Iron Overload: What Hematologists Should Know

One patient, a 39-year-old woman, went to a dermatologist seeking care for fluid-filled blisters over the backs of her hands and arms. Another patient, a 56-year-old man, sought care from his general practitioner owing to fatigue.

Their presentations were quite different, but the two patients shared one thing in common: iron overload. Both ended up in the care of hematologists who diagnosed their conditions as porphyria cutanea tarda (PCT) and hemochromatosis, respectively.

A pair of hematologists discussed the treatment of these disorders at the American Society of Hematology (ASH) 2024 Annual Meeting and in reports in Hematology: American Society of Hematology Education Program. Here’s a look at the guidance they provided.

Porphyria Cutanea Tarda: Skin Trouble

Testing revealed that the female patient had a highly elevated porphyrin levels: Her urine uroporphyrin was 3959  nmol/L (normal, < 30 nmol/L) and plasma uroporphyrin was 2.0 µg/dL (normal, < 1.0  µg/dL). Her serum ferritin level was also high, at 420 ng/mL (normal, < 200 ng/mL).

Rebecca Karp Leaf, MD, of Massachusetts General Hospital and Harvard Medical School, diagnosed her with PCT, a disorder of heme biosynthesis that often presents with skin manifestations.

As co-founder and co-director of the Boston hospital’s Porphyria Center, Karp Leaf is a leading expert in PCT, a rare disease that affects 5-10 people per 100,000. In addition to speaking at the ASH meeting in December, she described PCT in a December 2024 article in Hematology: American Society of Hematology Education Program. 

PCT is caused by inhibition of an enzyme in heme biosynthesis and leads to accumulation of porphyrins in the liver and plasma, Karp Leaf said. Through a complex process, excess of iron leads to inhibition of the enzyme, which leads to a buildup of toxic porphyrins, she said. The condition causes painless, blistering lesions on sun-exposed skin, scarring, skin fragility, dark urine, and liver disease. 

PCT most commonly occurs in middle age after the age of 40 and affects men more than women. “It’s the only porphyria that can occur absent a genetic variant,” she said, and 75% of cases have no genetic component. 

Options for Treatment Include Antivirals and Phlebotomy

Risk factors for PCT include alcohol use, smoking, exogenous estrogen, hepatitis, and HIV mutations. 

In regard to treatment, “modification of risk factors can be variably helpful: alcohol and smoking cessation, stopping exogenous estrogen, sun-protective clothing, and steroid-containing creams for lesions,” Karp Leaf said. “Most patients typically require further therapy to reduce liver porphyrins.”

Urine and plasma tests can help with diagnosis, she said. In patients with hepatitis C (HCV), “direct-acting antivirals can actually lead to resolution of PCT without any other therapy. We suspect that with effective antiviral treatment for HCV, the incidence of PCT will really go down.”

Therapeutic phlebotomy — blood removal — is another option. “It’s one of my favorite therapies because you don’t have to give somebody a drug. You can just take out iron,” Karp Leaf said. “Typically, we’ll start with venesection of 450 ccs of whole blood every 2 weeks, We target a ferritin level of 20 [ng/mL] but permit it up to 50 [ng/mL], or a little bit higher.”

The treatment leads to resolution of blisters in about 2-3 months, she said, and normalization of porphyrins by 13 months. Patients typically require about 6-8 treatments, she said. 

Another option is iron chelation, iron removal via medicine, “but it’s expensive, has side effects, and is really not recommended if other treatments are available,” she said. 

Hydroxychloroquine Can Be Helpful Too

Low-dose hydroxychloroquine can also be effective at 100 mg twice a week, “much lower than what we use in autoimmune disease,” Karp Leaf said. “We suspect that it’s taken up by the hepatic lysosomes and causes release of porphyrins. It causes clinical remission in about 6 months.”

However, higher doses can lead to liver injury, and the drug’s use is limited in end-stage kidney disease since porphyrins are excreted in the urine. These patients are especially difficult to treat, she said.

