Saul Malozowski

Evaluation and Treatment of Adult Growth Hormone Deficiency: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The aim was to update The Endocrine Society Clinical Practice Guideline on Evaluation and Treatment of Adult Growth Hormone Deficiency (GHD) previously published in 2006. CONSENSUS PROCESS Consensus was guided by systematic reviews of evidence and discussions through a series of conference calls and e-mails. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocrine Society. A second draft was reviewed and approved by The Endocrine Society Council. At each stage of review, the Task Force received written comments and incorporated substantive changes. CONCLUSIONS GHD can persist from childhood or be newly acquired. Confirmation through stimulation testing is usually required unless there is a proven genetic/structural lesion persistent from childhood. GH therapy offers benefits in body composition, exercise capacity, skeletal integrity, and quality of life measures and is most likely to benefit those patients who have more severe GHD. The risks associated with GH treatment are low. GH dosing regimens should be individualized. The final decision to treat adults with GHD requires thoughtful clinical judgment with a careful evaluation of the benefits and risks specific to the individual.

Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial

OBJECTIVE Randomized treatment comparing an intensive glycemic treatment strategy with a standard strategy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was ended early because of an unexpected excess of mortality in the intensive arm. As part of ongoing post hoc analyses of potential mechanisms for this finding, we explored whether on-treatment A1C itself had an independent relationship with mortality. RESEARCH DESIGN AND METHODS Participants with type 2 diabetes (n = 10,251 with mean age 62 years, median duration of diabetes 10 years, and median A1C 8.1%) were randomly assigned to treatment strategies targeting either A1C <6.0% (intensive) or A1C 7.0–7.9% (standard). Data obtained during 3.4 (median) years of follow-up before cessation of intensive treatment were analyzed using several multivariable models. RESULTS Various characteristics of the participants and the study sites at baseline had significant associations with the risk of mortality. Before and after adjustment for these covariates, a higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year. Higher average A1C was associated with greater risk of death. The risk of death with the intensive strategy increased approximately linearly from 6–9% A1C and appeared to be greater with the intensive than with the standard strategy only when average A1C was >7%. CONCLUSIONS These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD.

Growth Hormone Research Society Workshop Summary: Consensus Guidelines for Recombinant Human Growth Hormone Therapy in Prader-Willi Syndrome

Context: Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events. Objective: The aim of the study was to formulate recommendations for the use of rhGH in children and adult patients with PWS. Evidence: We performed a systematic review of the clinical evidence in the pediatric population, including randomized controlled trials, comparative observational studies, and long-term studies (>3.5 y). Adult studies included randomized controlled trials of rhGH treatment for ≥ 6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials, and pharmaceutical registries. Methodology: Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (http://bit.ly.PWGHIN). Conclusions: Following a multidisciplinary evaluation, preferably by experts, rhGH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental, and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer, or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental, and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks.

Benign intracranial hypertension in children with growth hormone deficiency treated with growth hormone

We report 13 cases of benign intracranial hypertension (IH) in children with growth hormone (GH) deficiency treated with GH in the United States. The group consisted of eight boys and five girls, 3 to 16 years of age (median, 9 years). The interval from starting GH therapy to diagnosis of IH was 2 weeks or less in six patients, between 2 and 12 weeks in four, 8 months in one, 5 years in one, and unknown in one. Seven patients were not known to have previously described IH risk factors; the other six had at least one factor each. All patients but one had headache, nausea, vomiting, and visual changes. All had papilledema, and cerebrospinal fluid pressures were elevated (> 250 mm H2O) in all nine patients tested. The GH dosage range was 0.17 to 0.35 mg per kilogram body weight per week (median, 0.30 mg/kg per week) for the 11 patients with dosage data. After discontinuation of GH and treatment with lumbar punctures and/or medications, signs and symptoms resolved in eight children; in two of these children signs and symptoms reappeared when GH therapy was restarted. In four patients signs and symptoms resolved while GH therapy was continued; one child was treated with a ventriculoperitoneal shunt because of an arachnoid cyst, after which GH was restarted without subsequent IH. In the 12 patients with idiopathic GH deficiency the course of IH was benign, with complete resolution of all signs and symptoms. Because doses and scheduling of GH administration have changed since the introduction of recombinant GH, higher doses and increased frequency of administration may be contributing to the development of IH in some patients. We suggest beginning therapy at the lowest recommended dose, with gradual titration to higher doses, and the performance of routine funduscopic examinations during initiation of GH therapy and whenever signs or symptoms of IH develop.

