Amoebic liver abscess

Amoebic liver abscess
Classification and external resources
Gross pathology of liver containing amoebic abscess
ICD-10	A06.4
ICD-9	006.3
MedlinePlus	000211
eMedicine	article/183920
MeSH	D008101

A amoebic liver abscess is a type of liver abscess caused by amebiasis.

Clinicals

Symptoms

• Pain right hypochondrium referred to right shoulder
• Pyrexia (100.4 F)
• Profuse sweating and rigors
• Loss of weight
• Earthy complexion

Signs

• Pallor
• Tenderness and rigidity in right hypochondrium
• Palpable liver
• Intercostal tenderness
• Basal lung signs

Diagnosis

• Blood CP
• Haemoglobin Estimation
• Stools Examination (Trophozoites and Cysts)
• Radiography
• Aspiration Exploratory
• Medical ultrasonography and CT Scanning
• Sigmoidoscopy
• Liver function tests
• Serological Tests

Management

• Metronidazole^[1] 800 mg TDS for 5–10 days
• Aspiration
• Repeated Imaging Of Liver

Treatment must also include a lumenal amoebicide to prevent reinvasion of tissues by amoebae still in the intestines (see Amoebiasis).

Amoebicidal drugs

The treatment of invasive amoebiasis should be directed to all sites where E. Histolytica may be present. Hence the ideal amoebicide should be able to act within the intestinal lumen, in the intestinal wall, and systemically, particularly in the liver. Systemic amoebicidal drugs include emetine, dehydroemetine, chloroquine diphosphate, metronidazole, and tinidazole.
Emetine: Ipecac or ipecacuanha consists of the dried rhizome and roots of Cephaelis ipecacuanha. The medical virtues of ipecac are almost entirely due to the action of its alkaloids-emetine and cephaline. Till today, emetine remains one of the best drugs for treating amoebic liver abscess. It has a direct action on the trophozoites. Its greater concentration and duration of action in the liver as compared to that in the intestinal wall explains its high efficacy in amoebic liver abscess and also its low parasitic cure rate for intestinal amoebiasis. The drug is detoxicated and eliminated slowly. It may, therefore, produce cumulative effects. In man, emetine poisoning is characterized by muscular tremors, weakness and pain in the extremities which tend to persist until drug administration is stopped. Gastro-intestinal symptoms include nausea, vomiting and bloody diarrhoea. The latter may be mistaken for a recurrence of amoebic dysentery. Many clinicians fear the occurrence of cardiac toxicity due to this drug and hence avoid using it. Serious cardiac toxicity, however, is rare. In more than twenty years' experience, I have seen only two patients who developed an enlarged heart with congestive cardiac failure. Both recovered with the treatment for heart failure and withdrawal of emetine. One patient who was given fifteen injections of emetine in a dose of 60 mgm. per day, died. Overdosage of emetine produces focal necrosis of cardiac muscle resulting in cardiac failure and sudden death. Emetine, like digitalis may produce mild ST and T wave changes in the electrocardiogram which does not necessarily mean serious toxicity. In fact, they are encountered, though less commonly, after the use of chloroquine and metronidazole as well. Toxic effects on the myocardium have been described even in doses generally considered safe. These are rise in pulse rate, fall in systolic blood pressure and ST-T changes in the electrocardiogram. The other rare E.C.G. changes include deformity of QRS complexes, prolongation of PR interval, atrial premature beats, and atrial tachycardia. In adults, fatal cases have been reported with a total dose of 0.6 G. or less. The incidence of toxic heart damage greatly increases in patients with anaemia. In patients having myocardial disease or marked hypertension, emetine can be used for amoebic liver abscess, as the benefits from it may outweigh possible hazards. This situation is unlikely to arise these days, as equally good alternative drugs like metronidazole are available. Patients receiving emetine should be monitored for changes in pulse, blood pressure and electrocardiography. Absolute bed rest during and several days after emetine therapy has been recommended, although we^[who?] have often seen patients in whom no untoward reactions have occurred in spite of neglecting the above precaution. Theoretically the use of emetine in children is not advised. However, in practice it has been used as discussed elsewhere. It should not be administered during pregnancy unless absolutely necessary. Although emetine is undeniably moderately toxic, the risk of using it would be worth accepting in such a serious illness were it not for the fact that less toxic drugs like chloroquine and metronidazole are now available. In practice, emetine still produces a more dramatic clinical response thanchloroquine or metronidazole. This point would score in favour of emetine in places where facilities for a proper diagnosis are not available and a therapeutic test remains as the only weapon with a practitioner. Emetine should always be given deep intramuscularly or deep subcutaneously but never intravenously. The total dose in amoebic liver abscess should not exceed 650 mg. or 10 mg/kg. This should be given over a period of 10 days in a dose of 6G65 mg. daily. A relapse rate of 7% follows one such course. Therefore, the treatment could be repeated after a period of 2–6 weeks. Of late such a need does not arise, as drug combinations are commonly used. When parenteral emetine is combined with oral chloroquine or two courses of emetine are given, the relapse rate can be brought down to 1 percent.
Dehydroemetine: It is a synthetic compound developed by Osbond et al. and Brossi et al. in 1959. It is as effective as emetine in its amoebicidal properties. Given parenterally dehydroemetine is surprisingly painless. Oral tablets have been introduced. But for some reason, these tablets have not become popular. A high cure rate can be obtained with this drug. Compared to emetine, its concentration in the heart is less. Electrocardiographic changes are not seen so often. When present, they are more transient than with emetine. Dehydroemetine is excreted by the kidneys, heart and the other organs more rapidly than emetine. Therefore, a daily dose of 1.25 mg or 1.5 mg/kg body weight is necessary. The total daily dose should not exceed 90 mg. The course should not be repeated in less than 14 days.
