Venditti Elisa & Sofia Elizabeth Cena
RELATIONSHIP BETWEEN CENTRAL SEROUS CHOROIDITIS AND HIGH LEVELS OF HOMOCYSTEINE
This essay wants to analyse the implications of hyperhomocysteinemia (elaborating on knowledges which are already express about this subject) , particularly focusing on a ocular disease which has so far an uncertain cause and pathogenesis from the literature. We’ll try to explain how high levels of homocysteine ,in our opinion, can contribute to development of this disease.
1) Definition of disease:
Central serous chorioretinopathy (CSC) is comprised in chorio-retinal disorders, which are characterized by neurosensory retinal serous detachment from pigmented epithelium , that is the outer layer of retina. It’s still a disease with unknown etiology.
Data related to epidemiology of CSC have never been subjected to systematic review, but literature reports that CSC affects mostly the male’s gender with a ratio 4:1. The CSC is usually present by early adulthood and does n’t seem to have upper limits of age.
The diagnosis of CSC is based on the presence of neurosensory retinal detachment, due to accumulation of serous fluid between retinal outer segment (the layer of photoreceptors) and the retinal pigmented epithelium. Furthermore, the latter shows focal or multifocal lesions.
CSC is usually associated with blurred vision, central scotomas, metamorphopsia, hypermetropization and reduced contrast sensitivity. Since the damage usually affects the central part, patients may have no symptoms.
In order to diagnose CSC, the instrumental tests rest on:
fluorescein angiography: This is a key element for differential diagnosis and for planning treatment appropriately.
OCT: is able to highlight the small serous detachments that would be difficult to detect with the slit lamp and it’s also excellent for evaluating the resolution of detachment after treatment.
Example of normal OCT (https://docs.google.com/open?id=0B_DCg9_2B1vLR3MzSXo5TEQzTW8)
Example of OCT with central serous choroiditis
The CSC can be divided into two subtypes:
Acute form: in which both retinal detachment and symptoms last less than six months, and only occasionally the retinal detachment from pigmented epithelium may break.
Chronic form: it‘s often bilateral and shows retinal abnormalities such as migration of the pigment, spider veins and absence of capillary perfusion in lifted retina.
No medical treatment so far has proved to be useful for the CSC. Systemic corticosteroids (cortisone) have been shown to exacerbate the CSC. Other suggested therapies, as beta-blockers and acetazolamide (diamox), have been ineffective.(Oftalmologia clinica; Kansky.)
The CSC is a disease that usually has a good visual prognosis, especially if treated and managed. Available treatments are laser photocoagulation and photodynamic therapy, although the treatment of CSC is based on clinical observation. In any case, these are symptomatic therapies, not aim for resolution of CSC’s cause . The high frequency of spontaneous resolution of this disease inclines towards a conservative approach, adjuvanted by psychological counseling. (La corioretinopatia sierosa centrale: dalla definizione alla terapia; Dr. Mauro Cassinerio)
2) Medical history and ocular evaluation
1) PATIENT NUMBER 1:
Name: A. R.
Gender: Female
Age: 55 years
Date of birth: 05/01/1957
Work Activities: Housewife
Weight: 60kg
Height: 152 cm
BMI: 26
FAMILY HISTORY
Father .died at the age of 82 for I.M.A.
Mother: alive, 84 years old, suffering from diabetes mellitus type 2
Relatives: unremarkable
PHYSIOLOGICAL HISTORY
Normal somato-psychic development
Menarche at 13 years old, regular menstrual cycles
A full-term pregnancy (at age of 32)
Smoker
Habitual consumption of carbonated drinks, not alcohol
Intake of 3-4 cups of coffee /die
Diet: daily intake of fruits and vegetables; favored the consumption of pasta and white meat; high intake of cakes and simple sugars
Physical activity absent
MEDICAL HISTORY
From birth:
presence of Lisch nodules, however, they are not associated with neurofibromatosis
At 16 years old:
Event:
Acute abdomen
Diagnosis:
Acute appendicitis (required hospitalization)
Therapy:
Surgical: appendectomy
Exams:
***
At 32 years old:
Event:
First full-term pregnancy with caesarean section
Diagnosis
***
Therapy
***
Exams
***
PATHOLOGICAL SPECIALISTIC HISTORY:
At 50 years old:
Event:
Onset of intraocular pain (left eye)
Exams:
Ophthalmologic evaluation. Results at fundus examination: outcomes of upper temporal thrombosis
Diagnosis:
Left-eye thrombosis of CRV’s (central retinal vein) superior temporal branch
Therapy:
Seleparina ( 2 vials /die)
Cardioaspirina 100mg (1die)
LAST OPHTHALMOLOGICAL EXAMINATION:
Event: check-up
Exams:
Haematological:(https://docs.google.com/open?id=0B_DCg9_2B1vLMmlmODdnYXE1M2c; https://docs.google.com/open?id=0B_DCg9_2B1vLS1FsbnNOSkMweXM )
Diagnosis:
Central serous choroiditis (left eye)
Clinical case at OCT: (https://docs.google.com/open?id=0B_DCg9_2B1vLRURGNHY5eDlraEU)
Therapy:
Established topical and systemic anti-inflammatory therapy
Use of ocular hypotensive
2) PATIENT NUMBER 2:
Name: U. A.
