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HYPOGLYCEMIA UPDATE By-Dawit Ayele Nov,2006. OUTLINE. -Hypoglycemic disorders-in diabetics -non diabetics -Complications -Diagnosis -Management. I-Hypoglycemic disorders in Diabetes. Study –2/3 of patients admitted for hypo are diabetics
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OUTLINE -Hypoglycemic disorders-in diabetics -non diabetics -Complications -Diagnosis -Management
I-Hypoglycemic disorders in Diabetes Study –2/3 of patients admitted for hypo are diabetics -2/3 used alcohol Clinical context - Hyperglycemia treatment were it not for hypo. would be easy. - Hypoglycemia makes diabetes mgt complex. Due to this :-chronic complications-retinopathy,neuropathy etc..progress despite aggressive attempts. -plasma glucose may be <50mg/dl in ~10% of the time. -average 2 episodes of sxic hypoglycemia per week & severe temporarily disabling hypoglycemia 1-2Xa year. -2-4%of death of such people
Risk Factors I-Excess insulin: 1-Ill timed,wrong type & high dose 2- glucose influx 3- insulin independent glucose utilization. 4-endogenous glucose production(alcohol,renal parenchyma dis.) 5- insulin sensitivity.(post exercise) 6- insulin clearance.(renal failure)
II-Interplay of insulin excess & compromised glucose counterregulation A-Absolute insulin deficiency(-ve C-Peptide) ß-cell destruction:no in insulin in response to glucose hence:No in glucagon in response to glucose B-History of severe hypglycemia or aggressive therapy per se.(lower glucose goals,lower Hgb A1c) Episodes of attenuated autonomic hypoglycemia including epinephrine activation & sxs in response to glucose defective glucose counter regulation& hypoglycemia unawareness
II-Non-Diabetic Hypoglycemic Disorders • A-The Fasting(Post absorptive)hypoglycemias i-Drugs Insulin,sulfonylureas -Most common causes(in rx of diabetes) -sometimes taken surreptitiously -taken for criminal intent -pharmacy/other error Mechanisms--described
Drugs con’t • Ethanol -Inhibits gluconeogenesis(deplets cofactor key to entry of gluconeogenesis precursors.) -inhibits cortisol &GH responses. -Doesn’t inhibit glycogenolysis. Clinical alcohol induced hypo. Typically follows 6-36 hours post binge of moderate to heavy alcohol while the patient eats little. Prolonged hypoglycemia in diabetics who took alcohol is potentially fatal.
Drugs con’t • Salicylates —in large doses(4-6gm/d) & sulfonamides Can cause hypoglycemia in children. Mechanism is unknown but it may involve increased insulin secretion from the pancreas. · Quinine plasma insulin:glucagon ratio
Drugs con’t • Pentamidine: is ß-cell toxin,especially in prolonged duration of Rx, dose,renal insufficiency. *Initially can cause hypo. By causing insulin release;later cause diabetes. Study-Rx for PCP-7%experienced hypoglycemia -14%hypoglycemia followed by diabetes. -18%diabetes without hypoglycemia
Drugs con’t • Non selective ß-blockers:(eg.Propranolol) cause hypoglycemia especially in insulin treated diabetes patients by: - symptoms of developing hypoglycemia - impair epinephrine mediated glucose counterregulation. so better use selective ß-blockers Atenolol/Metoprolol in diabetics on Rx.
ii-Critical Illnesses • Common in hospitalized patients 2nd to drugs. • -Extensive liver disease -esp.rapid & massive destruction.eg-fulminant viral hepatitis,fatty liver due to alcohol,cholangitis&biliary obstruction &10malignant tumors( IGFIIproduction) -Unusual in common forms of cirrhosis & hepatitis&metastatic liver disease.
Illness con’t • Severe Cardiac Failure -Unknown pathogenesis -Possibly due to hepatic congestion, hypoxia&gluconeogenetic precursor limitation. -inhibited gluconeogenesis(studies showed increased blood lactate)
Illness con’t • Renal failure -Unknown pathogenesis -Compromised glucose counter regulation is probable -Studies suggest : glucose turnover gluconeogenesis(fasting glucose level & no increase in lactate) usually cachectic loss of precursor for gluconeogenesis in diabetic nephropathy with exogenous insulin Rx insulin clearance
Illness con’t • Sepsis -relatively common cause -glucose utilization by macrophage rich tissue stimulated by cytokines(TNF,IL6) -hypoglycemia develops when hepatic glucose production decreases due to: - hepatic responsiveness to appropriate glucoregulatory stimuli. -hepatic hypo perfusion(esp.in septic shock)
Hormonal Deficiencies • glucagon& epinephrine + insulinhypoglycemia • “ “ -insulin+hypoglycemia • Cortisol,GH or both(hypopituitarism) no hypo in most adults; -can occasionally cause during high glucose utilization(exercise/pregnancy/alcohol) Children esp.neonates would have hypoglycemia preceded by caloric deprivation • Epinephrine secretion due to cortisol defn.might contribute to mild hypoglycemia. such patients have no glucagon
- Non ß-cell tumors • Small percentage of patients developed severe hypo. • Usually large tumors of mesenchymal & epithelial cell types ~2-4kgs located 1/3in chest&2/3retroperitoneum. • -no single pathogenetic mechanism explains all cases -Major cause appears to be glucose utilization due to tumoral secretion of IGFII(index study 25 out of 28 pts had IGFII) - Other factors --glu.utilization by tumor & sk.ms,metastatic hepatic tissue replacement, gluconeogenesis…
Endogenous Hyperinsulinism • Pancreatic ß-cell d/o-- Insulinoma Rare 0.4/100,000 Early1920-insulin discovered for diabetes Rx -clinical events of insulin identified as new disease hyperinsulinism. 1927-malignant pancreatic islet-cell tumor found in a patient with severe hypoglycemia tumor extracts caused marked hypo.in rats. 1929-1st cure of insulinism by tumor removal. -Mechanism of insulin maintenance –unknown Study-variant of insulin mRNA with translation efficiency -**Hypoglycemia-due to hepatic glucose output rather than glucose utilization.
