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CASE REPORT



Usefulness of Magnetic Resonance Imaging for the Diagnosis of Hemochromatosis with Severe Hepatic Steatosis in Nonalcoholic Fatty Liver Disease Yuichi Nozaki 1, Noriko Sato 2, Tsuyoshi Tajima 3, Kanehiro Hasuo 3, Yasushi Kojima 1, Kumiko Umemoto 1, Saori Mishima 1, Shintaro Mikami 1, Tomohiro Nakayama 3, Toru Igari 4, Junichi Akiyama 1, Masatoshi Imamura 1, Naohiko Masaki 1 and Mikio Yanase 1

Abstract The ratio of the number of patients with non-alcoholic steatohepatitis (NASH) to the total number of patients with liver dysfunction has increased in many countries around the world. Liver dysfunction is also caused by multiple blood transfusions in patients with leukemia and other hematological diseases, with liver dysfunction often accompanied by secondary hemochromatosis. This study describes a 25-year-old man with secondary hemochromatosis combined with NASH. Magnetic resonance imaging was useful for visualizing the distributions of both iron and fat in the liver of this patient in order to make a differential diagnosis and to evaluate the effect of treatment. Key words: MRI, hemochromatosis, hepatic steatosis, iron, lipid, NAFLD

(Intern Med 55: 2413-2417, 2016) (DOI: 10.2169/internalmedicine.55.6650)

Introduction The number of patients visiting the hospital to evaluate liver dysfunction resulting from non-alcoholic fatty liver disease (NAFLD) has gradually increased (1). The diagnosis of liver diseases is based on a medical interview, physical examination, blood examination, imaging and biopsy findings. Magnetic resonance imaging (MRI) has been reported to be an appropriate modality for detecting hepatic fat and iron deposition in patients with diffuse liver diseases (2). Fatty liver can be diagnosed using the gradient-echo (GRE) technique, by the difference in signal intensity between in-phase and opposed-phase images of the liver parenchyma. The iron distribution in the liver appears as a diffuse low signal intensity of the liver parenchyma on T2- and T2*-weighted images. NAFLD is a common chronic liver disease and a major

cause of liver dysfunction. NAFLD includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), with NAFL representing the first phase of NASH. NASH, which is characterized by steatosis, can subsequently develop into fatty liver disease with associated inflammation, with the potential to result in cirrhosis and/or hepatocellular carcinoma (3). The increased number of young patients with NAFLD/NASH associated with metabolic syndrome has therefore become an important epidemiologic problem (1). Hemochromatosis is another common diffuse liver disease that includes primary and genetic hemochromatosis as well as secondary and transfusional iron overload (4). Frequent multiple blood transfusions, such as those in patients with leukemia, can give rise to liver dysfunction with secondary hemochromatosis (5). This report describes a patient with combined hemochromatosis and NASH, showing that MRI was useful for visualizing the distributions of both iron and fat in the liver.



Department of Gastroenterology, National Center for Global Health and Medicine, Japan, 2 Department of Pediatrics, National Center for Global Health and Medicine, Japan, 3 Department of Radiology, National Center for Global Health and Medicine, Japan and 4 Department of Pathology, National Center for Global Health and Medicine, Japan Received for publication October 4, 2015; Accepted for publication December 27, 2015 Correspondence to Dr. Yuichi Nozaki, [email protected]

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Table. Patient Parameters before and after Treatment. Before treatment After treatment WBC (/ȝL) 6,330 6,480 RBC (106/ȝL) 4.46 4.63 Hb (g/dL) 14.5 15.1 Ht (%) 42.6 43.8 MCV (fl) 95.5 94.6 MCHC (%) 34 34.5 26.4 27.4 Plt (104/ȝL) T-Bil (mg/dL) 0.9 0.9 AST (IU/L) 67 30 ALT (IU/L) 165 52 ALP (IU/L) 275 248 Ȗ-GTP (IU/L) 79 70 Blood Sugar (mg/dL) 90 86 HbA1c (%) 4.9 5.0 Cholesterol (mg/dL) 300 304 Triacylglycerol (mg/dL) 351 307 LDL-cholesterol (mg/dL) 189 188 Uric acid (mg/dL) 7.8 7.4 Ferritin (ng/mL) 1,789.7 421.6 Fe (ȝg/dL) 186 157 UIBC (ȝg/dL) 163 230 Liver/ Spleen ratio 0.87 0.75 WBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, Ht: hematocrit, MCV: mean cell volume, MCHC: mean cell hemoglobin concentration, Plt: platelet, T-Bil: total-bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, Ȗ-GTP: Ȗ-glutamyltransferase, LDL: low-density lipoprotein, UIBC: unsaturated iron binding capacity

Figure 1. Abdominal non-contrast CT examination in our patient, showing hepatomegaly and diffuse hypoattenuated areas in the liver.

