P. Bello Gutiérreza and L. Mohamed Dafab
a Pediatrics Department.
Rey Juan Carlos University Hospital.
Minutes, Madrid.
España b Pediatra.
Madrid Health Service.
Spain
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Two monozygotic twins of three years old are evaluated in the health center due to dysthermia without thermometering of 24 hours of evolution, abdominal pain, vomiting, dark yellow urine, color.
Physical examination revealed marked weakness, jaundice, and hepatomegaly of 1 cm. Sounds to hospital emergency departments to rule out acute hepatitis.
In the hospital, the family was re-history, without a history of interest, or ingestion of food on the previous days, or use of new substances or feverish conditions.
Physical examination revealed weakness and jaundice, as well as mild hepatomegaly.
Arterial hypertension was 76/41 mmHg and heart rate was 79/53 mmHg, with 143-150 beats per minute (lpm).
Location.
Affiliates at that time.
Hemoglobinuria is observed in the urine system.
Complete blood count and blood chemistry were obtained, which showed anemia with elevated bilirubin, LDH and AST (Tables 1 and 2).
Coombs was negative.
Peripheral blood smears without specific findings except lysis.
Spontaneous diuresis and tachycardia up to 180 bpm.
Anemization progressed in the following analytical controls; therefore, it was decided to transfuse a mental concentrate.
Intravenous therapy with cefoxime was initiated to check for the affectation of the general state with distermia (sustained after 48 hours, after sterilization of cultures and evolution), as well as fluid therapy with bicarbonate.
They are admitted to the plant.
With the measures initiated, the hemoglobin figures go back to stabilization of the lytic crisis within 48 hours after admission.
A complete study of hemolytic anemia was extracted.
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The mother later admits a similar picture to the current five years before, after ingestion of a condom.
Rehistory of the family, they admit intake of the same three days before the onset of symptoms.
After stabilizing the lytic crisis, treatment with folic acid was started and follow-up visits were made to complete the etiological study.
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Pathogeny.
Genetic aspects
The deficit of this enzyme, in the presence of certain oxidants, increases the vulnerability of red blood cells to destruction, since they are not able to reverse the oxidative action.
Although the mechanism of action of oxidative stress hemolysis is unknown, the effect of hemoglobin binding and decreases in mean life expectancy is unknown.
G6PDH is present in all cells, varying its concentration according to tissues.
In healthy red blood cells, this enzyme works in 1-2% of your ability.
This provides an idea of the reducing potential that is lost when there is a DG6PDH.
The DG6PDH has a pattern of inheritance linked to the X chromosome. The gene linked to this alteration is in the long arm of this chromosome (Xq28).
Males are hemizygous for this alteration and may be normal in enzymatic activity or deficient.
In the case of women, due to the Lyon effect, they can be heterozygous (behavior as mosaics) and similar clinical cases have been described in behavior to those of the male hemizygous.
Homozygous women are not rare in populations with high incidence of G6PDH3.
DG6PD is one of the enzyme disorders with the greatest genetic heterogeneity.
More than 140 mutations have been described, with more than 400 biochemical variants of the enzyme.
According to enzyme activity and clinical manifestations the World Health Organization (WHO) has five classes listed below:
• Class I: its prevalence is uncommon and usually the level of deficiency is severe that manifest as non-spherocytic hemolytic anemia or chronic anemia in the presence of normal erythrocyte function.
• Class II: more prevalent in the Mediterranean and Asia.
Here the level of deficiency is also severe and enzyme activity is less than 10% of normal.
• Class III: present in 10% of black men in the United States.
It includes variants with moderate level of deficiency and enzyme activity of 10 to 60% of normal.
• Class IV: is a rare variant where enzyme deficiency is usually mild or none, and the level of enzyme activity is 60 to 150% of normal.
• Class V: there is no enzyme deficiency, it is also rare in terms of prevalence and enzyme activity is greater than 150% of normal.
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Clinical
Given the great genetic heterogeneity, the clinical presentation is also quite variable.
Most patients with this deficit are usually asymptomatic.
Symptomatic clinical forms are:
• Acute haemolytic anaemia (from drugs or infections).
