Case 2 -
"Acute Hepatitis" Developing 10 Months after
Allogeneic Hematopoietic Stem Cell Transplantation
Fred Hutchinson Cancer Center
Click on each slide thumbnail image for an enlarged view
A 40 year-old with ALL received an allogeneic matched sibling hematopoietic stem cell
transplant (HCT) in 2002.The only posttransplant (PT) problem, mild skin graft-versus-host disease
(GVHD), resolved with prednisone. At six months, tapering of prophylactic prednisone and cyclosporin
were completed. At 8.5 months PT she finished a 2 week course of famciclovir for zoster. Two weeks
later, the LFTs revealed a normal bilirubin with elevations of alkaline phosphatase (AP)406, SGOT 112,
and SGPT 133. Within 2 weeks, SGOT had risen to 2,086, SGPT 1,641, AP 347. The first liver biopsy was
performed 26 days after the onset of LFT elevations, 10 months PT. Foscarnet was given for three weeks
for treatment of preemptive zoster hepatitis. In the ensuing month the SGOT/SGPT and AP levels markedly
declined. However, the SGOT rose again to 475 and the bilirubin continued to rise, peaking at 30 mg/dl
33 days later when a second liver biopsy was done, 11 months PT. The patient had a history of hepatitis
A reactivity pretransplant, but was currently IgM negative. The patient was CMV antibody positive but
multiple PCR studies for circulating CMV were negative. Tests for hepatitis viruses B and C were
negative. All cultures were negative. There was no indication of any potentially hepatotoxic drugs.
Case 2 - Figure 1 - Low power view showing marked lobular hepatitis with portal inflammation
Case 2 - Figure 2 - Marked lobular hepatitis with prominent sinusoidal lymphocytosis
Case 2 - Figure 3 - Shrunken interlobular bile duct with compression of lumen
Case 2 - Figure 4 - Lobular disarray with hepatocellular swelling
Case 2 - Figure 5 - Portal inflammatory infiltrate with plasma cells; interlobular bile duct with epithelial injury
Case 2 - Figure 6 - Portal tract without identifiable interlobular bile duct
The first liver biopsy performed 10 months PT had a striking lobular hepatitis with
lymphocytes and Kupffer cells filling many of the sinusoids, associated with many scattered acidophilic
hepatocytes. Portal spaces were expanded by an infiltrate of lymphocytes and plasma cells spilling over
into the surrounding periportal hepatocytes. The larger bile ducts appeared unremarkable. Some of the
interlobular bile ducts had swollen cytoplasms, with nuclear dyspolarity, anisonucleosis, segmental loss
of nuclei and scattered intraepithelial lymphocytes.
The second liver biopsy displayed pronounced cholestatic changes with canalicular bile
plugs and marked swelling of pigment-laden hepatocytes in zone 3, associated with focal hepatocytolysis
and sinusoidal fibrosis. Inflammation within the acinus and portal spaces was less pronounced. The
larger portal spaces contained proliferated ductules. The interlobular ducts were shrunken, having only
two or three remaining nuclei within eosinophilic syncytium without a central lumen. The bile ducts in
the smallest portal spaces were nearly destroyed.
Followup: Treatment with high dose steroids and cyclosporin led to rapid
improvement in liver tests, achieving a normal bilirubin within two months.
Chronic Graft-versus-Host Disease of the Liver: Presentation as an Acute Hepatitis
The sudden development of marked elevations of serum aminotransferase enzymes following
allogeneic HCT is a medical emergency since these tests may presage acute liver failure. Potential
causes of the clinical presentation can be deduced from the PT time interval. Within the first three
weeks, the most likely cause is severe veno-occlusive disease, also known as sinusoidal obstruction
syndrome, resulting from hepatocyte ischemia caused by the severe congestion and obstruction of blood
flow in zone 3. Beyond day 30 the most likely etiology is from cytopathic viruses such as adenovirus,
varicella and herpes simplex occurring roughly in that frequency. Following immune reconstitution beyond
3 months PT, infections caused by hepatitis B, varicella zoster, adenovirus or hepatitis C may result in
severe hepatitis and occasionally fulminant hepatic failure. Other than hepatitis caused by these
viruses, extreme elevations are unusual after day 100.
