Recombinant human GH replacement therapy and thyroid function in a large group of adult GH-deficient patients: when does L-T(4) therapy become mandatory?

The effect on thyroid function of GH administration to 66 adult patients with severe GH deficiency was studied. Seventeen patients were euthyroid, and 49 had central hypothyroidism and were adequately treated with L-T(4). Forty patients were assigned to a low recombinant human GH (rhGH) regimen (3 microg/kg body wt.d for 3 months followed by 6 microg/kg body wt.d for another 3 months) and 26 to a higher one (6 microg/kg body wt.d for 3 months followed by 12 microg/kg body wt.d for another 3 months). Serum IGF-I, TSH, free T(4) (FT(4)), free T(3) (FT(3)), reverse T(3), T(4)-binding globulin, and antithyroid autoantibody (TgAb and TPOAb) were measured in basal condition and after 3 and 6 months of therapy. Normalization of IGF-I levels was obtained after 6-month rhGH treatment in 67% of patients, independently from the dose, whereas a significant reduction in FT(4) and reverse T(3) levels was recorded (P < 0.01), without variations in all the other parameters studied, including serum TSH, FT(3), and T(4)-binding globulin circulating levels. Antithyroid autoantibodies were detected in 11 of 66 patients (16.6%). Eight of 17 (47%) euthyroid subjects and 9 of 49 (18.3%) central hypothyroid patients, despite adequate substitution at baseline, showed FT(4) levels under the normal range at the end of the study. Altogether, 17 of 66 patients (25.7%) worsened their thyroid function. This study shows that GH deficiency masks in a consistent number of adult patients a state of central hypothyroidism. Therefore, during rhGH treatment, a careful monitoring of thyroid function is mandatory to start or adjust L-T(4) substitutive therapy.     

Use of angiotensin-converting enzyme inhibitors in patients with heart failure and renal insufficiency: how concerned should we be by the rise in serum creatinine?

