Path 874 to 882
Hepatic Complications of Organ or Bone Marrow Transplantation
 Liver damaged by toxic drugs or graft-versus-host disease in bone marrow transplant or host-versus-graft
disease in liver transplant
 Liver transplants tolerated better than other solid organs
 Acute graft-versus-host disease – 10-50 days after bone marrow transplantation, donor lymphocytes attack
epithelial cells of liver, resulting in hepatitis w/necrosis of hepatocytes and bile duct epithelial cells and
inflammation of parenchyma and portal tracts
 Chronic graft-versus-host disease – 100+ days after transplant; portal tract inflammation, selective bile duct
destruction, and eventual fibrosis
o Portal vein and hepatic vein radicles may show endothelitis (subendothelial lymphocytic infiltrate lifts
endothelium from BM)
o Cholestasis can happen in acute or chronic graft-versus-host disease
 Acute rejection in liver transplant – infiltration of mixed inflammatory cells (eosinophils into portal tracts), bile
duct and hepatocyte injury, and endothelitis
o Severity of rejection graded on BANFF scheme
 Chronic rejection – severe obliterative arteritis of small and larger arterial vessels (arteriopathy) results in
ischemic changes in liver parenchyma
o Bile ducts destroyed because of direct immunological attack or obliteration of arterial supply
Hepatic Disease Associated With Pregnancy
 Viral hepatitis – most common cause of jaundice in pregnancy; pregnancy doesn’t specifically alter course of
liver disease except in HEV infection (more severe in pregnant patients w/fatality rate of 10-20%)
 Very small subgroup develop hepatic complications directly attributable to pregnancy: preeclampsia and
eclampsia, acute fatty liver of pregnancy, and intrahepatic cholestasis of pregnancy
 Preeclampsia – characterized by maternal hypertension, proteinuria, peripheral edema, coagulation
abnormalities, and varying degrees of disseminated IV coagulation
o HELLP syndrome – subclinical hepatic disease that may be primary manifestation of preeclampsia;
Hemolysis, Elevated Liver enzymes, and Low Platelets
o Liver normal size, firm, pale w/small red patches due to hemorrhage
o Occasionally yellow or white patches of ischemic infarction
o Periportal sinusoids contain fibrin deposits w/hemorrhage into space of Disse, leading to periportal
hepatocellular coagulative necrosis
o Blood under pressure may coalesce and expand to form hepatic hematoma
o Dissection of blood under Glisson’s capsule may lead to catastrophic hepatic rupture
o Modest to severe elevation of serum aminotransferases and mild elevation of serum bilirubin
o Hepatic dysfunction sufficient to cause coagulopathy signifies far-advanced potentially lethal disease
 Eclampsia – preeclampsia w/hyperreflexia and convulsions
 Acute fatty liver of pregnancy (AFLP) – presents w/spectrum of hepatic dysfunction, elevated serum
aminotransferase levels, hepatic failure, coma, or death
o Affected women present in latter half of pregnancy, usually in 3rd trimester
o Symptoms directly attributable to incipient hepatic failure (bleeding, nausea, vomiting, jaundice, coma)
o 20-40% of cases may be coexistent w/preeclampsia
o Diagnosis rests on biopsy identification of characteristic microvesicular fatty transformation of
hepatocytes; in severe cases, lobular disarray w/hepatocyte dropout, reticulin collapse, and portal tract
inflammation; Dx depends on high index of suspicion and confirmation of microvesicular steatosis
o In subset of patients, both baby is homozygous for deficiency of mitochondrial long-chain 3-hydroxyacylCoA; causes hepatic dysfunction in mother because long-chain 3-hydroxylacyl metabolites produced by
fetus or placenta washed away into maternal circulation and cause hepatic toxicity
 Intrahepatic cholestasis of pregnancy – onset of pruritus in 3rd trimester, darkening of urine and occasionally
light stools and jaundice
o Serum bilirubin (mostly conjugated) high; ALK slightly elevated
o Liver biopsy reveals mild cholestasis w/o necrosis
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Altered hormonal state of pregnancy combines w/biliary defects in secretion of bile salts or sulfated
progesterone metabolites to engender cholestasis
o Mother at risk for gallstones and malabsorption
Nodules and Tumors
 Nodular hyperplasias – focal nodular hyperplasia or nodular regenerative hyperplasia
o Common factor is focal or diffuse alterations in hepatic blood supply arising from obliteration of portal
vein radicles and compensatory augmentation of arterial blood supply
o Focal nodular hyperplasia – well-demarcated, poorly encapsulated nodule; spontaneous mass lesion in
otherwise normal liver, most frequently in young to middle-aged adults
 Lesion lighter than surrounding liver
 Central gray-white, depressed stellate scar from which fibrous septa radiate to periphery;
central scar contains large vessels w/fibromuscular hyperplasia w/narrowing of lumen; radiating
