Granulomatous hepatitis
The
most common causes of granulomas in the liver are infections, sarcoidosis,
primary biliary cirrhosis and drugs.
Granulomas
are uncommon in hepatitis C but can occur in patients treated with interferon.
Talc granulomas can occur in intravenous drug users and can be detected by
viewing under polarised light. Other systemic granulomatous disease such as
chronic metal toxicity (such as beryllium or copper) can also involve the
liver. Finally, a study of granulomatous hepatitis cases over a 13-year period
identified 11% as idiopathic. These cases can present with fever of
unknown origin and generally respond favourably to steroids.
The granulomas can be present in the portal
tracts or the parenchyma and lack necrosis. Unlike in primary biliary
cirrhosis, the granulomas are not centred on the bile ducts. Granulomas also
can occur with other patterns of liver injury such as acute hepatitis, cholestasis
or steatosis.
The term fibrin-ring granuloma has been used for small granulomas that
consist of a ring of fibrin arranged around a central fat vacuole (fig 10).
Epithelioid histiocytes are present around the ring of fibrin. In atypical
cases, the fibrin is intermixed with the histiocytes and does not form a
well-defined ring. More typical granulomas without the fibrin ring generally
are present in other areas of the biopsy. Fibrin-ring granulomas have been
described with allopurinol, BCG vaccination and intravesical therapy for
carcinoma. These granulomas were first described in the rickettsial disease Q
fever (Coxiella burnetti) but also occur in boutonneuse fever (Rickettsia
conorii), leishmaniasis, toxoplasmosis, cytomegalovirus infection and Hodgkin
lymphoma.
Steatosis and
steatohepatitis
Macrovesicular steatosis
Macrovesicular
steatosis includes large and small droplet fat. The term “large droplet fat” is
used when at least half the hepatocyte cytoplasm is occupied by a single lipid
vacuole, while multiple lipid vacuoles are seen in small droplet fat. The
latter often is confused with true microvesicular steatosis which, unlike small
droplet fat, affects the liver in a diffuse fashion. Macrovesicular steatosis
can be seen in association with steroids, nitrofurantoin, gold, methotrexate,
NSAIDs such as ibuprofen, indomethacin and sulindac, and antihypertensives such
as metoprolol, chlorinated hydrocarbons such as carbon tetrachloride and
chloroform, or chemotherapeutic agents such as 5-fluorouracil, cisplatin
and tamoxifen.
Microvesicular steatosis
Exclusive
or predominant microvesicular steatosis diffusely affecting the liver is a
result of mitochondrial injury and often occurs as an adverse effect of
drugs/toxins such as cocaine, tetracycline, valproic acid and zidovudine (fig
11). Acute exposure to
alcohol (alcohol foamy liver degeneration) and paediatric Reye syndrome
also show diffuse microvesicular steatosis. Other non-drug related aetiologies
include acute fatty liver of pregnancy and genetic diseases such as carnitine
deficiency.
Steatohepatitis
By definition, steatohepatitis is
characterised by steatosis, lobular inflammation and hepatocellular injury in
the form of hepatocellular ballooning (with or without acidophil bodies or
Mallory hyaline) or pericellular fibrosis. A few drugs (notably amiodarone and
irinotecan) play a direct aetiological role in steatohepatitis. Most other
drugs exacerbate or precipitate steatohepatitis in the presence of other risk
factors such as obesity and diabetes.
Amiodarone
Amiodarone, a potent antiarrhythmic agent,
causes elevated liver enzymes in up to 30% of patients and steatohepatitis
in 1–2% of patients. Amiodarone
steatohepatitis is characterised by prominent Mallory hyaline (occasionally in
zone 1) and neutrophilic satellitosis, while steatosis is less conspicuous (fig 12).
It is also associated with a different type of lipid accumulation called
“phospholipidosis” characterised by accumulation of drug in the lysosomes.
This leads to “foamy” appearance of
hepatocytes and Kupffer cells. The foamy areas show lamellar lysosomal
inclusion bodies on electron microscopy (fig 13).
Chemotherapy-induced steatohepatitis
Steatosis and steatohepatitis have been
reported with chemotherapeutic agents. The latter especially is associated with
irinotecan, a drug often used preoperatively in colorectal cancer with hepatic
metastases. This has been referred to as chemotherapy-associated
steatohepatitis in the oncology literature. Other chemotherapeutic agents such
as oxaliplatin have been variably implicated.
Vascular abnormalities
Several vascular
patterns of injury are recognised, each with distinctive morphological features
and drug associations.
Sinusoidal obstruction syndrome
Sinusoidal obstruction syndrome (SOS;
veno-occlusive disease) is due to endothelial cell injury to small hepatic
venules that manifests histologically as endothelial swelling and thrombosis (fig
14). The resultant
venous outflow obstruction leads to sinusoidal dilatation, congestion,
hepatocellular necrosis, and can result in centrilobular fibrosis. Cytotoxic/chemotherapeutic
drugs such as oxaliplatin (used in colorectal cancer) can cause injury to
sinusoidal endothelial cells and hepatic stellate cells.
Peliosis hepatis
Peliosis
is characterised by blood-filled cavities without an endothelial lining in the
hepatic parenchyma (fig 15). This phenomenon most commonly is associated
with androgens or contraceptive steroids. Thiopurine-derived chemotherapeutic
drugs also have been implicated. Peliosis also occurred with the intravenous
contrast agent thorium dioxide (Thorotrast), which has been discontinued due to
the high risk of angiosarcoma. Sinusoidal dilatation may accompany peliosis or
may occur independently, particularly with androgenic or oestrogenic steroid
use.
Hepatic vein thrombosis
Hepatic vein thrombosis is a rare complication
of some drugs, including oral contraceptives and dacarbazine, and presents
clinically as Budd-Chiari syndrome.
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