PURPOSE: To determine the association between the early rise in serum creatinine levels associated with the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and the long-term renoprotective properties of these drugs in patients with chronic renal insufficiency. BACKGROUND: Large-scale clinical trials have demonstrated survival benefits of ACE inhibitors in patients with heart failure. In patients with renal insufficiency, whether associated with diabetes mellitus or not, use of ACE inhibitors is associated with slowing in the progression of renal disease. In fact, patients who have the most advanced renal insufficiency at baseline are the ones who show the maximum slowing of the disease progression, but these patients are also more likely to show an early rise in serum creatinine levels after ACE inhibitor therapy. There is evidence that patients with renal insufficiency often do not receive ACE inhibitors. There is also evidence that patients with heart failure are not receiving this life-saving drug or are receiving it at dosages lower than that used in the clinical trials. One of the main reasons for this underutilization of ACE inhibitors in patients with heart failure is the underlying renal insufficiency or the rise in serum creatinine level after initiation of therapy with an ACE inhibitor. METHODS: The authors reviewed 12 randomized clinical trials of ACE inhibitor or ARB therapy in patients with preexisting chronic renal insufficiency, with or without diabetes mellitus or heart failure. Studies were included for review if they met the following criteria: subjects were randomized to receive ACE inhibitor; subjects were followed up for a minimum of 2 years; and most of the subjects had baseline chronic renal insufficiency (>or=25% loss of renal function), irrespective of cause. Of the 12 studies that met these criteria, six were multicenter double-blind placebo-controlled studies. The other six were smaller randomized studies. The studies had a mean +/- standard deviation follow-up of 3.2 +/- 0.3 years. One thousand one hundred two patients were randomized to receive ACE inhibitors or ARBs. Of these, 705 (64%) had data on renal function at baseline (within 6 months of the start) and at the end of the study. The authors examined the changes in serum creatinine levels or glomerular filtration rates (GFR) in patients who were randomized to receive ACE inhibitors. The authors also assessed the blood pressures achieved in the trials. RESULTS: Patients with preexisting chronic renal insufficiency who achieved their blood pressure control goals were likely to demonstrate an early rise in serum creatinine levels, approximately 25% above the baseline (approximately 1.7 mg/dL) after initiation of ACE inhibitor or ARB therapy. This rise in serum creatinine was more acute (by approximately 15% from the baseline) during the first 2 weeks of therapy and was more gradual (additional approximately 10%) during the third and fourth weeks of therapy (Figure 1). The serum creatinine level was likely to stabilize after about 4 weeks, provided patients had a normal salt and fluid intake. In addition, patients who did not show a rise in serum creatinine level during the first 2 to 4 weeks of therapy, were less likely to experience one after that period, unless they were dehydrated from use of diuretics or gastroenteritis or had used a nonsteroidal antiinflammatory drug (NSAID). In spite of this early rise in serum creatinine in patients with chronic renal insufficiency (a serum creatinine level of >or=124 micromol/L or >or=1.4 mg/dL) who were randomized to receive an ACE inhibitor, these patients receiving the drug showed a 55% to 75% lower risk of worsening renal function than those with normal renal function receiving the drug. The rate of risk reduction was inversely related to the severity of renal impairment at baseline, but data were limited on the benefit of ACE inhibitors in patients with more advanced renal insufficiency (GFR <30 mL/min). The authors noted that those aged 65 and older were likely to have much lower GFRs for given levels of serum creatinine than younger patients and were therefore likely to have advanced renal insufficiency at serum creatinine levels as low as 2 mg/dL (vs 4 mg/dL for younger patients). Patients with normal renal function were likely to show a much smaller rise in serum creatinine level (approximately 10% above the baseline of 0.9 mg/dL), mostly occurring during the first week after initiation of therapy, with subsequent stabilization, whereas patients with normal renal function suffering from heart failure, volume depletion, or bilateral renal artery stenosis experienced a significant rise (approximately 225% above baseline) in serum creatinine level, much higher in magnitude and rate than that experienced by those with renal insufficiency (Figure 1). Serum creatinine levels in these patients sharply increased (by approximately 75% above baseline) in the 2 weeks after the initiation of therapy with an ACE inhibitor, followed by an even sharper increase (another approximately 150%) during the subsequent 2 weeks. Patients with chronic renal insufficiency (serum creatinine>1.5 mg/dL) who received therapy with ACE inhibitors had about a five times higher risk of developing hyperkalemia than those with normal renal function, whereas presence of heart failure increased the risk of hyperkalemia by about three times over those without heart failure. Concomitant use of diuretics was associated with an approximately 60% reduction in risk of hyperkalemia. CONCLUSION: The authors conclude that, in patients with renal insufficiency (serum creatinine>1.4 mg/dL) treated with ACE inhibitors, there is a strong association between early (within the first 2 months) and moderate (not exceeding 30% over baseline) rise in serum creatinine and slowing of the renal disease progression in the long run. The authors recommend that ACE inhibitor therapy should not be discontinued unless serum creatinine level rise above 30% over baseline during the first 2 months after initiation of therapy or hyperkalemia (serum potassium level >or=5.6 mmol/L) develops.     

When should iron chelation therapy be considered in patients with myelodysplasia and other bone marrow failure syndromes with iron overload?

Despite the absence of a robust evidence base, there is growing consensus that effective treatment of iron overload leads to decreased morbidity and premature mortality in patients with good prognosis myelodysplastic syndromes (MDSs). Furthermore, new treatment modalities, including disease-modifying therapies (lenalidamide and azacytidine) and reduced intensity conditioning therapies for allogeneic blood stem cell transplants, are offering the prospect of longer survival for patients with traditionally less favourable prognosis MDS, who might also benefit from iron chelation. This article proposes assessment of patients with MDS and related bone marrow failure syndromes to determine suitability for iron chelation. Iron chelation therapy options and monitoring are discussed.     

Growth hormone deficiency in adults with hypopituitarism—What are the risks and can they be eliminated by therapy?