In 2000, Strasser, et al, reported a series of 14 long lived allogeneic HCT recipients, from our
institution and several others sent in consultation, who had a clinical presentation of chronic GVHD that
resembled acute hepatitis.  Characteristics of these 14 patients are summarized from Tables I and II of
that report. All patients were transplanted for malignancy; the majority received HLA sibling identical
allografts. Six had no acute GVHD, and 4 had only skin and gut involvement. Beyond day 80, half of
these patients had chronic GVHD but in only 2 of 14 was there liver involvement. The hepatitic
presentation occurred from day 74 to day 749, median day 294. Elevations in alkaline phosphatase were
roughly 3x (peak 11x) in comparison to the marked median and peak elevations of aminotransferases, SGOT
1,100 and SGPT of 1,600 u (700-2500), and total bilirubin of 12mg/dl(1-56), respectively.
Clinical events preceding the hepatitic onset: The typical clinical
presentation was preceded by the recent cessation or tapering of the anti-GVHD immunosuppressive drugs to
minimal doses. Withdrawal from immunosuppression routine tapppering in 9, however, in 4r patients the
drugs were abruptly discontinued, 1 patient stopped the medicine of her own accord, and 3 patients who
developed leukemic relapse had immunosuppression withdrawn rapidly, aiming to induce a
graft-versus-leukemia effect (GVL). Two of these patients then rapidly developed jaundice and
transaminitis soon after receiving of donor lymphocytes infusions (DLI).
In 2002, Akpek et al from Johns Hopkins reported that 30% of their patients who had received DLI for a
GVL developed hepatitic onset of GVHD an average of 35 days following DLI. They further noted a marked
difference in the maximum aminotransferases between this hepatitic variant and "classical" GVHD occurring
in the usual PT setting. 
Histologic Features of Hepatitic Onset of Chronic GVHD
The characteristic features of the 11 patients with liver biopsies in Strasser's study
was a striking lobular hepatitis with a marked necroinflammatory infiltrate, numerous acidophilic bodies,
moderate to marked hepatocyte arrest and disarray of the cords, prominence of sinusoidal Kupffer cells
and lymphocytes. Biopsies from 4 of the patients contained striking confluent perivenular hepatocyte
dropout with collections of pigmented macrophages and a mixed lymphocytic/plasmacytic infiltrate. Portal
spaces in most were expanded by a mixed inflammatory infiltrate of lymphocytes, many plasma cells,
pigmented macrophages and a few eosinophils. Mild changes of portal endothelialitis were present in 2
patients. The portal inflammation frequently spilled out into the surrounding periportal hepatocytes.
The damaged bile ducts present in all of the biopsies were characterized by shrunken, withered outlines
with compression or loss of the lumen. The epithelial nuclei display dyspolarity, anisonucleosis,
hyperchromatism and focal loss of contiguous nuclei, resulting in segments of swollen eosinophilic
vacuolated anucleate cytoplasms. Intraepithelial lymphocytes were frequent but apoptotic epithelial
cells were rarely identified. These bile duct changes are characteristic of those produced by GVHD.
Treatment and Clinical Course
In those patients in whom the diagnosis was promptly made at presentation, the
institution of cyclosporin, or sirolimus plus steroids and ursodeoxycholate, led to progressive and often
rapid improvement with eventual normalization of liver tests. When the diagnosis was not made
immediately and the administration of appropriate immunosuppressive therapy delayed, at least one of the
patients developed progressive cholestatic abnormalities, including jaundice with bilirubin of 23. This
patient had four liver biopsies between days 184-580 showing a sequence of ductopenia followed by marked
ductule proliferation. He was eventually salvaged with high-dose immunosuppressive therapy, ultimately
achieving normal hepatic function by 12 months.. A similar sequence of events has also been reported by
Freese, et al, following successful treatment of rejection after orthotopic liver transplantation. 
However, if the diagnosis of chronic GVHD is delayed some patients may fail to respond to late
introduction of high-dose immunosuppressive therapy and later die with progressive cholestasis.  These
patients had portal fibrosis with marked cholestasis and loss of small bile ducts without cirrhosis The
few reports of cirrhosis developing after intractable chronic hepatic GVHD were completed prior to the
identification of hepatitis C. Even if the reports of cirrhosis caused by GVHD are correct, they are of
largely of historical note because with earlier diagnosis and more effective therapies for GVHD cirrhosis
has not since been reported.