Gender: Male
Age: 50 years
Date of birth: 06/12/1961
Work Activities: handworker
Weight: 80kg
Height: 175 cm
BMI: 26.1
FAMILY HISTORY
Father: alive, 86 years old, suffering from hypertension
Mother: alive, 80 years old, suffering from hypercholesterolemia
Relatives: two brothers, one of whom died at age of 56 because of a stroke
PHYSIOLOGICAL HISTORY
Normal somato-psychic development
Suitable for military
Smoker
Consumption of 1-2 glasses of wine with meals
Intake of 4 cups of coffee /die
Diet: daily intake of fruits and vegetables favored the consumption of red meat
Physical activity absent
MEDICAL HISTORY
At 40 years old:
Event:
Sharp pain at right hypochondrium
Diagnosis
Gallstones
Therapy
Surgery: cholecystectomy
Exams: ***
PATHOLOGICAL SPECIALISTIC HISTORY
At 50 years old:
Event:
Occurrence of visual field’s problems in the periferical part of left eye
Exams
Ocular examination
Diagnosis
Optic nerve ischemia secondary to central retinal arteritis
Therapy
Celestone cronodose
LAST OPHTHALMOLOGICAL EXAMINATION:
Event: check-up
Exams:
Haematological:(https://docs.google.com/open?id=0B_DCg9_2B1vLS2NJeUlCWTZiNlE)
Diagnosis:
Central serous choroiditis (left eye)
Clinical case at OCT:(https://docs.google.com/open?id=0B_DCg9_2B1vLZndJVUNqb0N6VDA)
Therapy:
Established topical and systemic anti-inflammatory therapy
Use of ocular hypotensive
3) PATIENT NUMBER 3:
Name and Surname: P.
Gender: Female
Age: 59 years
Date of birth: 06/12/1952
Work Activities: Housewife
Weight: 55kg
Height: 160 cm
BMI: 21.5
FAMILY HISTORY
Father: alive, 79 years old, suffering from hypercholesterolemia
Mother: living 75 years old, suffering from diabetes type 2
Relatives: unremarkable
PHYSIOLOGICAL HISTORY
Normal somato-psychic development
Menarche at 12 years old, regular menstrual cycles
Miscarriage at the age of 22 years old
A full-term pregnancy (at age of 25)
No smoker
No alcohol intake
Intake of 3-4 cups of coffee /die
Diet: daily intake of fruits and vegetables
Physical activity absent
MEDICAL HISTORY
At 22 years old:
Miscarriage
At 23 years old:
Event:
Acute abdomen
Diagnosis:
Acute appendicitis (required hospitalization)
Therapy:
Surgical: appendectomy
Exams:
***
At 25 years old:
Event:
First full-term pregnancy with caesarean section.
Diagnosis:
***
Therapy:
***
Exams:
***
PATHOLOGICAL SPECIALISTIC HISTORY
A 59 years old:
Event:
Appearance of a central dark spot (right eye)
Exams
Ocular examination
Diagnosis:
Central serous choroiditis
Therapy:
AC inhibitors
Ocular hypotensive
NEVANAC eye drops + Ananase 100mg tablets
LAST OPHTHALMOLOGICAL EXAMINATION:
Event: check-up
Exams:
Haematological: (https://docs.google.com/open?id=0B_DCg9_2B1vLRU1DTzFCYWxQcWM; https://docs.google.com/open?id=0B_DCg9_2B1vLTG1YdHlZeEgtM0U)
Diagnosis:
Central serous choroiditis
Clinical case at OCT: (https://docs.google.com/open?id=0B_DCg9_2B1vLa2lMbENoQ1l1WUE)
Therapy:
Established topical and systemic anti-inflammatory therapy
Use of ocular hypotensive
3) Molecular basics of the events described, considering all symptoms and using links to pertinent informations
I. Reflections:
Homocysteine is a sulfur-containing amino acid , with molecular weight of 135.186, which is formed as a result of loss of a methyl group from methionine, an essential amino acid, that must be introduced into the body with diet.