B-Post prandial(reactive hypoglycemia) • Occurs only after meals & self limited • Occurs in children with certain rare enzymatic defects.(fructose intolerance..) • In some individuals who have undergone gastric surgeryrapid passage of food from stomach to intestinerapid in plasma glucoseinduce extuberent insulinhypoglycemia
Complications • 1-recurrent/persistent psychosocial morbidity(Emotional lability,irritability,depression). • 2-Fear of hypoglycemia-barrier for diabetic control. • 3-Seizure • 4-permanent neurologic deficit (including cognitive impairment) • 5-Coma • 6-Death
Approach to the patient • Steps:- • 1-Recognition & documentation • 2-Diagnosis of hypoglycemia • 3-Urgent treatment • 4-Prevention of recurrent hypoglycemia
Recognition & documentation • Draw blood before glucose administration • Convincing documentation-Whipple’s triad • Obscure cause-check additional assays -glucose -insulin -C-peptide -sulfonyluria levels -Cortisol -Ethanol
Note-Normal blood glucose with free symptoms doesn’t exclude hypoglycemia -Distinctly low plasma glucose without history of corresponding symptoms is probably laboratory error. eg.abnormally high leukocyte,erythrocyte,platelet count;delayed separation of serum from elements
Diagnosis of Hypoglycemia • Hypoglycemia: -non specific manifestations -vary among individuals -change from time to time -Episodic Diagnosis :can not be made solely on sn&sx &on basis of plasma glucose Whipple’s triad is the clinical key for diagnosis.
Diagnosis con’t **72-Hours supervised test -oldest best established & probably most reliable test for evaluation of hypoglycemia. -Its though complicated & expensive-reserved for those w/o reasonable diagnosis. Approach to testing: Purpose-provoke homeostatic response Reasons-confirm hypoglycemia is cause of pts’sx. -check if reversing it relieves sxs(whiple’s triad)
Diagnosis con’t Protocol of Mayo clinic: -Date onset of fast;continue non essential medics. -Allow calorie free & caffeine free beverages -Ensure patient is active during waking hrs. -Collect blood specimens for pl.glu,insulin,C-peptide & pro-insulin Q6hrly till Pl.Glu.<60then Q 1-2hrly Test end points:-Pl. glu.<45mg/dl -pt has sx or sn of hypoglycemia -72 hrs have elapsed
-Steps after fast end:-measure plasma ß-hydroxybutyrate& sulfonylurea concn. -1mg of glucagon given IV& plasma glu.measured 10,20,30minutes later -Patient is fed. By observing the biochemical values along with sn & sx its usually possible to distinguish various causes!!
Diagnosis con’t • Interpretation: - ß-hydroxybutyrate value+vigorous plasma glucose response to IV glucagonHypoglycemia mediated by insulin or insulin like factor • Plasma insulin,C-peptide,& pro insulin valueInsulinoma& sulfonyluria induced hypo. • Plama sulfonyluria is present only when drug administered • plasma insulin values& C-peptide valuesexogenous insulin administration(Rxic overdose/deliberate suicidal or factitious) • Plasma concentration of ß-cell polypeptideshypoglycemia not mediated by insulin or insulin like factor
Urgent Treatment • 1-Oral treatment prefered -20-30gm of glucose(in form of fast acting CHO-hard candy,glucose tab.,sweetened fruit etc..) -this should be followed by long acting CHO to prevent recurrent sxs. 2-Parentral therapy -if neuroglycopenia precludes oral feeding the patient needs IV glucose 25gm using 50%solution followed by constant 5-10%dextrose infusion.
If IV Rx is not practical especially in T1DM SC or IM glucagon o.5-1mg will result in recovery of consciousness in 10-15 min.
Prevention of recurrent hypo • D/C offending drug or dose • Treat underlying critical illness • Replace deficient hormones.eg-cortisol&GH • Surgical,radiotherapeutic or chemo of non- ß-cell tumor. • Resect 10 pancreatic tumors-insulinoma • Auto immune hypoglycemia-often self limiting • glucosidase inhibitor for post prandial hypo due to surgery(delays CHO digestion& glucose absn.) • Frequent feeding & avoidance of fasting.
Recommendations • For all insulin Rxed patients particulrly those about to begin intensive insulin: -Take detailed Hx-major episodes,frequency,how treated -Intensive therapy-increase risk so explain to the patient -Check adequacy of counterregulatory hormone. -Education for patient-recognition & Rx hypo. -Education for family & friends –recognition & treatment of hypo. -At every clinic visit ask about hypoglycemia,check bld.glucose measuring equipment as well if possible
REFERENCES • WILLIAMS ENDOCRINOLOGY • UPTODATE 14.1 • HARRISON’S 16TH EDITION • INTERNET SOURCES