There is a long list of drugs and infectious agents that have been associated with acute hemolysis.
In the case of drugs, haemolysis is not clinically detectable until 24-72 hours after administration.
The characteristic feature is dark urine with hemoglobinuria.
Anaemia is exacerbated up to 7-8 days after dosing, when haemoglobin begins to recover (see references to related drugs below).
In the case of infections, it has been described for hepatitis A and B viruses, cytomegalovirus, pneumonia, typhoid fever and agents such as E. coli, Salmonella and Streptococcus group B2.
The mechanism of hemolysis due to this cause is unknown, although an explanation could be the reactions resulting from phagocytic activity within the infection.
• Favism.
Although the clinical evidence has not been fully demonstrated, most authors declare that digestive tract toxicity is determined by the toxicity that produce elements of the beans, such as vicinum and convicine, when they are hydrolyzed.
• Non-spherocytic congenital haemolytic anaemia
It is a form of chronic hemolysis, grouped in WHO type I.
These are sporadic cases.
It is a typically extravascular hemolysis, which should be suspected by a compatible history (neonatal stricture, chronic degenerative that is exacerbated by oxidative stimuli analytical, anemia, as well as corpus collection of data).
• Neonatal hyperbilirubinaemia.
It is more typical and severe in preterm infants than in terms.
It usually occurs between days 1 and 4 of life, such as physiological, with the same complications and treatment.
The mechanism of haemolysis is not fully understood.
This defect should be considered in cases of jaundice in the first 24 hours, with high values, or in cases of family history prior to birth.
Of the two most frequent variants, G6PD A- (WHO Regulation III) affects mainly Africans and their descendants.
Symptoms are usually mild because only 20-30% of deficient erythrocytes suffer hemolysis.
It usually occurs infrequently as favismism.
The Mediterranean (G6PD) form, which is considered WHO Class II, mainly affects populations of Greek origin Media, patients, and Spanish, Arabic, as in the case of Jewish people.
This variant also produces more severe neonatal hyperbilirubinemia and favism much more frequently.
Patients with G6PDPH are more vulnerable to sepsis and related complications.
Favism
It is known since the twentieth century, and although initially identified as belonging to Mediterranean countries, it has spread as this product has been consumed in other countries.
It is thought to be the most common form associated with the Mediterranean variant of G6PDH, but there must be multiple individual factors, since not all patients develop symptoms before intake or in relation to the amount taken.
It is associated with the ingestion of raw, fresh or dried figs by inhalation during the passage in the field also by contact with the breast milk or animal that has ingested7.
As characteristic features, symptoms appear 5-24 hours after ingestion with the following differential elements: hemoglobinuria more severe than in other clinical forms, bilirubin with lower values than in other forms of acute failure that precipitates from acute ischemia or acute ischemia.
Sometimes there is lymphadenopathy.
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Patient management
Although the most effective strategy in the G6PDH is the prevention of hemolysis, through the avoidance of the trigger, this precise approach to knowledge of the defect by the patient and his family.
This implies that only when a previous crisis has occurred is aware of this situation.
In cases of debut, or transgress with triggers, symptoms depend on the intensity of anemia and the speed of its establishment.
Management, therefore, will be based on the approach of hemolytic anemias.
The initial history should include basic aspects:
• Personal history:
- Age, gender and ethnicity: DG6PDH is associated with males because it is X-linked in black populations and malaria-endemic areas.
- chronicity of symptoms to assess the condition.
- Previous similar episodes in known cases.
- Infectious symptoms accompanying or in previous days as possible triggers.
- Drugs you take or have recently taken or have recently taken
- Appearance of urine.
• Family history: family history of anemia, biliary lithiasis, hysterectomy (hereditary hemolytic anemias).
Cases of similar episodes in the family
A physical examination should be performed aimed at identifying the impact of the hemolytic crisis (which is the most common form) and its effects on the skin and skin (paleness, hypotension, hepatomegaly); cardiac auscultation (cardiac discoloedema).
Chronic forms are less symptomatic.
Investigations
Acute hemolytic crisis should be referred to a hospital for studies, evaluation and treatment:
• Blood count + lymphocytes + cross-tests + direct Coombs.