Chloroquine: The introduction of cinchona into therapeutics was due to the discovery of its efficacy in malaria. In 1921, John^[who?] used quinine hydrochloride, an alkaloid of cinchona in the treatment of amoebic liver abscess. Later when synthetic derivatives of quinine were introduced, chloroquine phosphate, a 4-aminoquinoline was found to be less toxic than the parent drug. The drug was first quoted in the treatment of this condition in very early reports by Conan (1948)15, Murgatroyd and Kent (1948). It is absorbed rapidly and completely from the gastrointestinal tract. It is found to be very effective in invasive amoebiasis although the drug is a weaker amoebicide when compared to emetine. It is only feebly amoebicidal in the intestinal lumen. The high concentration in the liver parenchyma and the lung allows the drug to act upon E. Histolytica in cases of amoebic liver abscess and pleuropulmonary amoebiasis. It is usually well tolerated, but in some individuals it may cause mild headache, itching, nausea, vomiting or blurred vision. Rarely incoordination, convulsions, peripheral neuritis and bleaching of hair can occur. Diminution of T waves has been noticed on routine electrocardiographic recordings. Retinopathy does not occur with the usual dosage for amoebic liver abscess. Psychic disturbances though rare may interfere with the safe operation of machines and vehicles. The drug may be toxic to children in large doses18 and causes deafness in the foetus. Each 0.5 G. tablet contains chloroquine diphosphate equivalent to 0.3 G. of the base. For the treatment of amoebic liver abscess, it is administered in doses of 0.6 G. base per day in 2 to 3 divided doses orally for 2 days followed by 0.15 G. base twice daily for 2 to 3 weeks. However, Plorde recommends that it be given as 0.6 G. base initially, 0.3 G. base six hours later and then 0.3 G. base twice daily for fourteen to twenty eight days.19 Chloroquine is also available in an injectable form. Since it is quite toxic by this route, it should not be used for more than 24–48 hours after which oral therapy should be continued. Rarely, when patients of amoebic liver abscess are vomiting, injection chloroquine can be used in a dose of 0.3–0.6 G. base in 24 hours not exceeding 0.9 G.). Chloroquine given alone is a safer drug than emetine in amoebic liver abscess, but unfortunately the relapse rate is almost 25%. Rarely repetition of the course may induce a dramatic response.
Ambilhar: Until 1964, all available amoebicides were selective in their sites of action. The development of newer nitro-imidazole derivatives led to Niridazole. It was given in a daily dose of 25–30 mgm. per kg to 50 patients for seven days. The cure rate was found to be 84% with serious side effects in one patient. An Indian study of 30 patients on this drug revealed that it acted as a contact amoebicide and also against the invasive forms.23 The therapeutic action of Ambilhar was found to be significantly better than that produced by a combination of dehydroemetine and chloroquine.
Metronidazole: This is another derivative of the parent drug and its results are better than niridazole. This amoebicide acts directly on the trophozoites of E. Histolytica. Studies showed that because of very high concentration in the liver extremely small amounts of the drug were effective in amoebic liver abscess, but with such low doses, eradication of amoebae in the bowel was uncertain. The drug is quickly absorbed, partly metabolized, and rapidly excreted without any cumulative effect. It is more active in the tissues than in the gut lumen. It follows that a higher dosage is needed in the cure of luminal than systemic infection. The side effects of metronidazole are infrequent. Gastro-intestinal symptoms and headache occur occasionally. Heavy coating of tongue, brownish urine, metallic taste, dry mouth, and nausea occur more often. Vertigo, incoordinate ataxia, and paraesthesias have been reported on rare occasions. Tsai et al. observed psychosis which usually disappeared within a day or two after metronidazole was withdrawn, but tremors and muscle spasm lasted for several days. It has an antabuse-like action and alcohol should be avoided during its use. A transitory leucopenia may occur. Cardiovascular symptoms are rare. Treatment should be discontinued promptly if ataxia or any other symptoms of C.N.S. involvement occur. Only a few years ago when metronidazole was introduced it was considered to be the last word in the therapy of amoebiasis. However, the recent evidence that this drug is carcinogenic and possibly mutagenic in animals is disturbing. Due to such reports the use of the drug remains controversial, especially as metornidazole is a very widely and commonly used antibiotic. The potential risk in human beings must be weighed against the severity of the disease. The oral dose of 400 mg. thrice daily for 5 days suffices for the treatment of amoebic liver abscess. Adams29 in his analysis of 2,074 cases of liver abscess preferred metronidazole to other amoebicidal agents. A single oral dose of 2.5 G. metronidazole combined with closed aspiration has also produced dramatic response and cure in patients with amoebic liver abscess. Recently the use of intravenous preparation of metronidazole has been reported. Studies by Lazarachick et a revealed presence of anaerobic bacteroides in as many as 26% cases of amoebic liver abscess with so called 'sterile' pus. Intravenous metronidazole is a drug of choice for anaerobic infections Therefore it may be of extra advantage, if used in amoebic liver abscess. Metronidazole should not be used as a single agent for the eradication of bowel infection.33 When used alone, a few cases are known to have developed amoebic liver abscess, months after apparently successful cure of dysentery. Cases refractory to metronidazole have been occasionally described.
Tinidazole: This nitroimidazole compound, like metronidazole, has shown a marked therapeutic response in amoebic liver abscess. Occasional side effects include nausea and dizziness. Tinidazole is not widely available though it is more effective than metronidazole. Zuberi and Ibrahim found tinidazole to be effective in 86.7% cases of intestinal amoebiasis and in 100% cases of amoebic liver abscess. Luminal amoebicides like halogenated oxyquinolines, e.g. diiodohydroxyquinoline in a dose of 0.6 G. thrice daily for 3 weeks, diloxanide furoate 0.5 G. three times a day for 10 days and sometimes tetracyclines 1-2 G./day for 5 days should be used concurrently with any of the above drugs as adjuncts to eliminate intestinal infection.




