THE ABSENCE OF THYROID DISEASE IN AN AUSTRALIAN HEPATITIS C COHORT TREATED WITH TRIPLE COMBINATION THERAPY: A PARADIGM SHIFT.

OBJECTIVE: To assess the prevalence of thyroid disease in triple combination therapy with interferon (IFN)-α, ribavirin (RBV), and protease inhibitors (boceprevir and telaprevir) for the treatment of chronic hepatitis C virus (HCV) infection in an Australian hepatitis C cohort. Also, to compare with those who received dual RBV and IFN in the past. METHODS: A preliminary, retrospective, and nested case control study of thyroid disease in patients who underwent triple combination therapy for chronic HCV infection compared with dual therapy at a major tertiary referral hospital center. Fifty-nine patients were treated with such therapy at the Hunter New England Area Hepatitis C Treatment Center. Of these, 38 were treated with boceprevir and 21 with telaprevir. All had genotype 1 HCV infection. The main outcome measures included (1) the prevalence of thyroid disease (TD), including hyperthyroidism and hypothyroidism, and (2) thyroid outcome comparison with patients who had received dual therapy. RESULTS: There was no case of TD detected for the entire duration of therapy with triple anti-HCV therapy. There was a significant absence of TD in the protease inhibitor-treated group. CONCLUSION: No case of TD was detected during the treatment of HCV patients with protease inhibitor-based triple therapy. The reasons for this are unclear. Larger studies are necessary to confirm this finding.

Thyroid disease is a favorable prognostic factor in achieving sustained virologic response in chronic hepatitis C undergoing combination therapy: A nested case control study.

BACKGROUND: Interferon-α in combination with ribavirin is the current gold standard for treatment of chronic hepatitis C. It is unknown if the development of autoimmune thyroid disease (TD) during treatment confers an improved chance of achieving sustained virologic response. The aim of this study is to assess the chance of achieving sustained virologic response (SVR) in patients who developed TD during treatment when compared with those who did not. METHODS: We performed a tertiary hospital-based retrospective nested case-control analysis of 19 patients treated for hepatitis C who developed thyroid disease, and 76 controls (matched for age, weight, gender, cirrhosis and aminotransferase levels) who did not develop TD during treatment. Multivariate logistic-regression models were used to compare cases and controls. RESULTS: The development of TD was associated with a high likelihood of achieving SVR (odds ratio, 6.0; 95% confidence interval, 1.5 to 24.6) for the pooled group containing all genotypes. The likelihood of achieving SVR was increased in individuals with genotype 1 HCV infection who developed TD (odds ratio, 5.2; 95% confidence interval, 1.2 to 22.3), and all genotype 3 patients who developed TD achieved SVR. CONCLUSIONS: Development of TD during treatment for hepatitis C infection is associated with a significantly increased chance of achieving SVR. The pathophysiogical mechanisms for this observation remain to be determined. TRIAL REGISTRATION: The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRB12610000830099.

Hypercalcaemia due to Sarcoidosis during Treatment with Avelumab for Metastatic Merkel Cell Carcinoma.

Merkel cell carcinoma is a rare but aggressive skin cancer. Response to chemotherapy is not durable but avelumab, an anti-PD-L1 inhibitor, showed promising ongoing response in a phase II trial. Checkpoint inhibitors including avelumab are known to cause overactivation of the immune system, leading to immune-related adverse events (irAE). We describe the first reported case of hypercalcaemia secondary to reactivation of sarcoidosis in a patient with metastatic Merkel cell carcinoma on avelumab. Hypercalcaemia was managed with corticosteroids to full resolution and avelumab therapy was safely continued.

A novel missense LIPA gene mutation, N98S, in a patient with cholesteryl ester storage disease.