Case Report A 25-year-old man was referred to the Department of Gastroenterology and Hepatology in our institution for a further assessment of liver dysfunction. He had a previous medical history of acute lymphocytic leukemia. Complete remission was achieved following a bone marrow transplant at 5 years of age. He did not smoke or drink alcohol habitually, and he was not taking any medications. He had no pertinent family medical history. At 5 years of age, after having received multiple blood transfusions (over 20 units of red blood cells), he temporarily received iron chelation therapy; subsequently, however, he stopped making regular outpatient visits. At 15 years of age, he was diagnosed with liver dysfunction and a fatty liver during a medical checkup. He was referred to our department after his liver dysfunction worsened. At the time of his first visit, his height was 165.5 cm and his body weight was 58.6 kg (body mass index, 22.0 kg/m2). His vital signs on examination were within the normal range, and a physical examination showed no significant abnormalities. However, blood tests revealed elevated serum liver enzyme levels [aspartate aminotransferase (AST), 67 IU/L; alanine aminotransferase (ALT), 165 IU/L; and γglutamyltransferase, 79 IU/L]. Markers of iron metabolism were also abnormal (ferritin, 1,789.7 ng/mL; Fe, 186 μg/dL; unsaturated iron binding capacity, 163 μg/dL). Laboratory data showed abnormal lipid and uric acid metabolism (lowdensity-lipoprotein cholesterol, 189 mg/dL; total-cholesterol, 300 mg/dL; triglyceride, 351 mg/dL; uric acid, 7.8 mg/dL),

but his glucose metabolism appeared to be normal (Table). His serum concentration of antinuclear antibody was slightly high (21.0 according to an enzyme linked immunosorbent assay), whereas other markers associated with causes of liver dysfunction, such as hepatitis B surface antigen, antihepatitis C virus antibody, and serum concentrations of immunoglobulin (Ig) G, IgM, and antimitochondrial antibody, were all within normal ranges. Liver fibrosis and liver tumor markers were normal. Abdominal ultrasound (US) showed hepatomegaly and brightness of the liver. Similarly, abdominal non-contrast computed tomography (CT) revealed hepatomegaly and diffuse low-attenuated areas in the liver, suggesting diffuse fatty liver (Fig. 1). Although these findings only suggested a diagnosis of fatty liver, his medical history of multiple blood transfusions and laboratory data showing a high serum ferritin level suggested the simultaneous occurrence of hemochromatosis. Abdominal MRI was performed to evaluate the extent of iron deposition in the liver. The application of an axial T1-weighted fat-suppressed GRE pulse sequence showed the signal intensity of the liver to be relatively high for in-phase and low for opposed-phase images. This loss of liver signal intensity between the in-phase and opposed-phase images suggested fat deposition in the liver (Fig. 2). In contrast, the axial T2-weighted and long echo time (TE) images showed diffuse low-signal intensity areas in the liver and spleen, thus indicating the distribution of iron in these organs (Fig. 2). A histologic examination of a transcutaneous liver biopsy, following Hematoxylin-Eosin and Masson staining and silver impregnation, showed lobular inflammation, hepatocellular ballooning degeneration, Mallory-Denk bodies, and perisinusoidal fibrosis in the presence of macrovesicular hepatocellular steatosis, consistent with a diagnosis of NASH [Matteoni classification (6) type IV, Brunt classification (7) Grade 2/Stage 1] (Fig. 3). Further histological examinations of iron-stained liver tissue specimens showed iron deposition in hepatocytes and Kupffer cells throughout the hepatic lobes (Fig. 3). Based on these findings, this patient was diagnosed with secondary hemochromatosis combined with NASH. He was initially

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Figure 2. Axial T1-weighted fat-suppressed GRE pulse sequences during abdominal MRI, showing high signals on in-phase images and low signals on opposed-phase images. Axial T2-weighted and long TE images showed diffuse low signal intensity areas in the liver and spleen.

Figure 3. A histological examination of liver tissue stained with Hematoxylin and Eosin staining, silver impregnation, and Masson staining methods, showing lobular inflammation, hepatocellular ballooning degeneration, a Mallory-Denk body (arrow), and perisinusoidal fibrosis in the presence of macrovesicular hepatocellular steatosis, consistent with a diagnosis of NASH (Matteoni classification type IV, Brunt classification Grade 2/Stage 1). The iron-staining method showed iron deposition in hepatocytes and Kupffer cells throughout the hepatic lobes.

prescribed deferasirox, an oral iron chelating agent, at a dose of 1,000 mg per day. Two months later, his liver function had improved and his serum ferritin level had decreased

(Fig. 4A). This recovery of liver dysfunction was accompanied by a reduction in iron deposition in the liver, as shown by follow-up long TE (TR/TE=250/10) MRI, and the low-

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Figure 4. A: The liver function improved as the serum ferritin level decreased. B: After treatment, the low signal intensity in the liver and spleen improved on the long TE sequences of MR images.

intensity signals in the liver and spleen on the long TE images had also improved(Fig. 4B). This patient experienced no adverse events during oral iron chelation treatment. As his serum ferritin level was lower than 500 ng/mL, the oral iron chelation was discontinued and he was started on treatments to improve his quality of life and to treat dyslipidemia and hyperuremia. The patient has not experienced a recurrence of iron overload for 3 years after treatment. Written informed consent was obtained from the patient for publication of this case report.

