The interaction of cationic liposomes with the skin-associated bacterium Staphylococcus epidermidis: effects of ionic strength and temperature

OBJECTIVE: Treatment with recombinant interferon-alpha (rIFN-alpha) may induce autoimmunity. We have evaluated the effect of rIFN-alpha on pre-existing thyroid disease with special reference to changes in TSH receptor antibody. DESIGN AND PATIENTS: Five patients, who had a history of autoimmune thyroid disease diagnosed between 2 and 16 years earlier (three patients had Graves' disease while two had Hashimoto's thyroiditis), were treated with rIFN-alpha for chronic hepatitis C. Before, during and after rIFN-alpha therapy, we determined thyroid function, antithyroid antibody, thyroid echogenicity and the surface phenotype of the peripheral and intrathyroidal lymphocytes. RESULTS: Four of the patients developed overt hypothyroidism after 4-7 months of rIFN-alpha therapy, and two of them had a preceding history of low-uptake thyrotoxicosis. Recovery of thyroid function was observed in all four patients. Strongly positive blocking type TSH receptor antibody was detected and an increase in the percentage of CD19 positive cells in the intrathyroidal lymphocytes was also observed in three of the patients even though the goitre size increased in two of them. One of the patients became thyrotoxic later when stimulating type TSH receptor antibody became positive. Another patient suffered from reversible hypothyroidism although stimulating type TSH receptor antibody remained strongly positive throughout the clinical course. CONCLUSIONS: Our data thus indicated a high incidence of an unusual type of reversible hypothyroidism with TSH receptor antibodies in patients with chronic hepatitis C and pre-existing autoimmune thyroid disease after recombinant interferon-alpha therapy through a mechanism involving both the humoral and cellular immune systems.     

Interferon-alpha induced thyroid dysfunction: three clinical presentations and a review of the literature

Three patients who developed symptomatic, autoimmune-mediated thyroid dysfunction during treatment with interferon-alpha (IFN-alpha) for chronic active hepatitis C with liver cirrhosis, age-related macular degeneration with foveal involvement, and chronic myelogenous leukemia, respectively, are described. The first two patients developed autoimmune hypothyroidism that required thyroxine replacement, and the third developed autoimmune thyroiditis with transient thyrotoxicosis. The clinical manifestations were protean, and required a high index of suspicion for diagnosis, the failure of which led to significant morbidity. A literature review revealed that the mean incidence of IFN-alpha induced thyroid dysfunction was 6%. Spontaneous resolution occurred in more than half with discontinuation of IFN-alpha treatment. Hypothyroidism was induced more frequently than hyperthyroidism. At least one positive thyroid autoantibody titer was found in 17% of patients receiving IFN-alpha. Risk factors for developing thyroid dysfunction with IFN-alpha treatment were female sex, underlying malignancy or hepatitis C, higher doses of IFN-alpha for longer durations, combination immunotherapy (especially with interleukin-2), and the presence of thyroid autoantibodies prior to or during treatment.     

Primary end points in phase III clinical trials of severe head trauma: DRS versus GOS. The American Brain Injury Consortium Study Group

Analysis of patients with persistent hypothyroidism due to Hashimoto's thyroiditis suggested that metabolism of thyroxine (T4), including deiodination to triiodothyronine (T3), was reduced in the elderly. The increase in the serum levels of T4 after oral administration of T4 was augmented in the elderly, whereas increase in the serum T3 level was not. Possibly due to the reduction in the pituitary deiodinase, suppression by T4 administration of serum thyrotropin (TSH) level was the same in elderly as in younger subjects despite a larger increase in the serum levels of T4 in the elderly. Consequently, the amount of T4 required to maintain a normal serum TSH level did not differ between elderly and younger subjects. Other characteristics of elderly patients with Hashimoto's thyroiditis were that goiter size was smaller, that hypothyroidism was more frequent, and that Graves' disease was less frequent.     

Pituitary diseases-2. Diseases of the anterior pituitary gland

Radioimmunoassay of thyroxine and triiodothyronine in a 14-year-old girl with primary hypothyroidism and nodular goitre as a result of Hashimoto's thyroiditis gave falsely low values due to the presence of hormone-binding antibodies. Such antibodies occur in Hashimoto's thyroiditis and thyroid carcinoma. Their presence requires special methods for determining these hormones.     

