1) Definizione del paziente e della storia
Anno di nascita : 1985
Peso: 57 Statura: 1,72 BMI: 19,7
Anamnesi patologica prossima
Ammissione in DEA alle 3 del mattino in condizioni di confusione.
Anamnesi riportata dal marito. La sera precedente, sessione di esercizi in palestra per un'ora. Iniezione di insulina al dosaggio standard, seguita da pasto leggero e consumo di qualche birra e un bicchiere di superalcolico dopo cena.
Glicemia al reflettometro: 21 mg/dl.
Prima iniezione di glucagone (1 mg) da parte del marito senza effetto. Dose ripetuta successivamente con recupero della coscienza dopo qualche minuto accompagnato da due emissioni di vomito.
Anamnesi patologica remota
13 anni: anemia sideropenica da ipermenorrea
26 anni: diabete mellito tipo 1
26 anni: ipertensione arteriosa
Insulina Novorapid prima dei pasti, per un totale di circa 35 UI
Lantus 25 UI la sera
Ramipril 2,5 mg/die
Yasmin 21 1cp/die
Presa in carico in DEA
PAO: 110/70 mmHg
FC: 68 bpm
Sat O2: 93% AA
T°: 37 °C
Glicemia al reflettometro: 30 mg/dl
La paziente è confusa, disorientata e rifiuta qualunque intervento.
EO neurologico, cardiopolmonare e addominale nella norma.
Agli esami ematochimici e ionogramma nessuna alterazione di specie. Confermata l'ipoglicemia a 30 mg/dl.
La paziente risponde alla somministrazione di 50 ml di soluzione glucosata al 35% in bolo.
Segue infusione di soluzione glucosata al 10% a 100 ml/h.
Quindici minuti dopo, la glicemia è 122 mg/dl e la paziente si rialimenta per bocca.
2) Le basi molecolari degli eventi descritti, tenendo conto di tutti i sintomi ed utilizzando i link alle informazioni pertinenti
So, what happened?
In the case report, the patient presents a severe alcohol induced hypoglycemia : alcohol ingestion enhances the hypoglycemic effect of exogenous insulin in diabetic patients, up to life-threatening consequences as unconsciousness and death.
Patients with DM insulin dependent need to inject insulin before every meal (three times per day) in order to avoid glucose increase. At the same time, insulin therapy must be adjusted in order to avoid extremely low blood glucose (especially below 55mg/dl), which is especially dangerous for CNS homeostasis. Diabetics need to recognize early hypoglycemia signs due to the adrenergic reaction, like sweating, palpitations, sensation of hunger, anxiety and "inner trembling”. Nursing care for diabetic patients with alcohol-induced hypoglycemia,1998
Alcohol can modify glucose homeostasis through two different mechanisms :
1) a direct pathway, which concerns the alteration of hepatic gluconeogenesis and glycogenolysis ;
2) an indirect one, through its effects on cognitive function .
Furthermore, in this case the combination of heavy alcohol consumption with vigorous exercise precipitated the conditions of the patient: exercise increases hypoglycemic risk, not only during or immediately following exercise, but several hours later as well, due to depletion of liver and muscle glycogen and the subsequent demand of these tissues for glucose to restore these pools.
An additional danger derives from the fact that glucagon may be less effective in reversing hypoglycemia in the absence of adequate glycogen stores. In the case presented, inadequate response to glucagon was probably caused by incomplete replenishment of glycogen stores after exercise due to alcohol consumption.
1) Direct action
Human body processes alcohol “preferentially” over the production of glucose, so alcohol consumption can induce hypoglycemia in people low in glucose stores. Since the central nervous system gets energy mainly by glucose metabolism, a lack of glucose can bring to permanent brain damage and death.
The consumption of glucose by the entire human body is around 160g per day, with the brain using about the 60-75% of it. The amount of glucose produced every day from glycogen is 190g and the glucose placed in bodily fluids is about 20g per day. Everyday our body uses almost as much glucose as it produces it, so all the glucose available can be used up if a fasting period of a day or a period of acute physical exercise occur.