Lysosomal acid lipase plays an important role in maintaining cellular cholesterol homeostasis. Complete absence of lysosomal acid lipase activity results in Wolman disease and usually death in infancy, whereas partial deficiency of lysosomal acid lipase results in cholesteryl ester storage disease (CESD). We describe a 26 year-old female with CESD who presented with recurrent right upper quadrant abdominal pain. Abnormal liver function tests and a subsequent liver biopsy revealed features consistent with CESD. Sequencing of the LIPA gene revealed that she was a compound heterozygote for the previously reported exon 8 splice junction mutation and a novel missense mutation (N98S) in exon 4. The splice junction mutation allows some (approximately 3%) normal splicing to occur, and therefore gives rise to residual lysosomal acid lipase activity. Asn98 in lysosomal acid lipase is highly conserved among species and mutation of this residue could influence catalytic activity or accessibility to the active site. In summary, we describe a CESD patient compound heterozygous for the LIPA exon 8 splice junction mutation and a novel missense mutation, N98S.

Hepatitis C infection and thyrotoxic periodic paralysis--a novel use of an old drug.

Hypokalaemic thyrotoxic periodic paralysis is an enigmatic and uncommon condition which occurs exclusively in males of Asian descent. The underlying causes of thyrotoxicosis may be any of the well-recognized etiologies including a toxic multinodular goiter, Graves' disease or iodine excess. Beside thyrotoxicosis, a number of other hormonal factors have been hypothesized to contribute to hypokalaemic thyrotoxic periodic paralysis, particularly postprandial hyperinsulinaemia and testosterone. We hereby present a case of a 48-year-old hepatitis C positive gender-assigned man in whom all of these factors are proposed to interact, lending further support to these hypotheses. The patient presented with interferon-induced thyroiditis causing acute generalized weakness whilst undergoing combination interferon-alpha-2beta and ribavirin therapy. As part of his hepatitis C infection, marked insulin resistance with hyperinsulinaemia was also present, exacerbating the paresis. Initial treatment with beta-blocker failed to normalize his serum potassium concentration, requiring the novel use of spironolactone, despite euthyroidism. This continued to be required until his testosterone supplement dissipated.

Reversible hypothyroidism and Whipple's disease.

BACKGROUND: The major cause of primary hypothyroidism is autoimmune mediated with progressive and permanent destruction of the thyroid gland resulting in life-long replacement therapy. Treatable and reversible hypothyroidism is unusual and here forth is such a case due to infection of the thyroid gland with Tropheryma whippleii, Whipple disease. CASE PRESENTATION: A 45 year-old female presented with symptoms and signs consistent with primary hypothyroidism, which was also confirmed biochemically. Her response to thyroxine replacement therapy was poor however, requiring a significantly elevated amount. Further investigation revealed the presence of Whipple's disease involving the gastrointestinal trace and possibly the thyroid gland. Her thyroxine requirement decreased drastically following appropriate antimicrobial therapy for Whipple's disease to the extent that it was ceased. Thyrotropin releasing hormone testing in the steady state suggested there was diminished thyroid reserve due to Whipple's disease. CONCLUSION: This is the first ante-mortem case report studying the possible involvement of the thyroid gland by Whipple's disease. Despite the normalization of her thyroid function test biochemically after antibiotic therapy, there is diminished thyroid reserve thus requiring close and regular monitoring.

Difficulties in diagnosing and managing coexisting primary hypothyroidism and resistance to thyroid hormone.

