The Hepatic Vasculature:Missed Lesions, Missed Diagnoses

James M. Crawford, M.D., Ph.D.Department of Pathology and Laboratory Medicine

North Shore-Long Island Jewish Health System

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Case presentation73 yo female

-h/o hypertension, GE reflux

-Elective EGD for abd pain, nausea, distention, bloating, constipation x months-No abnormalities identified on esophagogastroduodenoscopy-Video capsule placed without complications

-6h later: returned for download of video capsule-Complained of epigastric pain, chest and back. Admitted for further eval.-Cardiac enzymes negative-CT: multiple foci of sub-diaphragmatic free air lateral to esophagus

-Presumed diagnosis of esophageal perforation-CT follow-up at 2 days: ‘perforation improving’

-5th day of admission: syncopal episode, thought due to dehydration (was NPO)

-6th day of admission: Hct declined from 29.6 to 11.9; Hb from 11.1 to 4.2 g/dl-transferred to MICU, treated for dehydration and hypotension (no blood given)-cardiac arrest, unable to be resuscitated

Case 3 Case 3

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Case presentation (Cont’d)Autopsy findings:-2 liters free blood in abdomen-Subcapsular hepatic hematoma (10.0 x 8.0 cm), left lobe of liver

-ruptured capsule-Left hepatic artery dissection, communicating with subcapsular hematoma

-rupture of left hepatic artery, into dissection-Main hepatic artery, right hepatic artery: dissection, without rupture

Hepatic Vascular LesionsClinical History: often not suspected

Pathology Examination (gross and microscopic): - may be missed- if seen, may be misinterpreted- if correctly diagnosed, may be completely change course

of clinical management

Hepatic Vascular LesionsTwo angles on hepatic vascular disease:

- Histopathologic examination of percutaneous liver biopsies

- Examination of explanted liver

- Post-mortem examination

Generally not an issue in partial hepatectomy resections

NOTE: Transplant pathology and nodular lesions are not covered in this presentation

Vascular Pathology of the Liver:a conceptual framework

Inflow: Hepatic ArteryPortal VeinPresinusoidal

Sinusoidal: CirrhosisOther

Outflow: Hepatic VenousOutflow Obstruction

Ca: 1550

Liver Vasculature: Basic facts

Normal Liver: 1200-1400 g = 2.5% of body weight

Blood Flow: 25% of cardiac output2/3 via portal vein1/3 via hepatic artery

Portal vascular tree: 17 to 20 orders of dichotomous branchesPortal vein blood enters parenchyma directly via “septal venules”Hepatic arterial blood supplies: bile ducts, capsule, vasa vasorum

enters parenchyma as post-capillary blood in portal blooddirect arteriolar supply of parenchyma is negligible in humans

Hepatic venous tree: fewer ramifications than portal treedrains into: right, middle, and left hepatic veins

Liver Vasculature: “third inflow”- Cholecystic veins through the gallbladder bed*- Extrahepatic parabiliary venous system- Extragastric paraumbilical venous system through falciform ligament

Implications: - Apparent “pseudolesions” on CT perfusion studies,

which are, in fact, artefact of differential blood flow- May rarely create local metabolic changes, e.g. differential steatosis

Yoshimitsu et al, Radiographics 2001; 21: S81-S96

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PortalVein

Bile HepaticDuct Artery

The perfect Portal Tract

Approximately 11 portal tracts/biopsy (range: 3-23) = 6 per cm (14G)62% contain a portal vein, 91% a hepatic artery, and 93% a bile ductBUT: 2.3 bile ducts, 2.6 hepatic arteries, and 0.7 portal veins per PT

Crawford AR et al., Hepatology 1998; 28: 323-331

Liver TransplantationOther: Systemic vascular disease

Intraabdominal inflammationulcerative colitis, peritonitisintra-arterial chemotherapyendoscopic injection of sclerosing agents

Hepatic Artery Thrombosis

Cholangitis Infarction

Hepatic artery occlusion in the liver transplant: infarction of the biliary tree

Parenchymalinfarction

Hilarinfarction

Hepatic Artery Thrombosis

Polyarteritis Nodosa

Systemic Vascular Disease:Polyarteritis nodosaRheumatologic disorders with vasculitisSystemic amyloidosisHyaline arteriosclerosis

