CT and MRI of diffuse liver disease

CT a n d M R I of D i f f u s e Liver D i s e a s e Nell M. Rofsky and Haskel Fleishaker CT and MRI contribute important information to the clinical evaluation of diffuse liver disease. In some cases, these modalities can establish a diagnosis that was not ascertained histologically, which is often the case when sampling errors prevent a definitive tissue diagnosis. Characteristic alterations of liver attenuation on CT, signal changes on MRI, and morphological changes appreciated with both modalities can be used to diagnose fatty infiltration, some parenchymal deposition diseases, and cirrhosis. Furthermore, hepatocellular disease can be confirmed in the setting of indeterminate clinical and laboratory findings. Significant overlap in the imaging findings of this wide range of disorders continues to limit specificity; however, at a minimum, these techniques provide a rapid means to a noninvasive evaluation that often guides clinical decisions. Faster scanning techniques available with CT and MRI may provide additional information by assessing contrast dynamics. This review of CT and MRI in diffuse liver disease considers the diagnostic utility and clinical implications of these modalities. Pathological findings relevant to imaging considerations are discussed.

Copyright © 1995by W.B, Saunders Company

BROAD RANGE of disorders can affect

the hepatic parenchyma, producing difA fuse liver disease. The liver, however, exhibits a

limited range of responses to injury, which results in similar clinical and histological findings. This presents a significant diagnostic challenge to the radiologist as well as the clinician and pathologist. The role of CT and MRI traditionally has been to rule out those conditions that might produce findings mimicking diffuse liver disease such as biliary tract obstruction and focal masses. Recent advances in imaging have extended this role to the noninvasive diagnosis of specific diffuse hepatocellular conditions. Furthermore, serial imaging studies may be used to follow the course of a diffuse disorder, evaluate potential complications, and monitor response to therapy. This review serves as a practical update emphasizing the current role of CT and MRI in the more commonly encountered diffuse liver disorders. Newer developments that have amplified the role of noninvasive imaging in these conditions are highlighted. FATTY INFILTRATION

Hepatic steatosis, or fatty metamorphosis, results from metabolic derangements caused by a variety of pathological processes. The most common causes are alcohol abuse, diabetes From the Department of Radiology, New York University Medical Center, New York, NY. Address reprint requests to Neil M. Rofsky, MD, Department of Radiology, HW-207, New York University Medical Center, 560 FirstAve, New York, N Y 10016. Copyright © 1995 by W.B. Saunders Company 0887-2171/95/1601-000355. 00/0 16

mellitus, and obesity, t Fatty change has been noted in 80% to 90% of liver biopsy specimens from alcoholic patients and in 50% to 90% of patients with diabetes or obesity.2 Fatty liver also has been observed in approximately 25% of nonalcoholic, previously healthy adult males as an incidental finding at autopsy after accidental death) In most patients, fatty liver is clinically silent. In some processes, such as acute fatty liver of pregnancy or alcoholic steatohepatitis, fatty liver may present with clinical findings ranging from asymptomatic elevation of liver function tests (LFTs) to hepatic encephalopathy.

Radiological Findings The distribution of fatty infiltration is variable. It can be diffuse and homogeneous, or diffuse with regions of focal sparing. Focal forms can be segmental, with sharp demarcation between the involved lobe or segment and normal parenchyma; it also may appear as a discrete nodule, mimicking a mass lesion. Fatty infiltration is usually encountered on imaging studies as an incidental finding. It becomes particularly important to recognize focal fatty liver in situations where this disorder may be confused with a mass. In addition, it is important to recognize the limitations involved in detecting focal lesions in the presence of fatty infiltration.4

CT of Fatty Liver CT is an excellent modality for the diagnosis of fatty liver. Fatty deposition lowers the attenuation value of liver parenchyma. The high degree of correlation between hepatic attenuation

Seminars in Ultrasound, CT, andMRI, Vo116, No 1 (February), 1995: pp 16-33

CT AND MRI OF DIFFUSE LIVER DISEASE

values and triglyceride levels on biopsy has been demonstrated in an animal model. 5 Normal unenhanced liver parenchyma measures 45 to 65 Hounsfield units (HU). 6 The attenuation value of unenhanced liver is generally greater than that of spleen. In fatty infiltration this relationship is reversed. 7 In more severe cases, parenchymal attenuation values decline below those of unenhanced portal and hepatic venous structures. The relative densities of the liver and spleen are variable on contrast-enhanced CT, particularly with the use of rapid injection rates. The spleen may normally show a higher attenuation than liver when scanned early in the injection. Higher splenic attenuation is a result of the higher proportion of arterial blood supply to the spleen as compared with the liver, which receives a combination of both portal venous and arterial flow. The diagnosis of fatty infiltration, therefore, is more reliably made on noncontrast scans that are not affected by contrast dynamics. A confident diagnosis of fatty infiltration on noncontrast CT can be made when the spleen shows an attenuation value at least 10 HU greater than that shown by the liver. A difference of at least 25 HU is required on contrast-enhanced scans 8 (Figs 1 and 2). Several CT signs have been found useful in differentiating focal fat from a mass lesion. The absence of mass effect or contour deformity and