OBJECTIVE: To report a case of resistance to thyroid hormone compounded by autoimmune primary hypothyroidism and to discuss the unusual pattern of results of thyroid function tests. METHODS: A clinical case history is presented and illustrated with laboratory findings. The difficulty of monitoring the patient's response to levothyroxine supplement is also discussed, and relevant issues are addressed, including reviews of the literature. RESULTS: A 45-year-old woman presented with longstanding and nonspecific symptoms of general anxiety and lethargy. Clinically, she was assessed to be euthyroid with no goiter. Her thyrotropin (thyroid-stimulating hormone or TSH) level was 43.6 (1/4)IU/mL, free thyroxine was 27.6 pmol/L, and free triiodothyronine was 7.8 pmol/L. Her anti-thyroid peroxidase titer was 1:102,400. Primary hypothyroidism was diagnosed, and treatment with 50 (1/4)g of levothyroxine daily was initiated, with progressive dose escalation. The patient, however, had thyrotoxic symptoms when her TSH was rendered "normal." The patient then discontinued her levothyroxine therapy, with a consequent elevation of her TSH level to 170.8 (1/4)IU/mL in conjunction with severe lethargy and lassitude. Biochemical evidence of metabolic disturbances was also present at the time, with hypercholesterolemia and elevated creatine kinase concentration. Rechallenge with levothyroxine resulted in considerable improvement in her biochemical findings and symptoms. CONCLUSION: This patient has an interesting combination of autoimmune primary hypothyroidism and resistance to thyroid hormone. Levothyroxine replacement therapy was complicated by the nonspecificity of symptoms and the lack of an established TSH target value in this condition. Consideration should be given to using the affected family members' mean TSH level, when available, as a target guide for replacement therapy.

The spectrum of thyroid dysfunction in an Australian hepatitis C population treated with combination Interferon-alpha2beta and Ribavirin.

BACKGROUND: The study aims to assess the pattern of thyroid response to combination Interferon-alpha2beta (IFN-alpha) and Ribavirin (RBV) anti-viral therapy in an Australian hepatitis C cohort. These include the prevalence of thyroid dysfunction (TD) including hyperthyroidism and hypothyroidism and their possible predictors, the common overall pattern of thyroid function tests whilst receiving therapy and TD outcomes, and the correlation with HCV status outcome. METHODS: A retrospective analysis of all medical records was performed to assess thyroid function in Hepatitis C Virus (HCV) patients who were treated at the Hunter Area hepatitis C treatment center between 1995 and March 2004. The centre is part of the John Hunter hospital, a major tertiary referral centre in New South Wales, Australia. RESULTS: There were 272 cases available for review. The prevalence of TD is 6.7 percent and is made up predominantly of females (80 percent). There were 3 (1.1 percent) cases of hyperthyroidism with 2 (67 percent) females. Thirteen out of fifteen (80 percent) cases of hypothyroidism were females with the overall prevalence of 5.5 percent. The majority of hypothyroid patients still required Thyroxine supplement at the end of follow up. CONCLUSION: Ninety three percent of HCV treated patients have intact thyroid function at the end of treatment. The predominant TD is hypothyroidism. The predominant pattern of thyrotoxicosis (TTX) is that of thyroiditis although the number is small. Graves' like disease was not observed. People with pre-existing thyroid auto-antibodies should be closely monitored for thyroid dysfunction, particularly hypothyroidism.

Test and teach. Number Fifty-three. Diagnosis: Diabetes-related dyslipidaemia.

Mixed dyslipidaemia is common in people with diabetes and occurs in up to 20% of cases. Diabetes keto-acidosis can occur in patients with type 2 diabetes. Hypertriglyceridaemia is a well-recognised cause of pancreatitis. Other common causes of pancreatitis include gall stones, alcohol, drugs (azathioprine and dideoxyinosine) and post-endoscopic retrograde cholangiopancreatography (ERCP). Therapeutic options for acute and severe dyslipidaemia include insulin therapy, fibric acid derivatives, fish oils and, rarely, nicotinic acids. Hospitalisation may be required for plasmapheresis in specialised centres.

Vitamin D Levels Are Associated with Expression of SLE, but Not Flare Frequency.