Pancreatitis Associated with Atypical Antipsychotics: From the Food and Drug Administration's MedWatch Surveillance System and Published Reports

Study Objective. To investigate the relative numbers and clinical characteristics of pancreatitis in patients treated with the atypical antipsychotic agents, clozapine, olanzapine, and risperidone, versus the conventional neuroleptic, haloperidol.

Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage: Secondary analysis of the ACCORD clinical trial data

BackgroundHypoglycemia is a common complication of diabetes treatment. This paper describes symptoms, predecessors, consequences and medications associated with the first episode of severe hypoglycemia among ACCORD participants with type 2 diabetes, and compares these between intensive (Int: goal A1C <6.0%) and standard (Std, goal A1C 7–7.9%) glycemia intervention groups.MethodsInformation about symptoms, antecedents, and consequences was collected at the time participants reported an episode of severe hypoglycemia. Data on medications prescribed during the clinical trial was used to determine the association of particular diabetes drug classes and severe hypoglycemia.ResultsThe most frequently reported symptoms in both glycemia group were weakness/fatigue (Int 29%; Std 30%) and sweating (Int 26%; Std 27%), followed by confusion/disorientation (Int 22%; Std 29%) and shakiness (Int 21%; Std 19%). Approximately half of all events were preceded by a variation in food intake (Int 48%; Std 58%). The most common consequences were confusion (Int 37%; Std 34%), loss of consciousness (Int 25%; Std 25%), and hospitalization (Int 18%; Std 24%). The highest rates of hypoglycemia were found among those participants treated with insulin only (Int 6.09/100 person yrs; Std 2.64/100 person yrs) while the lowest were among those prescribed oral agents only (Int 1.93/100 person yrs; Std 0.20/100 person yrs).ConclusionsSevere hypoglycemia episodes were frequently preceded by a change in food intake, making many episodes potentially preventable. Symptoms of confusion/disorientation and loss of consciousness were frequently seen. The highest rates of hypoglycemia were seen with prescription of insulin, either alone or in combination with other medications.Clinical Trial RegistrationNumber: NCT00000620

Prepubertal gynecomastia during growth hormone therapy

We report 22 cases of prepubertal gynecomastia diagnosed during growth hormone (GH) treatment. The age and dose range were 2 to 12 years and 0.18 [corrected] to 0.3 mg/kg per week, respectively. In most of the patients, gynecomastia appeared between 0.5 and 7 months after GH was started. Three boys were using drugs other than GH. This condition appears to be self-limited and benign.

Aseptic necrosis in HIV seropositive patients: a possible etiologic role for megestrol acetate.

The association between pharmacologic doses of corticosteroids and the development of aseptic bone necrosis has been well documented. Recent reports have described the corticosteroid activity of megestrol acetate. A retrospective review of adverse events reported to the U.S. Food and Drug Administration identified three human immunodeficiency virus (HIV) seropositive patients who developed avascular necrosis of the femoral head during treatment with megestrol acetate. All were males, ages 34, 36, and 55 years, and were on therapy for 6, 1.5, and 18 months, respectively, when symptoms of aseptic necrosis occurred in the absence of antecedent trauma. Megestrol acetate doses were 640, 320, and 600-1200 mg/d, respectively. Two patients had no history of corticosteroid use whereas the third had taken an undisclosed dose and duration of corticosteroids concurrent with pentamidine administration. Notably, despite the predominant use of megestrol in women for hormone sensitive malignancies, none of the reports of aseptic necrosis occurred in this population. Megestrol acetate may be associated with the development of avascular necrosis via its glucocorticoid-like effects. Cachectic acquired immunodeficiency syndrome (AIDS) patients may have additional risk factors that predispose them to aseptic necrosis when receiving megestrol acetate.