Nomenclature, Grading and Prognostic Features
The "natural" history of GVHD, in reality, applies only to the experimental models where
the allogeneic strain differences between donor and host can be tightly controlled and the process is
untreated.  In the usual clinical setting, patients receive multiple potent immunosuppressive drugs to
prevent or combat established GVHD. The typical syndrome of "classical" clinical hepatic GVHD is
progressive cholestasis with elevations of bilirubin, alkaline phosphatase, and gamma glutamyl peptidase
with only modest elevations of aminotransferases. Hepatic GVHD often occurs with other organs involved
in the acute or chronic phase. However, as in this case, it may present as the solitary organ
involved. This is particularly vexing in the setting of an allogeneic HCT using umbilical cord blood or
T-cell depleted donor cells and the expectation that since there was no acute GVHD there will be no
chronic GVHD. 
Clinically, GVHD is administratively defined as acute or chronic depending on whether the symptoms and
signs are present before or after a certain date, typically between day 80 and 100. Though acute and
chronic GVHD share certain histologic features they differ in that the latter has sclerodermatous skin
manifestations, keratoconjunctivitis sicca with involvement of the lacrimal glands, salivary glands, and
upper aerodigestive tract and small airways. However, unlike cutaneous chronic GVHD, there is not a
clear dichotomy between the histology of acute and chronic hepatic GVHD. Histologic analysis of
sequential liver biopsies has shown that the degree of bile duct damage/destruction, portal fibrosis and
cholestasis is proportionate to the duration of GVHD , and the absence of immunosuppression.  The
degree of allogenicity likely influences histology; however, this is difficult to assess in the clinical
complex setting. 
Several different schema have been used to grade and prognosticate the manifestations of
acute and chronic GVHD. However, as treatment options have improved, the utility of such schema has been
questionable, with refractoriness to corticosteroids refractory gut disease, or the presence of extensive
chronic GVHD remaining as the most important prognostic variables. Initial attempts at grading liver
GVHD by Lerner  were based on the number of portal spaces with damaged bile ducts. However, serial
liver biopsies indicate that, the number of portal spaces affected as well as the extent of bile duct
damage reflect the duration of GVHD . Analogous to the grading and staging of chronic viral hepatitis
C, some of the features that might portend severity also indicate chronicity. For example, the degree of
hepatocellular-cholestasis, ballooning is a reflection of the duration of GVHD while the
periportal-cholangiolar bile thrombi, due to the coexistence of gut GVHD showering the portal blood with
lipopolysacccharide stimulating release of TNF- a and inducing bile ductule proliferation. . At the
December 2003 American Society of Hematology meeting Lie et al presented data on 38 additional cases of
hepatitic onset GVHD  and Couriel et al from 41 biopsies with liver GVHD including 12 cases of Chronic
GVHD.  These two studies confirmed that response to therapy was unrelated to the degree of lobular
inflammation, acidophilic body formation, and fibrosis. But, in the study by Couriel, as well as
Strasser's study , patients with more severe bile duct injury or loss had a slower response to therapy,
but it did not reach significance . To summarize, no multivariate analysis has ever demonstrated that
any histologic grading schema of hepatic GVHD has significant prognostic value independent of response to
treatment, though delay will result in a longer recovery period.
The nomenclature developed for use in liver allografting has been applied to the diagnosis
and implied in the grading of GVHD. Although both processes involve alloimmune-related destruction of
the bile ducts, there are several striking dissimilarities. First, the time course is quite different.