In the case of the 39-year-old patient, Karp Leaf recommended that the woman reduce her alcohol intake and begin using a copper intrauterine device for contraception instead of a combined oral contraceptive pill, which allowed her to undergo phlebotomy.

“She needed about eight sessions of therapeutic phlebotomy to achieve a ferritin of 30 [ng/mL], and her lesions resolved in 6 months,” Karp Leaf said. “Her plasma porphyrins resolved by 12 months. Her liver biochemistries were a bit elevated, and they subsequently normalized.”

Karp Leaf said she sees the patient about once a year. 

Hemochromatosis: It’s (Probably) a Family Affair

In an adjoining presentation at ASH and in a December 2024 article in Hematology: American Society of Hematology Education Program, hematologist Domenico Girelli, MD, PhD, with the University of Verona, Italy, told colleagues about the 56-year-old male patient with fatigue. He also had a mildly enlarged liver, hyperferritinemia (890  µg/L vs normal value < 300 µg/L) and a mildly increased alanine aminotransferase level (46 U/L vs normal value < 40 U/L).

The patient was diagnosed with hemochromatosis, a genetic disorder caused by mutations that leads to increased transferrin saturation, Girelli said. 

“By definition, hemochromatosis is characterized by the absence of signs of a primary red blood cell disorder — different from other disorders like transfusion iron overload or iron-loading anemias,” he said. 

It’s also important to consider other possible causes of hyperferritinemia, because most cases of the symptom aren’t related to iron overload, he said. “A careful clinical history and a few laboratory parameters including transferrin saturation are generally sufficient for the differential diagnosis.”

As Girelli noted, “hemochromatosis can have a wide clinical spectrum ranging from mild to severe forms, which are strongly influenced by the co-presence of risk factors like alcohol [use], blood transfusion, and genetic factors captured by polygenic risk score.”

In Many Cases, Hemochromatosis Can Be Successfully Treated

According to Girelli, it’s important to understand the disease stage, because this information can predict the probability of advanced liver fibrosis, which can be a sign of a worse prognosis.

“The strongest clinical predictors of advanced liver fibrosis are ferritin higher than 1000 [µg/L] and the presence of arthropathy [joint disease],” he said. “If both are absent and the patient is asymptomatic, there is no need for further investigation. If both are present, further investigation — including cardiac MRI and full endocrine profile — are indicated. Liver biopsy may be indicated only in uncertain cases.”

Fortunately, “most patients are diagnosed in preclinical or early stage, and their prognosis is excellent, with a normal life expectancy,” he said 

Phlebotomy remains the standard of care for hemochromatosis in uncomplicated cases. “It is safe, cheap, well-tolerated, and significantly reduces mortality and morbidity, especially when it is started before the development of cirrhosis,” he said. 

Family Members Should Be Tested for Genetic Traits

It’s important to advise patients prior to phlebotomy to avoid undercooked seafood and wound contact with sea water because of the risk for sepsis due to the pathogen Vibrio vulnificus, Girelli said. 

And it’s a good idea to test family members to see if they share a genetic risk for hemochromatosis, he said. The 56-year-old patient’s brother turned out to also have genetic risk, and his iron levels were very high. He had recently been diagnosed with seronegative arthritis that could be classified as secondary to hemochromatosis.

For management, Girelli said, patients should minimize or avoid alcohol consumption, eat a healthy diet, and avoid vitamin C and iron supplements even in multivitamin compounds. Patients should be encouraged to exercise and maintain an ideal weight. 

The 56-year-old patient fared well, reaching a ferritin target of 50 mg/mL after multiple phlebotomy procedures that removed nearly 5 g of iron.

The patient tolerated the treatment and his fatigue resolved, Girelli said. “The maintenance treatment consisted of 3 phlebotomies per year. The patient remained asymptomatic and was eventually enrolled as a regular blood donor.”

Karp Leaf disclosed relationships with Alnylam, Recordati, and Disc Medicine. She is a member of the Porphyrias Consortium, part of the Rare Diseases Clinical Research Network, funded by the National Institutes of Health and led by the National Center for Advancing Translational Sciences (NCATS). The consortium is funded by NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases. Girelli had no disclosures.