Case 4 -
Reactive, Granulomatous Hepatitis Due to Chronic Granulomatous Disease with Sclerosing Cholangitis-like Changes
National Cancer Institute
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The patient is a 23 year old man with a history of recurrent pulmonary, hepatic and bone infections
since young childhood. These infections have required repeated hospitalizations and chronic
administration of antibiotics and antifungals. This time he was admitted for investigation of sinusitis
and during the work-up was noted to have an elevated liver associated enzymes (Alkaline phosphatase 866
(range 37-116), ALT 52 (range 6-41), AST 37 (range 9-34) and total bilirubin of 0.6 mg/dL). Imaging
using ultrasound, CT and MRI showed multiple hepatic lesions consistent with abscesses. A CT guided
aspirate grew Staph. aureus and Strep. mitis. He was started on Ceftriaxone, Vancomycin and Rifampin and
discharged, but returned one week later with right upper quadrant pain, fatigue and chills. He was taken
to surgery where drains were placed and wedge resections of liver were performed. One of the specimens
was a wedge of liver measuring 7 x 4.5 x 3 cm. Sectioning revealed multiple small firm white nodules
measuring up to 0.4 cm, but no frank abscesses. Hemorrhage and fibrosis was noted on one edge of the
specimen. The section submitted for review was selected from an area without obvious gross parenchymal
Case 4 - Figure 4 - One of numerous collections of pigmented macrophages (40x, H&E)
Case 4 - Figure 5 - Scattered granulomas were seen. This one may have been located in or near a portal area (20x, H&E)
Case 4 - Figure 6 - Another example of the granulomatous inflammation (20x, H&E)
The section provided for evaluation shows a large variety of changes. At the edges of the section
there is extensive hemorrhage with fibrin deposition and areas of coagulative necrosis. The hemorrhage
tracks deeper into the specimen along portal tracts and large central veins. These changes are all acute
and probably related to the surgical procedure. The liver parenchyma is involved by a diffuse
inflammatory process. The portal areas are expanded by a mild to moderate infiltrate consisting of
lymphocytes and macrophages. Granulomas are common. Some portal areas contain collections of
eosinophils. At the edges of nearly all of the portal areas, there is infiltration and disruption of the
limiting plate by lymphocytes. The sinuses are mildly dilated and there are foci of spotty necrosis
associated with lymphocytes and micro-granulomas. Many of the large central veins show perivenular
inflammation and granuloma formation. The granulomas themselves show a variety of morphologies, from
aggregates of large pigmented macrophages, to small, well-defined epithelioid giant-cell granulomas, to
larger, more ill-defined epithelioid granulomas that are infiltrated by lymphocytes and eosinophils.
Some of the portal granulomas seem to be occupying positions where ducts ought to be and a number of
smaller portal tracts lack an identifiable duct. In some large portal areas, there is periductal edema
and inflammation with infiltration of the duct by lymphocytes. Other portal areas show constriction of
the duct by concentric fibrosis to the point of complete obliteration of the lumen and replacement of the
duct by a round fibrotic scar. The hepatocytes at the edges of these portal areas have pale rarefied
cytoplasm (cholatestasis, pseudoxanthomatous change). Rare cholestatic rosettes can be seen in the
parenchyma. Sections taken from the abscesses (one digital slide provided) showed multiple, large
necrotizing granulomas with irregular borders surrounded by a cuff of fibroinflammatory granulation
tissue that varied from several millimeters to more than a centimeter in thickness.
Reactive, Granulomatous Hepatitis Due to Chronic Granulomatous Disease with Sclerosing Cholangitis-like Changes
The pathologic differential diagnosis should always begin with a careful consideration of the
pathologic changes first and only after that adding the clinical information. In this case, the liver is
diffusely involved by a necroinflammatory process that is characterized by portal and lobular lymphocytic
inflammation, interface hepatitis and lobular spotty necrosis, non-necrotizing granulomas and duct injury
with duct loss. The broadest differential would include chronic hepatitic diseases such as chronic viral
and autoimmune hepatitis, granulomatous diseases such as sarcoidosis and disseminated granulomatous
infections and chronic cholestatic diseases such as primary biliary cirrhosis (PBC), sclerosing
cholangitis and others (see Table below).