Fig 1. Diffuse fatty infiltration. On this contrast-enhanced CT scan, the liver is markedly diminished in attenuation as compared with the spleen. The patient has ovarian cancer and is being treated with chemotherapy. The liver density is less than that of adjacent ascites (arrows). There is no distortion of the hepatic vasculature.

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the presence of undisturbed venous structures traversing a region of low attenuation have been considered key diagnostic features of focal fat. 9"11 A recent report, however, has demonstrated the presence of traversing vessels in metastatic lesions, rendering this finding less reliable. 12 Some MRI sequences may provide a more direct means of identifying fatty deposition, avoiding this pitfall. Finally, focal fat has a propensity to occur adjacent to the falciform ligament, and this distribution can also serve as a distinguishing feature. 13 The differentiation of focal sparing in a diffusely fatty liver from mass lesion can be difficult in some cases. Focal sparing from fatty infiltration is, in a sense, the mirror image of fatty infiltration. The diagnosis is suggested when a geographic area of relatively higher attenuation is seen in a typical location, such as (1) the medial segment of left lobe adjacent to porta hepatis, (2) adjacent to gallbladder fossa, and (3) the subcapsular region. 4,14 In atypical cases of focal sparing from fatty infiltration, MRI may be useful in establishing the diagnosis.

MRI of Fatty Liver Routine spin echo imaging is relatively insensitive to fatty infiltration. However, when the liver is normal on multiple spin-echo pulse sequences, MRI is useful for excluding mass

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Fig 2. Fatty infiltration with regional sparing. (A) The narrow-window image of a contrast-enhanced CT shows decreased attenuation in most of the liver, consistent with fatty infiltration. The spared posterior segment of the right lobe is normal in density. The focal mass (arrow) is a cholangiocarcinoma. (B) In-phase breathhold GRE image at 1.0T (160/6.6/70 °) shows the liver to be brighter in signal intensity compared with the spleen and paraspinal muscles. Aortic pulsation artifacts are seen in the phase-encoding direction in the left lobe. (C) All segments of the liver, except the posterior right lobe, show decreased signal intensity on the opposed-phase image (160/4.4/70°), This finding is characteristic of fatty infiltration. The relative signal intensity of the mass (arrow) compared with the spleen has not changed significantly. (D) Note the relatively increased signal (lighter} in the region of fatty infiltration, compared with the posterior right lobe (darker), as seen on this TSE T2 sequence (5,000/120). Arrow points to tumor.

lesions in cases of suspected focal fatty deposition seen on ultrasound or CT. Chemical shift techniques can readily diagnose fatty infiltration, whether it is diffuse or focal. These techniques exploit the difference in precessional frequency between fat and water protons. This difference results in periodic cycling of protons in such a way that at various moments in time the protons may be in phase (signals are additive) or out of phase (signals are destructive) (Fig 3). Voxels that contain both fat and water will decrease in signal

intensity when the constituent protons are out of phase. The simplest method to exploit this phenomenon is breathhold gradient echo (GRE) imaging. The TEs at which opposed-phase and inphase images are generated vary with the proton precessional frequencies that in turn vary with magnetic field strength. However, at a given field strength, the appropriate TEs can be easily ascertained with several breathhold acquisitions. By varying the TE, opposed-phase images can be recognized by the presence of

CT AND MRI OF DIFFUSE LIVER DISEASE

OUT of •

19

IN

TE

Fig 3. Schematic diagram of chemical shift phase effect. Water and fat protons precess at different frequencies. As a result, the signals periodically interfere destructively (OUT of 4) and constructively (IN 6). The net signal intensity is deCreased when fat and water protons are out of phase and is increased when they are in phase.