Growth hormone (GH) deficiency develops early in patients with hypothalamic-pituitary disorders and is therefore common among these patients. GH deficiency in adults is associated with increased morbidity, increased body fat mass, abdominal obesity, dyslipidaemia, reduced exercise capacity, impaired cardiac function as well as reduced self-reported well-being and impaired quality of life. Since recombinant human GH became available as replacement therapy more than 25 years ago, randomised controlled trials and long-term studies, together with meta-analyses, have shown improved outcomes in adult patients with hypopituitarism receiving GH. Many of the features associated with GH deficiency in adults improve, or even normalize, and the safety profile is reassuring. The increased interest in GH deficiency in adults with hypothalamic-pituitary disorders has also contributed to the identification of other factors of importance for an outcome such as the replacement of other pituitary hormone deficiencies, and the management of the underlying hypothalamic-pituitary disease, most commonly a pituitary tumour. In this narrative review, we summarize the burden of GH deficiency in adults with hypopituitarism, the impact of GH replacement on the outcome, as well as safety. Based on currently available data, GH replacement should be considered routine management of adults with hypopituitarism.     

How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

In the last 15 years the management of inflammatory bowel disease has evolved greatly,largely through the increased use of immunomodulators and,especially,anti-tumor necrosis factor(anti-TNF) biologic agents. Within this time period,confidence in the use of anti-TNFs has increased,whilst,especially in recent years,the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines,combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease,especially those who are recently diagnosed. Concurrently,therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and antiTNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent,or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also,however there are few data to support this. Similarly,the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention,including post hoc analyses of the pivotal registration trials,has focused on the optimization of anti-TNF agents,when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy,including an evaluation of recent data addressing unanswered questions regarding the optimal timing,dosage and duration of immunomodulator therapy in combination therapy patients.     

Adjuvant endocrine therapy in women with oestrogen‐receptor‐positive breast cancer: how should the skeletal and vascular side effects be assessed and managed?

Adjuvant endocrine therapy provides oncological benefits in women with early oestrogen‐receptor‐positive breast cancer, but has adverse effects consequent to induced oestradiol deficiency. Bone loss is accelerated, predisposing to increased fracture risk. Metabolic effects include changes in lipid metabolism and body composition although effects on cardiovascular risk are still unclear. Women commencing endocrine therapy should be proactively counselled about and monitored for these and other therapy‐related complications including arthralgia and vasomotor symptoms. We provide strategies for prevention and management of these adverse effects, based, where available, on randomized controlled trial evidence specific to breast cancer survivors receiving endocrine treatment.     

Is the management of thyroid nodules and differentiated thyroid cancer in accordance with recent consensus guidelines? – Results of a national survey

Objective To assess approaches to patients with a potentially malignant thyroid nodule and patients with differentiated thyroid carcinoma and compare them with the European Consensus and Guidelines by the American Thyroid Association. Design A survey of the 388 active members of the Belgian Thyroid Club. Methods A questionnaire addressing the management of an index case and four clinical variations (including variations in the size of the tumour and histological type). The index case was a 40‐year‐old euthyroid woman with a 3‐cm solitary thyroid nodule. Fine‐needle aspiration (FNA) cytology showed cellular aspirates with numerous follicular cells and no colloid. Results The overall response rate was 41%. For the index case, respondents favoured a right lobectomy. Variations in size and histopathology of the nodule altered the management. In the case of a papillary thyroid carcinoma (PTC) of 3 cm in diameter, a total thyroidectomy and prophylactic central lymph node dissection was preferred. After a lobectomy showing a 3·5‐cm follicular thyroid carcinoma (FTC), completion surgery followed by radioiodine administration was the most frequent proposal. For the follow‐up of the index case with a low‐risk disease, determination of serum thyroglobulin (Tg) after recombinant human TSH (rhTSH) administration was considered by the majority of respondents. For the follow‐up of a clinical variation with residual disease, immediate planning of a new treatment was (mistakenly) not considered by a majority of respondents. Conclusions In most cases, respondents were in accordance with the guidelines, although there were some unexpected variations.     

