Paroxysmal nocturnal hemoglobinuria (PNH) represents a rare and severe disorder of hematopoietic cells that is genetic but acquired later in life. Because it is a somatic mutation, germ cells are not affected. If left untreated, the disease can be fatal mainly due to the development of multiple thromboses.
What is paroxysmal nocturnal hemoglobinuria?
Paroxysmal nocturnal hemoglobinuria is a disease of the hematopoietic cells that is often severe. It is characterized by hemolysis, thrombus formation, and reduced blood cell production. Individual or all blood lineage cells may be affected. While all patients with PNH show the symptoms of hemolysis, the other symptoms are very variable. In about 35 percent of cases, the disease can be fatal, mainly due to the large number of thromboses that occur. Due to the constant hemolysis, there is a chronic anemia, which is accompanied by severe states of exhaustion. Although the disease is not curable, it can be well controlled therapeutically. With lifelong consistent treatment, a good quality of life is achieved with normal life expectancy. PNH has an estimated prevalence of approximately 16 per 1 million population, making it one of the very rare diseases.
Causes
Paroxysmal nocturnal hemoglobinuria is caused by a somatic mutation of the PIG-A gene. This gene is located on the X chromosome and is responsible for encoding the enzyme N-acetylglucosaminyltransferase. N-acetylglucosaminyltransferase catalyzes the formation of the so-called glucosylphosphatidylinositol anchor (GPI anchor), which ensures the anchoring of protective proteins on the cell surface of blood cells. These proteins include CD55 and CD59. With their anchoring on the cell membrane of the hematopoietic cells, they serve to protect them from attack by the part of the immune system known as the complement system. In the absence of these anchor proteins, hematopoietic stem cells and blood cells are destroyed
In addition to increased hemolysis, fewer blood cells are also regenerated. This leads to a pronounced chronic anemia. At the same time, thromboses develop in many parts of the body, which can be dangerous. PNH is an acquired disease, which occurs for the first time especially between the ages of 25 and 45. The underlying gene mutation is not already present since birth. It arises in the context of a somatic mutation of the PIG-A gene within multipotent hematopoietic stem cells. No cases of PNH are otherwise found in the family or relatives. Because germ cells are not affected, there is no possibility of this disease being passed on to offspring.
Symptoms, complaints, and signs
The main symptom of paroxysmal nocturnal hemoglobinuria is chronic hemolysis. Because of the somatic mutation, so-called mosaics are present. There are both healthy and defective blood cells. All mutated blood cells have lost protection from the complement system due to the missing anchor and are destroyed. However, the diseased erythrocytes are particularly affected. The most dangerous symptom, however, is the tendency to thrombosis in both the venous and arterial systems. This is the case in approximately 50 percent of patients with PNH. Thrombosis is also responsible for most deaths, affecting one-third of those with the disease. Other symptoms include severe fatigue, abdominal cramps, headaches, dysphagia, nausea, chest pain, back pain or impotence. The pain is caused by small thrombi. They can be mild but also so severe that even opiates have to be administered as painkillers. The pain is also explained by the lack of nitric oxide (NO), which binds to released hemoglobin. Since NO is responsible for smooth muscle relaxation, the lack of NO there leads to increased tension states. The severity of the disease also depends on how much blood is affected by the mutation. If the immune cells of the blood are mutated at the same time, the immune system is also severely weakened.
Diagnosis and course of the disease
Diagnosis involves using flow cytometry to examine the blood cells for the presence of the protective proteins.This method can be used to identify the cells that lack protection from the complement system. A definitive diagnosis is made when at least two cell lines, such as erythrocytes or granulocytes, lack protective factor.
Complications
In the worst case, death of the affected person may occur due to this disease. However, this usually occurs when the affected person suffers from multiple thromboses that were not prevented. The risk of developing thromboses is significantly increased in patients. In most cases, these are also responsible for the patient’s death. Those affected suffer from pain that occurs in different places. There is pain in the head or also in the abdomen. In many cases, there is also chest pain, which can spread to the back. Men may also suffer from potency problems due to the disease. Furthermore, there is a permanent nausea or difficulty swallowing. In many cases, ordinary painkillers are no longer sufficient to relieve the pain. The quality of life of the affected person is considerably reduced by the disease. The treatment takes place without complications. With the help of blood transfusions or a stem cell transplant, the symptoms can be reduced. However, the patient’s life expectancy is usually reduced due to the disease.
When should you see a doctor?
In any case, this disease must be examined and treated by a physician. Without treatment, death usually results because the disease leads to the development of thrombosis. Those affected suffer from various complaints that do not always directly indicate the disease. There may be pain in the head or abdomen, accompanied by nausea or back pain. Often, a potency disorder can also point to this disease. If the discomfort is permanent and does not disappear on its own, a visit to a doctor is definitely necessary. The pain can also be so extreme that the affected person loses consciousness. A weakened immune system can also indicate this disease. A doctor should also be consulted in case of frequent colds or other infections. The initial diagnosis of the disease can be made by the general practitioner. However, a specialist is required for further treatments. Whether there will be a decreased life expectancy due to the disease cannot be generally predicted.
