Jaundice, Cirrhosis and a Mass
Meghan Ho BSc, (University of Toronto 1T2)*
Stephen G.F. Ho MD, FRCP(C)1
Zamil Karim MD, FRCPC2 (University of Toronto 0T7)
Nancy Fu BPharm, MD2
Yuan Yuan Chan PhD, MD2
Eric M. Yoshida MD, MHSc, FRCPC2, (University of Toronto Medical School Class 8T6)
From the University of Toronto Faculty of Medicine*, the UBC Department of Radiology1 and
the UBC Division of Gastroenterology2, University of British Columbia, Vancouver, BC,
Canada.
Address Correspondence to:
Ms. Meghan Ho
meghan.ho@mail.utoronto.ca
Abstract
A 40 year old woman with decompensated cirrhosis, including marked jaundice, coagulopathy
and hypoalbuminemia, and a large liver mass suspicious for hepatocellular carcinoma with
atypical radiologic features is reviewed. The diagnosis and possible therapeutic modalities of
hepatocellular carcinoma are discussed.
Keywords: Liver mass, hepatocellular carcinoma, cirrhosis, jaundice
Case History
A 40 year old woman with a history of hypothyroidism, gestational diabetes and pre-diabetes,
and a ureteric stone, presented to a community hospital with a 2 week history of painless jaundice and
a 1 week history of nausea, vomiting, and general malaise. There was no significant travel history,
blood transfusion or street drug use. She had a remote smoking history, and alcohol consumption was
4-5 drinks per week x 15 years. The family history revealed two first-degree relatives with alcoholic
liver disease but was negative for autoimmune disease or malignancy.
Her reported physical
examination findings were notable for scleral icterus, as well as multiple spider angiomata on her face.
She was noted to be obese. Laboratory investigations revealed a hemoglobin of 109 g/L (normal 135160), platelets of 88 counts/L (normal 150-300), an INR of 2.0 (normal < 1.2), total bilirubin of 355
µmol/L (normal < 22), GGT 229 U/L (normal < 55), AST 206 (normal < 35), albumin 24 g/L (normal 3545). ALT and ALP were within normal limits. HIV, Hepatitis B and C serology were negative; EBV,
CMV and Hepatitis A were IgG seropositive indicating past exposure. The alpha fetoprotein was 259
µg/L (normal < 11). An autoimmune work-up was negative, including anti-smooth muscle, anticardiolipin, ANCA, liver kidney microsomal type 1 antibody, anti-mitochondrial antibodies, and ANA.
Iron profile revealed a ferritin of 1,562, but an iron saturation of 3% and serum iron of 8.
Abdominal ultrasound showed hepatomegaly of 26 cm, fatty infiltration of the liver, and
splenomegaly of 15 cm, with minimal ascites. Sludge was present within the gall bladder but there was
no evidence of cholelithiasis or intrahepatic duct dilatation. Abdominal CT with single portal venous
phase showed hepatomegaly, heterogeneous liver enhancement and three ill-defined hypodense liver
masses (the largest being 6.8 cm x 4.7 cm) suspicious for malignancy. There was evidence of portal
hypertension, moderate splenomegaly, variceal formation in the splenic hilum and recanalization of
the umbilical vein. The pancreas, kidneys, and adrenal glands were within normal limits.
At the community hospital, a low-grade fever was treated with ceftriaxone despite negative
pan-culture. An ultrasound-guided liver biopsy revealed non-specific inflammation, with evidence of
cirrhosis (bridging portal fibrosis and perivenular fibrosis) and steatosis, moderate neutrophilic
infiltration in the parenchymal lobules, moderate portal inflammation, but no evidence of malignancy or
Mallory hyaline bodies. The patient was started on methylprednisolone 60 mg BID, presumably for
alcoholic hepatitis based on the liver biopsy, and transferred to a tertiary care facility for further
management.
At the tertiary care hospital, a triphasic CT scan of the liver with arterial, portal venous and
delayed phase imaging was obtained, showing multiple low-attenuation ill-defined liver lesions on
arterial phase imaging, the largest being 6.2 cm. The lesions were less well-defined on portal venous
imaging, however due to suboptimal examination, an MRI was recommended to rule-out multifocal
hypovascular hepatocellular carcinoma (HCC). The MRI revealed a large subcapsular mass in
segment 6 measuring 6 cm x 3.5 cm without significant arterial enhancement or washout of the
contrast on the portovenous phase that remained suspicious for HCC (figure).
