A Case-Based Review of Iron Overload With an Emphasis on Porphyria Cutanea Tarda, Hepatitis C, C282Y Heterozygosity, and Coronary Artery Disease
Clinical Manifestation
Patients with PCT typically develop blisters, skin fragility, and peeling with sun exposure or minor trauma. They also may experience delayed wound healing in sun-exposed skin.3 The photosensitivity of PCT is believed to be related to the saturation of highly carboxylated uroporphyrins in the liver, which are then released into the circulation. Sun exposure then activates these products facilitating an immune reaction and subsequent skin damage.2 In chronic cases, fibrotic reactions and scaring occur which can be mistaken for scleroderma. Other skin manifestations include hyperpigmentation, hypertrichosis, alopecia due to scaring and purplish heliotrope suffusion of periorbital areas.
Patients can develop cirrhosis due to accumulation of porphyria in the hepatocytes and subsequent parenchymal damage. Hepatocellular carcinoma surveillance is recommended for patients with PCT, although its incidence is rare in those patients.
Diagnosis and Treatment
PCT is mainly a clinical diagnosis. Physicians should consider PCT in patients with photosensitivity and blisters after minor trauma (Figure 2). The urine of a patient with PCT is often pink or red when exposed to air or light due to its high concentration of porphyrin products. Mild elevation of liver enzymes and fatty liver on ultrasound are also noted. Evidence of iron overload is seen in most cases. Screening for risk factors like HCV, HIV, hepatitis B virus, and HH is recommended. Confirmation of PCT typically requires measurement of the porphyria level in a 24-hour urine collection.
Avoiding sun exposure is fundamental in decreasing the development of skin lesions and scaring. Additionally, patients should be advised about the adverse effects of alcohol, smoking, and estrogen therapy on PCT. Treatment of PCT is frequently focused on iron overload and subsequent increased porphyrin oxidation.1,2 Iron can increase reactive oxygen species (ROS), which, in turn, increases the rate of oxidation of uroporphyrinogens. Excess iron also decreases the activity of UROD and increases δ-aminolevulinic acid (ALA) production (the precursor of uroporphyrinogen). Phlebotomy to treat iron overload should be done to a target ferritin level of 20 ng/mL. Clinical manifestations, including skin lesions, typically will normalize before the laboratory findings. Therapeutic remission is expected after 6 to 7 phlebotomy attempts, while clinical improvement can occur after 2 to 3 phlebotomies.
In addition to phlebotomy, 4-aminoquinoline medications (chloroquine and hydroxychloroquine) can be used effectively to treat PCT. Hydroxychloroquine is generally preferred due to its better safety profile. Although the exact mechanism of action of 4-aminoquinolines is not clear, it has been suggested that they bind to porphyrins and form water-soluble products, which are then excreted in the urine. Again, clinical remission occurs much sooner than chemical remission, (3 months vs 12 months). A 4-aminoquinoline should not be used in patients with severe liver disease, renal insufficiency, pregnancy, or G6PD deficiency. When used, they should be used in lower than typical doses due to the rapid removal of accumulated porphyrin from the hepatocytes potentially causing necrosis and acute hepatitis.
Iron chelation also is effective, but it is slower in achieving remission and more expensive than phlebotomy. Treatment of PCT should be individualized. For example, 4-aminoquinolines are contraindicated for patients with end-stage renal disease (ESRD), while phlebotomy could present a problem for patients with preexisting anemia. In this instance, removing 50 cc of blood every 2 weeks may be safe and effective. Furthermore, 4-aminoquinolines in patients with severe iron overload and phlebotomy have been used together. Plasmapheresis is still another option in patients with ESRD.
The use of direct antiviral agents (DAA) in the treatment of HCV has shown promising results in maintaining undetectable viral loads and concurrent remission of PCT. Several studies have shown that treatment of HCV with a DAA obviates the need for treatment PCT.3-5 Treatment of HCV with interferon (IFN) and ribavirin have shown mixed results in controlling PCT, possibly due to their ineffectiveness in maintaining a suppressed viral load. Some studies even showed worsening of PCT with IFN/ribavirin.6