Portal Vein Obstruction

Portal vein thrombosis:Surgical complications, traumaIntrabdominal sepsis, phlebitisHepatocellular carcinomaMalignancy in pancreas, hepatic hilumThrombogenic disorders, Pancreatitis(can occur in setting of cirrhosis)

acute thrombosis of portal vein

Case presentationHistory:21 yo female Norwegian MIT student, in good health.2w PTA developed “upper respiratory syndrome” with cough,

sore throat, myalgias. No fevers, chills, chest pain.Day of admission: fever, chills, severe occipital headache,

lower back pain, diffuse abdominal pain, nauseated

Physical Examination:Lethargic and disoriented, fever of 104ºF, tachycardic,

tachypneic, hypotensive, orthostatic: admit to MICULUQ scar, no history available

Case presentationHistory:21 yo female Norwegian MIT student, in good health.2w PTA developed “upper respiratory syndrome” with cough,

sore throat, myalgias. No fevers, chills, chest pain.Day of admission: fever, chills, severe occipital headache,

lower back pain, diffuse abdominal pain, nauseated

Physical Examination:Lethargic and disoriented, fever of 104ºF, tachycardic,

tachypneic, hypotensive, orthostatic: admit to MICULUQ scar, no history available

Hospital Course:Developed respiratory distress, acidosis, oliguria, hypotensionExpired 14h after admission, 24h after onset of acute symptoms

Cavernous transformation of the portal vein

umbilical vein catheterization 2d →portal vein thrombosis, splenectomy age 5, Age 18: pneumococcal sepsis → death

Hepatoportal Sclerosis:Dense sclerosis of portal tractsObliteration of portal vein radiclesNo fibrous septa or cirrhosisIdiopathic vs. smoldering inflammation

arsenic, myeloproliferative syndromes, peritonitisazathioprine, cyclophosphamide, methotrexate

Presinusoidal Obstruction(Non-cirrhotic portal hypertension) Case presentation

58 year old white male-endstage liver disease, “cryptogenic cirrhosis”-endstage renal disease, secondary to hypertension and diabetes mellitus

Liver/kidney transplant performed

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Case presentationFinal Diagnosis:-Consistent with partially reversed cirrhosis-suspect etiology = non-alcoholic fatty liver disease

Fiel I, Thung S, Prodromos H, et al. HPS. Am J Surg Path 2007; 31: 607-614

Incomplete Septal Cirrhosis

Reversal of Cirrhosis

Treated hemochromatosis

Hepatocellular carcinoma in “reversed cirrhosis”Blumberg RS, Gastroenterology 1988; 95:1399-1402

1957: initial diagnosis, age 37

1985: phlebotomy x 28 years, age 65

Reversal of Cirrhosis

Treated hemochromatosisTreated autoimmune hepatitis, Wilson’s?Treated viral hepatitis?

NOTE: vascular lesion remains →“non-cirrhotic” portal hypertension

1957: initial diagnosis, age 37

1985: phlebotomy x 28 years, age 65 Hepatocellular carcinoma in “reversed cirrhosis”Blumberg RS, Gastroenterology 1988; 95:1399-1402

Incomplete Septal Cirrhosis:No substantive portal tract fibrosisFibrous septa (complete bridging and incomplete): no cirrhosis

note: approximation of portal tracts and terminal hepatic veinsDe novo parenchymal fibrosing injury vs. partially resorbed cirrhosis

Hepatoportal Sclerosis:Dense portal tract fibrosis, obliteration of portal vein radiclesNo significant parenchymal fibrosisDe novo portal fibrosing injury vs. partially resorbed cirrhosis

Non-cirrhotic portal hypertensionde novo injury vs. reversal of cirrhosis

Wanless IR et al., Arch Pathol Lab Med 2000; 124: 1599-1607

Case 2

Incomplete Septal Cirrhosis ???

Presinusoidal Obstruction

Nodular Regenerative Hyperplasia:No fibrosis at allNodules throughout the liverSmoldering vascular injuryCompensatory hyperplasia

Rheumatologic conditions, BMTx, Solid organ TxDiagnosis very difficult on liver biopsy

(AASLD Post-graduate Course 1987)

(Non-cirrhotic portal hypertension)

Incomplete Septal Cirrhosis:No substantive portal tract fibrosisFibrous septa (complete bridging and incomplete): no cirrhosis

note: approximation of portal tracts and terminal hepatic veinsDe novo parenchymal fibrosing injury vs. partially resorbed cirrhosis

Hepatoportal Sclerosis:Dense portal tract fibrosis, obliteration of portal vein radiclesNo significant parenchymal fibrosisDe novo portal fibrosing injury vs. partially resorbed cirrhosis