Manifestation of primary hyperthyroidism after pituitary adenomectomy: a case report

We report a 47-year-old Japanese man who presented with visual disturbance due to a pituitary tumor with suprasellar extension. The patient had mild secondary hypothyroidism preoperatively, and was started on administration of levothyroxine sodium immediately before transsphenoidal surgery. After the operation, levothyroxine sodium was continued for several months. Pathological examination of the surgical specimen, together with endocrinological investigation revealed that the suprasellar tumor was a FSH-producing pituitary adenoma. Since 3 months after the operation, he has developed muscle weakness and finger tremor. He was found to be thyrotoxicosis, and levothyroxine sodium was discontinued. Seven weeks after levothyroxine sodium was discontinued, thyrotoxicosis continued, with a positive thyrotropin binding inhibitory immunoglobulin (TBII) and a high diffuse 123I-uptake by the thyroid. He was started on thiamazole 30 mg/day. Although his thyroid dysfunction improved within 2 months, hyperthyroidism worsened repeatedly on attempts to discontinue thiamazole, and he required continuous treatment at 2.5 mg/day. Patients with occult autoimmune thyroiditis rarely progress to thyrotoxicosis after operations on other endocrine organs such as the adrenal or parathyroid gland. In patients with pituitary adenoma, thyroid function and thyroid-associated autoantibodies should be investigated pre- and post-operatively.     

Combined deficiency of thyroid stimulating hormone and growth hormone in a diabetic patient with Hashimoto thyroiditis

We report the case of a 36-year-old female patient with insulin dependent diabetes who developed hypothyroidism of pituitary origin after giving birth. She had low levels of free T4 and TSH with no response to i.v. TRH. Antimicrosome antibodies were increased (1/25000), suggesting Hashimoto's thyroiditis. The other hormones were normal except for a low level of growth hormone and insulin growth factor 1. There were no antibodies against the pituitary. MRI of the pituitary was normal. We suspect a vascular origin for this partial pituitary deficiency.     

Expression of androgen receptor, gross cystic disease fluid protein, and CD44 in salivary duct carcinoma

Although disorders of thyroid function may cause a wide range of muscle disturbances, an overt myopathy has been rarely reported as an isolated clinical presentation of hypothyroidism. We observed 10 patients (5 males and 5 females) who had been referred to the department of neurology because of muscular fatigability, myalgia, cramps, or proximal weakness. Laboratory investigation showed that all patients had hypothyroidism due to Hashimoto's thyroiditis (atrophic variant in 9/10). Classic symptoms/signs of hypothyroidism such as lethargy, constipation, cold intolerance, myxedematous facies, and/or bradycardia were absent, as assessed independently by the three coauthoring thyroidologists. Muscular complaints improved greatly and then disappeared after substitutive levothyroxine treatment. Muscle biopsy revealed nonspecific changes. Nicotinamide adenine dinucleotide reductase (NADH-TR)-hyporeactive cores were present in two patients (10% and 90% of type 1 fibers). On electron microscopy, the core areas showed disorganized myofibrils, Z-band streaming, rod formation, and paucity of mitochondria and glycogen granules. Desmin intermediate filaments were overexpressed only in some cores. The similarity of the pattern of desmin expression between hypothyroid cores and target lesions of denervated fibers supports the hypothesis that, at least in some of our patients, myopathy was the result of an impaired nerve-mediated action of thyroid hormones on skeletal muscle. Our observations suggest that an isolated myopathy as the sole manifestation of hypothyroidism is not a rare event. We postulate that our cases may constitute a peculiar subgroup of Hashimoto's thyroiditis patients: (1) the strikingly abnormal F/M ratio of 1:1; (2) the relatively younger age; (3) the rarity of the goitrous variant; (4) the unusual finding of antithyroglobulin (Tg-Ab) > antithyroid peroxidase (TPO-Ab). Thorough evaluation of thyroid function is appropriate in patients with myopathy of uncertain origin.     

Infantile and juvenile hypothyroidism with the gland in place and low radio-iodide uptake

27 hypothyroid infants of children, with a low iodine uptake in spite of a thyroid gland or thyroid tissue in normal pretracheal place, have been studied. 21 cases are related to primary thyroid involvement leading to vanishing iodine or technetium uptake. In 8 of these cases, clinical onset in late childhood, high frequency of antithyroid antibodies and of familial thyroid dysfunction were similar to those found in childhood's thyroiditis. 8 other cases had a precocious onset (first months in 6, first year in 1, second year in 1) with some pretracheal iodine uptake when first studied and no uptake at further examinations, 1 patient having received no treatment from first to second study, the others being without treatment from more than two months and certain of them receiving injections of TSH. The last 5 cases of this group were those of children born to 2 mothers with treated hypothyroidism, with low iodine uptake in pretracheal place. The role of genetic factors and auto-immunity in theses cases is discussed. The 6 other patients had clinically isolated hypothyroidism secondary to TSH deficiency, eventually associated to clinically inapparent GH or ACTH deficiencies, most of them by hypothalamic defect with normal response to TRH.     