               

                                              

















                                         

Haemophilia

Haemophilia
Classification and external resources
Deficiency in coagulation factor VIII is the most common cause of haemophilia.
ICD-10	D66-D68
ICD-9	286
OMIM	306700 306900 264900
DiseasesDB	5555 5561 29376
MedlinePlus	000537
eMedicine	med/3528
MeSH	D025861

Haemophilia (/hiːməˈfɪliə/; also spelled hemophilia in North America, from the Greek haima αἷμα 'blood' and philia φιλία 'love'^[1]) is a group of hereditary genetic disorders that impair the body's ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken. Haemophilia A (clotting factor VIII deficiency) is the most common form of the disorder, present in about 1 in 5,000–10,000 male births.^[2] Haemophilia B (factor IX deficiency) occurs in around 1 in about 20,000–34,000 male births.
Like most recessive sex-linked, X chromosome disorders, haemophilia is more likely to occur in males than females. This is because females have two X chromosomes while males have only one, so the defective gene is guaranteed to manifest in any male who carries it. Because females have two X chromosomes and haemophilia is rare, the chance of a female having two defective copies of the gene is very remote, so females are almost exclusively asymptomatic carriers of the disorder. Female carriers can inherit the defective gene from either their mother or father, or it may be a new mutation. Although it is not impossible for a female to have haemophilia, it is unusual: a female with haemophilia A or B would have to be the daughter of both a male haemophiliac and a female carrier, while the non-sex-linked haemophilia C due to coagulant factor XI deficiency, which can affect either sex, is more common in Jews of Ashkenazi (east European) descent^[3] but rare in other population groups.
Haemophilia lowers blood plasma clotting factor levels of the coagulation factors needed for a normal clotting process. Thus when a blood vessel is injured, a temporary scab does form, but the missing coagulation factors prevent fibrin formation, which is necessary to maintain the blood clot. A haemophiliac does not bleed more intensely than a person without it, but can bleed for a much longer time. In severe haemophiliacs even a minor injury can result in blood loss lasting days or weeks, or even never healing completely. In areas such as the brain or inside joints, this can be fatal or permanently debilitating.

Signs and symptoms

Characteristic symptoms vary with severity. In general symptoms are internal or external bleeding episodes, which are called "bleeds".^[4][5] Patients with more severe haemophilia suffer more severe and more frequent bleeds, while patients with mild haemophilia usually suffer more minor symptoms except after surgery or serious trauma. Moderate haemophiliacs have variable symptoms which manifest along a spectrum between severe and mild forms.
In both haemophilia A and B, there is spontaneous bleeding but a normal bleeding time, normal prothrombin time, normal thrombin time, but prolonged partial thromboplastin time. Internal bleeding is common in people with severe haemophilia and some individuals with moderate haemophilia. The most characteristic type of internal bleed is a joint bleed where blood enters into the joint spaces.^[6] This is most common with severe haemophiliacs and can occur spontaneously (without evident trauma). If not treated promptly, joint bleeds can lead to permanent joint damage and disfigurement.^[6] Bleeding into soft tissues such as muscles and subcutaneous tissues is less severe but can lead to damage and requires treatment.
Children with mild to moderate haemophilia may not have any signs or symptoms at birth especially if they do not undergo circumcision. Their first symptoms are often frequent and large bruises and haematomas from frequent bumps and falls as they learn to walk. Swelling and bruising from bleeding in the joints, soft tissue, and muscles may also occur. Children with mild haemophilia may not have noticeable symptoms for many years. Often, the first sign in very mild haemophiliacs is heavy bleeding from a dental procedure, an accident, or surgery. Females who are carriers usually have enough clotting factors from their one normal gene to prevent serious bleeding problems, though some may present as mild haemophiliacs.