characteristic chemical shift or "India ink" artifact; a dark line is "etched" at tissue boundaries where fat and water interface (Fig 4). Fatty infiltration is recognized as regions of liver that show a decrease in signal intensity on opposed-phase images as compared with inphase images; the spleen or skeletal muscle may be used as a convenient reference (Figs 2 and 4). The degree of signal cancellation becomes more conspicuous with increased fatty deposition. KeePing the T E as short as possible helps avoid confusion with possible T2* effects that

could also result in signal loss within the liver (eg, iron deposition). Occasionally, regions of fatty infiltration may show increased signal intensity on both T1- and T2-weighted sequences. With hybrid rapid acquisition with relaxation enhancement (RARE) (turbo-spin-echo [TSE] of fast spin-echo [FSE]) sequences, fat signal intensity is brighter when compared with conventional SE images and, therefore, fatty infiltration may result in a more conspicuous increase in signal intensity with the hybrid RARE technique (Fig 2). CIRRHOSIS Cirrhosis is a generic term for chronic endstage liver disease, representing the sequela of many different hepatic insults. The etiologic classification is quite extensive (Table 1). Morphologically, cirrhosis can be defined as a diffuse process of architectural disorganization characterized by fibrosis and the formation of parenchymal (regenerative) nodules. 15,16 The disorganization of the hepatic architecture affects the vasculature, impeding drainage of blood from the liver, and ultimately results in portal hypertension. Regenerative nodules are a histological component of the cirrhotic liver. These nodules of tissue are derived from portions of preexisting lobules that are altered by hepatocyte regeneration. 17,18 A classification

Fig 4. Diffuse fatty infiltration. (A) In-phase breathhold GRE image at 1.0T (160/6.6/70 °, TR/TE/flip angle) demonstrates the liver to be brighter in signal intensRy compared with the spleen and paraspinal muscles. An incidental adrena! mass is noted (large arrow). (B) Opposed-Phase GRE image (160/4.4/70 °) demonstrates lower signal intensity in the liver than in the spleen and paraspinal muscles. This low signal intensity is diagnostic of fatty infiltration. Note the characteristic "India ink" artifact where the stomach interfaces with adjacent fat (small arrows). The signal decrease in the adrenal mass (large arrow) on the opposed-phase image (as compared with Part A) is consistent with an adrenal adenoma.

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ROFSKY AND FLEISHAKER Table 1. Major Etiologies of Cirrhosis

Hepatitis Alcoholic Viral Autoimmune Biliary disorders Chronic biliary obstruction Primary biliary cirrhosis Sclerosing cholangitis Biliary diseases of childhood Metabolic disorders Hemochr0matosis Wilson's disease Glycogen storage disease ~l-Antitrypsin deficiency Othm's Drug induced Chronic hepatitis Biliary Steatohepatitis Cardiovascular Passive cardiac congestion Budd-Chiari syndrome Veno-occlusive disease Miscellaneous Sarcoid Cryptogenic

scheme based on the size of regenerative nodules divides cirrhosis into micronodular, macronodular, and mixed forms. This classification has certain implications for the pathologist but is limited clinically by the dynamic nature of cirrhosis, which demonstrates changing nodular size (from smaller to larger) during the course of the disease. Furthermore, the clinical course and etiology cannot be determined reliably by the morphological patterns Observed histologically19; therefore, from an imaging perspective, there is little rationale for such an approach. The histological diagnosis of cirrhosis can be difficult and is dependent on the size of the specimen. 19 Needle biopsy specimens may not sufficiently sample parenchymal nodules or fibrosis~ both of which are key components in establishing the diagnosis. Cross-sectional imaging allows for the detection of gross morphological features of cirrhosis and plays an important role in the assessment of complications and disease progression. Imaging also may be used as a screening tool for the detection of hepatocellular carcinoma, which is seen more commonly in patients with cirrhosis.

C T in Cirrhosis

The major CT findings in cirrhosis are alterations in liver size and lobar distribution, parenchymal nodularity, and attenuation of hepatic vasculature. Splenomegaly, venous collaterals, and ascites, which are evidence of portal hypertension, are important ancillary findings. (The vascular manifestations of cirrhosis are discussed elsewhere in this issue.) The cirrhotic liver classically exhibits atrophy of the right 10be in conjunction with hypertrophy of the caudate lobe and lateral segment of the left lobe 20,21 (Fig 5). However, a variety of gross morphological alterations can be seen, including diffuse atrophy, diffuse hepatomegaly, and more focal atrophic changes. Colonic interposition between the liver and anterolateral abdominal wall and counterclockwise rotation of the gallbladder are additional findings that frequently are associated with the lobar changes of cirrhosis. A quantitative approach for assessing the caudate lobe/right lobe ratio has been reported. The diagnosis of cirrhosis can be made with a 96% confidence level if the caudate lobe/right lobe ratio exceeds 0.6521; however, the sensitivity of the caudate lobe/right lobe ratio, measured sonographically, was found to be dependent on the etiology of cirrhosis. 22Furthermore, a variety of noncirrhotic conditions can result in changes in lobar proportion similar to those seen in cirrhosis. These conditions include congenital anomalies of lobation, postsurgical changes, and vascular insults, whether pathological or the consequence of embolotherapy. 23 In our practice, hepatic lobar anatomy is assessed qualitatively as one factor in the overall evaluation for cirrhosis. The quantitative assessment of total liver volume has been useful in the overall evaluation of diffuse liver disease in our practice. The detection of hepatic enlargement or atrophy can be a key finding in the presence of unexplained hepatocellular dysfunction. A large liver volume is indicative of a more acute insult, such as hepatitis. A small hepatic volume indicates a chronic process and, when this finding is coupled with other imaging abnormalities, such as portal hypertension or regenerative nodules, a diagno-