Treatment of acromegaly with SS analogues: should GH and IGF-I target levels be lowered to assert a tight control of the disease?

BACKGROUND: in acromegaly, the criteria for the cure of the disease after neurosurgery have become tighter and tighter. In contrast, the evaluation of control of disease activity during medical treatment is based upon the normalisation of IGF-I levels and epidemiological criteria, i.e. lessening GH (assessed by RIA) to levels reported to normalise increased mortality. The aim of this study was to evaluate GH and IGF-I suppression during prolonged SS analogues (SA) treatment. The concordance between "safe" GH and normalised IGF-I levels during SA was also assessed, according to gender and gonadal status. DESIGN: multicentre, retrospective. Patients. GH/IGF-I levels were evaluated in 207 acromegalic patients (132 females, aged 20-85 yr) during a prolonged treatment (longer than 12 months) with individually tailored doses of depot SA( lanreotide or octreotide-LAR in 97 and 110 patients, respectively). Final IGF-I levels were transformed in z-scores using data collected in a large cohort of normal subjects of 3 different age groups (20-40 yr old, 41-60 yr old, 61-80 yr old, n=160, 148, 115, respectively), that allowed to set up quartiles of normality (I = 3rd-25th percentile, II = 26th-50th, III = 51th-75th, IV = 76th-97th). RESULTS: fifty-nine and 19.3% of patients achieved GH levels <2.5 and <1 microg/l, respectively. IGF-I were normalised (z-score between 2 and -2) in 58.4% of patients. The distribution of normal IGF-I values among quartiles was uneven: 7%, 19%, 25%, and 49% of values were distributed in the I, II, III, and IV quartile, respectively. The concordance between GH and IGF-I values was poor: 28.4% of patients attaining GH values <2.5 microg/l had still pathological IGF-I (even 12.5% of those with GH <1 microg/l), and 39.3% of those with GH levels still above the "safe" limit had "nor IGF-I. Although proportions of IGF-I normalisation were not different between males and females, the regression line obtained between GH and IGF-I z-score showed the same slope but with a significantly lower intercept in regularly cycling women than in males and in postmenopausal females. Thus for any GH value, cycling females had lower IGF-I than menopausal women and males, and their IGF-I normalisation could be achieved by higher GH values. By ROC analysis, the achievement of normal IGF-I was predicted by the GH value of 1.8 microg/l in males and 2.4 microg/l in females. Conclusions: in acromegalic patients on SA treatment, GH and IGF-I levels are often not concordant. In addition to age, sex is to be taken into account in the evaluation of hormonal targets. A better refinement of GH and IGF-I targets to be reached while on treatment with SA is warranted.     

Bone protective therapy in the young patient with fractures and chronic disease: what drug(s) should be given and for how long?

Fractures are fortunately rare in younger people even with severe chronic disease but when they occur they need to be carefully evaluated. When considering such a patient there needs to be an assessment of the risk of future fractures and their type, a search for potentially modifiable risk factors and an evaluation of the risks vs. benefits of bone protective therapy. These factors will have to be considered in the context of the underlying chronic disease and the way that this impacts on the patient. In those individuals where bone protective therapy is given a clear plan is needed relating to how long the treatment is used and what type of monitoring is warranted.     

What do we know about the epidemiology of avoidant/restrictive food intake disorder in children and adolescents? A systematic review of the literature

Background

Avoidant/restrictive food intake disorder (ARFID) was a new diagnosis in DSM-5. This systematic review explores what is known to date about the epidemiology of ARFID in children and adolescents.

Method

Embase, Medline and PsycInfo were used to identify studies meeting inclusion criteria. PRISMA guidelines were followed.