Complications

Severe complications are much more common in severe and moderate haemophiliacs. Complications may be both directly from the disease or from its treatment:^[7]

• Deep internal bleeding, e.g. deep-muscle bleeding, leading to swelling, numbness or pain of a limb.
• Joint damage from haemarthrosis (haemophilic arthropathy), potentially with severe pain, disfigurement, and even destruction of the joint and development of debilitating arthritis.
• Transfusion transmitted infection from blood transfusions that are given as treatment.
• Adverse reactions to clotting factor treatment, including the development of an immune inhibitor which renders factor replacement less effective.
• Intracranial haemorrhage is a serious medical emergency caused by the buildup of pressure inside the skull. It can cause disorientation, nausea, loss of consciousness, brain damage, and death.

Haemophilic arthropathy is characterized by chronic proliferative synovitis and cartilage destruction.^[8] If an intra-articular bleed is not drained early, it may cause apoptosis of chondrocytes and affect the synthesis of proteoglycans. The hypertrophied and fragile synovial lining while attempting to eliminate excessive blood may be more likely to easily rebleed, leading to a vicious cycle of hemarthrosis-synovitis-hemarthrosis. In addition, iron deposition in the synovium may induce an inflammatory response activating the immune system and stimulating angiogenesis, resulting in cartilage and bone destruction.^[9]

Life expectancy

Like most aspects of the disorder, life expectancy varies with severity and adequate treatment. People with severe haemophilia who don't receive adequate, modern treatment have greatly shortened lifespans and often do not reach maturity. Prior to the 1960s when effective treatment became available, average life expectancy was only 11 years.^[6] By the 1980s the life span of the average haemophiliac receiving appropriate treatment was 50–60 years.^[6] Today with appropriate treatment, males with haemophilia typically have a near normal quality of life with an average lifespan approximately 10 years shorter than an unaffected male.^[10]
Since the 1980s the primary leading cause of death of people with severe haemophilia has shifted from haemorrhage to HIV/AIDS acquired through treatment with contaminated blood products.^[6] The second leading cause of death related to severe haemophilia complications is intracranial haemorrhage which today accounts for one third of all deaths of patients with haemophilia. Two other major causes of death include hepatitis infections causing cirrhosis and obstruction of air or blood flow due to soft tissue haemorrhage.^[6]

Causes

• Haemophilia A is a recessive X-linked genetic disorder involving a lack of functional clotting Factor VIII and represents 80% of haemophilia cases.
• Haemophilia B is a recessive X-linked genetic disorder involving a lack of functional clotting Factor IX. It comprises approximately 20% of haemophilia cases.^[11]
• Haemophilia C is an autosomal genetic disorder (i.e. not X-linked) involving a lack of functional clotting Factor XI. Haemophilia C is not completely recessive, as heterozygous individuals also show increased bleeding.^[12]

Genetics

X-linked recessive inheritance

Females possess two X-chromosomes, males have one X and one Y-chromosome. Since the mutations causing the disease are X-linked, a woman carrying the defect on one of her X-chromosomes may not be affected by it, as the equivalent allele on her other chromosome should express itself to produce the necessary clotting factors, due to X inactivation. However, the Y-chromosome in men has no gene for factors VIII or IX. If the genes responsible for production of factor VIII or factor IX present on a male's X-chromosome are deficient there is no equivalent on the Y-chromosome to cancel it out, so the deficient gene is not masked and he will develop the illness.
Since a male receives his single X-chromosome from his mother, the son of a healthy female silently carrying the deficient gene will have a 50% chance of inheriting that gene from her and with it the disease; and if his mother is affected with haemophilia, he will have a 100% chance of being a haemophiliac. In contrast, for a female to inherit the disease, she must receive two deficient X-chromosomes, one from her mother and the other from her father (who must therefore be a haemophiliac himself). Hence haemophilia is far more common among males than females. However, it is possible for female carriers to become mild haemophiliacs due to lyonisation (inactivation) of the X-chromosomes. Haemophiliac daughters are more common than they once were, as improved treatments for the disease have allowed more haemophiliac males to survive to adulthood and become parents. Adult females may experience menorrhagia (heavy periods) due to the bleeding tendency. The pattern of inheritance is criss-cross type. This type of pattern is also seen in colour blindness.
A mother who is a carrier has a 50% chance of passing the faulty X-chromosome to her daughter, while an affected father will always pass on the affected gene to his daughters. A son cannot inherit the defective gene from his father.
Genetic testing and genetic counselling is recommended for families with haemophilia. Prenatal testing, such as amniocentesis, is available to pregnant women who may be carriers of the condition.
As with all genetic disorders, it is of course also possible for a human to acquire it spontaneously through mutation, rather than inheriting it, because of a new mutation in one of their parents' gametes. Spontaneous mutations account for about 33% of all cases of haemophilia A. About 30% of cases of haemophilia B are the result of a spontaneous gene mutation.
If a female gives birth to a haemophiliac child, either the female is a carrier for the blood disorder or the haemophilia was the result of a spontaneous mutation. Until modern direct DNA testing, however, it was impossible to determine if a female with only healthy children was a carrier or not. Generally, the more healthy sons she bore, the higher the probability that she was not a carrier.
If a male is afflicted with the disease and has children with a female who is not even a carrier, his daughters will be carriers of haemophilia. His sons, however, will not be affected with the disease. The disease is X-linked and the father cannot pass haemophilia through the Y-chromosome. Males with the disorder are then no more likely to pass on the gene to their children than carrier females, though all daughters they sire will be carriers and all sons they father will not have haemophilia (unless the mother is a carrier).