CT AND MRI OF DIFFUSE LIVER DISEASE

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Fig 5. Lobar changes of cirrhosis. Contrast-enhanced CT scan shows atrophy of the right lobe with hypertrophy of the caudate lobe (C) and lateral segment of the left lobe (L). Splenomegaly, recanalization of the umbilical vein (arrow), and other venous collaterals indicate portal hypertension.

sis of cirrhosis becomes apparent. The imaging diagnosis of cirrhosis is especially important in light of known limitations of liver biopsy, in which sampling errors may yield nonspecific fibrotic changes. In known cirrhotics, liver volume can be used tc follow the course of disease, to help determine prognosisl and t o diagnose superimposed bouts of alcoholic hepatitis: Liver volume is calculated by tracing the liver contour (with user-generated regions of interest) on multiple contiguous images (Fig 6). The

summed two-dimensional areas of contiguous 10-mm sections are used to calculate a threedimensional volume. Scanning techniques that employ thinner sections require a correction factor for the total volume. The liver contour may have a nodular appearance that is the result of regenerating nodules, fibrous scarring, and/or asymmetric parenchymal atrophy (Fig 7). Regenerative nodules are usually isodense with background parenchyma on CT 2~ but may appea r hyperdense. 24 The

Fig 6. Calculation of liver volume. The liver contours are traced with user-generated regions of interest. The areas obtained on contiguous sections are summed for calculation of liver volume.

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Fig 7. Cirrhosis. This contrastenhanced CT scan shows hepatic surface nodularity, hypertrophy of the caudate lobe, and lesser omental venous collaterals (black arrows).

nonspecific appearance may be confused with malignancy. Distortion of the underlying hepatic vasculature Can be manifested as inhomogenous contrast enhancement 25 and attenuation of the intrahepatic vessels. MRI in Cirrhosis

Like CT, MRI can be used to analyze hepatic contour and lobar proportion in cirrhotic patients. However, the superior soft tissue con-

Fig 8. Multinodular cirrhosis and biopsy-proven hepatoma. TSE T2-weighted sequence (5,000/120) shows innumerable nodules of various sizes, many of which are hypointense compared with the background (arrows). The dominant mass in the medial segment of the left lobe (curved arrow) !s hyperintense compared with background, indicative of a hepatoma. The recanalized umbilical vein (serpentine structure) and ascites are evidence for portal hypertension.

trast afforded by MRI provides additional information. Findings associated with cirrhosis, such as linear signal irregularities, nodular texture, and low-signal-intensity nodules, can be demonstrated (Fig 8 and 9). 26,27Furthermore, MRI can assess the vascular manifestations of cirrhosis without intravenous contrast (as is discussed elsewhere in this issue). On Tl-weighted images (TlWIs), regenerative nodules can be hypointense, isointense, or hyperintense in relation to background liver5 8,29

CT AND MRI OF DIFFUSE LIVER DISEASE

The increased MRI signal intensity has been correlated histologically with steatosis 3° but is probably also related to the altered contrast between regenerating tissue and background abnormal liver. On T2-weighted images (T2WIs), signal intensity of regenerative nodules has not been shown to increase, which distinguishes these nodules from hepatocellular carcinoma (HCC). Regenerative nodules are typically isointense or hypointense in relation to background liver (Fig 8). We have noted excellent soft tissue contrast with short inversion time recovery (STIR) sequences (Fig 9), facilitating demonstration of regenerative nodules and hepatomas. Tl-weighted dynamic GRE gadolinium-enhanced contrast studies also may be used to identify briskly enhancing tumor nodules, providing distinction from regenerative nodules (Fig 10). In this regard, subtraction imaging has been found to be useful in patients with multinodular cirrhosis, especially when nodules are hyperintense on precontrast studies? 1 The appearance of siderotic regenerating nodules has been shown to be a sign that is somewhat specific for cirrhosis (Fig 11). Approximately 25% of regenerative nodules have been shown to accumulate more iron than surrounding parenchyma. 3; These nodules can be exposed occasionally with CT but more reliably with MRI. 33 In the latter study, the low-signal nodules were shown better with GRE images using a relatively long TE than with GRE

