322
non-B hepatitis. In the United States approximately 1.4% of the population is infected. Infection is acquired by either blood product transfusions or intravenous drug abuse. It is a common infection in hemophiliacs. In some patients the mode of transmission is not known. Vertical and sexual transmission is uncommon.
Hepatitis during the acute phase is invariably mild and often subclinical, but most infections become chronic. The clinical course of hepatitis C infection is unpredictable.A rough estimate of mean time between initial infection and diagnosis of chronic hepatitis is 10 years, 10 years more for cirrhosis to develop, and another 10 years before hepatocellular carcinoma is discovered, although considerable individual variation exists. Even with advanced disease, half the patients are asymptomatic. Normal biochemical tests do not exclude viral replication in anti- HCV–positive individuals. Different viral genotypes are associated with different severity of liver disease. For instance, HCV type 1b is overrepresented in patients developing cirrhosis and hepatocellular carcinoma and influences the carcinoma risk in cirrhosis.
An association exists between HCV infection and autoimmune diseases. Infection leads to autoimmune hepatitis, membranoproliferative glomerulonephritis, thyroiditis, and such skin disorders as porphyria cutanea tarda and possibly lichen planus.A relationship with Sjögren’s syndrome and possibly even Behçet’s syndrome is suspected. An association with Guillain-Barré syndrome (an acute demyelinating neuropathy believed to have an autoimmune basis) has been suggested. It has been implicated in periarteritis nodosa.
Unlike many other human viruses, hepatitis C virus is an RNA virus and does not appear to be integrated into host cell genome. Carcinogenesis of HCV infection is generally explained by its ability to cause hepatic inflammation, regeneration, fibrosis, and eventual cirrhosis, yet some patients appear to progress from chronic hepatitis directly to carcinoma without developing cirrhosis.
An interesting association appears to exist between HCV serology and primary hepatic lymphoma. Hepatitis C virus is both hepatotropic and lymphotropic and in some patients results in a mixed essential cryoglobulinemia, a lymphoproliferative condition that on occasion
ADVANCED IMAGING OF THE ABDOMEN
evolves into non-Hodgkin’s lymphoma. The virus is detected in some lymphoma tissue. Anti–hepatitis C virus antibodies are detected in almost half of B-cell non-Hodgkin’s lymphoma patients. Likewise, an occasional patient with chronic HCV infection develops reactive lymphoid hyperplasia (pseudolymphoma), with imaging suggesting a focal hepatocellular carcinoma; biopsy should be diagnostic.
Gray-scale US findings do not correlate with liver biopsy findings in patients with chronic HCV infection. Imaging does detect perihepatic lymphadenopathy, however, with number and size related to HCV activity (30). Gray-scale US can document the response to therapy. Lymph nodes appear hyperintense relative to the liver on T2-weighted MRI.
No current immunization is available against this virus. Interferon is the treatment of choice for chronic HCV infection, but relapse rate is high.
Hepatitis D
Humans are probably the only host for hepatitis D virus. Its major focus in the United States is in drug addicts. It progresses to chronic hepatitis and cirrhosis.
Hepatitis E
Hepatitis E has a worldwide distribution and is a cause of considerable morbidity and mortality in the developing world. This virus is spread through contaminated water. Infected individuals develop cholestatic jaundice, generally with few sequelae, although in pregnancy it has led to fulminant hepatic failure.
Hepatitis G
Hepatitis G virus (HGV) is a RNA virus in the family Flaviviridae and is transmitted by blood transfusion. Both acute and chronic infections occur, but its role in hepatitis is uncertain. Parenteral transmission appears common, and IV drug users, hemodialysis patients, and hemophiliacs are prone to this infection, often in association with HBV and HCV infections.
Hepatitis G virus appears to be sensitive to interferon therapy.
323
LIVER
Epstein-Barr Virus
Infectious mononucleosis (Epstein-Barr virus infection) is a rare cause of hepatitis; it has led to fulminant hepatic failure.
Imaging
Hepatitis has no specific imaging findings, with imaging generally performed to exclude other disorders. Necrosis and regeneration on precontrast CT appear as hypodense regions. Periportal edema is seen as periportal hypodense regions on CT and hyperintense regions on T2-weighted MRI. Ultrasonography is usually normal, although at times a heterogeneous hyperechoic appearance is found.
During the initial stage of severe acute hepatitis, a transient decrease in portal blood velocity is followed by a rebound, but in chronic viral hepatitis decreased portal blood velocity correlates with the degree of fibrosis.
