Iron Studies Vital for Diagnosis and Staging of Liver Disease

Research has found that iron overload is present in 10% to 30% of patients with chronic liver disease. As a result, understanding how to evaluate and interpret iron studies is an essential skill for clinicians, said Vinday Sundaram, MD, MSc, during his presentation on this topic at the Liver Meeting Digital Experience, the virtual meeting of the American Association for the Study of Liver Diseases (AASLD) on Friday, November 13, 2020.

Dr Sundaram is the director of Hepatology Outcomes Research and assistant medical director of Liver Transplantation at Cedars-Sinai Medical Center in Los Angeles, California.

Hereditary hemochromatosis (HH), which leads to increased iron stores, results from genetic mutations and is classified into 4 types. The most common, type 1, accounts for 90% of all cases of hereditary hemochromatosis. Ferroportin disease results from a genetic mutation in the SLC40A1 gene. It causes loss of function in ferroportin transport and its hallmark is iron deposition in the Kupffer cells rather than hepatic cells.

Secondary iron overload is hemochromatosis that is not caused by a genetic mutation. Rather, it often results from inflammatory diseases, malignancies, or liver diseases including hepatitis, fatty liver disease, and cirrhosis.

Dr Sundaram explained that the key compounds assessed in an iron study are hepcidin, a hormone synthesized and secreted by the liver in response to circulating iron levels, which inhibits iron absorption from the intestine; ferroportin-1, which is a transmembrane protein found in intestinal cells that facilitates iron transport; transferrin, a glycoprotein synthesized by the liver that carries iron in circulation; and serum ferritin, a protein that stores and releases intracellular iron.

He reviewed the case of a man aged 54 years who was referred for elevated alanine transaminase (ALT) and aspartate aminotransferase (AST), while the remainder of his liver panel, complete blood count, and creatinine were within normal limits. The patient had a history of class 1 obesity and diabetes mellitus, no family history of liver disease, only social drinking, and no tobacco use. Genetic tests showed the patient carried none of the mutations associated with hereditary hemochromatosis, and viral and autoimmune hepatitis panels were negative.

However, the patient’s iron panel showed elevated ferritin at 1012 ng/mL and transferrin saturation of 38%. Ultrasound showed fatty infiltration with a normal liver contour.

He explained that several causes should be considered in light of these results, including the possibility of nonalcoholic fatty liver disease (NAFLD) or a nongenetic-related iron overload. Ultimately, the patient underwent a liver biopsy, which found steatosis without steatohepatitis, diffuse iron deposition in the Kupffer cells, and stage 1 fibrosis, which pointed to a diagnosis of ferroportin disease.

Dr Sundaram further explained that liver biopsy is most often used for the staging of fibrosis, especially when serum ferritin is more than 1000 ng/mL, or to diagnose secondary iron overload. It can help to distinguish between the types of HH, as well.

He noted that serum ferritin is an important marker of end-organ damage and predictor of advanced fibrosis in HH. A study of 182 patients with HH with no risk factors for nonalcoholic steatohepatitis (NASH), who were light drinkers, revealed that 22% of the patients had cirrhosis; of patients with serum ferritin levels above 1000 ng/mL, 45% were found on biopsy to have cirrhosis. “This underscores the importance of fibrosis staging in patients with type 1 HH, particularly when they show serum ferritin levels above 1000,” Dr Sundaram said.

He stated that “[Magnetic resonance imaging] has recently become a very valuable tool in the evaluation of patients with elevated iron studies.” It can quantify hepatic iron content and, in combination with elastrography, can stage fibrosis, when used with appropriate software, such as T2 spin echo or Ferriscan. It is also useful in distinguishing ferroportin disease, in which iron is deposited in the spleen as well as the liver, from type 1 HH.  “This is particularly useful because there is no genetic test for ferroportin disease,” he explained.

The management of both type 1 HH and ferroportin disease is essentially the same: phlebotomy performed weekly to remove 500 mL of blood, with the goal of reaching a serum ferritin level of 50 to 100 ng/mL, Dr Sundaram said. Once the goal is achieved, the patient can reduce phlebotomy to 3 to 4 times year. Neither condition warrants dietary restrictions, he said, but patients with type 1 HH are advised to avoid vitamin C and iron supplementation.

Patients with ferroportin are at somewhat higher risk of developing anemia during treatment. “When counseling a patient, I also caution patients that some conditions such as diabetes, cirrhosis, arthralgias, and hypogonadism, may not improve with treatment.”

Some patients with baseline anemia or needle phobia may not be candidates for phlebotomy; in these cases, chelating agents may be used but are not considered first-line agents. The US Food and Drug Administration has approved 3 agents, which have range of adverse effects.

Proton pump inhibitors (PPI) can be used as an adjunctive treatment, because gastric acid inhibition can reduce release of iron from food, Dr Sundaram noted. A randomized controlled trial found that patients who took 40 mg of pantoprazole daily were able to reduce their phlebotomy treatments significantly, from 1.3 to 2.6 treatments over 12 months. However, due to their adverse effects, PPIs are not currently recommended for patients in the setting of phlebotomy for iron overload.

Secondary iron overload is generally due to iron-loading anemia or repeated blood transfusions. In patients with secondary iron overload, chelation is the preferred treatment. “A serum ferritin level above 1000 is a reasonable threshold to initiate treatment,” he stated.

In patients with other liver diseases, such as NAFLD, there is no indication for phlebotomy, Dr Sundaram said.

He reviewed the algorithm from the American College of Gastroenterology guideline, which calls for initially checking the serum transferrin iron saturation (TS) and serum ferritin levels among patients at risk of or suspected to have hemochromatosis. If the TS level is at or above 45% or serum ferritin levels are elevated, patients should then undergo testing for the homeostatic iron regulator (HFE) genotype. The results of such genetic tests and of subsequent evaluations of serum ferritin will guide treatment, whether that includes phlebotomy, evaluation for other liver diseases, or liver biopsy for staging or to rule out other diseases.

 

—Rebecca Mashaw

 

Reference:

Sundaram, V. Interpretation and evaluation of elevated iron studies in the patient with liver disease. Talk presented at: American Association for the Study of Liver Diseases annual meeting. November 13, 2020. Virtual.