The term, vanishing bile duct, or paucity of interlobular bile ducts, is typically applied to chronic
rejection. In contrast, this occurs both early and late after HCT. Second, endothelialitis is an
uncommon feature for identifying GVHD as it was seen, in 7-15% of biopsies. Last, the vasculopathy that
occurs in some long-lived survivors with liver allografts is never seen following hematopoietic stem cell
Immunopathogenesis of Hepatic GVHD
A principle unanswered question remains: why there is selective targeting of certain
epithelia by GVHD, including the small bile ducts and adjacent ductules, In murine studies by Howell et
al, where strain differences could be tightly controlled, the V b receptors of the T cell infiltrating
the liver were polyclonal and directed at multiple non-MHC antigens selective for the liver.  The
dynamics of the GVHD process begins when the donor T cells recognize host allogeneic-antigens presented
on host dendritic presenting cells.  Experimentally, this initiating step is enhanced by the
chemo/irradiation therapy given for conditioning, which results in release of lipopolysaccharide into the
circulation, which in turn activates host antigen-presenting cells and stimulates monocytes and
macrophages to secrete inflammatory cytokines. Ichiba and Ferrara et al at the University of Michigan,
looked at the expression of genes in a murine model of GVHD after two time points.  Beyond day 7 there
was marked up-regulation of IFN- d, MHC II molecules, and genes related to leukocyte trafficking in the
spleen, but not the liver. In related studies, Braun et. al. with John Vierling at UCLA studied the gene
expression of immortalized biliary epithelial cells(BEC) exposed to pro-inflammatory cytokines, TNF- a
and IFN-g.  The up-regulated genes expressed in the immortalized BEC included adhesion molecules,
receptors for IL-1, IL-4 and interleukin-1, pro-apoptotic and anti-apoptotic genes MHC class 1 and II,
matrix metaloproteases and caspases. Braun, et al, hypothesize that the cytokine-chemokines secreted by
the BEC lining only the small to medium-sized caliber ducts lead to the attraction, and
susceptibility to death by cytotoxic T cells. Unlike the selective targeting of small bile ducts, the
individual hepatocyte necrosis seen particularly in our cases of hepatitic GVHD is likely explained by
the intensity of the lymphocytic inflammation with cytokine up-regulation of the death receptor pathway
on hepatocytes. 
Cytopathic virus infection
Even prior to liver biopsy, patients with the clinical features of this case should be given empiric
treatment for acute herpes simplex, varicella zoster or adenovirus with high-dose anti-viral agents such
as acyclovir and cidofovir until the biopsy has excluded them. The histologic features of these
infections show random punched-out areas of necrosis, nicely demonstrated on the PAS stain. Viral
inclusions can be seen at the edge of the necrotic areas with adenovirus or zoster, as well as in the
bile ducts. In our experience, herpes simplex hepatitis may not be associated with obvious viral
inclusions. Immunostains and rapid shell vial culture rapidly confirm the diagnosis. Recently, Bründler
et al, described adenovirus ascending cholangiohepatitis in three children, two with liver transplants
and one with acquired HIV infection.  These patients presented with marked elevations of AST and GGT
to nearly 2,000 units. Histologically, the biopsies revealed cholangiohepatitis with progressive loss of
interlobular bile ducts with adenovirus inclusions noted within the biliary tract. It was hypothesized
that the adenovirus occurred as a result of ascending infection from the gastrointestinal tract to the
biliary tree. To my knowledge, no such cases have been reported after HCT.
Hepatitis C and B The
frequency of hepatitis C has been markedly reduced since the initiation of effective blood screening.
Whereas 15 years ago one-third of all HCT patients became hepatitis C positive. Today, the incidence is
under 0.3%.  However, there are still many earlier survivors with chronic hepatitis C, and given the
high prevalence of chronic GVHD, it is likely that some patients may harbor both conditions. The
distinction of these two entities can be difficult to discern, especially when there is marked portal
fibrosis, though destruction of the bile ducts is much more a feature of chronic GVHD.  Chronic viral
hepatitis C does not lead to expression of MHC class II on the bile duct epithelium whereas it does in
primary biliary cirrhosis (PBC)  and GVHD (unpublished observations}
HCT recipients with chronic C are susceptible to a severe, potentially fatal rebound hepatitis
following withdrawal of immunosuppressive therapy, during which time immunosuppression allows for marked
viral proliferation unimpeded by the host immune system.  As hepatitic flares of GVHD may also be seen
during tapering of immunosuppressive drugs used for GVHD prophylaxis, deciding whether the transaminitis
is related to a flare of viral hepatitis or GVHD is crucial, since GVHD requires immunosuppressive
treatment to prevent progressive liver injury The acute exacerbations of hepatitis C are usually
self-limited and rarely lead to fulminant rebound hepatitis C. However, with followup in long- term HCT
survivors, the cumulative incidence of cirrhosis increased from 0.6% at 10 years to 3.8% at 20 years.