• Peripheral blood smear.
When normal, it leads to a specific membrane defect.
• Blood chemistry.
The following shall be observed:
- Elevation of LDH, total bilirubin and AST.
- Renal profile: Assessment of renal impairment due to acute damage to hemoglobin metabolites.
- haptoglobin: low (<30 mg/dl).
• Urine: Hemoglobinuria, urobilinogen.
• If there is concomitant infectious symptoms:
- Infectious serology if compatible data exist: Epstein, cytomegalovirus, herpes simplex virus, varicella-zoster virus, human immunodeficiency virus, hepatitis, Mycoplasma.
- Culture: throat swabs for bacteria/virus; coprocultive; blood and urine cultures; thick smear if obtained from an endemic area for malaria.
Studies addressing hemolytic crisis for a specific final diagnosis will depend on the orientation of the clinical picture and suspicion.
In the case of DG6PDH, a specific enzymatic study was performed to determine the enzymatic activity.
Complete characterization of the enzyme is only rarely performed (definition of a new variant, population studies, rare cases and need for prenatal diagnosis)2.
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Treatment of acute haemolytic crisis in G6PDH
• General measures:
- Hospital admission in all cases for close monitoring.
The need for intensive care should be considered if hemolysis is not controlled, frequent transfusions are required, or if there is sustained hemodynamic instability after transfusion of concentrated intensive care units.
- Withdrawal of the triggering external agent in the case of drugs and somatic foods.
- Specific antibiotic treatment if there are infectious symptoms consistent with bacterial infection.
Urinary retention and alkalinization if data on intravascular hemolysis are available:
- 5% dextrose serum: baseline requirements + 50%.
Do not add potassium.
- sodium bicarbonate 1 M:
• Folic acid: one 5 mg/day tablet during the course of your haemolytic crisis.
• Transfusion of concentrate (+)
- If data on active intravascular haemolysis (haemoglobinuria) persist:
- If there are no data on active intravascular haemolysis: observation with frequent clinical and laboratory
• Clinical-analytical controls in the acute phase: control of anemia and spinal cord response (with biochemical tests with LDH every 6-8-12-24 hours with clinical check-ups, urine tests and continuous hemoglobinuria tests).
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Life with DG6PDH.
Considerations of outpatient management
Once the patient has been diagnosed with G6PDH and has overcome the stage of hemolytic crisis, further management is proposed.
In the case of favismism, since these patients do not have transfusion dependence, it is not necessary to establish a specific follow-up.
In cases of G6PD with chronic course, periodic monitoring should be followed, due to the risk of hemolytic crisis.
According to the Spanish Society of Hematology and Hemotherapy (SEHH), patients should know that the most effective strategy in the management of this entity is the prevention of hemolysis.
They should be informed about how to avoid factors associated with oxidative stress.
A number of drugs should be avoided9 and paracetamol is recommended if analgesia is needed.
In the case of favismism, food may be subject to a normal diet, except for the intake of certain products containing favis or potash which are prohibited.
It is also recommended to avoid contact with the herd.
These patients should seek medical attention for infectious diseases, even if they are banal, in order to assess the onset of a hemolytic crisis.
If you have chronic diseases such as diabetes, you should be closely monitored.
On the other hand, the American Family proposes that in addition to the fact that patients with G6PD should avoid exposure to drugs that can trigger hemolytic crisis and the ingestion of a known geographical origin of G6PD, according to neonatal screening.
The DG6PDH does not appear to affect life expectancy, quality of life or daily activity of those affected.
Fortunately, many patients with this disorder are asymptomatic throughout their lives, completely outside their condition2.
Patients and their families can find resources in the associations of patients with G6PDH (not in Spanish), such as:
• Association Française des personnes atteintes du deficit géntique en G6PD or Favisme (VIGIAP): www.Fravisme.com
• Associazione Italiana Favismo - Deficit di G6PD (Italia): www.g6pd.org/it.
• Volsen.nl.
© 2012 Sociedad Colombiana de Anestesiología y Reanimación.
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Corresponding address: Pablo Bello Gutiérrez pablo.bello@hospitalreyjuancarlos.es
