Liver iron overload symptoms mimic those of liver graft-versus-host disease (GVHD). The liver is one of the target organs for acute and chronic GVHD. Iron overload may manifest as GVHD exacerbation, causing unnecessary continuation or dose increases of immunosuppressive therapy. Like patients with chronic hepatitis, iron overload may worsen the course of GVHD. In addition, iron overload can increase the risk of opportunistic infections.
What Are Some Potential Causes of Hepatoxicity Besides Liver GVHD?
In addition to GVHD of the liver, there are many other potential etiologies of hepatotoxicity. Liver function tests (LFTs), including proteins, bilirubin, and liver enzymes, can be elevated for multiple reasons post transplant. The timing of a rise in LFTs and additional symptoms become essential in ruling out different causes, including:
- Sinusoidal obstructive syndrome (SOS), formerly called veno-occlusive disease
- Drug-induced liver injury (DILI) from cytotoxic therapy, GVHD prevention, supportive therapy
- Infection or sepsis-associated liver injury (particularly viral reactivation and fungal infection)
- Biliary obstruction, steatosis
- Iron overload and hepatic uptake
Although LFT results are commonly abnormal post stem cell transplantation, supporting a diagnosis of liver GVHD is challenging, particularly if there are no other clinical signs.
How Does Iron Normally Regulate?
Under normal physiologic conditions, the body carefully regulates iron to maintain homeostasis and minimize free iron that is toxic to cells. Unbound—or free—iron forms reactive oxygen species leading to organ damage. The duodenum absorbs dietary iron and then circulates it in the plasma bound to transferrin. The erythroid precursors and the mature erythrocytes (red blood cells) use most of the iron to make hemoglobin. The body’s muscle fibers and other tissues use approximately 10%-15% of iron stores. The parenchymal cells of the liver and the reticuloendothelial macrophages store iron. The macrophages provide usable iron by degrading hemoglobin in worn-out erythrocytes. Sloughing mucosal cells, menstruation, and other blood losses cause a small amount of iron loss.
What Is Iron Overload?
Iron overload is simply a condition in which the body stores too much iron. Rarely is the condition genetic or hereditary, called hemochromatosis. Patients with blood cancer often receive blood transfusions to manage the disease or treatment-induced anemia. Each unit of packed red blood cells contains approximately 250 milligrams of iron. Iron overload can start with as few as 10 lifetime blood transfusions.
Unfortunately, humans have no mechanism to get rid of excess iron. With chronic iron overload, the body’s iron transport and storage capacity are overburdened, so it stores the iron in vital organs resulting in damage; storage in the liver results in hepatotoxicity (Table).
Damage to Organs Caused by Iron Overload
| Organ | Damage |
| Gonads | Infertility, lack of sexual development, sexual dysfunction |
| Heart | Cardiomyopathy, cardiac impairment, cardiac failure |
| Liver | Cirrhosis, fibrosis |
| Pancreas | Diabetes mellitus |
| Pituitary gland | Impaired growth, infertility |
| Thyroid | Hypothyroidism |
How Is Iron Overload Diagnosed?
Consistently high iron tests, such as serum ferritin level >1000 mcg/L and transferrin saturation (TSAT) >40%, may indicate too much iron in the body and help early identification of patients at risk for iron overload. Serum ferritin is an easy, convenient lab test to estimate total body iron, but it does not give iron concentration in specific organs such as the heart or liver. Liver iron content (LIC), also called hepatic iron concentration (HIC), is another way to measure total body iron stores since the liver is the primary location for iron storage. Significant iron overload is defined as an HIC >3 times the upper limit of normal. A liver biopsy or MRI may give more information about hepatic iron distribution. However, liver biopsies can be challenging in patients with thrombocytopenia. In addition, iron is often unevenly distributed, so measuring iron by invasive liver biopsy may give underrepresentation findings.
In a study published in Transplantation and Cellular Therapy examining patterns of liver injury associated with hepatic dysfunction in chronic GVHD, of the 27 patients with adequate liver tissue, 18 (66.7%) were found to have iron overload. Although the researchers’ primary aim was to diagnose liver GVHD, there were multiple findings on liver biopsy.
What Is the Treatment for Iron Overload?
Patients may receive iron-chelating agents (eg, deferoxamine, deferasirox) that tightly bind the iron and transport it for excretion. Phlebotomy may be an option for patients who are not anemic.
Nurses need to be aware that iron from transfusions may accumulate in vital organs, including the heart and liver. Patients with acute leukemia and sickle cell disease are at high risk for iron overload, which can affect pretransplant morbidity. When patients develop posttransplant liver complications, distinguishing liver GVHD from hepatic damage from iron overload is often challenging.