Nocturnal thyrotropin surge in growth hormone-deficient children

Because some patients with growth hormone (GH) deficiency are found to be hypothyroid after initiation of treatment with GH, we assessed the predictive value of the nocturnal thyrotropin surge (a sensitive test for central hypothyroidism) in 56 untreated GH-deficient children and adolescents. Eighteen patients had a subnormal thyrotropin surge (mean 18% (range -30% to 46%)), significantly less than that of 96 normal control subjects (mean 124%; 95% confidence limits, 47% to 300%; p less than 0.01); 13 of the 18 had a subnormal total thyroxine (T4) level or a subnormal free T4 level, or both. These 18 patients were given thyroid hormone replacement therapy; GH deficiency was confirmed during treatment with thyroxine. Of the remaining 38 patients, who had no initial evidence of dysfunction of the hypothalamic-pituitary-thyroid axis, 23 were re-examined while they were receiving GH treatment. Hypothyroidism developed in none of those 23 children during GH therapy. The nocturnal thyrotropin surge test and determination of iodothyronine levels were repeated in 14 of these euthyroid patients. There was no significant change in mean thyrotropin surge (129% (range +49% to +300) vs 125% (range +51% to +222%)), mean serum level of total T4 (111 +/- 4 vs 103 +/- 3 nmol/L), mean serum level of free T4 (19 +/- 0.7 vs 18 +/- 0.8 pmol/L), mean serum level of triiodothyronine (2.5 +/- 0.1 vs 2.5 +/- 0.1 nmol/L), or mean serum level of thyrotropin (2.9 +/- 0.3 vs 2.9 +/- 0.5 mU/L (mean +/- SEM)). We conclude that GH treatment does not appreciably alter thyroid function in GH-deficient patients who have no evidence of thyroid axis dysfunction before GH treatment.

