Advertisements
Feeds:
Posts
Comments

Posts Tagged ‘Hypoglycemia’


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Congenital hyperinsulinism is a medical term referring to a variety of congenital disorders in which hypoglycemia is caused by excessive insulin secretion. Congenital forms of hyperinsulinemic hypoglycemia can be transient or persistent, mild or severe. These conditions are present at birth and most become apparent in early infancy. The severe forms can cause obvious problems in the first hour of life, but milder forms may not be detected until adult years. Mild cases can be treated by frequent feedings, more severe cases can be controlled by medications that reduce insulin secretion or effects, and a minority of the most severe cases require surgical removal of part or most of the pancreas to protect the brain from damage due to recurrent hypoglycemia.

Types of congenital hyperinsulinism:

1. Transient neonatal hyperinsulinism

2. Focal hyperinsulinism

  • Paternal SUR1 mutation with clonal loss of heterozygosity of 11p15
  • Paternal Kir6.2 mutation with clonal loss of heterozygosity of 11p15

3. Diffuse hyperinsulinism

a. Autosomal recessive forms

  • i. SUR1 mutations
  • ii. Kir6.2 mutations
  • iii. Congenital disorders of glycosylation

b. Autosomal dominant forms

4. Beckwith-Wiedemann syndrome (thought to be due to hyperinsulinism but pathophysiology still uncertain: 11p15 mutation or IGF2 excess)

Congenital hyperinsulinism (CHI or HI) is a condition leading to recurrent hypoglycemia due to an inappropriate insulin secretion by the pancreatic islet beta cells. HI has two main characteristics:

  • a high glucose requirement to correct hypoglycemia and
  • a responsiveness of hypoglycemia to exogenous glucagon.

HI is usually isolated but may be rarely part of a genetic syndrome (e.g. Beckwith-Wiedemann syndrome, Sotos syndrome etc.). The severity of HI is evaluated by the glucose administration rate required to maintain normal glycemia and the responsiveness to medical treatment. Neonatal onset HI is usually severe while late onset and syndromic HI are generally responsive to a medical treatment. Glycemia must be maintained within normal ranges to avoid brain damages, initially, with glucose administration and glucagon infusion then, once the diagnosis is set, with specific HI treatment. Oral diazoxide is a first line treatment.

In case of unresponsiveness to this treatment, somatostatin analogues and calcium antagonists may be added, and further investigations are required for the putative histological diagnosis:

  • pancreatic (18)F-fluoro-L-DOPA PET-CT and
  • molecular analysis.

Indeed, focal forms consist of a focal adenomatous hyperplasia of islet cells, and will be cured after a partial pancreatectomy.

Diffuse HI involves all the pancreatic beta cells of the whole pancreas. Diffuse HI resistant to medical treatment (octreotide, diazoxide, calcium antagonists and continuous feeding) may require subtotal pancreatectomy which post-operative outcome is unpredictable.

The genetics of focal islet-cells hyperplasia associates

  • a paternally inherited mutation of the ABCC8 or
  • the KCNJ11 genes, with
  • a loss of the maternal allele specifically in the hyperplasic islet cells.

The genetics of diffuse isolated HI is heterogeneous and may be

  • recessively inherited (ABCC8 and KCNJ11) or
  • dominantly inherited (ABCC8, KCNJ11, GCK, GLUD1, SLC16A1, HNF4A and HADH).

Syndromic HI are always diffuse form and the genetics depend on the syndrome. Except for HI due to

  • potassium channel defect (ABCC8 and KCNJ11),

most of these HI are sensitive to diazoxide.

The main points sum up the management of HI:

  • i) prevention of brain damages by normalizing glycemia and
  • ii) screening for focal HI as they may be definitively cured after a limited pancreatectomy.

Source & References:

http://en.wikipedia.org/wiki/Congenital_hyperinsulinism

http://www.ncbi.nlm.nih.gov/pubmed/20550977

 

Advertisements

Read Full Post »


Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Hypopituitarism is a partial or complete insufficiency of pituitary hormone secretion that may be derived from pituitary or hypothalamic disease. Onset can be at any time of life. Intrinsic pituitary disease, or any process that disrupts the pituitary stalk or damages the hypothalamus, may produce pituitary hormone deficiency. The clinical presentation of hypopituitarism widely varies, depending on patient age and on the specific hormone deficiencies, which may occur singly or in various combinations. As a general rule, diagnosis of a single pituitary hormone deficiency requires evaluating the other hormone axes.