The response of the body to these occurences is to increase gluconeogenesis mainly from the following: lactate produced from glycolysis in skeletal muscle and red blood cells, glycogenolysis in the liver, alanine via the pyruvate-alanine cycle (a.k.a. The Cori-cycle), and other amino acids received via the diet or from the breakdown of muscle during starvation.
Because the rate of glycogenolysis in the liver is 300 times faster than glycogen biosynthesis, once the body has utilized its day's supply of glucose, hepatic glucose output becomes dependent on gluconeogenesis. And this is where the crux of the problem lies: alcohol blocks gluconeogenesis.
This means that those who fast or exercise before drinking are most likely to experience hypoglycemia.
Hypoglycemia and Alcohol Intoxication
HOW ALCOHOL INHIBITS GLUCONEOGENESIS
The main mechanism alcohol uses to impair glucose homeostasis is the inhibition of gluconeogenesis. In addition, alcohol interferes with the production and storage of glycogen, another essential source of glucose, and inhibits lipolysis, which normally provides substrates for gluconeogenesis.
Alcohol metabolism is mainly set in the liver by alcohol dehydrogenase, according to the following reaction:
EtOH + NAD+ -----> Acetaldehyde + NADH + H+
The most important thing to notice in this reaction is the production of NADH. The [NAD+]/[NADH] ratio in the cytosol of cells is a major regulatory mechanism. As the [NADH] increases, the ratio decreases, so that AcetylCoA production is inhibited as well as the tricyclic acid cycle. In fact, the [NAD+]/[NADH] ratio decreases and inhibits pyruvate dehydrogenase (the concentration of NADH on the following reaction increases):
Pyruvate + NAD+ + CoA-SH ----> Acetyl-CoA + NADH + CO2
The excess NADH slows the TCA cycle, and the build-up of acetyl-CoA stimulates gluconeogenesis.
The role of NADH
What’s more, NADH and pyruvate increase in the cytosol determines the reversal of the direction of the following reaction:
Lactate + NAD+ ------> Pyruvate + NADH + H+
Due to this, lactic acid is produced and lactic acidosis can occur, although it is usually mild.
Alanine is transported from the muscle tissue to the liver mitochondria where alanine aminotransferase converts it to pyruvate. In order, oxaloacetate and malate are derived from pyruvate in the mitochondria. The malate is carried out of the mitochondria in the cytosol where, normally, it is reconverted to oxaloacetate from which it continues in gluconeogenesis:
Malate NAD ----> Oxaloacetate + NADH
The excess of NADH in the cytosol inhibits this reaction too. This means that the primary paths for gluconeogenesis ( pyruvate and alanine) are inhibited and that pyruvate is being produced in excess. The body is left with glycolysis for energy production and no glucose for maintenance of critical tissues.
Hypoglycemia and Alcohol Intoxication
Why not in the normal subjects?
However, no impairment in glucose blood levels is observed in healthy individuals, in which the reduction in hepatic glucose production is accompanied by a similar reduction in peripheral glucose utilization, producing a neutral net effect on blood glucose concentration. The compensation is obtained through a reduction of peripheral (and especially muscular, and not in adipose tissue) insulin sensitivity, preventing hypoglycemia in situations where hepatic glucose output is reduced.
2) Cognitive effects of alcohol ingestion
Alcohol is known to have a depressant effect on the subcortical structures of the central nervous system, which causes motor and intellectual activity to become confused.
How can this contribute to the genesis of hypoglycemia?
Through the alteration of cognitive functions, alcohol may affect the subjective perception of the early symptoms of hypoglycaemia and impair the person’s ability to assess the balance of physical activity and food intake and manage insulin doses. This leads to a failure on blood glucose control.
Alcohol Ingestion and Glycaemic Control in Patients with Insulindependent Diabetes Mellitus, 1997
3) Eventuali proposte di terapia, volta al ripristino delle condizioni ottimali
Diabetics patients need to be informed about the necessity of adapting insulin doses after physical exercise and before alcohol ingestion.
So prevention is the best therapy for this kind of hypoglycemical events.
Alessandro Galluzzo e Francesca Romano