Chronic liver failure induced by long-term administration of tegafur: a case report

A 55 year-old man was admitted with massive ascites. Although the laboratory data on admission were compatible with hepatic cirrhosis and remarkable esophageal varices were observed during endoscopy, the imaging findings such as computed tomography and ultrasonographic examination did not confirm hepatic cirrhosis. The patient had no history of alcohol abuse, blood transfusions or acute hepatitis. Serological markers related to viral and autoimmune hepatitis were all negative. Seven years ago, the patient had undergone an operation for colon cancer and has been taking tegafur since then for a total of 55 months. Tegafur was suspected as the causative agent for the liver dysfunction of this patient and the administration of tegafur was stopped. His laboratory data improved gradually and the ascites vanished. The first liver biopsy performed 6 months after discontinuation of tegafur still revealed chronic active hepatitis. However, at the liver biopsy performed 18 months after withdrawal of tegafur, inflammatory activity had subsided and the third liver biopsy, performed 34 months thereafter, revealed further improvement of the pathological changes that had occurred in the liver. We therefore conclude that the administration of tegafur may have caused chronic active liver injury with portal hypertension manifested as ascites and esophageal varices.     

Hashimoto's thyroiditis and insulin-dependent diabetes mellitus: differences among individuals with and without abnormal thyroid function

Insulin-dependent diabetes mellitus probands from the Familial Autoimmune and Diabetes Study were evaluated for autoimmune thyroid disease (n = 265). The prevalence of Hashimoto's thyroiditis was 26.6%; 42.0% of these individuals were euthyroid, and 58.0% were hypothyroid. There was a female predominance among hypothyroid and euthyroid Hashimoto's cases compared to those with no thyroid disease (75% vs. 72.4% vs. 41.6%; P < 0.001). Insulin-dependent diabetes mellitus patients with hypothyroid Hashimoto's thyroiditis were more likely to report another autoimmune disease compared to euthyroid Hashimoto's patients or individuals with no thyroid disease (30.8% vs. 17.2% vs. 13.9%; P < 0.01). Sex-specific analysis revealed that this difference was significant for men but not for women. Both euthyroid and hypothyroid Hashimoto's cases were more likely to have a family history of the disease (66.7% vs. 69.2% vs. 47.7%; P < 0.05). No differences were observed in the prevalence of DQA1*0501-DQB1*0201 or DQA1*0301-DQB1*0302 across the three groups. Body mass index, lipid levels, glycemic control, and diabetes complications were also similar. However, euthyroid Hashimoto's women were more likely to report spontaneous abortions than those with hypothyroid Hashimoto's thyroiditis or no thyroid disease (23.8% vs. 61.5% vs. 29.1%; P < 0.05). These data suggest that gender-specific risk factors may be primary determinants of Hashimoto's thyroiditis and other autoimmune diseases among women. However, disease-specific determinants may also increase susceptibility to other autoimmune diseases.     

Case report: Hashimoto''s thyroiditis associated with Wegener''s granulomatosis

Wegener's granulomatosis is a well-defined systemic vasculitic syndrome that primarily affects the upper and lower respiratory tracts and the kidney. Hashimoto's thyroiditis is another autoimmune syndrome with the thyroid as its primary target organ. The relation between Hashimoto's thyroiditis and Wegener's granulomatosis is not reported in the English literature. In this article, the authors describe a patient with Hashimoto's thyroiditis in whom fulminant Wegener's granulomatosis subsequently developed. The immunologic similarities between these two diseases leads to the consideration that Wegener's granulomatosis possibly may be another immunologic disorder associated with Hashimoto's thyroiditis.     

Postpartum thyroiditis and Basedow disease

BACKGROUND: The postpartum period is characterized by a rebound in autoimmunity secondary to immune tolerance induced by pregnancy, creating favorable conditions for flare up of Graves' disease or autoimmune thyroiditis. Postpartum thyroiditis is a recognized clinical entity. CASE REPORT: Six years after onset of Graves' disease treated with antithyroid drugs, a 25-year-old woman had a high serum level of antithyroperoxidase antibodies a few months before she became pregnant. Six weeks after delivery, she developed signs of hyperthyroidism and goiter. The diagnosis of postpartum thyroiditis was retained. Her condition regressed spontaneously to euthyroidism then hypothyroidism. DISCUSSION: The therapeutic options involved underline the importance of distinguishing between Graves' disease and postpartum thyroiditis. The diagnosis of postpartum thyroiditis is based on history taking, clinical findings, and laboratory tests, especially isotope uptake.     