Etiology

Hypopituitarism has multiple possible etiologies either from congenital or acquired mechanisms. The common endpoint is disrupted synthesis or release of 1 or more pituitary hormones, resulting in clinical manifestations of hypopituitarism. Genetic causes of hypopituitarism are relatively rare. However, research since the late 20th century has brought considerable advances in the understanding of the various genetic causes of congenital hypopituitarism. Inheritance patterns may be autosomal recessive, autosomal dominant, or X-linked recessive. The phenotype and severity of clinical findings in congenital hypopituitarism are determined by the specific genetic mutation. Causes of hypopituitarism can be divided into categories of congenital and acquired causes.

Congenital causes of hypopituitarism include the following:

  • Perinatal insults (eg, traumatic delivery, birth asphyxia)
  • Interrupted pituitary stalk
  • Absent or ectopic neurohypophysis
  • Pallister-Hall syndrome

Multiple Pituitary Hormone Deficiency is rare in childhood, with a possible incidence of fewer than 3 cases per million people per year. The most common pituitary hormone deficiency, growth hormone deficiency (GHD), is much more frequent; a US study reported a prevalence of 1 case in 3480 children.A 2001 population study in adults in Spain estimated the annual incidence of hypopituitarism at 4.2 cases per 100,000 population. Because hypopituitarism has congenital and acquired forms, the disease can occur in neonates, infants, children, adolescents, and adults.

Prognosis

With appropriate treatment, the overall prognosis in hypopituitarism is very good. Sequels from episodes of severe hypoglycemia, hypernatremia, or adrenal crises are among potential complications. Long-term complications include short stature, osteoporosis, increased cardiovascular morbidity/mortality, and infertility. Previous findings of increased cardiovascular morbidity and decreased life expectancy in adults with hypopituitarism were thought to be largely secondary to untreated GHD.

Mortality/morbidity

Morbidity and mortality statistics generally cannot be viewed in isolation but must instead be related to the underlying cause of hypopituitarism. For example, morbidity and mortality are minimal in the context of idiopathic GHD compared with hypopituitarism caused by craniopharyngioma. Recognition of pituitary insufficiency and appropriate hormone replacement (including stress doses of hydrocortisone, when indicated) are essential for the avoidance of unnecessary morbidity and mortality. Clinical manifestations of isolated or multiple deficiencies in pituitary hormones (anterior and/or posterior) can result in significant sequelae that include any of the following:

  • Hypoglycemia – Can cause convulsions; persistent, severe hypoglycemia can cause permanent CNS injury.
  • Adrenal crisis – Can occur during periods of significant stress, from ACTH or CRH deficiency; symptoms include profound hypotension, severe shock, and death.
  • Short stature – Can have significant psychosocial consequences.
  • Hypogonadism and impaired fertility – From gonadotropin deficiency
  • Osteoporosis – Results in increased fracture risk

GHD is believed to be an important contributing factor to morbidity and mortality associated with hypopituitarism. In a 2008 study, childhood onset GHD was associated with an increased hazard ratio for morbidity of greater than 3.0 for males and females. Causes of morbidity and mortality are multifactorial and relate to the specific cause of hypopituitarism, as well as to the degree of pituitary hormone deficiency.

Source References:

http://tbccn.org/CCJRoot/v9n3/pdf/212.pdf

http://emedicine.medscape.com/article/922410-overview

Read Full Post »


 

Reporter: Aviva Lev-Ari, PhD, RN

Glucose in the ICU — Evidence, Guidelines, and Outcomes

Brian P. Kavanagh, M.B., F.R.C.P.C.

September 7, 2012 (10.1056/NEJMe1209429)

Just over a decade ago, a single-center Belgian study showed that normalization of blood glucose in critically ill patients lowered hospital mortality by more than 30%.1 Although subsequent studies were unable to reproduce these findings, the appeal of such a straightforward intervention was too great to resist: guidelines from professional organizations2,3 were published, and editorial commentary4 highlighted initiatives by the Institute for Healthcare Improvement, the Joint Commission on Accreditation of Healthcare Organizations, and the Volunteer Hospital Association that incorporated tight glucose control as a standard. Indeed, the prestigious Codman Award of the Joint Commission was presented in 2004 for a program of glycemic control in critical care that “saved” patients’ lives.5 Tight glucose control for critically ill patients was in vogue.