Severity

There are numerous different mutations which cause each type of haemophilia. Due to differences in changes to the genes involved, patients with haemophilia often have some level of active clotting factor. Individuals with less than 1% active factor are classified as having severe haemophilia, those with 1-5% active factor have moderate haemophilia, and those with mild haemophilia have between 5-40% of normal levels of active clotting factor.^[6]

Diagnosis

Haemophilia A can be mimicked by von Willebrand disease.

• von Willebrand Disease could significantly affect as many as 1 in 10,000 people.^[13]
• von Willebrand Disease type 2A, where decreased levels of von Willebrand Factor can lead to premature proteolysis of Factor VIII. In contrast to haemophilia, vWD type 2A is inherited in an autosomal dominant fashion.
• von Willebrand Disease type 2N, where von Willebrand Factor cannot bind Factor VIII, autosomal recessive inheritance. (i.e.; both parents need to give the child a copy of the gene).
• von Willebrand Disease type 3, where lack of von Willebrand Factor causes premature proteolysis of Factor VIII. In contrast to haemophilia, vWD type 3 is inherited in an autosomal recessive fashion.

Additionally, severe cases of vitamin K deficiency can present similar symptoms to haemophilia. This is because vitamin K is necessary for the human body to produce several protein clotting factors. This vitamin deficiency is rare in adults and older children but is common in newborns. Infants are born with naturally low levels of vitamin K and do not yet have the symbiotic gut flora to properly synthesise their own vitamin K. Bleeding issues due to vitamin K deficiency in infants is known as "haemorrhagic disease of the newborn", to avoid this complication newborns are routinely injected with vitamin K supplements.

Laboratory findings in various platelet and coagulation disorders (V - T)

Condition	Prothrombin time	Partial thromboplastin time	Bleeding time	Platelet count
Vitamin K deficiency or warfarin	Prolonged	Normal or mildly prolonged	Unaffected	Unaffected
Disseminated intravascular coagulation	Prolonged	Prolonged	Prolonged	Decreased
Von Willebrand disease	Unaffected	Prolonged or unaffected	Prolonged	Unaffected
Hemophilia	Unaffected	Prolonged	Unaffected	Unaffected
Aspirin	Unaffected	Unaffected	Prolonged	Unaffected
Thrombocytopenia	Unaffected	Unaffected	Prolonged	Decreased
Liver failure, early	Prolonged	Unaffected	Unaffected	Unaffected
Liver failure, end-stage	Prolonged	Prolonged	Prolonged	Decreased
Uremia	Unaffected	Unaffected	Prolonged	Unaffected
Congenital afibrinogenemia	Prolonged	Prolonged	Prolonged	Unaffected
Factor V deficiency	Prolonged	Prolonged	Unaffected	Unaffected
Factor X deficiency as seen in amyloid purpura	Prolonged	Prolonged	Unaffected	Unaffected
Glanzmann's thrombasthenia	Unaffected	Unaffected	Prolonged	Unaffected
Bernard-Soulier syndrome	Unaffected	Unaffected	Prolonged	Decreased or unaffected
Factor XII deficiency	Unaffected	Prolonged	Unaffected	Unaffected
C1INH deficiency	Unaffected	Shortened	Unaffected	Unaffected

Management

Commercially produced factor concentrates such as "Advate", a recombinant Factor VIII, come as a white powder in a vial which must be mixed with sterile water prior to intravenous injection.