septa show foci of intense lymphocytic infiltrates and exuberant bile duct proliferation along
septal margins; parenchyma between septa show normal hepatocytes w/thickened plate
architecture characteristic of regeneration
 Long-term use of anabolic hormones or contraceptives implicated in development of focal
nodular hyperplasia
o Nodular regenerative hyperplasia – liver entirely transformed into roughly spherical nodules w/o fibrosis
 Plump hepatocytes surrounded by rims of atrophic hepatocytes
 Can lead to development of portal hypertension and occurs in association w/conditions
affecting intrahepatic blood flow (solid-organ or bone marrow transplant or vasculitis)
 Can occur in HIV patients
 Cavernous hemangiomas – blood vessel tumors; most common benign liver tumors; discrete red-blue, soft
nodules, generally located directly beneath capsule
o Tumor consists of vascular channels in bed of fibrous CT
o Don’t perform blind percutaneous biopsy on this
 Hepatic adenomas – benign neoplasm developing from hepatocytes; most frequently occur in young women
who have used oral contraceptives
o Subcapsular adenomas have tendency to rupture, particularly during pregnancy under estrogen
stimulation, causing life-threatening intraperitoneal hemorrhage
o Rarely transform into carcinomas, particularly when adenoma arises in individual w/glycogen storage
disease and adenomas in which mutations of β-catenin gene present
o Mutations in HNF1α or β-catenin can contribute
o Multiple hepatic adenoma (adenomatosis) syndromes can occur in individuals w/maturity-onset
diabetes of young (MODY3) w/HNF1 mutations
o Pale, yellow-tan, frequently bile-stained nodules; often beneath capsule
o Usually well demarcated, but encapsulation may not be present
o Composed of sheets and cords of cells that resemble normal hepatocytes or have some variation in cell
and nuclear size
o Abundant glycogen may generate large hepatocytes w/clear cytoplasm
o Steatosis commonly present
o Portal tracts absent; prominent solitary arterial vessels and draining veins distributed through tumor
 Most primary liver cancers arise from hepatocytes (HCC)
 Cholangiocarcinomas – carcinomas of bile duct
 Angiosarcoma of liver – association w/exposure to vinyl chloride, arsenic, or Thorotrast; metastasize widely and
generally kill within a year
 Hepatoblastoma – most common liver tumor of young childhood; usually fatal in a few years if not treated
o Epithelial type – small polygonal fetal cells or smaller embryonic cells forming acini, tubules, or papillary
structures vaguely recapitulating liver development
o Mixed epithelial and mesenchymal type – contains foci of mesenchymal differentiation (primitive
mesenchyme, osteoid, cartilage, or striated muscle)
o Characteristic features is frequent activation of WNT/β-catenin signaling pathway
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Chromosomal abnormalities common; FOXG1 (regulator of TGF-β pathway) highly expressed in
some subsets
 May be associated w/familial adenomatous polyposis syndrome and Beckwith-Wiedmann
syndrome
 Therapy raised 5-year survival to 80%
Hepatocellular carcinoma (HCC) – 4 major etiologic factors: chronic viral infection (HBV, HCV), chronic
alcoholism, NASH, and food contaminants (primarily aflatoxins)
o Other conditions that predispose are tyrosinemia, glycogen storage disease, hereditary
hemochromatosis, non-alcoholic fatty liver disease, and α1-antitrypsin deficiency
o Cirrhosis present in 75-90% of HCC patients, usually in setting of other chronic liver diseases
o Aflatoxin – produced by Aspergillus flavus that contaminates peanuts and grains; can bind covalently
w/cellular DNA and cause specific mutation in p53
o Progression to HCC results from rapid cell turnover (repeated damage and regeneration) accumulating
mutations in KRAS and p53, resulting in constitutive expression of c-MYC, c-MET, TGF-α, and IGF-2
 50% of HCC cases associated w/activation of WNT or AKT pathways
o Depending on integration site, HBV integration may activate proto-oncogenes that contribute
o HBV-X protein (transcriptional activator of multiple genes) might be cause of cell transformation
o HCV doesn’t produce oncogenic proteins, but there are indications that HCV core and NS5A proteins
may participate in development of HCC
o Morphology – unifocal large mass, multifocal (widely distributed, various size), or diffusely infiltrative
(permeating widely, sometimes involving whole liver)
 All 3 patterns cause liver enlargement
 Diffusely infiltrative tumor may blend imperceptibly into cirrhotic liver background
 Usually paler than surrounding liver; can take on green hue when composed of welldifferentiated hepatocytes capable of secreting bile
 All patterns have strong propensity for invasion of vascular structures; can invade portal veins or
inferior vena cava, extending to right side of heart
 Metastasis outside liver primarily by vascular invasion