The publication in 2009 of a large international trial (the Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation [NICE-SUGAR] study6) followed that of several negative trials. The NICE-SUGAR study, which involved more than 6100 patients, showed that tight glycemic control didn’t decrease mortality — it increased it. Most guidelines were hastily revised. However, in the same year a separate study by Vlasselaers et al.7 in pediatric intensive care unit (ICU) patients, most of whom had undergone cardiac surgery, showed that normalizing glucose decreased mortality from 6% to 3%, keeping open the question — at least in critically ill children.

The study by Agus et al.8 now reported in the Journal provides new key data. A total of 980 children (up to 36 months of age) admitted to an ICU after cardiac surgery were randomly assigned to usual care or tight glucose control. The results are clear — there was no significant difference in the incidence of health care–associated infections (the primary outcome) or in any of the secondary outcomes, including survival. Moreover, the rate of hypoglycemia (blood glucose level <40 mg per deciliter [2.2 mmol per liter]) in the intervention group (3%) was far less than that previously reported (25%).7 These findings contrast sharply with those of Vlasselaers et al.,7 who found that secondary infections, length of stay, and mortality were reduced. Faced with contradictory results from two large clinical trials, how does the clinician know which results are correct?

First, biologic plausibility is important in attributing a survival benefit to a specific intervention. In the first pediatric ICU study, the additional deaths in the control group did not appear to be due to causes related to hyperglycemia,7 a finding that suggests that the benefit was unlikely to be reproducible. The current authors, exclusively studying children after cardiac surgery, recognized that mortality in this population is usually due to prohibitive anatomy or surgical challenge; these are circumstances not amenable to correction by metabolic control.

Second, might differences in the target plasma glucose explain the discrepant findings? Agus et al. aimed for a higher target range of plasma glucose in the intervention group (80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) than was targeted in the first pediatric study (infants, 50 to 80 mg per deciliter [2.8 to 4.4 mmol per liter]; children, 70 to 100 mg per deciliter [3.9 to 5.6 mmol per liter]).7 Perhaps the lower glucose target is preferable? The weight of evidence is against this, and if this target were used, the incidence and severity of hypoglycemia would have been greater, as previously reported.7 Hypoglycemia is never to a patient’s benefit, and its negative impact on neurocognitive development in children is of particular concern.

It seems that — as in adults — claims for survival benefit in critically ill children are incorrect. Furthermore, there is no reason why the effects of glucose control in children would be opposite to those in adults. In aggregate, the data do not support a basis for embarking on a pediatric megatrial.

Assuming the results of the NICE-SUGAR study6 are generalizable, we must be grateful for the future lives saved by avoiding the practice of normalizing glucose in the ICU. At the same time, we should reflect on why a large study with mortality as an end point was needed in the first place.

Perhaps the most important question from a decade of studying glucose control in the ICU is how influential practice guidelines advocating tight glucose control were developed2,3 yet turned out to be harmful — an issue noted in the lay press.9 Guideline writers, reflecting on the experience, must accept that there are multiple sources of clinical knowledge10 and must pay careful attention to trial characteristics — especially study reproducibility — in order to provide advice that genuinely helps clinicians. Clinicians in turn should use guidelines wisely, recognizing that no single source of knowledge is sufficient to guide clinical decisions.10

Is the door closed on studying glucose homeostasis in the critically ill? No, but it should be closed on the routine normalization of plasma glucose in critically ill adults and children.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

This article was published on September 7, 2012, at NEJM.org.

SOURCE INFORMATION

From the Department of Critical Care Medicine and Anesthesia, Hospital for Sick Children, University of Toronto, Toronto.

Source:

http://www.nejm.org/doi/full/10.1056/NEJMe1209429?query=OF

REFERENCES

    1. 1

      van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-1367
      Full Text | Web of Science | Medline

    1. 2

      American College of Endocrinology and American Diabetes Association Consensus statement on inpatient diabetes and glycemic control. Diabetes Care 2006;29:1955-1962
      CrossRef | Web of Science

    1. 3

      Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med 2004;30:536-555
      CrossRef | Web of Science | Medline

    1. 4

      Angus DC, Abraham E. Intensive insulin therapy in critical illness. Am J Respir Crit Care Med 2005;172:1358-1359
      CrossRef | Web of Science | Medline

    1. 5

      The Joint Commission. 2004 Ernest Amory Codman Award winners (http://www.jointcommission.org/2004_ernest_amory_codman_award_winners).

    1. 6

      The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;360:1283-1297
      Full Text | Web of Science

    1. 7

      Vlasselaers D, Milants I, Desmet L, et al. Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet 2009;373:547-556
      CrossRef | Web of Science | Medline

    1. 8

      Agus MSD, Steil GM, Wypij D, et al. Tight glycemic control versus standard care after pediatric cardiac surgery. N Engl J Med 2012. DOI: 10.1056/NEJMoa1206044.