Though there is no cure for haemophilia, it can be controlled with regular infusions of the deficient clotting factor, i.e. factor VIII in haemophilia A or factor IX in haemophilia B. Factor replacement can be either isolated from human blood serum, recombinant, or a combination of the two. Some haemophiliacs develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as porcine factor VIII.
If a patient becomes refractory to replacement coagulation factor as a result of circulating inhibitors, this may be partially overcome with recombinant human factor VII (NovoSeven), which is registered for this indication in many countries.
In early 2008, the US Food and Drug Administration (FDA) approved Xyntha (Wyeth) anti-haemophilic factor, genetically engineered from the genes of Chinese hamster ovary cells. Since 1993 (Dr. Mary Nugent) recombinant factor products (which are typically cultured in Chinese hamster ovary (CHO) tissue culture cells and involve little, if any human plasma products) have been available and have been widely used in wealthier western countries. While recombinant clotting factor products offer higher purity and safety, they are, like concentrate, extremely expensive, and not generally available in the developing world. In many cases, factor products of any sort are difficult to obtain in developing countries.^{[citation needed]}
In Western countries, common standards of care fall into one of two categories: prophylaxis or on-demand. Prophylaxis involves the infusion of clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneous bleeding episodes. On-demand treatment involves treating bleeding episodes once they arise. In 2007, a clinical trial was published in the New England Journal of Medicine comparing on-demand treatment of boys (< 30 months) with haemophilia A with prophylactic treatment (infusions of 25 IU/kg body weight of Factor VIII every other day) in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group had a normal index joint-structure on MRI.^[14] Prophylactic treatment, however, resulted in average costs of $300,000 per year. The author of an editorial published in the same issue of the NEJM supports the idea that prophylactic treatment not only is more effective than on demand treatment but also suggests that starting after the first serious joint-related haemorrhage may be more cost effective than waiting until the fixed age to begin.^[15] This study resulted in the first (October 2008) FDA approval to label any Factor VIII product to be used prophylactically.^[16] As a result, the factor product used in the study (Bayer's Kogenate) is now labelled for use to prevent bleeds, making it more likely that insurance carriers in the US will reimburse consumers who are prescribed and use this product prophylactically. Despite Kogenate only recently being "approved" for this use in the US, it and other factor products have been well studied and are often prescribed to treat Haemophilia prophylactically to prevent bleeds, especially joint bleeds.^[17]

Gene therapy

On 10 December 2011, a team of British and American investigators reported the successful treatment of haemophilia B using gene therapy. The investigators inserted the F9 gene into an adeno-associated virus-8 vector, which has a propensity for the liver, where factor 9 is produced, and remains outside the chromosomes so as not to disrupt other genes. The transduced virus was infused intravenously. To prevent rejection, the patients were primed with steroids to suppress their immune response.^[18] In October 2013, the Royal Free London NHS Foundation Trust in London reported that after treating six people with haemophilia in early 2011 with the genetically modified adeno-associated virus, two years later all of the patients were still producing blood plasma clotting factor.^[19]

Preventive exercises

It is recommended that people affected with haemophilia do specific exercises to strengthen the joints, particularly the elbows, knees, and ankles.^[20] Exercises include elements which increase flexibility, tone, and strength of muscles, increasing their ability to protect joints from damaging bleeds. These exercises are recommended after an internal bleed occurs and on a daily basis to strengthen the muscles and joints to prevent new bleeding problems. Many recommended exercises include standard sports warm-up and training exercises such as stretching of the calves, ankle circles, elbow flexions, and quadriceps sets.

Alternative medicine

While not a replacement for traditional treatments, preliminary scientific studies indicate that hypnosis and self-hypnosis may be effective at reducing bleeds and the severity of bleeds and thus the frequency of factor treatment.^{[21][22][23][24]} Herbs which strengthen blood vessels and act as astringents may benefit patients with haemophilia, however there are no peer reviewed scientific studies to support these claims.^[21]

Contraindications

Anticoagulants such as Heparin and Warfarin are contraindicated for people with haemophilia as these can aggravate clotting difficulties. Also contraindicated are those drugs which have "blood thinning" side effects. For instance, medicines which contain aspirin, ibuprofen, or naproxen sodium should not be taken because they are well known to have the side effect of prolonged bleeding.^[25]
Also contraindicated are activities with a high likelihood of trauma, such as motorcycling and skateboarding. Popular sports with very high rates of physical contact and injuries such as American football, hockey, boxing, wrestling, and rugby should be avoided by people with haemophilia.^[25][26] Other active sports like soccer, baseball, and basketball also have a high rate of injuries, but have overall less contact and should be undertaken cautiously and only in consultation with a doctor.^[25]

Epidemiology

Haemophilia is rare, with only about 1 instance in every 10,000 births (or 1 in 5,000 male births) for haemophilia A and 1 in 50,000 births for haemophilia B.^[27] About 18,000 people in the United States have haemophilia. Each year in the US, about 400 babies are born with the disorder. Haemophilia usually occurs in males and less often in females.^[28] It is estimated that about 2500 Canadians have haemophilia A, and about 500 Canadians have haemophilia B.^[29]

History

"About seventy or eighty years ago, a woman by name of Smith, settled in the vicinity of Plymouth, New Hampshire, and transmitted the following idiosyncrasy to her descendants. It is one, she observed, to which her family is unfortunately subject, and had been the source not only of great solicitude, but frequently the cause of death. If the least scratch is made on the skin of some of them, as mortal a hemorrhagy will eventually ensue as if the largest wound is inflicted. (…) So assured are the members of this family of the terrible consequences of the least wound, that they will not suffer themselves to be bled on any consideration, having lost a relation by not being able to stop the discharge occasioned by this operation."