The patient was Child-Pugh Class C, and as such, presented a challenging management
question given her poor liver function (Model for End-Stage Liver Disease, MELD Score = 26), and
multiple, large (>3 cm) lesions. If the mass was HCC, locoregional therapy such as transarterial
chemoembolization (TACE) therapy was deemed not feasible given the degree of hepatic
decompensation. A transplant work-up was initiated and she was discharged with a plan for further
follow-up with the liver transplant program.
A follow-up MRI approximately three months later
revealed that the 6 cm mass was unchanged, with no arterial enhancement or portal venous washout,
therefore being less suggestive of HCC (Figure 1). Her liver transplant work-up continues.
Figure 1: Focal partially exophytic lesion with contour abnormality in segment VI (white arrows)
demonstrates no significant enhancement on arterial phase. This post gadolinium enhanced image
obtained at 3 minutes demonstrates similar signal intensity of the lesion to surrounding liver.
Discussion
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality;
worldwide, it is the fourth most common cause of cancer-related death (1). Moreover, the incidence of
HCC is on the rise (2) both world-wide and in Canada (3) where the incidence has been increasing for
the past three decades. Although cirrhosis from chronic hepatitis B and C are well known to be
associated with HCC, it is important to appreciate that patients with cirrhosis of any etiology, are also
at increased risk (4). The finding of a liver mass in a patient with known liver disease, can present a
conundrum in terms of establishing a precise diagnosis. In considering a liver biopsy, it is important to
keep in mind that liver biopsies can be associated with bleeding, and in the setting of HCC, it is wellknown that malignant cells from HCC can track along the path of the biopsy needle, converting a
previously contained HCC to a metastatic situation (5). Currently, a radiologic diagnosis of HCC on
CT scan or MRI is acceptable for a definitive diagnosis (6). HCCs are hypervascular tumours that,
unlike the rest of the liver parenchyma, are not perfused by the portal venous blood flow. Hence, on
definitive imaging, the HCC enhances on the arterial phase and washes out on the portal venous
phase (6).
Therapeutic Options for HCC
Assuming that our patient’s liver mass is an HCC, what are the possible treatment options?
Since 80-90% of HCC patients have liver cirrhosis, their functional reserve is limited, and is an
important consideration of management (7). Treatment options for HCC, which range widely and vary
based on extent of disease and the degree of underlying liver cirrhosis, include surgical resection and
transplantation, loco-regional therapy including radiofrequency ablation (RFA) (either percutaneous or
at laparotomy) and embolic therapies such as transarterial chemoembolization (TACE), as well as
systemic pharmacologic treatments such as the multikinase inhibitor agent sorafenib. Currently, the
surgical therapies, and RFA for optimal lesions, are the only curative treatments available for HCC,
with 5-year survival rates of 60-70% (8).
Surgical Resection and Liver Transplantation
Localized resection of small tumours is most beneficial in patients without underlying liver
cirrhosis, resulting in 5-year survival rates of up to 74% (2). Resection may be contraindicated in
patients with compromised liver function, decompensation, or portal hypertension, as it may lead to
liver failure in these patients (1). Large tumour size or multiple tumour foci may also limit resection as
a treatment option, due to the increased risk of vascular spread compared with well-circumscribed,
solitary lesions (2). Post-resection recurrence rates have been reported as high as 70% after five
years, with the majority of cases being due to dissemination from the primary tumour (2). Thus, both
the risk of recurrence and the overall surgical risk, based on tumour characteristics, must be weighted
when considering surgical resection. Risk factors for recurrence include tumour rupture, venous
invasion, cirrhosis, high viral replication in hepatitis, and multiple tumour foci (1). For cases of
recurrence post-resection, the best treatment options may be salvage liver transplantation or other
localized, non-surgical therapies (2).