Autoimmune hepatitis with antibodies against liver cytosol (anti-LC1)

Antibody against liver cytosol (anti-LC1) was proposed in 1988 as a new and very specific immunoserologic marker of autoimmune hepatitis of childhood and young age. In adults, anti-LC1 might be masked by the presence in serum of anti-LKM1, usually associated with antibodies to hepatitis-C virus. We report the case of a 60-year-old woman who had active chronic hepatitis not related to infection by hepatitis C virus, with autoantibody reacting against liver cytosol as the unique marker of autoimmune hepatitis. Treated with corticosteroids (prednisone, 1 mg/kg per day), coagulation disorder, bilirubin, transaminase activity and immunoglobulins normalized in the following months. A year and a half later, autoantibodies anti-LC1 and p-ANCAs were no longer detected. We have only found one report of a young patient with anti-LC1 autoimmune hepatitis who had cirrhosis and portal hypertension, in national publications.     

Increased serum concentration of soluble CD30 in patients with Graves' disease and Hashimoto's thyroiditis

This study investigated serum levels of the soluble form of CD30 (sCD30), which is mainly secreted from T helper 2(Th2) cells, in autoimmune thyroid diseases. The possible relationship of sCD30 to autoantibody production was also evaluated. Serum levels of sCD30 were determined by an enzyme-linked immunosorbent assay in 71 patients with Graves' disease, 37 patients with Hashimoto's thyroiditis, and 21 normal donors. Compared with normal subjects (7.1 +/- 4.5 U/mL), sCD30 was increased in patients with Graves' disease (29.2 +/- 25.2 U/mL, P < 0.0001) and in patients with Hashimoto's thyroiditis (29.9 +/- 26.9 U/mL, P < 0.0001). In Graves' disease, sCD30 levels were higher in thyrotoxic patients (41.7 +/- 31.2 U/mL, P < 0.001) than in remission patients (15.8 +/- 11.0 U/mL), and a significant correlation was observed between sCD30 levels and serum activities of TSH receptor antibody (r = 0.444, P < 0.0001). In Hashimoto's thyroiditis, sCD30 levels were higher in patients with transient destructive thyrotoxicosis caused by the aggravation of the disease (48.8 +/- 34.4 U/mL, P < 0.05) than in euthyroid patients (24.2 +/- 19.4 U/mL). These data suggest that serum sCD30 is a valuable marker of disease activity and support an important role of the Th2-type immune response in the pathogenesis in Graves' disease and Hashimoto's thyroiditis.     

Apolipoprotein E polymorphism is associated with plasma cholesterol response in a 7-day hospitalization study for metabolic and dietary control in NIDDM

An 81-year-old woman in whom liver dysfunction had been pointed out 3 years previously was diagnosed as having liver cirrhosis due to lupoid hepatitis. Considering the poor prognosis of cirrhosis and her age, immunosuppressive therapy was not adopted. Nine months later, a small liver tumor was found by ultrasonography and was diagnosed as hepatocellular carcinoma (HCC). The tumor was treated with transcatheter arterial embolization, but grew continuously. She also developed gingival lymphoma that was successfully treated. Three years after initial diagnosis of lupoid hepatitis, she died of hepatic failure. An autopsy was performed and confirmed the clinical diagnosis, liver cirrhosis with HCC. HCC is regarded as a rare complication of lupoid hepatitis, but cases of HCC complicating lupoid hepatitis may increase with progress in treatment methods and elongation of survival. The present case suggests that any malignancy can be developed in long-term surviving patients with lupoid hepatitis.     

Spontaneous regression of renal cell carcinoma: a pitfall in diagnosis of renal lesions

Lobar atrophy is a rare morphologic change of the liver. We describe a 73-year-old woman with mild liver dysfunction and history of Sj?gren's syndrome who had right hepatic lobar atrophy. Serum biochemistry levels were as follows: albumin, 4.5 g/dl; total bilirubin, 1.0 mg/dl; alanine aminotransferase, 25 international units/l; aspartate aminotransferase, 27 international units/l; alkaline phosphatase, 333 international units/l; and gamma-glutamyl transpeptidase, 332 international units/l. Serological data were as follows: rheumatoid factor, 27.9; anti-nuclear antibody, 1:640; and antismooth muscle antibody, 1:80. Viral markers for hepatitis B were all negative. Anti-hepatitis C virus (anti-c-100) was negative. Portal hypertension developed thereafter, and the patient died of hepatic failure at age 76. Postmortem examination revealed autoimmune hepatitis with moderate fibrosis, portal vein thrombus, and complete obstruction of the right hepatic duct due to hepatolithiasis. Terminal hepatic failure resulted from combination of decreased hepatic volume due to the right lobar atrophy, exacerbation of autoimmune hepatitis in the remnant left hepatic lobe, decreased portal venous blood flow due to thrombosis, portal hypertension, and cholangitis with hepatolithiasis. This is the first reported case of hepatic lobar atrophy due to autoimmune hepatitis. From a clinical standpoint, patients with hepatic lobar atrophy, even if asymptomatic, should be followed up with careful attention to progression of liver diseases, portal hypertension, and biliary complications.     