John C. Otto, 1803^[30]

Scientific discovery

The first medical professional to describe a disease was Abulcasis. In the tenth century he described families whose males died of bleeding after only minor traumas.^[31] While many other such descriptive and practical references to the disease appear throughout historical writings, scientific analysis did not begin until the start of the nineteenth century.
In 1803, Dr. John Conrad Otto, a Philadelphian physician, wrote an account about "a hemorrhagic disposition existing in certain families" in which he called the affected males "bleeders".^[32] He recognised that the disorder was hereditary and that it affected mostly males and was passed down by healthy females. His paper was the second paper to describe important characteristics of an X-linked genetic disorder (the first paper being a description of colour blindness by John Dalton who studied his own family). Otto was able to trace the disease back to a woman who settled near Plymouth in 1720. The idea that affected males could pass the trait onto their unaffected daughters was not described until 1813 when John Hay published an account in The New England Journal of Medicine.^[33][34]
In 1924, a Finnish doctor discovered a hereditary bleeding disorder similar to Haemophilia localised in the "Åland Islands", southwest of Finland.^[35] This bleeding disorder is called "Von Willebrand Disease".
The term "haemophilia" is derived from the term "haemorrhaphilia" which was used in a description of the condition written by Friedrich Hopff in 1828, while he was a student at the University of Zurich.^[32][36] In 1937, Patek and Taylor, two doctors from Harvard, discovered anti-haemophilic globulin.^[37] In 1947, Pavlosky, a doctor from Buenos Aires, found haemophilia A and haemophilia B to be separate diseases by doing a lab test. This test was done by transferring the blood of one haemophiliac to another haemophiliac. The fact that this corrected the clotting problem showed that there was more than one form of haemophilia.

European royalty

Main article: Haemophilia in European royalty

Queen Victoria passed haemophilia on to some of her descendants.

Haemophilia has featured prominently in European royalty and thus is sometimes known as 'the royal disease'. Queen Victoria passed the mutation for Haemophilia B^[38][39] to her son Leopold and, through some of her daughters, to various royals across the continent, including the royal families of Spain, Germany, and Russia. In Russia, Tsarevich Alexei Nikolaevich, son of Nicholas II, was a descendant of Queen Victoria through his mother Empress Alexandra and suffered from haemophilia.
It was claimed that Rasputin was successful at treating Tsarevich's haemophilia. At the time, a common treatment administered by professional doctors was to use aspirin, which worsened rather than lessened the problem. It is believed that, by simply advising against the medical treatment, Rasputin could bring visible and significant improvement to the condition of Tsarevich.
In Spain, Queen Victoria's youngest daughter, Princess Beatrice, had a daughter Victoria Eugenie of Battenberg, who later became Queen of Spain. Two of her sons were haemophiliacs and both died from minor car accidents. Her eldest son, Prince Alfonso of Spain, Prince of Asturias, died at the age of 31 from internal bleeding after his car hit a telephone booth. Her youngest son, Infante Gonzalo, died at age 19 from abdominal bleeding following a minor car accident where he and his sister hit a wall while avoiding a cyclist. Neither appeared injured or sought immediate medical care and Gonzalo died two days later from internal bleeding.

Blood contamination issues

Main article: Contaminated haemophilia blood products

Ryan White was an American haemophiliac who became infected with HIV/AIDS through contaminated blood products.

Prior to 1985, there were no laws enacted within the U.S. to screen blood. As a result, many haemophilia patients who received untested and unscreened clotting factor prior to 1992 were at an extreme risk for contracting HIV and hepatitis C via these blood products. It is estimated that more than 50% of the haemophilia population, i.e. over 10,000 people, contracted HIV from the tainted blood supply in the United States alone.^[40]
As a direct result of the contamination of the blood supply in the late 1970s and early/mid-1980s with viruses such as hepatitis and HIV, new methods were developed in the production of clotting factor products. The initial response was to heat-treat (pasteurise) plasma-derived factor concentrate, followed by the development of monoclonal factor concentrates, which use a combination of heat treatment and affinity chromatography to inactivate any viral agents in the pooled plasma from which the factor concentrate is derived. The Lindsay Tribunal in Ireland investigated, among other things, the slow adoption of the new methods.