For homocysteine’s metabolism , see http://flipper.diff.org/app/items/info/566 .
Hyperhomocysteinemia is a condition of elevated levels of homocysteine in the blood. In Italy, most of the laboratories define hyperhomocysteinemia when homocysteine concentration is over 13 mmol / l for men , 1.10 mmol / l for women and 11.3 mmol / l for children up to age of 14 .
In order to measure plasmatic homocysteine is usually used a technique of high performance liquid chromatography, known by the acronym HPLC.
It’s a chromatographic technique that allows to separate two or more compounds present in a solvent(like blood) exploiting the balance of affinity between a "stationary phase" into the chromatographic column and a "mobile phase" (that is the solvent) flowing through it. A substance closer to the stationary phase takes longer time to pass through the chromatographic column (this is called “retention time”), compared to a substance with low affinity for the stationary phase and high affinity for the mobile phase.
The venous blood sample is injected at the top of the chromatographic column where it’s "pushed" through the stationary phase by the mobile phase (which has function of carrier) applying pressures of hundreds of atmospheres. In order to obtain an effective separation the filling-particles size is required to be very small (they usually have diameters from 3 to 10μm), for this reason it’s necessary to apply a high pressure if you want to maintain a speed of solvent’s flow, and an analysis time appropriate.
At the end of the column a detector and a computer allow a continuous analysis of the output of the column, and they are able to quantify and / or identify the substances injected.
Advantages of this technique are: the small size of column, which avoids problems of deviations longitudinal (longitudinal movements of the mobile phase) and of alternative way; speed of elution (passage of the mobile phase through column) constant and adjustable; execution speed reduced; small quantities of compound necessary for analysis (about 5-10 micrograms of solubilized sample in a suitable solvent) for a higher accuracy and precision.
The main disadvantage of HPLC device is that it’s more expensive compared to a traditional column chromatography , although it isn’t possible to compare these two methods because they have different fields of application (http://it.wikipedia.org/wiki/Cromatografia_liquida_ad_alta_prestazione).
Causes of hyperhomocysteinemia can be various and related to several factors like (http://www.nature.com/eye/journal/v22/n8/full/6703061a.html) :
1-Genetic factors:
-Polymorphisms of MTHFR reductase
-Polymorphisms of cystathionine b synthase
-Polymorphisms of methionine synthase
2-Nutritional factors
-Folate deficiency
-Vitamin B6 deficiency
-Vitamin B12 deficiency
-Excessive intake of methionine
-Alcoholism
3-Chronic disease
-Renal impairment
-Diabetes mellitus
-Hypothyroidism
-Psoriasis
-Cancer
-Organ transplantation
4-Other epidemiological factors
-Male gender
-Increasing age
-Smoking
-Post-menopause
Consequences of elevated levels of homocysteine and damage mechanisms are described in detail at link above to which we refer to systematic treatment.
We only want to recall schematically that (http://www.sciencedirect.com/science/article/pii/S0025712505702157 ) :
1. Hyperhomocysteinemia as pro oxidant activity as homocysteine is subjected to a reaction of autoxidation with production of hydrogen peroxide and homocystine.
2. Hyperhomocysteinemia acts by activating platelets, increasing synthesis of thromboxanes and altering coagulation and fibrinolysis by converting anticoagulant arrangement of blood vessels into pro coagulant, thus facilitating thromboembolic events.
3. Hyperhomocysteinemia induces expression of MCP-1 (monocyte chemoattractant protein 1) and IL-8 in endothelium with pro inflammatory effect.
4. Hyperhomocysteinemia induces smooth muscle cells proliferation that rapidly invade vascular intima in atherogenic areas
5. Hyperhomocysteinemia causes endothelial dysfunction and oxidative stress for its ability to give rise to reactive oxygen species and to inhibit the production of antioxidant molecules, especially NO. Furthermore, it inhibits the action of specific antioxidant enzymes such as glutathione peroxidase-1 and superoxide dismutase.
