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kidney MRI marchiafava syndrome

Image: “MRI: Low signal illustration of the kidneys due to iron deposits as Marchiafava syndrome” by Hellerhoff. License: CC BY-SA 3.0


Epidemiology of PNH

Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria is a rare disorder, with an incidence of 10 cases per million and a 50% mortality rate. It typically presents in males and females in early adulthood.

Etiology of PNH

PNH is an acquired defect in the myeloid stem cells with a mutation in the PIG-A gene that is located in the stem cells of the bone marrow. With a PIG mutation, affected red blood cells are known as “PNH RBCs.” The PNH RBCs lack the shield of proteins that protect healthy red blood cells from the complement system because of a deficiency in glycosylphosphatidylinositol (GPI). GPI has linked proteins on RBCs, neutrophils, and platelets. If absent, cells are susceptible to destruction.

PNH Pathophysiology and Pathogenesis

The predisposing factor in anyone with PNH is the inability to synthesize GPI. GPI is located on the X chromosome, rendering only one mutation necessary to eliminate GPI-linked protein expression. One essential GPI-membrane-linked protein is a decay-accelerating factor (DAF); this protein interacts with complement proteins to neutralize the complement attached to RBCs, neutrophils, and platelets. Without this protein, RBCs are susceptible to complement-mediated intravascular hemolysis. The destruction of RBC membranes by complement releases hemoglobin into the bloodstream and circulation.

Hematuria

Image 1: “Hematuria” by Dreamworks. License: CC BY-SA 3.0

The body has a certain threshold in which it can degrade plasma hemoglobin. However, once levels are reached, any extra hemoglobin leads to increased heme in the urine and plasma. This sequela leads to further pathologies as increased hemoglobin levels deplete nitric oxide levels in circulation. Nitric oxide is needed for vasodilation, smooth muscle relaxation, and vascular homeostasis. Decreased nitric oxide levels lead to vasoconstriction, smooth muscle contractions, and spasms.

PNH has a mortality rate of about 50% due to the pathophysiology of thrombosis, secondary to PNH. Hemolysis increases the number of thrombotic events, which, when logged in multiple organs, increase organ failure and insufficiency. Thrombotic events are also due to hypercoagulable states induced by free hemoglobin in the bloodstream.

Paroxysmal nocturnal hemoglobinuria is named for its episodic (paroxysmal) hemolysis that usually occurs at night due to acidotic activation. Mild respiratory acidosis appears to develop with shallow breathing during sleep. This activates the complement mechanism, leading to RBC, WBC, and platelet lysis. This lysis leads to hemoglobinemia and hemoglobinuria in the morning.

PNH Symptoms

Signs of paroxysmal nocturnal hemoglobinuria

PNH is usually symptomatic; only a small percentage of cases are asymptomatic. The first classic sign of PNH is hemolysis due to red blood cell lysis. This leads to symptoms like fatigue, jaundice, and hematuria.

The side effects of hemolysis can be broken down by different manifestations in the body’s organs and pathways. Renal insufficiency arises due to intravascular hemolysis in PNH. Toxicity increases due to direct free heme in the kidney. Chronic hemolysis increases renal iron deposition, leading to cortical scarring and infarcts.

Additionally, lysis leads to depletion of nitric oxide levels. Symptoms of decreased nitric oxide lead to smooth muscle dystonia, abdominal pain, cramping, and finally, erectile dysfunction. Abdominal pain is due to smooth muscle dystonia, leading to contraction of the visceral organs and vasculature, which causes spasms and pain. Lack of nitric oxide also leads to decreased vascular dilation in genital tissue, specifically the corpora cavernosa, leading to erectile dysfunction.

The most detrimental complication of PNH is thrombosis. It is the primary cause of death in over 40% of afflicted patients. Thrombi may lodge in the venous or arterial system, such as the hepatic, portal, or cerebral veins, causing cirrhosis, splenic congestion, and cerebral strokes, respectively. Symptoms may be insidious as clots aren’t found immediately. Skin necrosis, vein thrombosis, and pulmonary embolisms are some of the most frequent symptoms. Some clots are found incidentally, and many remain undetected, leading to increased mortality.

Anemia

Image 2: “A hand demonstrating extra pallor” by James Heilman, MD. License: CC BY-SA 3.0

Iron deficiency from blood loss leads to anemic like signs and symptoms, such as fatigue, pallor (Image 2), dyspnea, headaches, and tachycardia. Studies indicate patients with aplastic anemia (a disorder where the body halts production of new red blood cells due to bone marrow damage) are more susceptible to PNH.

Diagnosis of PNH

Paroxysmal nocturnal hemoglobinuria detected by flow cytometry

Typically, an evaluation for PNH consists of lab tests for hemolytic anemia and to rule out other causes of hemolysis. This includes autoimmune pathologies or injuries. The most common tests are:

  • CBC
  • RBC smear
  • Reticulocyte count
  • Direct Coombs testing
  • Urine hemoglobin or hemosiderin.

Flow cytometry (Image 3) is the most specific test used to confirm PNH. Patients at risk for PNH, aplastic anemia, or myelodysplastic disorder are screened yearly to monitor the development of subclinical PNH. A blood sample is incubated with tagged fluorescent antibodies that bind to GPI-linked proteins. The most commonly used antibodies are Fluorescent AERolysin (FLAER). This state-of-the-art laboratory test sends the patient’s blood for flow cytometry to detect CD59 (MIRL), a glycoprotein, and CD55 (DAF), to regulate complement action. Absence or reduced expression of both CD59 and CD55 on PNH RBCs is
diagnostic.

Cytometer

Image 3: “Schematic of a flow cytometer, from sheath focusing to data acquisition.” by Kierano. License: CC BY 3.0

A second diagnostic test would be the sugar water or sucrose lysis test. This test uses the ionic strength of serum that is reduced by adding an iso-osmotic solution of sucrose, which then activates the classic complement pathway, and complement-sensitive cells are lysed.

Lab values typically show anemia, increased reticulocyte count, increased LDH, free serum hemoglobin with red serum, a negative Coomb’s test, and iron deficiency. Paroxysmal nocturnal hemoglobinuria (PNH) leukocytes have a low leukocyte alkaline phosphatase (ALP) score.

PNH Therapy

Treatment of PNH is focused on targeting the underlying hemolytic defect and monitoring for progression. Patients with PNH have yearly screens for increased or decreased PNH clone sizes. Currently, the only therapies for classic PNH include hematopoietic cell transplantation (HCT) or complement inhibition with medications such as eculizumab. Those with multiple thrombi are treated with anticoagulation therapeutics. Iron supplementation, in conjunction with folate, is used for iron-deficient patients. Those with bone marrow failures, or malignancies, are treated with immunosuppressive therapy and weekly WBC monitoring.

Opioids and analgesics are used for those suffering from smooth muscle dystonia and spasms. Femal patients with PNH who plan to become pregnant risk increased maternal and fetal morbidity and mortality. Therefore, strict iron and folate supplementation, along with transfusions, may be needed during pregnancy.

Summary

Overall, paroxysmal nocturnal hemoglobinuria (PNH) is a rare but life-threatening disorder. Unexplained hemolytic anemia, thrombi, and hematuria increase mortality. All patients should have baseline testing and annual retesting. Management may be aggressive or mild, depending on symptoms and severity. There is still no cure for PNH, but management and research continue to help treat this hemolytic disease.

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