Treatment and therapy
There is no cure for PNH. However, there are some supportive treatments that can improve quality of life. First, regular blood transfusions or transfusions of red blood cell concentrates are necessary because of the chronic anemia. Folic acid or vitamin B12 are recommended to promote blood formation. Infections must be recognized early and treated by antibiotic administration because they can trigger hemolytic crises. Short-term administration of steroids can mitigate a hemolytic crisis. However, steroids should not be given permanently. Severe pain requires treatment with analgesics. If thrombosis has occurred, coumarins are given permanently as anticoagulants. The only real possibility to cure paroxysmal nocturnal hemoglobinuria after all is stem cell transplantation. However, it is associated with considerable risks, so that this therapy is only considered in very severe cases. Good experience has been made with the drug Eculizumab. This is a genetically produced monoclonal antibody that inactivates complement factor C5 of the complement system. This prevents the attack on the unprotected blood cells.
Prospect and prognosis
Prognosis is difficult in paroxysmal nocturnal hemoglobinuria. The clinical presentation of this acquired hematologic disorder can vary widely. In milder courses, the prognosis is more positive. In cases of severe stem cell damage, stem cell transplantation is often the only way to prolong life. Since the disease is due to a genetic mutation in the bone marrow, it is not curable. Paroxysmal nocturnal hemoglobinuria can only be treated symptomatically. Treatment is differentiated for symptomatic and asymptomatic courses. Patients with asymptomatic paroxysmal nocturnal hemoglobinuria receive prophylactic anticoagulant medication.In symptomatic patients, therapy with an antibody called eculizmab in combination with other supportive measures can repress symptoms. Bone marrow transplantation is another treatment option. However, it is associated with high risks because the immune system must be switched off before the transplant. Ultimately, the severity of the stem cell changes determines how good or bad the prognosis is. Half of those affected survive the diagnosis by only 15 years. In the past, the prognosis for paroxysmal nocturnal hemoglobinuria was worse than it is today. Modern treatment methods have significantly improved the prognosis for the symptomatic type of the disease. Nevertheless, it cannot be called good. However, survival and quality of life for those affected are better today than in the past.
Prevention
Prevention of paroxysmal nocturnal hemoglobinuria is not possible. However, persons already ill should protect themselves from infections to avoid triggering a hemolytic crisis. Sustained therapy with eculizumab prevents symptoms of PNH and allows normal life expectancy.
Follow-up
Because paroxysmal nocturnal hemoglobinuria is a genetic disorder, no causal therapeutic options currently exist. If affected patients are asymptomatic, they should initially wait or refrain from therapy. Prophylactically, only oral anticoagulation can be considered. In this case, constant monitoring of the coagulation parameters must be ensured. The follow-up therefore refers to the control and monitoring of the supportive therapies against the multiple symptoms of the disease. Long-term control of blood levels of VitB12 and folic acid are indicated to prevent changes in blood components and resulting symptoms. These deficiencies of VitB12 or folic acid can then be substituted with medication. Regular blood count checks are necessary to detect emerging infections early. If glucocorticoids are administered, multiple treatment monitoring measures must be taken. Since long-term use of cortisone can lead to decalcification of the bones, this promotes the development of osteoporosis. Calcium and VitD should be administered prophylactically. As blood glucose levels and blood pressure can also rise during the course of therapy, these parameters are also monitored regularly. In case of treatment with oral anticoagulation, regular coagulation parameter controls will take place. When taking coumarin, it is essential to watch for pharmacokinetic interactions with other drugs. Also, during therapy with monoclonal antibodies, the occurrence of side effects must always be monitored to intervene with medication if necessary.
What you can do yourself
Since the disease is based on a genetic defect, relatives of a patient, on their own responsibility and self-initiated, should initiate control of their genetic predispositions. Since the probability of occurrence of thrombosis is increased when people are in a rigid posture for too long, it is necessary to check the musculoskeletal system. Prolonged standing, squatting or sitting should be avoided. In addition, support of the circulatory system should take place in everyday life through various loosening-up exercises. In this way, blood stasis can be avoided and vessels in the organism are not constricted. The intake of harmful substances such as nicotine or medications that have side effects on the blood system should be avoided. In case of an existing disease, the taken preparations should be checked for their risks and the consultation with the attending physician should take place. In some cases it is necessary to change the treatment plan. If states of exhaustion, fatigue or an increased need for sleep occur, the affected person should react adequately to the signals of his body. The organism should not be put under excessive strain, as there is a risk of sequelae or complications. Changes in health sensations or an increase in complaints should be discussed immediately with a physician. Paroxysmal nocturnal hemoglobinuria can lead to a life-threatening condition if left untreated. Therefore, if self-help measures are not sufficiently effective, consultation with a medical professional is essential.