These characteristics are the base of hyperhomocysteinemia involvement as an independent risk factor in cardiovascular (e.g. atherosclerosis, heart attack), cerebrovascular (e.g. stroke), peripheral vascular events (e.g. arterial and deep venous thrombosis)( http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346700/ ). Moreover, there are studies that demonstrate an association between elevated blood levels of homocysteine and Alzheimer's disease, an increased risk of developing dementia and cognitive decay8, osteoporosis and fractures5, in pregnant women is associated with preeclampsia, placental detachment, miscarriage, low birth weight infants and with defects in the neural tube (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806892/, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3307082/ ), psoriasis (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368579/). Finally, there are also certain medications that may probably promote hyperhomocysteinemia such as cholestyramine, colestipol and bezafibrate (used for treatment of hypercholesterolemia), metformin, methotrexate, anticonvulsants, niacin, theophylline, L-DOPA, penicillamine, tamoxifen.
What most regards to our specific discussion, however, is that elevated plasmatic homocysteine was observed in patients suffering from many eye diseases including cataract, diabetic retinopathy, age-related macular degeneration, cystic retinal degeneration, central retinal artery and vein occlusion and optic nerve ischemia (http://journals.lww.com/retinajournal/Abstract/2006/01000/Moderate_Hyperhomocysteinemia_and_Early_Onset.11.aspx; http://www.sciencedirect.com/science/article/pii/S0161642000001810 )
In order to normalize this risk factor, which, as already said, can lead to different and serious diseases, many studies have been conducted but their final data are awaited.
However, there are epidemiological studies that have demonstrated the effectiveness of introducing dietary supplements of folic acid and vitamin B12, in order to prevent damage caused by hyperhomocysteinemia. In fact, it’s proven that a 36 months treatment with these substances reduces plasmatic homocysteine levels by 20% in treated population.
But this is only a first step towards a definitive therapy (http://www.cabdirect.org/abstracts/20103001220.html;jsessionid=022B29F9297D73C1B0E73661ED4256B6 ).
4) Possible explanations of clinical scene:
It’s known by the pathology that during an ischemic or thrombotic event (such as that which may come from mechanisms of vascular and coagulative damage due to hyperhomocysteinemia) there will be a decreased bloodstream, thus, in our case, there will be a decrease of' nutrients intake in retina.
This lack will have serious impact on retina, as death of retinal portion not supplied with blood. The main effect of a deficiency or complete lack of blood in each tissue is alteration of cellular respiration, and in particular the reduction of intracellular ATP, in favor of an accumulation of hypoxanthine; the latter, in fact, is the final product of metabolic degradation of adenosine. In fact, ischemia impaires intake of substrates for glycolysis, so this pathway is quickly compromised. Moreover, there will be also an accumulation of lactic acid and, consequently, an acidosis because ATP is not only synthesized through cellular respiration but also through the pathway of anaerobic glycolysis. Accumulation of these products leads to an alteration of ionic distribution ( in particular of intracellular calcium)and of membrane potential, disorganization cytoskeletal, cell swelling and finally necrosis .
If retina’s dead zone ,which isn’t intact and functioning anymore, doesn’t include the central part of visual field, patient can also be asymptomatic and he will not go to a ophthalmologist in order to have a examination, otherwise patient will manifest variables alterations of visual function that will alarm .
In this case, dead retina will consist of layers not perfectly adherent to each other, therefore, it will be more susceptible to traumatic, kinetic and motor insults of the eyeball. Consequently there will be an increased probability of retinal superficial portion detachment that causes the medical case of central serous choroiditis.
Furthermore, because of the detachment, it will be no longer possible to highlight the previous ischemia or thrombosis, because the lifted part of retina will impede ophthalmologist to see the previous event, so that ho will not be able to define a cause of choroiditis.
So we can deduce:
considering data from patients’ family histories which show a relative frequency of cardiovascular and cerebrovascular events in first-degree relatives (especially for patients 1 and 2)
taking account of patient’s symptoms;
taking vision of hematological exams in which, for all three patients, are present increased, more or less high, blood levels of homocysteine (in patients 1 and 2 is also associated with a condition of hypercholesterolemia that may in itself be a risk factor for thrombosis and ischemia but this same factor isn’t found in patient 3, who in spite of this has a significant hyperhomocysteinemia);
observed related medical cases at OCT that highlights a lifting of retinal layers, which is the classic report of central serous choroiditis
that hyperhomocysteinemia may underlie a possible pathogenetic common process that leads to the central serous choroiditis in the three cases presented.
Link to PDF file: https://docs.google.com/open?id=0B_DCg9_2B1vLTHctQVhiRXJ4cFE