Results

Thirty studies met inclusion criteria, with most coming from specialised eating disorder services where prevalence rates were 5%–22.5%. Three studies from specialist feeding clinics showed the highest prevalence rates, ranging from 32% to 64%. Studies from non-clinical samples reported ARFID prevalence estimates ranging from 0.3% to 15.5%. One study, using national surveillance methodology, reported the incidence of ARFID in children and adolescents reaching clinical care to be 2.02 per 100,000 patients. Psychiatric comorbidity was common, especially anxiety disorders (9.1%–72%) and autism spectrum disorder (8.2%–54.75%).

Conclusion

The current literature on the epidemiology of ARFID in children and adolescents is limited. Studies are heterogeneous with regard to setting and sample characteristics, with a wide range of prevalence estimates. Further studies, especially using surveillance methodology, will help to better understand the nature of this disorder and estimate clinical service needs.     

Cure for immune‐tolerant hepatitis B in children: is it an achievable target with sequential combo therapy with lamivudine and interferon?

We prospectively studied the HBsAg seroconversion with sequential combination therapy of lamivudine (LAM) and interferon (IFN) in hitherto untreatable ‘immune‐tolerant’ chronic hepatitis B in children. In this case–control study, 28 children with immune‐tolerant hepatitis B [HBsAg positive for >6 months with near normal aminotransferase level, minimal/no inflammation in liver histology and high viral load (HBV DNA>10⁷ copies/mL)] were treated with LAM alone at 3 mg/kg/day for 8 weeks followed by LAM plus IFN alpha (5 MU/m² three times a week) for another 44 weeks. They were compared with 34 untreated children. HBV markers (HBsAg, HBeAg, anti‐HBe, quantitative HBV DNA) were carried out at baseline, at the end of therapy and 6 monthly thereafter. The mean age was 5.9 ± 3.2 years and 24 were boys. End therapy response: HBe seroconversion was achieved in 11, and of these, five had complete response (HBsAg clearance), 11 did not respond and six had virologic response (DNA undetectable but no HBe seroconversion). Six months after therapy, 10 of the 11 (91%) originally seroconverted children remained seroconverted while one seroreverted. Six of the 28 (21.4%) children lost HBsAg and they remained HBsAg negative and anti‐HBs positive on follow‐up. After a mean follow‐up of 21.1 ± 11.9 months, the status remained same in the responders but one of the nonresponders HBe seroconverted (39.3%). There were no serious side effects of therapy. It is possible to achieve a cure in more than one‐fifth of immune‐tolerant children with hepatitis B with the sequential combination of LAM and IFN.     

Treat chronic hepatitis C virus infection in decompensated cirrhosis – pre‐ or post‐liver transplantation? the ironic conundrum in the era of effective and well‐tolerated therapy

The management of hepatitis C virus (HCV) infection in patients with decompensated cirrhosis has evolved dramatically over the past few years mainly due to the availability of all‐oral antiviral regimens. The currently approved all‐oral direct‐acting antivirals (DAA) containing sofosbuvir, ledipasvir, daclatasvir and ribavirin, in various combinations, have shown to be safe and effective in patients with decompensated cirrhosis with sustained virological response (SVR) rates nearly comparable to those with well‐compensated liver disease. Unique issues yet remain such as the challenges with renal insufficiency, tolerability of ribavirin and risk of further hepatic decompensation with a protease inhibitor‐based regimen. While most patients who achieve SVR have demonstrated improvement in hepatic synthetic function over the short course of follow, the long‐term beneficial effects are unknown. Further, the baseline predictors of improvement in hepatic function have not been well delineated and thus have left us in a quandary as to what we might expect with successful therapy and thus we are at a loss to well educate our patients. The major concern, in potential liver transplant candidates, is of unintended ‘harm’ by achieving SVR but without improvement in hepatic function to an extent where the patients might function well. As HCV therapies are as effective in liver transplant recipients, there is a growing sentiment in some of the transplant quarters that those with decompensated liver disease and awaiting liver transplant be treated for HCV after liver transplant. This strategy would thus eliminate any concern of leaving a patient in ‘no person's’ land by treating HCV successfully pretransplant but not to the point of functional normalcy, while also would maintain the risk of HCC. Yet a contrarian view would be that not all patients have access to liver transplantation (LT), cannot bear the cost, have comorbidities or contraindications to LT. While the debate continues, it is essential that we develop robust predictors of improvement in liver function so that we can carefully select our patients for therapy in the context of liver transplantation.     