For non-resectable HCC, liver transplantation with or without TACE or RFA is the most suitable
surgical treatment. Patients must undergo thorough evaluation to determine the appropriateness of
and eligibility for transplantation. The validated Milan criteria are currently considered the international
standard by which to judge transplant eligibility: patients are eligible for transplant if their tumour
burden consists of a single tumour < 5 cm, or up to 3 tumours, each < 3 cm in size, and without
vascular or extrahepatic involvement (9). However, studies on the usage of expanded criteria
(University of California San Francisco criteria of solitary lesions up to 6.5 cm or up to 3 lesions each
less than 4.5 cm in size with combined size < 8 cm) have reported similar survival outcomes to the
Milan criteria of over 70% at 5 years (10). In addition, downstaging protocols in which patients are first
treatment with localized invasive therapy such as TACE or RFA to down-size tumour size until
transplant criteria are met, have resulted in similarly successful results (2). The most important
predictor of transplant success (survival and recurrence) has been found to be the diameter of the
largest tumour, rather than the number of nodules (1). The largest barrier to transplantation as a
definitive therapy for HCC remains the significant discrepancy between organ donor need and
availability (11).
Loco-Regional Therapies
Percutaneous therapies include ethanol injection (PEI) to directly destroy tumour cells or
ablation by radiofrequency or microwaves. These therapies can be used to treat early-stage HCC
(small, solitary tumours), or be used pre-transplantation. RFA is the preferred therapy over PEI, as it is
better tolerated, requires fewer treatments, and has better survival outcomes (2). Microwave ablation
is an emerging therapy with theoretical advantages over RFA that has as of yet shown no significant
differences in efficacy when compared with RFA, but is currently undergoing further comparative trials
(2).
TACE is the first-line treatment for large, multi-focal HCC, or tumours not amenable to surgical
or ablative therapies without vascular invasion or extrahepatic spread (2). This procedure involves the
specific placement of an angiographic catheter to administer chemotherapy, typically doxorubicin, to
the hepatic artery feeding the tumour followed by embolization of the feeding hepatic artery with
resulting selective tumour ischemia. More recently, drug-eluting microspheres containing doxorubicin,
known as drug eluting beads (DEB) in the absence of HCC artery embolization have shown a better
safety profile and greater response rates compared with conventional TACE (2). Advances in catheter
design minimize the risks of non-selective chemoembolization and injury to collateral tissues, including
liver failure, cholecystitis, and upper gastrointestinal bleeding (7). Yttrium-90-labeled microspheres
take advantage of the hypervascularity of HCC in a similar manner to TACE, allowing for targeted
radiation to the tumour (2). Randomized controlled trials are needed to compare Y90 treatment with
the other HCC treatment modalities.
In addition to being used for downstaging, percutaneous strategies such as RFA and TACE
may be used to bridge patients while on a transplant waiting list, or may be used as neoadjuvant
treatments pre-transplant to improve transplant outcomes (1).
Pharmacologic Therapies
The anti-angiogenic drug sorafenib, a multikinase inhibitor used for advanced HCC, is the first
systemic chemotherapy that has demonstrated a survival advantage, albeit modest (approximately 3
months) in patients with compensated liver disease (12). Consequently, sorafenib is the first-line
therapy for unresectable HCC with preserved liver function for whom there are no other options (2).
Future Therapies
Bevacizumab, a vascular endothelial growth factor (VEGF) monoclonal antibody, sunitinib, a
multi-tyrosine kinase inhibitor, and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors
such as erlotinib, are currently being investigated for use in HCC treatment. In addition, mTOR
(mammalian target of rapamycin) inhibitors are undergoing early phase clinical trials after positive
preclinical data showed reduced tumour growth (8). Post-transplantation for HCC, the mTOR inhibitor
and immunosuppressive agent, sirolimus, has been demonstrated to improve outcomes (13). Phase I
clinical trials have been done on the use of bone marrow-derived stem cells to improve liver function
(7). Beneficial effects on serum bilirubin and albumin were observed up to 1 year, suggesting stem
cells as another potential pre-transplantation downstaging therapy (7).
Back to the Case: Final Clinical Comments
Our patient with decompensated cirrhosis either because of alcoholic liver disease or, more
likely, non-alcoholic hepatosteatosis (NASH), presented with a liver mass that was atypical for HCC on
imaging but was clinically suspicious for HCC. If the large mass was a HCC, she was not a feasible
candidate for any therapy. It was elected to follow her with serial imaging, which was the clinically
correct decision given that the subsequent scans do not suggest HCC.
assessment continues.
Conflicts of Interest: None.
Her liver transplant
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