Propylthiouracil-Induced Hepatotoxicity and Death. Hopefully, Never More

Addressing the dissimilar toxicities of the two most commonly used antithyroid medications, propylthiouracil (PTU) and methimazole (MMI), and focusing particularly on hepatotoxicity and death in children, Rivkees and Szarfman bring to the forefront an issue that time and time again has fallen off our radar screen: the use of PTU can result in tragic consequences and should never be used in children (1). The same statement could be made for adults, with the exception of use during early pregnancy when PTU use may avoid the potential for fetal malformations that may occur with MMI (2). However, the MMI teratogenic link seems tenuous. Rivkees and Szarfman (1) provide an in-depth history of these drugs and recount their well-known similar and distinct mechanisms of action. More importantly, using an elegant methodological approach focused on data mining, they underscore the following central issues. PTU is identified as being the third most frequent cause of drug-induced liver transplant in the United States (3), and administration can lead to severe liver injury and death. This seems clearer in children, and the rate is 17 times higher than the expected rate of liver failure in those not exposed. In the 40-yr period reviewed in Ref. 1, 14 of 23 (33%) cases of death from liver disease after PTU administration were in pediatric patients. In addition to causing fatal liver disease, PTU is also linked to a greater risk of vasculitis; glomerulonephritis and associated positive titers of antineutrophil cytoplasmatic antibody are 50 times higher than expected. However, these complications are generally clinically mild. MMI can also induce liver toxicity, but these effects are milder, confined to cholestasis, not associated with liver failure, and more frequent in people older than 61 yr of age. In children, in addition to the risk of liver failure, mild liver injury associated with PTU is four times higher than with MMI. As in most drug-induced hepatotoxicity, there are no effective tests or means to predict or prevent serious complications. With PTU, complications can occur at any time during treatment and are not dose related. Because many other therapeutic modalities are available that do not result in these complications, the recommendation that PTU should not be used in children seems crystal clear. The information provided in the article by Rivkees and Szarfman (1) complements the report by Emiliano et al. (4) on PTU and MMI, which appeared in the April issue of JCEM and describing prescription practices for MMI and PTU in the United States between 1998 and 2008, showing substantial increases in the use of these drugs. A shift from PTU to MMI as the most common antithyroid drug occurred in 1996 and has led to MMI dominance of the market; the authors speculate that this may have been fueled by the availability of a generic version of MMI. Women were prescribed PTU more frequently than were men. The only group where MMI use was lower was in females of childbearing age. The authors suggest that this tendency may be due to the previously described potential for fetal malformations associated with MMI during pregnancy. Data from this article also suggest that the use of other modalities for the initial treatment of hyperthyroidism—radioactive iodine and/or surgery—have been displaced by the use of these medications. Of concern is that these data indicate that in 22% of patients receiving antithyroid medication PTU continues to be used as the drug of first choice and that this rate has remained unchanged in the period studied, keeping the unease about hepatic toxicity unabated. These articles allow us to debunk the characterization that PTU liver damage is rare. In the absence of adequate data to properly assess drug use, the term “rare” properly suggests to the prescribing physician that complications may never occur. This mistaken message may, in turn, be conveyed to the patient. Data from the first article (1) indicate that the risk of severe liver damage in pediatric patients receiving PTU is quite alarming. Of concern is that a drug that is prescribed to a very limited number of patients is listed as the third cause of drug-induced liver transplantation, secondary to any medications in the United States. This puts this the term “rare complications” in a completely different light. The hope of Rivkees and Szarfman, Emiliano, and their co-workers is that the knowledge gained from these important studies will lead to a more restrictive use of PTU. It is important to note that, as stated by the authors, PTU-induced liver toxicity was recognized soon after this medication was introduced in 1947, and cases of liver injury have occurred year after year (5). How then it is possible that it took more than 60 yr to incorporate a black box into its label? Although it is impossible to properly answer this question, and we can only speculate, many factors contributed to the “hidden” hepatotoxicity signal. The process by which drugs were reviewed when these medications were introduced to the market more than six decades ago had different and less stringent requirements. Even if studies for approval were performed under current standards, it is very difficult to address rare events like severe hepatotoxicity, given that the conditions they treat are rare. One example of these rare conditions is hyperthyroidism in children. Because of the availability of different treatment modalities for hyperthyroidism, large series addressing a single pharmacological agent to treat it, both in children and adults, are usually retrospective analyses and seldom include more than 100 subjects. For complications that may occur in 1 of 2000 exposed individuals, the universe for a case to emerge would be approximately 6000 patients (6). Even if it were feasible to power a study to detect this problem, executing the study at the present time would be unethical. We believe that the most experienced pediatric thyroidologists and even the busiest centers in the world may never see in excess of hundreds of children that may need antithyroid drugs. Given that cases of liver damage are infrequent and that there is not a sophisticated database for patients over age 40, it would have been difficult to compile and analyze emerging information that may have resulted in labeling changes. In addition, the well-known level of underreporting of adverse events (7), particularly in children (8), further increased our inability to put all of the events filed throughout the years into the proper perspective and trigger a regulatory action. Given all of these variables, it is easy to understand how the PTU liver toxicities were never addressed before. Dr. Ana Szarfman has been working for years on mining the adverse event report system using algorithms that allow for ascertainment of rare and common events in an unbiased manner for many drugs undergoing preapproval evaluations as well as those already on the market (9,10). The partnership with Scott Rivkees was triggered by his suspicions that the liver complications were more common than initially thought and should be characterized as “common” rather than “rare.” Nevertheless, many barriers needed to be overcome. Because the system relies on spontaneous reports, mostly provided by health care professionals, these reports are compiled under numerous and distinct labels, although they may reporting an identical event. The first step was to assess which events fit where and whether they all met the same definitions. Once this was done, the number of events was compared to what is expected in the general population. This comparison ability is built into the mining process. The results that are conveyed in the Rivkees and Szarfman report (1) were previously reviewed by many stakeholders from numerous private and government institutions including, among others, representatives of numerous Food and Drug Administration (FDA) offices, the National Institute for Child Health and Human Development, the National Institute for Diabetes and Digestive and Kidney Diseases, and the United Network for Organ Sharing, as well as the Lawson Wilkins Pediatric Endocrine Society, The Endocrine Society, and the American Thyroid Association (ATA) at a special workshop that was held under the sponsorship of the Best Pharmaceuticals for Children Act (BPCA) on October 28, 2008 and at a meeting jointly sponsored by the FDA and the ATA on April 18, 2009 (11). These discussions underscored the presence of these severe events and in turn led to a thoughtful reassessment by the FDA and the addition of a black box into the label (12). Approximately 2 yr of hard work were needed to bring the safety alert related to PTU-induced hepatotoxic to generalized attention. Hopefully, this information will put an end to the continued prescribing of PTU other than as needed in pregnancy. In turn, this information should encourage the selection of alternative therapies for the treatment of hyperthyroidism, particularly in children. Equally as important as the uncovering of the PTU hepatotoxicity problem are the lessons learned in the process. The role of individual clinicians reporting drug-induced adverse events and reporting them to manufacturers and the FDA should be reemphasized. Without this information, the regulatory agencies cannot update their knowledge and in turn enhance our ability to safely prescribe medications. These experiences also teach us that close relationships among prescribers, academic organizations, and federal agencies can promote drug safety. Finally, the value of investing in the application of modern new computer-based methodology that can monitor and link prescribing and adverse event data is clearly apparent.