Does cancer that occurs during or after anti–tumor necrosis factor therapy have a worse prognosis? A national assessment of overall and site‐specific cancer survival in rheumatoid arthritis patients treated with biologic agents

Objective

Tumor necrosis factor (TNF) may affect tumor development and spreading. While data on the incidence of cancer following anti‐TNF therapy have been published, the purpose of this study was to examine the clinical presentation and outcome of cancers that develop during or after anti‐TNF therapy.

Methods

By linking data from Swedish clinical registries of rheumatoid arthritis (RA) patients, including Anti‐Rheumatic Therapy in Sweden (ARTIS), the Swedish Biologics Register, with nationwide data on hospitalizations and outpatient visits for RA, we assembled a cohort of 78,483 RA patients who were alive in 1999 or who entered the cohort thereafter. Of these, 8,562 patients started therapy with a biologic agent (98% started an anti‐TNF) during the period from January 1, 1999 to December 31, 2007. Linkage to the Swedish Cancer Register and other registers identified first primary cancers occurring during 1999–2007 as well as post‐cancer survival through March 31, 2009. Through this linkage, we identified 314 cancers in patients who were undergoing, or had a history of, treatment with biologic agents and 4,650 cancers in patients who were biologics‐naive at the time of cancer diagnosis. The distributions of tumor stage among the biologics‐exposed and the biologics‐naive patients were compared. The relative risk of death among the biologics‐exposed versus the 586 matched biologics‐naive cancer cases were assessed by Cox regression analyses. Through chart review in a defined subset, we gathered additional clinical information and validated the diagnoses.

Results

For all cancers combined, the distribution of cancer stages at the time of cancer diagnosis was largely similar between those in the biologics‐exposed and the matched biologics‐naive groups. Based on the total of 113 deaths among those with cancer in the biologics‐exposed group versus the 256 deaths among those with cancer in the biologics‐naive group, the relative risk of death following cancer associated with exposure to anti‐TNF was 1.1 (95% confidence interval 0.8–1.6).

Conclusion

During routine care, cancers that occur following anti‐TNF therapy are not characterized by any markedly altered stage at presentation or by altered post‐cancer survival rates.

     

How fit are children and adolescents with haemophilia in Germany? Results of a prospective study assessing the sport‐specific motor performance by means of modern test procedures of sports science

There are a lot of publications on the physical fitness of patients with haemophilia (PWH), however, most studies only reflect individual sport‐specific motor capacities or focus on a single fitness ability. They involve small patient populations. In this respect principal objective of this study was to compare the physical fitness in all respects and the body composition of young PWH to healthy peers based on the most valid data we could get. Twenty‐one German haemophilia treatment centres were visited from 2002 to 2009. PWH between 8 and 25 years were included. They performed a five‐stage fitness test covering the sport‐specific motor capacities for coordination, measured by one leg stand, strength, aerobic fitness and mobility as well as body composition. The patients' results were compared with age‐ and gender‐specific reference values of healthy subjects. Two hundred and eighty‐five PWH (mean age 13.2 ± 4.5 years, 164 PWH with severe disease) were included prospectively in the study. PWH are significantly below the reference values of healthy subjects in the one‐leg stand test, the mobility of the lower extremity, the strength ratio of chest and back muscles and the endurance test. In body composition, the back strength and the mobility of the upper extremity PWH are significantly above the reference values. There are no significant differences in abdominal strength. In conclusion we found specific differences in different fitness abilities between PWH and healthy subjects. Knowing this, we are able to work out exercise programmes to compensate the diminished fitness abilities for our PWH.