    1. 9

      Groopman J, Hartzband P. Why `quality’ care is dangerous. Wall Street Journal. April 9, 2009 (http://online.wsj.com/article/SB123914878625199185.html).

  1. 10

    Tonelli MR, Curtis JR, Guntupalli KK, et al. An official multi-society statement: the role of clinical research results in the practice of critical care medicine. Am J Respir Crit Care Med2012;185:1117-1124
    CrossRef | Web of Science

 

Read Full Post »


Risks of Hypoglycemia in Diabetics with Chronic Kidney Disease (CKD)

Reporter: Aviva Lev-Ari, PhD, RN

Risks of Hypoglycemia in Diabetics with CKD

By Mark Abrahams, MD

Reviewed by Loren Wissner Greene, MD, MA (Bioethics), Clinical Associate Professor of Medicine, NYU School of Medicine, New York, NY

Published: 03/13/2012

 http://www.medpagetoday.com/resource-center/diabetes/Risks-Hypoglycemia-Diabetics-CKD/a/31634

According to the National Institutes of Health (NIH), approximately 40% of adults with diabetes have some degree of chronic kidney disease (CKD).1 That’s a lot of patients—perhaps more than one might think.

What should we be doing differently for these patients? Sure, they should be getting an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) for renoprotection, and blood pressure and lipids should be aggressively managed, but how does (or should) our approach to managing their antidiabetic therapy change?

We might consider taking a more aggressive approach to their glycemic control. In clinical trials, tight glycemic control has been shown to be the primary determinant of decreased microvascular complications.1 However, once we’ve decided how aggressively to manage glycemia, the choice of which antidiabetic to use (and how to dose it) is especially important in these patients.

Unfortunately, when the therapeutic strategy is to maximize glycemic control, the risk of hypoglycemia also increases – in both frequency and severity.2 Patients taking oral antidiabetics that are primarily eliminated by the kidneys are particularly susceptible.1 Furthermore, it should be noted that older patients are also at higher risk.3

Dosing errors are common in CKD patients and can cause poor outcomes.3 Drugs cleared renally should be dose-adjusted based on creatinine clearance or estimated glomerular filtration rate (eGFR). Dose reductions, lengthening of the dosing interval, or both may be required.3

As metformin is nearly 100% renally excreted, it is contraindicated in a number of patients: when serum creatinine is higher than 1.5 mg/dL in men or 1.4 mg/dL in women, in patients older than 80 years, or in patients with chronic heart failure. The primary concern here is that other hypoxic conditions (e.g., acute myocardial infarction, severe infection, respiratory disease, liver disease) may increase the risk of lactic acidosis. Because of this danger, and despite the fact that metformin is usually the recommended first-line treatment for type 2 diabetes, one should use caution when considering metformin in patients with renal impairment.3

Similarly, sulfonylureas should be used with care in diabetics with CKD. The clearance of both sulfonylureas and their metabolites is highly dependent on kidney function. As such, severe and sustained episodes of hypoglycemia due to sulfonylurea use have been described in dialysis patients.2

Regardless of which antidiabetic agent is selected, HbA1c and kidney function should be regularly monitored and the antidiabetic regimen appropriately adjusted. As patients with type 2 diabetes tend to progress over time, most will require a combination of agents to achieve desired glycemic control. These combinations should be chosen carefully in patients with CKD.1

Finally, awareness of and screening for renal impairment in diabetics is a necessary precursor to successful intervention. In these patients, CKD is underdiagnosed and undertreated, and awareness of the disease is low among providers and patients alike.1

Early detection of disease via eGFR or urinary albumin excretion can lead to timely, evidence-based intervention and help prevent or delay progression of CKD. The benefit? Improved kidney and cardiovascular outcomes, and lower associated costs.1

References:

  1. Bakris GL. Recognition, Pathogenesis, and Treatment of Different Stages of Nephropathy in Patients With Type 2 Diabetes MellitusMayo Clin Proc. 2011;86:444-456.
  2. Cavanaugh KL. Diabetes Management Issues for Patients With Chronic Kidney DiseaseClin Diab. 2007;25:90-97.
  3. Munar MY, et al. Drug Dosing Adjustments in Patients With Chronic Kidney Disease. Am Fam Physician. 2007;75:1487-1496.

 

Read Full Post »