This study explores links between vitamin D deficiency (25(OH)D = 50 nmol/L) and serological autoimmunity (ANA > 1 : 80) and frequency of self-reported flares (SRF) in participants with clinical autoimmunity (SLE). 25(OH)D levels of 121 females were quantified and compared. The cohort consisted of 80 ACR defined SLE patients and 41 age and sex matched controls. Association analysis of log2 (25(OH)D) levels and ANA 80 positivity was undertaken via two-sample t-tests and regression models. Significant differences were found for 25(OH)D levels (mean: control 74 nmol/L (29.5 ng/ml); SLE 58 nmol/L (23.1 ng/ml), P = 0.04), 25(OH)D deficiency (P = 0.02). Regression models indicate that, for a twofold rise in 25(OH)D level, the odds ratio (OR) for ANA-positivity drops to 36% of the baseline OR. No link was found between SRF-days and 25(OH)D levels. Our results support links between vitamin D deficiency and expression of serological autoimmunity and clinical autoimmunity (SLE). However, no demonstrable association between 25(OH)D and SRF was confirmed, suggesting independent influences of other flare-inducing factors. Results indicate that SLE patients have high risk of 25(OH)D deficiency and therefore supplementation with regular monitoring should be considered as part of patient management.

Thyroid disease in chronic hepatitis C infection treated with combination interferon-α and ribavirin: management strategies and future perspective.

OBJECTIVE: Hepatitis C virus (HCV) infection is one of the major epidemics afflicting young people in both developed and developing countries. The most common endocrine disorder associated with this infection, especially in conjunction with interferon-α (IFN-α)-based therapy, is thyroid disease (TD). This review examines the development of TD before, during, and after the completion of treatment with combination IFN-α and ribavirin (RBV) for chronic HCV infection. We also summarize the current understanding of the natural history of the condition and propose management and follow-up guidelines. METHODS: PubMed was searched up to June 30, 2011 for English-language publications that contained the search terms "hepatitis C virus," "chronic hepatitis C," "HCV," "thyroid disease," "thyroiditis," "autoimmunity," "interferon-alpha," and "ribavirin." Additional publications were identified from the reference lists of identified papers. The included studies were original research publications and included combination IFN-α and RBV use in patients that developed TD. RESULTS: The prevalence of TD before combination IFN-α and RBV therapy ranges from 4.6 to 21.3%; during therapy, 1.1 to 21.3%; and after therapy, 6.7 to 21.3%. The most common TD is thyroiditis. Thyroid function testing (TFT) frequency and diagnostic criteria for various thyroid conditions are not standardized, and many of the existing studies are retrospective. CONCLUSION: Patients undergoing this therapy should be assessed with a standardized protocol to appropriately detect and manage developed TD. Based on the currently available literature, we recommend that patients receiving combination interferon-α and RBV therapy undergo monthly thyrotropin (TSH) level testing.

The reduced predictive value of interleukin 28b gene polymorphisms in a cohort of patients with thyroiditis developed during antiviral therapy for chronic hepatitis C: a preliminary study.

BACKGROUND: Single nucleotide polymorphism in the interleukin28B (IL28B) gene was recently shown to be associated with a significant increase in response to interferon-α and ribavirin treatment in patients with chronic hepatitis C. Similarly, thyroid disease (TD) occurring during treatment confer an improved sustained virologic response (SVR). OBJECTIVES: To determine the role of IL28B genotypes in a cohort of hepatitis C patients who develop TD during treatment and its relationship to SVR. PATIENTS AND METHODS: IL28B gene profiles including rs12979860, rs12980275 and rs 8099917 and their genotypes were determined in a cohort of 23 hepatitis C patients who developed TD during treatment and their relationship to SVR. RESULTS: Out of 23 studies cases, 19 has one or more favorable genotypes, of which 15 (78.9%) achieved SVR. Eleven has all three unfavorable genotypes and yet achieved 72.7 % SVR. The presence of more than one favorable genotype only correctly predicts SVR vs. non- SVR in ~50 % of cases, i.e. by chance. CONCLUSIONS: Despite the small number of subjects, the presence of one or more unfavorable IL28B genotype does not portend a poor SVR prognostic outcome. This suggests that TD in this clinical context may be a critical factor in the achievement of SVR, probably above that of the genetic predisposition.