 Lymph node metastases to perihilar, peripancreatic, and para-aortic nodes found in less than
half of HCCs that spread beyond liver
 Tumor recurrence likely to occur in transplanted donor liver
o Range from well-differentiated to highly anaplastic lesions
 In well-differentiated, hepatocyte-like cells either in trabecular pattern or acinar,
pseudoglandular pattern
 In poorly-differentiated forms, tumor cell take on pleomorphic appearance w/anaplastic giant
cells, can be small and completely undifferentiated, or may even resemble spindle cell sarcoma
o Fibrolamellar carcinoma – distinctive variant of HCC; occurs in young adults
 Usually don’t have underlying chronic liver diseases, so better prognosis
 Usually presents as single large, hard scirrhous tumor w/fibrous bands coursing through it
 Composed of well-differentiated polygonal cells growing in nests or cords, separated by parallel
lamellae of dense collagen bundles
 Abundant eosinophilic cytoplasm and prominent nucleoli
o Lab studies show elevated serum α-fetoprotein (in 50% of pts), false-positives found w/yolk-sac tumors
and non-neoplastic conditions (cirrhosis, massive liver necrosis, chronic hepatitis (esp. HCV), normal
pregnancy, fetal distress or death, fetal neural tube defects
o Staining for Glypican-3 used to distinguish early HCC from dysplastic nodules
o Most valuable for detection are imaging
o Natural course – progressive enlargement of primary mass until it disturbs hepatic function or
metastasizes (first to lungs then elsewhere); death occurs from cachexia, GI or esophageal variceal
bleeding, liver failure w/hepatic coma, or rupture of tumor w/fatal hemorrhage
o Majority of patients die in first 2 years; early detection can be removed w/good prognosis
o Kinase inhibitor sorafenib can prolong life of individuals w/advanced-stage HCC
Cholangiocarcinoma (CCA) – malignancy of biliary tree, arising from bile ducts in and outside liver
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Risk factors – primary sclerosing cholangitis (PSC), congenital fibropolycystic diseases of biliary system
(Caroli disease and choledochal cysts), HCV infection, and previous exposure to Thorotrast
o Major risk factor is chronic infection of biliary tract by liver fluke Opisthorchis sinensis and close relatives
o 80-90% of CCAs extrahepatic, including perihilar tumors (Klatskin tumors at junction of right and left
hepatic ducts forming common hepatic duct) and distal bile duct tumors
o Tumors of ampulla of Vater also include adenocarcinoma of duodenal mucosa and pancreatic carcinoma
 Collectively referred to as periampullary carcinomas
o 50-60% of all CCAs are Klatskin tumors; 20-30% distal tumors; 10% intrahepatic
o 2-year survival rate 15%
o Intrahepatic CCAs not usually detected until late in course; come to attention because of obstruction of
bile flow or symptomatic liver mass
o Hilar and distal tumors present w/symptoms of biliary obstruction, cholangitis, and RUQ pain
o Extrahepatic CCA morphology – firm, gray nodules in bile duct wall; some diffusely infiltrative, others
papillary polypoid lesions; most adenocarcinomas that may or may not secrete mucin
 Abundant fibrous stroma w/epithelial proliferation
 Klatskin tumors slower growth than other CCAs; prominent fibrosis, infrequent distal metastases
o Intrahepatic CCA morphology – follow intrahepatic portal tract system to create tree-like tumorous mass
 Massive tumor nodule may develop
 Vascular invasion and propagation along portal lymphatics give rise to extensive intrahepatic
metastases
 Most well to moderately differentiated sclerosing adenocarcinomas w/clearly defined glandular
and tubular structures lined by cuboidal to low columnar epithelial cells
 Neoplasms usually markedly desmoplastic w/dense collagenous stroma separating glandular
elements; results in firm gritty tumor
 Lymph node metastasis and hematogenous metastases to lungs, bones (vertebrae), adrenals,
brain, or elsewhere present in 50% of autopsies
 Mixed variants occur (HCC and CCA)
 Separate tumor masses of HCC and CCA in same tumor
 Collision tumors – HCC and CCA commingle at identifiable interface
 Tumors w/HCC and CCA intimately mixed at microscopic level; infrequent
o Can be caused by IL-6 overexpression that leads to activation of AKT and anti-apoptotic protein MCL-1
 Increased expression of COX-2, ERB-2, c-MET, KRAS
 Decreased p53 expression
 Amplification of epidermal growth factor receptors
Involvement of liver by metastasis more common than primary hepatic neoplasia
o Most commonly come from colon, breast, lung, and pancreas
o Typically, multiple nodular metastases found causing hepatomegaly
o Tendency for metastases to outgrow blood supply, producing central necrosis and umbilication when
viewed from surface of liver
o Takes massive destruction of liver or direct obstruction of bile ducts for jaundice and elevations of liver
enzymes to occur