Paroxysmal Nocturnal Hemoglobinuria (PNH): A Comprehensive Overview

By SWA

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired, life-threatening blood disorder characterized by the destruction of red blood cells (RBCs), a tendency to form blood clots, and impaired bone marrow function. The condition arises from a mutation in the PIGA gene, which leads to the absence of protective proteins on the surface of red blood cells, making them susceptible to the immune system’s complement pathway. Below is a detailed exploration of PNH, its symptoms, diagnostic methods, treatments, and the potential role of food sensitivities.

Key Features and Symptoms of PNH

  1. Hemolysis: The destruction of red blood cells, which can occur throughout the day but often peaks at night, giving rise to the term "nocturnal."

  2. Hemoglobinuria: The presence of hemoglobin in the urine, often noticeable as dark or cola-colored urine, especially in the morning.

  3. Fatigue and Weakness: Due to anemia from ongoing hemolysis, patients often experience significant fatigue and reduced energy levels.

  4. Abdominal Pain and Esophageal Spasms: These symptoms result from smooth muscle contractions triggered by hemolysis.

  5. Thrombosis (Blood Clots): PNH patients are at increased risk of developing blood clots, particularly in unusual sites such as the veins of the abdomen, brain, or skin.

  6. Pancytopenia: A reduction in red cells, white cells, and platelets, often associated with bone marrow failure syndromes like aplastic anemia.

  7. Jaundice: Yellowing of the skin and eyes due to increased bilirubin from the breakdown of RBCs.

  8. Dyspnea (Shortness of Breath): This symptom is common due to the decreased oxygen-carrying capacity resulting from low hemoglobin levels.

The Ham Test

Historically, the Ham test was used to diagnose PNH by placing red blood cells in an acidic environment to observe hemolysis. However, this test is now largely obsolete, replaced by more accurate flow cytometry tests that measure the absence of specific proteins (CD55 and CD59) on the surface of blood cells.

Jaundice in PNH

Jaundice in PNH results from the accelerated breakdown of red blood cells, releasing bilirubin, a yellow pigment that accumulates when the liver is overwhelmed. This accumulation leads to the characteristic yellowing of the skin and eyes, a common sign of hemolysis.

Meningitis and PNH

Meningitis is not directly related to PNH. However, due to their underlying condition, patients with PNH can be immunocompromised, making them potentially more susceptible to infections, including meningitis. The primary concern in PNH remains thrombosis rather than infectious complications.

To test for meningococcemia, a hematologist or other healthcare provider would typically perform the following:

  1. Blood Cultures: Blood samples are taken to check for the presence of Neisseria meningitidis bacteria in the bloodstream, which confirms meningococcemia.

  2. Complete Blood Count (CBC): This test evaluates the levels of different blood cells. In meningococcemia, abnormalities such as low platelet count (thrombocytopenia) or signs of infection (elevated white blood cells) might be observed.

  3. Coagulation Tests: Since meningococcemia can cause clotting problems, tests like prothrombin time (PT), partial thromboplastin time (PTT), and D-dimer may be ordered to assess blood clotting function.

  4. Blood Gases and Lactate Levels: These tests help assess oxygen levels and organ function, which can be impaired in severe meningococcemia due to septic shock.

Early diagnosis and treatment are crucial since meningococcemia can progress rapidly and become life-threatening.

 

Treatment of PNH

Treatment of PNH focuses on managing symptoms, preventing complications, especially thrombosis, and addressing the underlying defect.

Soliris (eculizumab) is a medication that works by inhibiting a part of the immune system called the complement system, which is involved in the body's defense against infections but can also contribute to certain diseases. Soliris is primarily used to treat conditions like paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), where the complement system becomes overactive and damages red blood cells.

However, in some cases, Soliris can cause hemolytic anemia, a condition where red blood cells are destroyed faster than the body can replace them. Here's how it can happen:

  1. Complement System Inhibition: Soliris blocks a key protein in the complement pathway (C5), which prevents the formation of a protein complex (MAC) that can destroy red blood cells. In conditions like PNH, this is beneficial because it reduces red blood cell destruction.

  2. Risk of Hemolysis: In some individuals, however, this inhibition may not fully prevent red blood cell destruction. Hemolysis (the breaking down of red blood cells) can still occur because blocking the complement pathway doesn't address all the potential triggers for red blood cell damage, especially if there are underlying conditions like infections that can activate other parts of the immune system.

  3. Vaccination Requirement: One of the side effects of Soliris is an increased risk of infection, especially with bacteria like Neisseria meningitidis (which causes meningitis). These infections can lead to a flare-up of hemolysis as the immune system responds to the infection.
    Neisseria meningitidis is a type of bacteria that can cause serious infections, including meningitis (inflammation of the brain and spinal cord) and bloodstream infections (meningococcemia). It spreads through respiratory droplets, and symptoms can progress rapidly, potentially leading to severe complications or death. Vaccination is recommended to prevent infection, especially for people at higher risk, such as those with weakened immune systems or on medications like Soliris that increase susceptibility to infections.

