Table 4.

Ferritin level and related morbidities.

Study	Study Subject	N, Study Design	Morbidity Ferritin Level (Patient Number)/Patient Number (%)		Note
Alberto Roghi et al., 2010 [47]	TI, regularly transfused (2–4 times/year) Infrequently (few) Transfusion naïve Iron chelation therapy ≥ 1 years Italy	49 age ≥ 18 years (range 23–64) Iron chelation Yes (n = 34), No (n = 15) Cross-sectional	No evidence of cardiac iron overload Lack correlation between cardiac T2 and LIC or serum ferritin Statistically significant positive but poor linearity between serum ferritin and LIC Multivariate analysis: LIC positive with ALT levels		No defined morbidity
The ORIENT study [42]	β-TI, age ≥ 2 years Hb 7–9 g/dL without regular BT, exclude iron chelation or fetal hemoglobin induction therapy before or throughout the observation period; no death or lost follow-up 5 centers in Middle East and Italy	52 patients 11-year Retrospective cohort	≥800 (n = 27) 300–800 (n = 17) ≤ 300(n = 8) Liver disease (non-B, C) 27(100%) 9 (52.9%) 0 Any type of morbidity Endocrine 15 (55.6%) 4 (23.5%) 0 Extramedullary 23 (85.2%) 6 (35.3%) 0 hemostasis, thrombosis, PHN adjusted for age, sex, splenectomy, mean Hb, ferritin ↑ 1 ng/mL: hazard ratio at least 1 morbidity 1.002, p = 0.002, multiple morbidity 1.011, p = 0.005		Mean annual % Hb ↓ 0.3%; mean ferritin ↑ 9%
KM Musallam 2011, 2013 [33,48]	β-TI, age ≥ 2 years with Hb 7 to 9 g/dL without regular transfusion at diagnosis No iron chelation or fetal hemoglobin-inducing agents 2 centers in Italy Transfusion history: 1. Every 1–3 m, regularly transfused 2. Occasionally transfused (severe anemia secondary to infection, surgery, or pregnancy) 3. Non-transfused	168 patients Cross-sectional	LIC cut-off (mg/Fe/g) dw(MRI):		adjusted for age, gender, transfusion status, splenectomy, etc.
			osteoporosis	≥9
			pulmonary hypertension	≥6
			thrombosis	≥7
			hypothyroidism	≥6
			hypogonadism	≥6
			vascular	≥7
			endocrine/bone	≥6
			LIC ≥ 5 mg/g dw vs. < 5 mg/g dw (MRI):
			osteoporosis	(58.2 vs. 28.6%)
			pulmonary hypertension	(43.9 vs. 18.6%)
			thrombosis	(34.7 vs. 14.3%)
			hypothyroidism	(24.5 vs. 8.6%)
			hypogonadism	(23.5 vs. 7.1%)
F E Chen et al., 2000 [49]	HbH Chinese patient review chart Jan 1998 to Dec 1999	114 patients Cross-sectional	Ferritin increased with age (p < 0.001) not related to transfusion history 6 patients liver biopsy for ↑ ferritin or abnormal liver function (all HBV(−), HCV(−), herbal(−), long-term iron therapy(−)), fibrosis in 5 and 2 out of 5 cirrhosis		9/80 HBsAg (+); 0/80 anti-HCV Ab(+)
Luke K L Chan et al., 2021 [50]	HbH Chinese patients ≥ 18 years 1 HCV carrier 1 alcoholic Transfusion history 35, iron chelation 9	80 patients Cross-sectional	Advanced liver fibrosis (transient elastography) Univariable, clinically significant age ≥ 65 years, moderate-to-severe liver overload (LIC ≥ 7 mg/g dry weight, MRI), serum ferritin 800 ≥ µg/L multivariable regression with clinical significance age ≥ 65 years, moderate-to-severe liver overload
Kunrada Inthawong, 2015 [51]	NTDT < 3 RBC/year in the last 5 years, age 10–50 years Exclude secondary pulmonary hypertension	76 patients Retrospective cohort	12 iron chelation Previous splenectomy, higher cumulative RBC transfusions (≥10 RBC) Nucleated RBC, a high non-transferrin-bound iron, but not ferritin or LIC associated with pulmonary hypertension (9.2%)
Aessopos A et al., 2001 [31]	60.9% not transfused or minimally transfused; rest start transfusion after age > 5 year Group A: no or rare transfusion Group B: occasional transfusion	110 β-TI Retrospective cohort for 2 years	Start Ferritin > 1000 ng/mL Stop < 1000 ng/mL Multivariate regression analysis: pulmonary hypertension not related to serum ferritin level, peak ferritin level, transfusion, etc.