                         

 

Hypermetropia

Hyperopia

Hypermetropia
Classification and external resources
ICD-10	H52.0
ICD-9	367.0
MedlinePlus	001020

Hypermetropia lens correction

Hyperopia or hypermetropia, from the Greek word "hyper-metropia : υπερ-μετρωπία" commonly known as being farsighted (American English) or longsighted (British English), is a defect of vision caused by an imperfection in the eye (often when the eyeball is too short or the lens cannot become round enough), causing difficulty focusing on near objects, and in extreme cases causing a sufferer to be unable to focus on objects at any distance. As an object moves toward the eye, the eye must increase its optical power to keep the image in focus on the retina. If the power of the cornea and lens is insufficient, as in hyperopia, the image will appear blurred.
People with hyperopia can experience blurred vision, asthenopia, accommodative disfunction, binocular disfunction, amblyopia, and strabismus,^[1] another condition that frequently causes blurry near vision.^[2] Presbyopes who report good far vision typically experience blurry near vision because of a reduced accommodative amplitude brought about by natural aging changes with the crystalline lens.^[2] It is also sometimes referred to as farsightedness, since in otherwise normally-sighted persons it makes it more difficult to focus on near objects than on far objects.^[3]
The causes of hyperopia are typically genetic and involve an eye that is too short or a cornea that is too flat, so that images focus at a point behind the retina.
The opposite of hyperopia is myopia.

Classification of hyperopia

Hyperopia is typically classified according to clinical appearance, its severity, or how it relates to the eye's accommodative status.^[1]

Classification by clinical appearance

• Simple hyperopia
• Pathological hyperopia
• Functional hyperopia

Signs and tests

A farsighted person has trouble reading the Jaeger eye chart (the chart for near reading), but find it easy to read the Snellen eye chart (the chart for distance).
A general eye examination, or standard ophthalmic exam may include:

• Eye pressure measurement (Tonometry)
• Refraction test, to determine the correct prescription for glasses
• Retinal examination
• Slit-lamp exam of the structures at the front of the eyes
• Test of color vision, to look for possible color blindness
• Tests of the muscles that move the eyes
• Visual acuity, both at a distance (Snellen), and close up (Jaeger)

Causes

Farsightedness is the result of the visual image being focused behind the retina rather than directly on it. It is mainly cause by two reasons-

• Low converging power of eye lens because of weak action of ciliary muscles.
• Eyeball being too short because of which the distance between eye lens and retina decreases.

Farsightedness is often present from birth, but children have a very flexible eye lens, which helps make up for the problem. As aging occurs, glasses or contact lenses may be required to correct the vision. Farsightedness is hereditary.

Diagnosis

Visual acuity is affected according to the amount of hyperopia, as well as the patient's age, visual demands, and accommodative ability.^[1]
In severe cases of hyperopia from birth, the brain has difficulty merging the images that each individual eye sees. This is because the images the brain receives from each eye are always blurred. A child with severe hyperopia has never seen objects in detail and might present with amblyopia or strabismus. If the brain never learns to see objects in detail, then there is a high chance that one eye will become dominant. The result is that the brain will block the impulses of the nondominant eye with resulting amblyopia or strabismus. In contrast, the child with myopia can see objects close to the eye in detail and does learn at an early age to see detail in objects.
The child with hyperopia will typically stand close in front of a television. One would have expected that the child would stand far away because the child is hyperopic, but because the brain has never learned to see detailed lines and object contours the child sees objects blurred. While children with myopia learn to see sharp lines because they can see perfectly well very close to their eyes, the brain of a child with hyperopia cannot see sharp lines, so they stand right in front of the television to at least see blurred images. This blurred vision may also cause a child to develop a squint because the two eyes do not detect sharp lines which the brain can use to map the separate images of the two eyes together to form a single image. Each eye functions independently. So a child with hyperopia from birth presents with decreased visual perception.
The parents of a child with hyperopia do not always realize that the child has a problem at an early age. A hyperopic child might have problems with catching a ball because of blurred vision and because of a decreased ability to see three-dimensional objects. The child will typically perform below average at school. As soon as a child starts identifying images, a parent might find that the child cannot see small objects or pictures.
In many circumstances mild to moderate hyperopia can be mistaken for ADHD; or other learning and personality disorders. One coping mechanism many children subconsciously use is constant head and body movement to attempt to maintain focus.

Treatment

Various eye care professionals, including ophthalmologists, optometrists, orthoptists, and opticians, are involved in the treatment and management of hyperopia. At the conclusion of an eye examination, an eye doctor (ophthalmologist or optometrist) may provide the patient with an eyeglass prescription for corrective lenses. Minor amounts of hyperopia are sometimes left uncorrected. However, larger amounts may be corrected with convex lenses in eyeglasses or contact lenses. Convex lenses have a positive dioptric value, which causes the light to focus closer than its normal range.
Hyperopia is correctable with various refractive surgery procedures, such as PRK, LASIK, Radial Keratocoagulation or Thermokeratoplasty.

Complications

Farsightedness can be a risk factor for Acute angle closure, Glaucoma^[4] and crossed eyes.