Unless there is good evidence of active GVHD in other organs, liver biopsy will be required to access
the need for anti viral therapy. PCR viral copy number is useful in determining the impact of the
hepatitis C infection.
Distinguishing a flare of chronic GVHD from Hepatitis B in an HCT recipient who develops
abnormal AST or ALT at the time of tapering of immunosuppressive drugs, particularly if there is evidence
of GVHD and the presence of HbsAg or HBV DNA in the serum poses a similar diagnostic dilemma with a far
greater risk of fatal rebound hepatitis. Liver biopsy with immunohistology to access the amount of
staining of core and surface antigens is crucial to determine the dominant process. However, both
conditions may coexist and require treatment. 
Cytomegalovirus With of the development of effective antiviral therapies
and effective screening of CMW negative blood products stem cells, disseminated CMV disease has become
uncommon except among recipients of HCT from unrelated donors, T-cell depleted grafts or those with
severe GVHD.  Liver involvement with CMV virtually always accompanies disseminated disease detectable
by antigenemic tests, almost never appears as an isolated liver disease, and only rarely results in
significant liver dysfunction.  CMV hepatitis in immunocompetent patient resembles anicteric
mononucleosis.The usual histology of CMV liver infection in immunoincompetent (HCT)patients include
sinusoidal neutrophilic microabscesses, intranuclear and intracytoplasmic inclusions, including those
found in bile ducts with sparse inflammation . PCR of liver tissue, the most sensitive test for
detection, cannot differentiate among viremia, latent infection or true hepatic infection. Informative
diagnostic modalities include in situ hybridization, shell vial culture and
immunocytochemistry using monoclonal antibodies against the viral proteins. 
Drug liver injury: This must
always be considered in this setting and should also include a careful clinical history to exclude herbal
medicines. Any drugs with known or suspected hepatotoxicity should be withdrawn.
Epstein et al. with Dame Sheila Sherlock published an article in Lancet 24 years ago in which they posited that chronic GVHD, a dry gland
disease that shares many features with PBC) , may share common a immunopathogenesis.  The initial
reports of chronic hepatic GVHD noted a variety of low titer auto-antibodies to ANA and AMA and ASMA.
However, a 1998 study by Quaranta et al, using sera and liver biopsies from patients with chronic hepatic
GVHD indicated that the AMA likely represented false positive passive transfer of antibody. Furthermore,
when liver biopsies with chronic GVHD were immunostained with a specific monoclonal antibody for PBC
epithelium, there was no reactivity. 
Chronic GVHD is associated with several autoimmune disorders including myasthenia gravis, bullous
pemphigoid, and polymyositis/polyserositis. At this time, I am unaware of any clearly documented cases
of primary biliary cirrhosis or primary sclerosing cholangitis occurring after HCT. In contrast, a few
anecdotal cases of autoimmune hepatitis(AIH) have been reported following HCT.  Certainly the
lymphoplasmacytic infiltrate in our patient requires consideration. Such patients with AIH, however,
would be expected to have the typical antibody profile and would be unlikely to have such high levels of
aminotransferases.  None of the chronic GVHD sera evaluated by Quaranta et al, were reactive to
liver/kidney or thyroidal microsomes. 
The incidence of chronic GVHD has increased with the widespread use of peripheral blood stem cells as
the source of the allogeneic graft, the increasing use of mismatched related and matched unrelated
donors, and the use of non-myeloablative(NMAB) conditioning regimens in older populations.  This can
result in a 70% cumulative incidence of chronic GVHD requiring treatment. In addition, NMAB HCT is
associated with the use of fewer systemic immunosuppressants in the first three months and delayed
institution of steroid treatment for GVHD, leading to the syndrome of severe late onset skin and gut GVHD
following tapering of immunosuppression. As a result we are now seeing many more cases with hepatitic
onset of chronic GVHD. What was once rare is now commonplace and needs be considered within the setting
of "hepatitis" developing late after HCT
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