Discussion The findings of this study show that MRI was useful for the diagnosis of a patient with a combination of secondary hemochromatosis and NASH. MRI was also useful for evaluating the effects of treatment. MRI was able to detect both iron and lipid deposition in the liver. In contrast, neither abdominal US nor CT images could visualize the distribution of iron. Lipid deposition produces a high echo signal on US and hypoattenuated areas on CT (8), while iron deposition produces increases in both the US echo signal and the CT attenuation (4). Thus, the echo level of the liver on US was relatively high, as it represented the sum of the

high echo levels for both lipids and iron. The attenuation of the liver on CT was also relatively high, reflecting the difference in the densities of the both components. In contrast to both US and CT, MRI was able to distinguish lipid from iron deposition by the use of different sequences. A liver biopsy was obtained from this patient to confirm the diagnosis of a combination of hemochromatosis and NASH. However, no invasive methods were needed to evaluate the effect of treatment of secondary hemochromatosis with an iron-chelating drug. Rather, we found that a follow-up MRI examination was sufficient. Similarly, MRI can be used to qualitatively estimate the level of fat deposition in the liver and to evaluate the effect of weight loss on the pathogenesis of NASH (9). NASH is a complex disease with no simple causes. A new disease model, multiple parallel hits hypothesis, has been proposed, suggesting that multiple hits may act in parallel, resulting in liver inflammation (10). The complicated pathogenesis of NASH reportedly involves insulin resistance, which is related to the metabolic syndrome, and oxidative damage, which may result from endoplasmic reticulum stress, adipocytokines, endotoxins and/or the degree of hepatic iron accumulation (11). Although its clinical significance and mechanism remain to be clarified, high serum fer-

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ritin levels are reportedly associated with the pathogenesis of NASH (12). Furthermore, excess iron distributed throughout the liver is common in NASH (13). Hepcidin may be directly responsible for iron disturbances in patients with NAFLD (14), and polymorphisms of the human hemochromatosis gene HFE may be a risk factor for both liver iron accumulation and the progression of NAFLD (15), although additional studies are needed to clarify the mechanism in detail. The hepatic iron deposition in our patient was mainly regarded as a manifestation of secondary hemochromatosis. This was based on the patient’s medical history of multiple blood transfusions (a known risk factor). Twenty years earlier, this patient had received more than 20 units of packed red blood cells. Moreover, he showed increases in both the serum iron and ferritin levels, and a large extent of hepatic iron distribution. A mutation analysis of the genes associated with hepatic iron overload, such as HFE, TFR2, HJV, HAMP, SLC40A1, and FTL, is necessary to determine the possibility of primary (hereditary) hemochromatosis, although the frequencies of these gene mutations have been reported to be quite low in the Japanese population (16). Hereditary hemochromatosis was unlikely in this patient, as he did not experience a recurrence of high serum levels of ferritin and hepatic enzymes for 3 years after treatment. Following a diagnosis of secondary hemochromatosis combined with NASH, our patient was temporarily treated with an iron chelator. Chelation therapy partly alleviated his liver dysfunction, as indicated by reductions in serum ferritin levels and iron deposition in the liver on long TE MRI. When his serum ferritin concentration became lower than 500 ng/mL, oral iron chelation was discontinued. As no pharmacological therapy for NASH has yet been approved in Japan, the current management paradigms are based on the presence of associated risk factors, in particular NAFLD. Our patient had dyslipidemia and hyperuricemia, both of which did not significantly improve after iron chelation. Therefore, behavioral modifications were recommended to further alleviate his liver dysfunction. The findings in this patient suggested that he first developed iron overload due to secondary hemochromatosis; this was followed by NASH associated with metabolic syndrome, but complicated by hemochromatosis. In summary, this case report of a patient with combined hemochromatosis and NASH as suggested by the MRI findings, which can visualize the distributions of both iron and fat in the liver, demonstrates that MRI is useful for making a differential diagnosis and evaluating the effects of treatment.

their valuable assistance. Financial Support This study was supported in part by a grant from the National Center for Global Health and Medicine (26A-107) to Y.N.

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The authors state that they have no Conflict of Interest (COI). Acknowledgement The authors thank Hisae Kawashiro and Nami Michiaki for

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