Fulminant Hepatic Failure/Necrosis
Clinical
Acute hepatic encephalopathy within 8 weeks of hepatocellular disease in an otherwise healthy patient is considered fulminant hepatic failure. In most patients the etiology is not known, while in others a viral infection or chemical or drug poisoning is the responsible agent. Even exertion-induced heat stroke has led to fulminant liver failure. Coagulopathy is a common feature. These patients have a high mortality rate. An uncommon cause for chronic liver failure is extensive liver involvement by a malignant vascular tumor.
Hypoglycemia is a complication of fulminant hepatic failure; causes appear multifactorial and include associated hyperinsulinemia and possible hypoglycemic agents secreted by the liver.
Therapy focuses on providing temporary liver function until subsequent resumption of regeneration. A number of artificial liver assist devices have been evaluated. Auxiliary liver transplantation, retaining the recipient liver, is one alternative. During immunosuppressive therapy, such an auxiliary liver functions normally while native liver function is almost absent; immunosuppressive therapy is with-
drawn after native liver function improves, and then the graft either atrophies or is removed. Technetium-99m–mebrofenin (2,4,6-trimethyl, 5-bromo iminodiacetic acid) (BrIDA) scintigraphy can distinguish the relative function of both donor and recipient livers.
In some patients liver transplantation is the only viable option. But a word of caution is warranted prior to liver transplantation in a patient with idiopathic fulminant hepatic failure. An occasional patient with massive liver necrosis is found to have diffuse liver carcinoma. Other rare causes of acute hepatic failure are diffuse cholangiocellular carcinoma and infiltration by acute lymphoblastic leukemia.
Imaging
Iodinated contrast agents should be used with caution in these patients to prevent accentuating associated renal failure.
Fulminant liver failure results in heterogeneous CT contrast enhancement. The periportal spaces enlarge, seen as periportal low attenuation regions. This is a nonspecific finding seen also in congestion, bleeding, and tumor infiltration. Serial CT reveals that liver volume changes little in survivors, while it decreases in nonsurvivors. Poorly defined hypodense regions develop in some patients, representing regenerating nodules; they enhance to isoor even hyperdense with contrast. An increase in, or late onset of, ascites is an ominous finding.
Necrotic liver parenchyma is hyperintense on T2-weighted SE images, whereas regeneration appears hypointense. In general, regenerating nodules have an opposite appearance to regions of necrosis.
Blood clearance and receptor indices from Tc-99m-GSA imaging of patients with fulminant hepatic failure and acute hepatitis allow distinction between the two entities (31); also, all fulminant hepatic failure survivors had receptor indices of 0.58 or more, but in five of six patients who later died, the receptor index was 0.58 or less. (The receptor index is the liver radioactivity divided by that of liver plus heart. The blood clearance index is the heart radioactivity at 15 minutes divided by that at 5 minutes after the injection.)
Serial Tc-99m-GSA scintigraphy monitors improvement; it predicts hepatic recovery
324
earlier than is possible with more conventional biochemical methods and provides information about both hepatic functional reserve and morphologic changes by detecting lobe enlargement or atrophy.
Serial determination of liver and spleen volumes appears related to prognosis. Thus in patients with severe acute hepatitis or with fulminant hepatic failure, a close relationship exists between survival and changing rates of liver and spleen volumes as measured by CT (32); a decrease in liver volume accompanied by a decrease in spleen volume implies a good prognosis; a decrease in liver volume without a decrease in spleen volume implies a bad prognosis.
Drug and Toxin-Related Hepatitis
Numerous antibiotics, other drugs, and chemicals result in cholestasis or, on a more chronic basis, lead to biliary obstruction. Even ecstasy, a synthetic amphetamine, has been implicated. Cholestasis, whether drug-induced or due to some other agent, is discussed later (see Metabolic and Related Disorders). The cholangitislike appearance seen after intrahepatic artery injection of various agents, termed secondary sclerosing cholangitis, is covered in Chapter 8.
Ductular obstruction, also termed cholangiolitis or cholangiopathy, ranges from an acute condition that is reversible when the inciting agent is withdrawn to progressive damage and a picture mimicking biliary cirrhosis.
ADVANCED IMAGING OF THE ABDOMEN
liver and spleen. These granulomas are readily detected by CT and are similar to those seen with tuberculosis.