Fig 9. Multinodular cirrhosis. This Turbo-STIR image (6490/ 60/140, TR/TE/TI) at 1.0T readily shows multiple hypointense regenerative nodules within the liver. Also, note the linear and curvilinear signal hyperintensities (large arrows), some of which surround nodules (short arrow). These signal abnormalities may result from fibrosis or compression of adjacent tissue.

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images using a short TE. The GRE images, in turn, were better than T2-weighted spin echo images. Sequences that are sensitive to susceptibility effects best demonstrate siderotic nodules in the liver as well as the spleen. Gamna-Gandy bodies (siderotic nodules) in the spleen have been shown in up to 12% of cirrhotic patients, 34,3s providing indirect evidence of portal hypertension (Fig 11). Frequently, siderotic nodules are depicted with sequences used for evaluating the vascular manifestations of cirrhosis. HEPATITIS

Hepatitis represents a nonspecific inflammatory response of the liver to a wide variety of agents that cause hepatocellular injury. The leading cause of hepatitis, both acute and chronic, is viral infection; other infectious causes include bacterial and fungal organisms. In addition, hepatitis can result from exposure to a wide variety of pharmaceutical and environmental agents as well as radiation therapy. Hepatitis can be self-limited or more progressive in nature, leading to a spectrum of liver injury that includes cellular dysfunction, necrosis, fibrosis, and cirrhosis. Chronic hepatitis may result from viral infection, autoimmune reactions, drug-induced injury, and inherited metabolic disturbances. Chronic hepatitis has been divided into chronic active and chronic persistent subtypes. Although chronic active hepatitis is generally associated with a worse prognosis,

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Fig 10. Multinodular cirrhosis (same patient as Fig 8). (A) On a precontrast, breathhold GRE (120/6/90 °) image, many of the nodules are hyperintense. The hepatoma has a hypointense "capsule" (arrow) and central "scar." (B) Immediate postcontrast GRE image shows marked enhancement of the dominant mass, consistent with a hepatoma. (C) At the equilibrium phase postcontrast, there is little distinction between the mass, nodules, and background tissue. Enhancement of the capsule is now evident. (D) Delayed postcontrast image shows the nodules and the mass to be hypointense relative to background tissue. The capsule demonstrates persistent enhancement.

Fig 11. Siderotic nodules in a cirrhotic liver. GRE image (39/ 10/30 ° ) shows innumerable punctate foci that are markedly hypointense compared with background liver. Low-signalintensity siderotic nodules (Gamna-Gandy bodies) are also present in the spleen, indicative of portal hypertension. Esophageal varices (curved arrow) are well demonstrated.

CT AND MRI OF DIFFUSE LIVER DISEASE

these distinctions are often not clinically relevant. The diagnosis of acute hepatitis is usually established by serological, virological, and clinical data. In atypical cases or when the diagnosis is not clinically apparent, liver biopsy is performed. 36Acute viral hepatitis, regardless of the cause, has similar pathological manifestations; therefore, etiologic distinctions cannot be made with imaging studies. The key role of radiological imaging is to rule out other conditions that can produce similar clinical and laboratory findings, such as biliary obstruction, hepatic abscess, widespread metastatic disease, and cirrhosis. CT and MRI in Hepatitis

The imaging findings in hepatitis are nonspecific and include hepatomegaly and periportal edema. Periportal edema is seen on CT as low-attenuation "tracking" that parallels the portal vessels (Fig 12). Periportal edema is recognized on T2-weighted MR images as signal hyperintensity in a distribution similar to the low attenuation seen with CT. Other conditions that may produce periportal tracking include passive hepatic congestion, periportal tumor or adenopathy, and trauma, and it also may occur after hepatic transplant. 37,38We have seen several cases of acute hepatitis that have shown heterogeneous parenchymal enhancement on contrast-enhanced CT (Fig 13). Periportal

Fig 12. Periportal edema. Regions of low attenuation parallel the portal vessels (periportal tracking) in a patient with acute viral hepatitis. Unlike biliary ductal dilatation, periportal tracking is seen on both sides of the portal vessels (arrows). Periportal edema can be seen in a variety of disorders (see text).

