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`1 of 5
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`Taro Pharmaceuticals, Ltd.
`Exhibit 1024
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`2 of 5
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1024
`
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`3 of 5
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1024
`
`
`
`JACCVol. 13, No.
`January 1989: 116-20
`
`|
`
`
`
`histologic confirmation of hemochromatosis is necessary.
`Generally,
`this has been accomplished by liver biopsy.
`Endomyocardial biopsy, however, may be indicated in pa-
`tients whose primary clinical manifestations are cardiac in
`origin. Furthermore.
`in experienced hands.
`transvenous
`right ventricular endomyocardial biopsy may be safer than
`percutaneousliver biopsy (16-18).
`Cardiac involvement in hemochromatosis. The hemody-
`namic and morphologic abnormalities of cardiac hemochro-
`matosis have been described aseitherdilated (2,5) or restric-
`tive (3) [cardiomyopathy]. Ofthe five patients with systolic
`functional abnormalities in this report, each hadadilated left
`ventricle and increased left ventricular end-diastolic pres-
`sure, No patient had the classic findings of restriction. Early
`cardiac involvement by hemochromatosis, however, may be
`manifested bydiastolic or restrictive dysfunction.
`In a previous echocardiographic study (19), the authors
`suggested that increased wall thickness maybe a feature of
`secondary posttransfusional hemochromatosis. However.
`others (8,9,14,20) have reported normal wall thickness in
`patients with nontransfusional hemochromatosis and cardiac
`dysfunction. In this study, all patients had normal ventricu-
`lar wall thickness as assessed by echocardiography. Accord-
`ingly. increased ventricular wall thickness does not appear
`to be a feature of nontransfusiona!l cardiac hemochromato-
`sis.
`
`OLSON ETAL.
`ENDOMYOCARDIAL BIOPSY IN HEMOCHROMATOSIS
`
`119
`
`Figure 1. Variation in quantity ofstainable iron deposition in en-
`domyocardial biopsy tissue in two cases.
`Iron accumulation is
`limited to myocytes and tends to be perinuclear. A, Mild (grade 2):
`B. severe (grade 4).
`(Gomori
`iron: original magnification x 100,
`reduced by 33%.)
`
`iron overload in patients with genetic hemochromatosis(15).
`In contrast, serum iron concentration is not as reliable (15).
`If screening test results are consistent with iron overload,
`
`Figure 2. Inverse relation between left ventricular ejection fraction
`(EF) and grade of deposition of stainable iron in six cases of
`hemochromatosis. This relation was not statistically significant
`(Spearman's rank correlation cocfficient = —0.80: p = 0.08).
`
`EF,%
`
`Iron, grade
`
`Endomyocardial biopsy in hemochromatosis. The micro-
`scopic features of endomyocardial biopsy tissue from four
`adolescents with transfusion-related hemochromatosis have
`been described (4). However, only one patient had cardiac
`dysfunction as determined by cardiac catheterization. Fur-
`thermore. in only one patient was abnormal accumulation of
`myocardial iron demonstrated, and this patient had normal
`cardiac function. These observationsled the investigators (4)
`to conclude that endomyocardial biopsy is an insensitive
`method for the determination of early myocardial iron dep-
`osition in transfusion-related hemochromatosis associated
`with thalassemia major.
`In contrast, the histopathologic characteristics of biopsy
`tissue from patients with nontransfusional cardiac hemo-
`chromatosis have been described in only two living patients
`(2,3); moreover, in one of these patients, biopsy tissue was
`obtained at pcericardiectomy because the patient was pre-
`sumed to have pericardial constriction. Observations from
`the current investigation of six patients suggest that histo-
`logically demonstrable myocardial
`iron is a consistent
`finding in endomyocardial biopsy tissue from patients with
`nontransfusional iron overload and associated cardiac dys-
`function. Although cardiac iron deposition in hemochroma-
`tosis tends to be greater in subepicardial than in subendo-
`cardial regions (1,13,14), this factor does not appear to be a
`problem in the detection of cardiac iron by endomyocardial
`biopsy.
`There was variation in the grade of stainable iron in
`
`40f5
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1024
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`
`5 of 5
`
`Taro Pharmaceuticals, Ltd.
`Exhibit 1024
`
`
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