To mitigate these risks, patients on Soliris are usually required to receive vaccinations against certain bacteria and are monitored closely for signs of hemolytic anemia. While Soliris can be life-saving in the conditions it treats, careful monitoring is essential to avoid complications like hemolytic anemia.

  1. Eculizumab (Soliris) and Ravulizumab (Ultomiris): These monoclonal antibodies inhibit the complement system, protecting red blood cells from hemolysis. They significantly reduce hemolysis, thrombosis risk, and fatigue in PNH patients (Risitano, 2019).

  2. Blood Transfusions: Used to manage severe anemia resulting from ongoing hemolysis.

  3. Anticoagulation Therapy: Prescribed to prevent blood clots, particularly in high-risk patients.

  4. Iron and Folate Supplementation: Essential to support red blood cell production due to increased turnover.

  5. Bone Marrow Transplant: The only potential cure for PNH, though it carries significant risks and is generally reserved for severe cases with bone marrow failure (Scheinberg et al., 2020).

  6. Supportive Care: Focuses on managing symptoms like abdominal pain, fatigue, and overall quality of life.

Food Sensitivity and PNH

Food sensitivity is not a direct feature of PNH, but some symptoms of PNH, such as abdominal pain and gastrointestinal discomfort, can mimic food sensitivities.

Food Sensitivity in PNH

  1. Abdominal Pain and Gastrointestinal Symptoms: PNH patients often experience abdominal pain that mimics food sensitivity reactions, though this pain is usually due to vascular complications or smooth muscle spasms rather than direct food reactions.

  2. Impact of Fatigue on Diet: Chronic fatigue associated with PNH can affect appetite and food choices, potentially leading patients to report feeling worse after eating certain foods.

  3. Digestive Symptoms and Complement Activation: Complement activation in PNH can trigger symptoms like cramps and bloating, which may be mistakenly attributed to food sensitivities.

  4. Exacerbation of Symptoms by Certain Foods: While no specific foods directly exacerbate PNH, some patients may find that high-fat or heavy meals worsen abdominal discomfort.

  5. Dietary Management: Maintaining a balanced diet rich in folate and iron is essential for supporting red blood cell production, and avoiding foods that exacerbate symptoms can help manage discomfort.

What Patients Should Know

  • Track Symptoms and Diet: Keeping a food and symptom diary can help identify triggers, although these symptoms are often related to PNH rather than true food sensitivities.
  • Hydration and Small Meals: Eating smaller, more frequent meals and staying hydrated may help manage abdominal symptoms.
  • Nutritional Support: Consulting a dietitian familiar with PNH can provide personalized dietary guidance.

Genetic Basis of PNH

Acquired Somatic Mutation

PNH is caused by a somatic mutation in the PIGA gene on the X chromosome, which affects hematopoietic stem cells in the bone marrow (Hill et al., 2021). The mutation is not inherited but occurs spontaneously, leading to the absence of GPI anchors needed for the attachment of protective proteins on red blood cells.

Loss of Protective Proteins

The PIGA mutation leads to a deficiency of proteins like CD55 and CD59 on the red blood cell surface, making the cells vulnerable to immune-mediated destruction (hemolysis).

Clonal Expansion

A single stem cell with the PIGA mutation can expand and produce a large population of abnormal blood cells, resulting in the clinical manifestations of PNH.

Is PNH Inherited?

PNH is not inherited and does not run in families. However, rare inherited forms, such as congenital PNH or inherited GPI deficiencies, involve different genes and present distinct symptoms.

Diagnosis and Genetic Testing

  • Flow Cytometry: The primary diagnostic method for PNH, detecting the absence of CD55 and CD59 on blood cells.
  • Genetic Testing: PIGA mutations can be confirmed through molecular genetic testing, which is more commonly used in research settings.

Implications of the Genetic Mutation in PNH

Understanding the genetic mutation underlying PNH allows for targeted treatments that inhibit complement activation, protecting red blood cells and preventing complications like thrombosis.

Conclusion

PNH represents a complex disorder combining genetic mutation and immune dysfunction. Accurate diagnosis and targeted treatments are crucial for managing the disease and improving patient outcomes. While food sensitivities are not directly associated with PNH, symptom overlap can complicate dietary management, highlighting the need for comprehensive care.

References

MalaCards - 724 diseases matching PNH

  • Hill, A., DeZern, A. E., Kinoshita, T., Brodsky, R. A. (2021). Paroxysmal nocturnal haemoglobinuria. Nature Reviews Disease Primers, 7(1), 1-22. Link
  • Risitano, A. M. (2019). Paroxysmal nocturnal hemoglobinuria and other complement-mediated hematologic disorders. Hematology Am Soc Hematol Educ Program, 2019(1), 440-449. Link
  • Scheinberg, P., Young, N. S., Barrett, J. (2020). Hematopoietic stem cell transplantation for severe aplastic anemia: a 2020 update. Blood, 136(Supplement 1), 10. Link

This comprehensive approach to PNH highlights the importance of individualized care, regular monitoring, and the integration of both medical and supportive strategies to improve quality of life for affected individuals.

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right.
Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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