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lymphadenopathy has been described as a finding in chronic active hepatitis and may at times be the only abnormality seen. 39 Geographic zones of increased parenchymal signal intensity have been noted on T2WIs, 4°,41 and this finding may be used to direct an MRI-guided biopsy. In a recent study, signal intensity ratios of liver to fat on STIR images at 0.5T were associated with the degree of histological severity in patients with chronic liver diseases, including hepatitis. 42 It remains to be seen if these ratios have prognostic implications or can be used to assess response to therapy. DRUG-INDUCED LIVER DISEASE

The liver is the primary organ in the metabolism of many drugs and toxins, making it highly vulnerable to drug-induced injury. A wide variety of drugs have been implicated in the etiology of hepatic injury. These drugs include analgesics, anti-inflammatories, anesthetics, anticonvulsants, antimicrobials, cardiovascular agents, hormones, immunosuppressives, chemotherapeutic agents, and psychopharmaceuticals. Lee 43 provides a complete list of such agents. The clinical spectrum of drug-induced liver toxicity is broad, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure. All forms of liver disease, both acute and chronic, can be mimicked by drug-induced injury. 43 The radiological findings are similarly nonspe-

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RADIATION DISEASE

Fig 13. Acute hepatitis. Contrast-enhanced CT scan in a patient with drug-induced hepatitis shows heterogeneous enhancement of the liver parenchyma.

cific, with typical signs of fatty infiltration, hepatitis, and cirrhosis seen on CT and MRI. Rare exceptions allow for a more specific diagnosis. Advanced amiodarone toxicity, for instance, results in hepatic deposition of the iodine-containing drug and its metabolites, producing increased liver attenuation values on CT. 44 This finding mimics hemochromatosis, which is discussed below. Thorotrast injection, which has been shown to cause hepatic angiosarcoma, may produce marked increase in attenuation of liver, spleen, and periportal lymph nodes. The altered liver attenuation may appear diffuse and homogeneous or assume a reticulated pattern. 45

Radiation-induced liver disease usually results from the incidental exposure of hepatic parenchyma that is included in the irradiated field. Radiation may cause hepatitis, venoocclusive disease, and/or parenehymal scarring and atrophy. The typical appearance of hepatic radiation injury on CT is a region of low attenuation that is sharply circumscribed and geographically demarcated in a nonanatomic distribution, corresponding to the radiation portal. The low attenuation reflects edema and/or fatty infiltration. 46 Radiation hepatitis can also present as an area of relatively increased attenuation within a diffusely fatty liver. This appearance is thought to represent relative sparing of the irradiated segment in a liver with advanced fatty infiltration (Fig 14). The signal intensity changes associated with radiation injury seen on MRI are nonspecific. The affected region is lower in signal on T1WIs and higher in signal on T2WIs in relation to uninvolved liver 46,47 (Fig 15). The sharp interface and nonanatomic distribution typify the otherwise nonspecific signal intensity changes. OTHER INFLAMMATORY DISORDERS

Candidiasis

Hepatic candidiasis is a manifestation of systemic fungal disease that is typically seen in

Fig 14, Radiation changes. Contrast-enhanced CT scan shows low-attenuation fatty liver. A well-demarcated (arrows) area of sparing is seen in the left (hepatic) lobe and the medial aspect of the right lobe. This highdensity area corresponds to the radiation port used for treatment of carcinoma of the pancreas,

CT AND MRI OF DIFFUSE LIVER DISEASE

immunosuppressed individuals, frequently complicating the treatment of hematologic malignancies. 48 The CT appearance is that of small low-attenuation lesions scattered throughout the liver49 (Fig 16). On MRI these lesions appear as hyperintense loci on T2-weighted and STIR images 5°,51 and are hypointense relative to the liver on T1WIs. Diffuse enhancement of lesions may be seen early after the bolus administration of gadolinium. A peripheral rimlike pattern may be seen on delayed postcontrast images. 5I The nonspecific appearance on both CT and MRI leads to a differential diagnosis that includes metastases, lymphoma, and leukemia, as well as other Opportunistic infections.

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Fig 16. Hepatic candidiasis in a patient with AIDS. Multiple ill-defined, low-attenuation lesions (arrows) are seen on this contrast-enhanced CT scan. Although these findings are nonspecific, this diagnosis should be considered in an immunocompromised patient.