Isolated ACTH deficiency

The isolated ACTH deficiency is a scarcely diagnosed disease of heterogeneous nature. Two patients with isolated deficiency of ACTH in whom the initial diagnosis was of primary suprarrenal failure are reported. In the first case this diagnosis was performed after hospital admission for deterioration of the level of consciousness and the development of an acute suprarrenal crisis in the course of nosocomial pneumonia. In the second case the clinical manifestations began as weakness, anorexia, weight loss and lymphocytosis with eosinophilia. In both patients an increase in the thyrotropic hormone was detected leading to suspicion of the existence of associated primary hypothyroidism. Finally, several studies were carried out (basal measurements of cortisol and ACTH, stimulation with continual perfusion of ACTH, insulinic hypoglycemia, global study of adenohypophysary function, ACTH CRF release factor test, computerized tomography of the pituitary region) in both patients leading to the definitive diagnosis of isolated ACTH deficiency of idiopathic cause of possible pituitary origin without the existence of other associated hormonal deficiencies.     

Anti-thyroid autoantibodies in hepatitis C. Thyroid function after interferon therapy in 4 patients

Four female patients had chronic hepatitis C associated with antithyroid autoantibodies. Hepatitis C virus infection was evidenced by liver biopsy and a positive-four-antigen recombinant immunoblot assay. All four patients were euthyroid before interferon therapy. Recombinant interferon alpha was given at a dose of 3 millions units three times a week for 6 months. At the end of the treatment, serum aminotransferase levels were within the normal range. Two patients progressed to hypothyroidism and 2 patients remained euthyroid. One year after the end of the treatment, only one patient had hypothyroidism and another had normal serum aminotransferase levels. These case-reports suggest that interferon administration may induce thyroid dysfunction in patients with antithyroid autoantibodies at the beginning of treatment. Thyroid dysfunction may be reversed when cytokine is withdrawn.     

Detection of hepatitis G virus from serum and liver of a patient with long-term liver dysfunction after autologous bone marrow transplantation

Long-term effects after blood or bone marrow transplantation (BMT) are emerging as an important issue, as more patients are included in BMT programmes and as this procedure becomes more successful. Long-term liver dysfunction, mainly due to chronic graft-versus-host disease or hepatitis C virus infection, is a well-known complication. Nevertheless, the diagnosis of liver disease in this patient group is sometimes difficult and, despite adequate studies, it may remain undetected. A novel hepatitis-associated virus, hepatitis G virus (HGV), has recently been identified. The virus belongs to the Flaviviridae family and is known to be parenterally transmitted, although there is no clear evidence to implicate this agent in causing acute or chronic hepatitis. We report a patient who developed mild, but persistent, abnormalities in transaminases for 2 years after an autologous BMT. HGV RNA was detected in both serum and liver. HGV RNA persisted in serum for at least 8 months. No other known hepatitis virus was found. This report provides the first direct evidence of a patient with long-term liver abnormalities after a BMT in whom the only known hepatitis virus isolated was the HGV.     

Azathioprine-induced myelosuppression due to thiopurine methyltransferase deficiency in a patient with autoimmune hepatitis

Azathioprine can cause severe myelosuppression. The inherited activity of the enzyme thiopurine methyltransferase has been recently recognised as a major factor in the susceptibility to myelosuppression. Thiopurine methyltransferase deficiency occurs at a frequency of one in 300 and is associated with profound myelosuppression after a short course of azathioprine. Very low thiopurine methyltransferase activity represents the TPMTL/TPMTL genotype, and can be detected before therapy with azathioprine is started. We describe the first documented case of azathioprine-induced severe myelosuppression due to thiopurine methyltransferase deficiency in autoimmune liver disease. The azathioprine dose was low (1 mg/kg) and pancytopenia occurred after 56 days therapy. It would be advisable to measure thiopurine methyltransferase activity before patients with autoimmune hepatitis are exposed to azathioprine.