Differential Diagnosis of (Non-Steatotic) Chronic
Necroinflammatory Diseases in Adults, adapted from Snover, DC. Biopsy Diagnosis of Liver
Disease, Williams & Wilkins, Baltimore, MD. 1992, pp 23-37.
|Basic Pattern of Injury|
|Chronic Hepatitic ||Granulomatous ||Chronic Cholestatic|
|Hallmark: Portal-dominant chronic inflammation with interface hepatitis ||Hallmark: Granulomas, without associated duct involvement ||Hallmark: Duct injury and or duct loss as dominant finding|
|Resolving acute hepatitis ||Infectious diseases (mycobacterial, fungal, viral (EBV, CMV), rickettsial) ||Primary biliary cirrhosis|
|Chronic viral (B, C or D) hepatitis ||Sarcoidosis ||Primary sclerosing cholangitis|
|Autoimmune hepatitis ||Idiopathic granulomatosis ||Acute cholangitis|
|Early stages of PBC or primary sclerosing cholangitis ||Primary biliary cirrhosis ||Graft-vs-host disease|
|Wilson's disease ||Foreign material ||Idiopathic adulthood ductopenia|
|Drug injury ||Drug Injury ||Drug Injury|
|Reactive hepatitis adjacent to mass lesion ||Malignancy (especially lymphoma) ||Secondary (acquired) sclerosing cholangitis|
|Chronic intermittent duct obstruction ||Crohn's disease ||Sarcoidosis|
| ||Chronic granulomatous disease |
| ||Common variable immunodeficiency |
In this case, although multiple inflammatory features are observed, the presence of duct injury and
loss takes the differential diagnosis out of the purely hepatitic disease into the granulomatous and/or
cholestatic diseases. Some diseases, such as sarcoidosis and PBC may have cholestatic and granulomatous
features. Once the basic pattern of injury has been defined, individual entities can be included or
excluded based on features that are more specific for particular diseases. The granulomas of sarcoidosis typically are well-circumscribed cellular spheres of epithelioid
histiocytes with little or no infiltration by lymphocytes or eosinophils. They may be found in portal
areas or in the lobular parenchyma and tend to be of the same degree of size and cellularity. True
necrosis is generally not seen, although there may be collagen degeneration in the centers of larger or
coalescent granulomas. Patients with hepatic sarcoidosis have developed chronic cholestasis from
secondary involvement of ducts by granulomas . Infectious granulomas may
come in all sizes and shapes, and with or without necrosis. They do not, however, typically cause duct
injury or paucity. Nevertheless, special stains for fungi, mycobacteria and atypical bacteria should be
done whenever faced with a biopsy full of granulomas, particularly one from a patient with a history of
recurrent infections. Primary biliary cirrhosis is a progressive, chronic
autoimmune disease of the liver characterized by destruction of small ducts
. The hallmark lesion
consists of an injured duct with reactive epithelial changes associated with an epithelioid cell
granuloma. Ducts may be incomplete or injured and ultimately disappear from the portal areas
completely. Portal based lymphoid follicles are common and are sometimes associated with injured ducts.
Eosinophils may be seen mixed into the portal inflammation. As the disease progresses, there is duct
loss, ductular reaction and cholatestasis. Fibrosis begins as expansion of portal areas and progresses
to portal-portal bridging and cirrhosis. Primary sclerosing cholangitis (PSC)
is a disease of large and small ducts, although there is a variant which is limited mainly to small
. The larger ducts become surrounded by a cuff of edematous, mildly inflamed connective
tissue, given the duct an "onion-skin" appearance. There is frequently evidence of epithelial damage,
with infiltration of the epithelium by lymphocytes or neutrophils. Gradually there is constriction of
the duct to the point where the lumen disappears completely and the duct is replaced by a dense
collagenous scar. Granulomas are not generally seen in PSC and the inflammation is usually sparse. As
with PBC, as the ducts disappear, there is ductular reaction and progressive fibrosis. Patients with PSC
are at risk for the development of cholangiocarcinoma.