Autoimmune Hepatitis
Although a primary diagnosis of autoimmune hepatitis is occasionally made, similar to granulomatous hepatitis, patients with autoimmune hepatitis have elevated autoantibodies, hyperglobulinemia, an abnormal serum aminotransferase level, and no other obvious liver disease. Current evidence points to an autoimmune basis as a pathway for a number of other disorders. An overlap of autoimmune hepatitis and primary sclerosing cholangitis exists; its relationship to primary biliary cirrhosis is not clear, although in patients with findings of both autoimmune hepatitis and primary biliary cirrhosis the latter diagnosis generally prevails. Adding confusion, some overlap exists with viral hepatitis and autoimmune cholangitis. It is thus a disease of exclusion.
Autoimmune hepatitis is associated with Felty’s syndrome, Sjögren’s syndrome, measles, interferon therapy, gastric carcinoid, celiac disease, and some drugs. In some patients antibodies against liver cytosol appear to be a specific immunoserologic marker of autoimmune hepatitis.
No specific imaging findings mark autoimmune hepatitis. Any detected abnormalities generally point toward another specific disease.
Granulomatous Hepatitis
Granulomatous hepatitis is not a specific disease but a histologic description. Although tuberculosis and sarcoidosis are commonly associated with liver granulomas, this condition also develops with a number of bacterial,fungal, and parasitic infections and a variety of drugs. An occasional lymphoma results in granulomas. A rare association exists between granulomas and Graves’ hyperthyroidism. Langerhans cell granulomatosis can result in liver nodules. Chronic granulomatosis is a cause of liver failure. A diagnosis is not always clear in a setting of granulomas.
Prior infection by histoplasmosis results in calcified granulomas scattered throughout the
Radiation Hepatitis
Radiation hepatitis manifests clinically as jaundice and hepatomegaly several weeks after radiation therapy. The presumed underlying mechanisms are Kupffer cell and vascular endothelial damage.
Imaging identifies the boundary between normal and irradiated liver to be sharply defined and corresponding to the radiation port, a finding not seen with overlapping ports. Once regeneration starts, the sharp boundary becomes less well defined. Radiation hepatitis is isoto hypodense relative to normal liver on CT (Fig. 7.12). Vessels in the involved region appear normal. Postcontrast, CT appearance is inconsistent and ranges from hypoto hyperdense.
325
LIVER
Figure 7.12. Radiation hepatitis after prior radiation therapy for breast carcinoma. CT outlines a focal, sharply defined anterolateral defect (arrow). (Courtesy of Patrick Fultz, M.D., University of Rochester.)
tis picture predominates. Whether this condition is called hepatitis, cholestasis, or cholestatic hepatitis is a moot point. Other cholestatic conditions, including neonatal hepatitis, are discussed in Chapter 8.
Cholestasis is a manifestation of paraneoplastic syndrome in patients with malignant lymphoproliferative diseases. Extrahepatic Hodgkin’s disease, renal cell carcinoma, and other cancers have been associated with cholestasis.
Acute vanishing bile duct syndrome is usually associated with drug or toxin use and is a rare cause of cholestasis. It develops mostly in adults. Rarely, cholestasis progresses to cirrhosis.
Idiopathic benign recurrent cholestasis is a rare disorder diagnosed mostly by exclusion.
Osteoporosis and osteomalacia develop in patients with chronic liver disease, especially those with chronic cholestasis.
The involved liver parenchyma is mostly hypoechoic on US.
Radiation hepatitis is hypointense on T1and hyperintense on T2-weighted MR images. Anecdotal reports describe iron colloidenhanced MRI showing decreased uptake in acute radiation-induced hepatic injury. Eventually abnormalities either resolve or the involved liver segments atrophy.
Metabolic and Related
Disorders
Cholestasis
An active bile acid transport system by hepatocytes into bile canaliculi is necessary for bile acid flow. Bilirubin, various phospholipids, and other components are secreted by canaliculi, while bile duct epithelial cells secrete a bicar- bonate-rich solution. A breakdown in any step of this complex chain results in cholestasis. Cholestasis, or cholestatic jaundice, is not a separate disease but a manifestation of a number of disorders discussed below.