Nodular Regenerative Hyperplasia:No fibrosis of portal tracts or parenchymaRegenerative nodules with intervening parenchymal atrophyDe novo smoldering vascular injury vs. partially resorbed cirrhosis

Non-cirrhotic portal hypertensionde novo injury vs. reversal of cirrhosis

Wanless IR et al., Arch Pathol Lab Med 2000; 124: 1599-1607

Sinusoidal Obstruction

Cirrhosis: causes of portal hypertensionIncreased sinusoidal resistancePortal-to-arterial shuntsFast vascular channels, arteriolar resistance

Crawford JM, in MacSween 4th Edition, 2002, Fig. 13.1

Crawford JM, in MacSween 4th Edition, 2002, Fig. 13.4: based on Wanless IR, Hepatology 1995; 21: 1238-1247

Imaging studies: thrombosis of larger portal veins: 17% of liversOkuda K, et al., Gastroenterology 1985; 89: 279-286

Autopsy: thrombosis of larger portal veins: 39% of liversobliteration of small hepatic veins: 74% of livers

Hou & McFadzean, J Pathol Bact 1965; 89: 473-480

Liver TX: obliterative lesions of portal veins: 36% of liversrelatively uniform distribution

obliterative lesions of hepatic veins: 70% of liversnon-uniform distribution

solitary portal vein obliteration → regional variation in nodule sizedual obliteration → confluent fibrosis and parenchymal extinction

Wanless IR et al., Hepatology 1995; 21: 1238-1247

Role of vascular thrombosis in development of cirrhosis

Sinusoidal DisordersAlcoholic Cirrhosis

Sinusoidal Spread of Cancer

Amyloid

Kappa Lambda

Sinusoidal Obstruction

Sickle Cell Disease: intravascular sickling

Sickle Cell Disease

Sinusoidal Obstruction

Sickle Cell Disease: intravascular sickling

Infiltrative malignancy: intravascular tumorbreast, lung, leukemia, melanoma

Amyloidosis, Congenital Syphilis

Ecclampsia: intravascular coagulation

Sickle Cell Disease Metastatic Malignant Melanoma

Sinusoidal Obstruction: DIC in Ecclampsia Ecclampsia

??? Congenital Syphilis

Venous Outflow Obstruction

Centrilobular congestionright heart failure: congestion only

Centrilobular hemorrhagic necrosis:congestion + forward flow ischemia“nutmeg liver”

Centrilobular hemorrhagic necrosis

Venous Outflow Obstruction

“Cardiac Cirrhosis” = Cardiac SclerosisChronic right sided heart failure only: veno-centric fibrosis onlyChronic right sided heart failure + hepatic vein thrombosis: rapid fibrosis

Cardiac sclerosis

Venous Outflow Obstruction

Hepatic vein thrombosis = Budd-Chiari Syndrome:Major hepatic veins, Hypercoagulable statesMyeloproliferative disorders: polycythemia veraCoagulative disorders: antiphospholipid syndromeIntra-abdominal cancers: HCCHormonal: pregnancy, oral contraceptives (+ other)

Obliterative hepatocavopathy(inferior vena cava thrombosis)

Idiopathic / coagulation disorders; associated with infections (in Nepal)

The IVC thrombosis resolves, leaving incomplete membranous web in IVC near hepatic vein orifices

Not to be confused with normal ‘eustachian valve’ in IVC

Sinusoidal Obstruction Syndrome

Veno-occlusive DiseaseTerminal hepatic veins, irregular distributionBM Tx; hypercoagulable statespyrrolizidine alkaloids (still)hepatic toxicity, endothelial damage, occlusion

Vascular Diseases of the LiverConclusion

Consideration of vascular disease is critical in differential diagnosisof virtually every hepatic pathology

Hepatic artery compromise:non-transplant setting: usually a smoldering subclinical processtransplantation setting: severe, usually leads to loss of organ

Portal vein compromise:large vessel: dramatic, may be life-threateningsmall vessel: subclinical, may give rise to pre-sinusoidal hypertension

Sinusoidal obstruction:Cirrhosis: sinusoids, small portal veins, small hepatic veinsAssortment of infiltrative disorders

Hepatic venous outflow obstruction:Large vessel: Budd-Chiari syndrome - acute, sub-acuteSmall vessel: Veno-occlusive disease (sinusoidal obstruction syndrome)