. In contrast, therapy was discontinued in the patient who developed aphthous stomatitis, owing to the painful lesions. CONCLUSIONS: This study demonstrated that alpha-interferon may rarely (3.3%) induce immune-mediated dermatological disorders, especially lichen planus. The development of these disorders may reflect a subclinical or covert autoimmune background of patients, as suggested by the presence, although in low titres, of antinuclear antibodies. However, when lichen planus developed, it was mild, did not require the discontinuation of therapy and resolved after alpha-interferon administration had ceased.     

Suicidal impulses in patients with chronic viral hepatitis C during or after therapy with interferon alpha

OBJECTIVE: The objective of this study was to evaluate key outcomes of a universal hearing screen/rescreen program for all births with transient evoked otoacoustic emissions in all 8 maternity hospitals in the state of Rhode Island over a 4-year period. STUDY DESIGN: This was a retrospective analysis of the hearing screen/rescreen refer data collected prospectively for 53,121 survivors born in Rhode Island between January 1, 1993, and December 31, 1996. Primary outcomes included the first-stage refer rates, rescreen compliance, diagnostic referral rates, identification rates, and the age of amplification. RESULTS: During this 4-year time period 11 infants were identified with permanent hearing loss, resulting in an impairment rate of 2 per 1000. The mean age of hearing loss confirmation decreased from 8.7 months to 3.5 months, and the age at amplification declined from 13.3 months to 5.7 months. CONCLUSION: We conclude that time and experience are important factors in the development and refinement of a universal hearing screen program. Hearing screen outcome data collected over a 4-year period in Rhode Island reveal a steady improvement in the percent of infants completing the 2-stage screen process, the stage 1 and stage 2 refer rates, compliance with rescreen and diagnostic testing, and significant improvement in the age of identification and age of amplification.     

The treatment of chronic viral hepatitis with recombinant alpha-2 interferon: meta analysis and clinical contribution

The Authors have developed a work of meta-analysis on the employment of IFN in the virus-correlated chronic hepatitis. They have examined World literature on: virus causing chronic hepatitis, type and duration of the treatment, criteria in the choice of the observed patients, clinical effects, effects on the virus, effects on the isto-pathologic situation. Have been considered the useful actions at the end of the treatment and in the follow-ups, so to evaluate the permanence of favourable effects. Have been also reminded the main collateral effects, even about frequency and intensity, as the various Authors relate. There are quite clear data indicating: efficacy in B-correlated chronic hepatitis greater than in C-correlated ones, greater efficacy in the treatments with Interferon with duration of more then 6 months in chronic hepatitis C. Doses greater than those generally employed appear not to give better results. The Authors moreover show the results of a clinical survey they made on patients with chronic hepatitis HBsAg+/HBeAg+ (treated with IFN-alpha 2r 5 MU t.i.w. for six months) and chronic hepatitis anti-HCV+ (treated with IFN-alpha 2r 3 MU t.i.w. for six months). The results confirm the efficacy of IFN in B-correlated chronic hepatitis (50% of sustained response) and its scarce efficacy in C-correlated chronic hepatitis for treatment shorter than 12 months (9.1% of sustained response).