Pneumocystis carinii Infection Multiple, dense foci of calcification in the liver as well as other viscera are frequently associated with Pneumocystis carinii infection. ~244 These lesions are best appreciated on noncontrast CT (Fig 17). However, the CT findings have been shown to be nonspecific and are seen also with cytomegalovirus and Mycobacterium avium-intracellulare infectionY

Granulomatous Diseases

Fig 15. Radiation changes in another patient treated for pancreatic carcinoma. (A) Tl-weighted image with inversion recovery technique (1,400/20/400) at 0.5T. A well-demarcated, nonsegmental region of decreased signal intensity (arrows) is seen in association with retraction of the hepatic capsule. Ascites (asterisk) is seen incidentally. (B) The affected region is hyperintense to the liver on a STIR image (1,400/30/ 110).

The granulomatous process represents a type of inflammatory process that can be seen with a variety of disorders. Causes include infectious diseases (viral, fungal, bacterial, and parasitic), toxic drug reactions, sarcoidosis, Wegener's granulomatosis, as well as other diseases. Calcified granulomas are best seen with CT and are recognized as sharply defined, frequently punctate calcifications. Tuberculosis and histoplasmosis are two of the most common diseases that produce calcified granulomas: The presence of low-density adenopathy indicates caseating necrosis and is highly suggestive of tuberculous granulomas. 56 Noncaseating granulomas, which may affect the liver, are the typical histological finding seen in sarcoidosis. Although usually small, these bulky, masslike loci of granulation tissue may be seen in the liver as well as the spleen. On CT, these appear as relatively low-attenuation le-

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Fig 17. Pneumocystis carinii. Noncontrast CT scan shows innumerable punctate calcific densities in the liver and the spleen.

sions that may mimic neoplastic masses 57 (Fig 18). MRI findings of granulomatous diseases are also nonspecific and include discrete parenchymal nodules, contour irregularity, spiculation of intrahepatic vascular branches, increased periportal signal, and patchy areas of heterogeneous signal. 5s Nodules have been described as small, low-signal-intensity lesions on T2WIs. 58 Larger lesions have also been described that

Fig 18. Sarcoidosis. The nonspecific finding s on this contrast-enhanced CT scan in a patient with breast cancer and sarcoidosis include numerous nodular hypointense lesions scattered throughOut the liver and Spleen. Multiple liver lesions were biopsied, and a diagnosis Of sarcoidosis Was established by demonstratin, noncaseating granulomas.

were isointense to slightly hyperintense on proton density images and slightly hypointense to liver on T2WIs. s9 STORAGE AND METABOLIC DISORDERS

Iron Accumulation

The liver is a major storage depot for iron and therefore is subject to the consequences of iron overload. Accumulated iron is preferentially distributed either in the reticuloendothelial cells or in parenchymal cells. In the liver, this distinction is seen microscopically as iron deposition within Kupffer cells or hepatocytes, respectively. The clinical implications and pathological consequences of iron accumulation are influenced by the pattern of iron deposition. Hepatocellular iron deposition results in cellular injury, whereas Kupffer cell deposition is relatively innocuous. These two patterns are most distinctive early in the course of iron overload. However, because iron can be relocated between the two cell populations, a combination of hepatocellular and Kupffer cell deposition can be found in the advanced stage of almost any iron overload disorder. The terminology of iron overload can be somewhat confusing. In this article, definitions are based on those used by Lee. 6° The term siderosis or hemosiderosis is used to designate the accumulation of stainable iron, regardless of

CT AND MRI OF DIFFUSE LIVER DISEASE

its degree or distribution. This term is generally used to denote reticuloendothelial cell overload, because it occurs in anemias requiring multiple transfusions. Hemochromatosis is the term used to designate disorders characterized by the pathological accumulation of iron within parenchymal cells of the liver and other organs; it does not require that organ damage be established. The prototypical cause of iron overload with hepatocyte deposition is hereditary hemochromatosis (primary or idiopathic hemochromatosis), an autosomal recessive disorder that is characterized by excessive absorption of iron with progressive accumulation in the liver and other organs. Effective treatment for hereditary hemochromatosis includes repeated phlebotomy and/or deferoxamine therapy. 61 In contrast to other forms of parenchymal and reticuloendothelial deposition, this disorder more commonly leads to cellular damage and organ dysfunction and is associated with hepatocellular carcinoma.

CT and MRI Findings The deposition of iron in various organs can alter the CT and MRI appearance. When iron is accumulated in sufficient amounts, it attenuates the CT x-ray beam to an appreciable degree,

Fig 19~ Transfusion iron overIoad--thalassemia. (A) Noncontrast CT scan shows a diffusely hyperdense liver relative to other soft tissues. Also note the hyperdense lymph nodes (arrows).