Drug-induced cholestasis is most often due to impaired hepatocellular bile secretion. With some drugs a cholangiolitis or even a cholangi-
Fatty Liver (Steatosis)
Clinical
Fatty infiltration (steatosis) ranges from diffuse to focal (Table 7.6). Drugs associated with steatosis include tetracycline and tamoxifen (used for adjuvant hormone therapy for breast cancer). Fatty liver develops in a setting of heterozygous hypobetalipoproteinemia, and this entity should be considered as a possible cause
Table 7.6. Conditions associated with fatty liver infiltration
Obesity Hyperlipidemia Starvation Alcohol
Diabetes mellitus Cystic fibrosis
Fatty liver of pregnancy Total parenteral nutrition
Familial heterozygous hypobetalipoproteinemia Drugs
Steroids
Certain hepatotoxins Metabolic liver disorders
Galactosemia Reye’s syndrome
Fructose intolerance Glycogen storage diseases
326
of an unexplained fatty liver. Acute fatty liver in pregnancy is discussed in a separate section.
Mild hepatic iron overload develops in some patients with nonalcoholic steatohepatitis, possibly due to the concomitant presence of the hemochromatosis gene mutation; homozygous or heterozygous mutations of this gene are common in patients with nonalcoholic steatohepatitis.
A minority of patients receiving intraperitoneal insulin during peritoneal dialysis develop subcapsular steatosis, seen with CT as subcapsular hypodense nodules or rindlike regions (33).
Steatosis generally improves once a known inciting agent is removed.
ADVANCED IMAGING OF THE ABDOMEN
to their cancellation. Thus on opposed-phase images normal liver parenchyma has an isointense signal and fat appears hypointense and these sequences are useful to detect liver fat. In-phase and opposed-phase GRE sequences provide complementary diagnostic information in the liver; in a fatty liver some focal lesions are obscured if only opposed-phase sequences are used, and for full assessment both are necessary. Fat detection is a complex MR topic, and both fat-suppressed and water-suppressed MRI have certain advantages in specific instances.
Postcontrast, simple fat deposition enhances in a similar pattern to normal liver parenchyma. Fat within abnormal tumors, on the other hand, tends to follow the underlying tumor enhancement pattern.
Diffuse Steatosis
Both CT and US provide qualitative rather than quantitative evidence of liver fat. Precontrast CT suggests steatosis if liver attenuation is less than the spleen; typical criteria for steatosis consist of liver attenuation 10 HU less than spleen or a liver-to-spleen ratio of <0.9. Postcontrast, the spleen is not an accurate reference standard; muscle tissue is an adequate standard only if fatty infiltration is pronounced. Contrastenhanced CT in fatty infiltration reveals normal vessels coursing through fat, rather than being displaced as is often the case with a neoplasm.
Ultrasonography of diffuse fatty infiltration reveals a hyperechoic pattern throughout the liver, to the point of masking the normally hyperechoic portal vein wall. Kidneys have been used as a standard to establish liver echogenicity. The hepatorenal echo intensity difference is greater in fatty livers than in normal livers; a hepatorenal difference of >7dB is a sensitive indicator of a fatty liver.
Because a normal pancreas is slightly more hyperechoic than a normal liver, it too is a useful landmark to detect increases in liver echogenicity.
Magnetic resonance spectroscopy measures the lipid volume fraction in liver steatosis. Spinecho (SE) sequences are relatively insensitive in detecting fatty infiltration. Chemical shift imaging using in-phase and opposed-phase SGE sequences distinguishes proton signals from water and fat. Imaging with fat and water protons in-phase results in their signals being additive, while opposed-phase imaging leads
Focal Fatty Infiltration
Pathogenesis of focal fatty infiltration is not clear. Focal infiltration has a predilection for sites close to the falciform ligament and adjacent to gallbladder fossa. An anomalous portal venous supply, such as aberrant gastric venous drainage, is associated with focal fatty infiltrations. The importance of different insulin levels in an aberrant portal vessel as an inductor of steatosis is conjecture.
Focal fatty infiltration is segmental and often wedge-shaped in appearance; it should not be spherical in outline. As the term suggests, fat infiltrates and should not displace vessels. Rarely, focal involvement appears as multiple small lesions mimicking metastases or abscesses. Some focal infarcts have a similar appearance.
Ultrasonography of focal fatty infiltration shows a normal liver parenchyma containing fatty hyperechoic regions.
The MRI typically reveals a wedge-shaped region, hyperintense on T1-weighted images and extending to the periphery. Magnetic resonance imaging appearance is not pathognomonic; an intrahepatic cholangiocarcinoma can have a similar appearance. Post-ferumoxides, fatty infiltration is relatively high in intensity in all on T1-weighted images, with these regions ranging from hyperto isointense on T2weighted images (34).
Kupffer cells tend to be present in fatty infiltration, evidenced by Tc-99m–sulfur colloid uptake. A minority of focal fatty infiltrations,