Once the pathologist has reviewed the histologic features and formulated a pathologic
differential diagnosis, then the clinical history and laboratory data should be reviewed. This is
particularly critical with non-neoplastic liver disease. In this case, the history indicated that the
patient had an underlying immunodeficiency, chronic granulomatous disease (CGD). Chronic granulomatous
disease is a rare (incidence ~1 in 200,000 to 250,000) defect in intracellular killing of pathogens
. It is inherited through both X-linked and autosomal recessive mechanisms. The
specific functional defect is in NADPH oxidase, a membrane-bound enzyme that catalyzes the oxidation of
O2 to superoxide anion, O-2. NADPH oxidase has four subunits, gp91phox,
which is on the X-chromosome and p22phox, p47phox and p67phox, which are on chromosomes 16, 7 and 1
respectively. About 70% of patients have the X-linked form of the disease. Because patients with CGD
cannot generate superoxide, they are particularly susceptible to infections from certain
catalase-positive organisms such as Staph. aureus, Burkholderia sp., Serratia marcescens, Nocardia sp., and Aspergillus sp. About a quarter of
patients with CGD will develop hepatic abscesses, which frequently require surgical intervention due to
the fact that CGD abscesses are multiloculated and embedded in a thick cuff of fibrous tissue and so are
not amenable to percutaneous drainage
. Aside from abscesses, which can be life-threatening,
patients with CGD can also develop granulomatous enteritis and genitourinary obstruction. They heal
wounds poorly, in part from the exuberant inflammatory response that develops against any infection or
injury. Biopsies will show a large variety of granulomatous reactions and typically there are
collections of pigmented macrophages at sites of inflammation and at sites of cell turnover or bacterial
surveillance, such as the mucosa of the GI tract. Beyond the development of hepatic abscesses and the
presence of granulomas and pigmented macrophages, little has been reported on the hepatic pathology of
In a patient with a systemic disease who develops manifestations of disease not previously
associated with the systemic disease, there are three general possibilities for interpretation of the new
The case under consideration has features of both PBC (granulomatous inflammation in portal areas with
duct loss) and PSC (injury of large ducts with progressive sclerosis and duct loss). There are also
clearly manifestations of the patient's systemic illness with both granulomatous inflammation and
numerous collections of pigmented macrophages. Given that the patient was young, male, AMA-negative
(determined later) and that his CGD might account for the presence of granulomas, the cholestatic injury
seemed to be more like PSC than PBC or other granulomatous or cholestatic disease. PSC is a rare
disease, and it is associated with underlying ulcerative colitis or Crohn's disease in 75-80% of cases.
It has a male predominance and although patients may have other autoimmune disease or have positive
serology, PSC is not considered to be a classic autoimmune disease and it does not respond to
immunosuppression. One important consideration is that there are a variety of other diseases and
conditions that may be associated with PSC-like pathology. These include the sclerosing cholangitis of
HIV , drug-induced injury from hepatic artery floxuridine infusions , rupture of echinococcal cysts
into the biliary tree and infiltration of the biliary tree by Langerhans' cell histiocytosis .
PSC-like changes have been seen in other primary immunodeficiency syndromes such as hyper-IgM
immunodeficiency . One model of the pathogenesis of PSC involves the presentation of a foreign
antigen, presumably an infectious agent, in the biliary tract. The presence of this antigen in a
susceptible host sets off a cascade of immune events that culminates in chronic damage to bile
. This model would bring together both patients with PSC and inflammatory bowel disease and
secondary sclerosing cholangitis associated with immunodeficiency. All of these patients would have
immune dysregulation combined with increased opportunity for pathogens to reach the biliary tree.
- The systemic disease is unrelated to the
development of the new lesion and the association is only coincidental.
systemic disease may modify the natural history and/or histologic appearance of the new lesion, but the
new lesion is one that may be seen in individuals without the systemic disease.
- The new lesion is a manifestation of the systemic disease, possibly unreported.
So in summary, careful consideration of the pathologic features of this complex case
permits the construction of a pathology-based differential diagnosis that can then be evaluated in light
of the patient's systemic disease. Patients with unusual manifestations of their primary disease may
require different management than patients with a new second disease. In this case, the initial
attention of the pathologist was focused entirely on the evaluation of the hepatic abscesses, because
abscesses are the known pathologic manifestation of CGD in the liver. A more objective, open-minded
approach allows all of the pathologic findings to be noted prior to interpretation in light of the
patient's medical history.
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