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resulting in increased CT density of the affected organs. To diagnose iron overload on CT, the liver should demonstrate attenuation values of more than 70 HU on noncontrast studies using 120 kV(p) technique (Fig 19). In one report, CT yielded a sensitivity of 60% in the diagnosis of hepatic iron overload,62 largely limited by the confounding effects of associated steatosis. High hepatic parenchymal attenuation values are not specific and can be seen in patients exposed to Thorotrast or gold therapy, and in patients with Wilson's disease and glycogen storage diseases. 63-65,66 With MRI, iron accumulation, regardless of the cause, results in characteristic low signal intensity of the liver parenchyma on T2WIs and T2*-weighted GRE images. Iron accumulation may even result in low signal intensity on TIWIs when the iron level is high enough (Fig 20). Skeletal muscle is a useful reference tissue, because it is less intense than normal liver on all sequences and does not accumulate iron. Iron deposition is most commonly seen as a diffuse process, but it can occasionally be focal. 67 The MRI findings do not seem to be adversely affected by superimposed steatosis. 68 The low-signal hepatic intensity changes that result from either parenchymal or reticuloendothelial accumulation are indistinguishable. How-

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Fig 20. Transfusion iron overload--thalassemia. (A) Tl-weighted spin echo MR image at 0.5T (300/20) shows diffuse low signal intensity in the liver. Note that the liver is hypointense compared with skeletal muscle. (B) T2-weighted MR image (2,000/100) shows similar findings. Low signal intensity of the bone marrow indicates reticuloendothelial deposition in this patient after splenectomy. The signal intensity of the cerebrospinal fluid identifies the T1 and T2 contrast that is otherwise difficult to appreciate.

ever, recognition of the extrahepatic signal intensity changes, also evident on MRI, can be useful in distinguishing the two patterns.69 Hemochromatosis can be diagnosed with MRI when the decreased signal intensity is confined to the liver without alteration of splenic signal intensity (Fig 21). In this condition, the pancreas may also show decreased signal intensity, a further indication of parenchymal iron deposition. In a recent study of patients with idiopathic hemochromatosis, the decreased signal intensity of the pancreas was associated with the presence of cirrhosis.7° In contrast to hemochromatosis, the diagnosis of hemosiderosis can be made when there is concomitant signal loss in the spleen and bone marrow as well as the liver, indicating reticuloendothelial deposition (Fig 20). When other parenchymal organs are also affected, (eg, the pancreas), an element of hemochromatosis is inferred. Early attempts to analyze liver iron content with MRI were plagued by extreme signal loss that precluded quantitative assessment and useful comparisons. More recently, the use of short TE sequences has allowed for correlations to made between liver/muscle MR signal ratios and serum ferritin levels, 71 and between 1/T2 liver values and hepatic tissue iron concentrations. 72 The use of dual-energy CT scanning (120

kV[p] and 80 kV[p]) has been suggested as a technique to quantify iron content. 73,74 The difference in hepatic attenuation values obtained using the two energies seems to be related in a predictable way to the levels of iron deposition.

Other Storage Disorders Rare storage diseases, such as Wilson's or Gaucher's, and the glycogen storage diseases often cause hepatic enlargement but do not yield specific imaging findings with CT or MRI. Likewise, there are no specific imaging findings in systemic amyloidosis, another cause of hepatic enlargement. A hyperdense liver may be seen on CT with Wilson's disease and the giycogen storage diseases75,76; however, this finding is not universally seen in these disorders, nor is it specific (as discussed earlier). CONCLUSION

The role of the radiologist in evaluating patients with diffuse liver disease continues to expand with innovations in cross-sectional imaging. These techniques can help establish specific diagnoses and noninvasively monitor the course of disease processes. This information may be essential in guiding clinical decisions. Advances in diagnostic accuracy may be achieved by studying multiphase contrast dynamics with

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Fig 21. Parenchymal iron overload. (A) Tl-weighted, breathold GRE MR image (140/6/ 70 °) at 1.0T demonstrates marked signal loss throughout the liver. The absence of signal loss in the spleen and bone marrow is consistent with the parenchymal pattern of iron deposition. (B) Marked hypointensity of the liver is also Seen with a Turbo "1"2 sequence (5,000/120).

newer rapid scanning techniques, such as spiral CT and fast MRI sequences. The development of MR techniques, such as diffusion and perfusion imaging, spectroscopic evaluation, and the use of targeted contrast agents, may in the

future provide additional diagnostic acumen. Awareness of current imaging applications and developing technologies will help secure the niche of radiology in this evolving area of medicine.

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