CHAPTER 12 Vascular Disorders

The hepatic arteries

The effects of occlusion of hepatic artery branches are unpredictable because of the liver’s double blood supply and variable collateral flow. Potential effects of thrombotic or other occlusion include infarction, and ischaemic damage to the biliary tree leading to stricture formation, cholangitis or duct rupture.¹^–³ The branches of the hepatic artery are sometimes involved in polyarteritis nodosa,²^,⁴ the arteritis of systemic lupus erythematosus,⁵ Schönlein–Henoch purpura³ and giant-cell arteritis.⁶ In the last the liver may contain granulomas of classical⁷ or fibrin-ring type.⁸ The arterial lesions of these systemic diseases are not often seen in needle biopsies of the liver. Vasculitis affecting small intrahepatic vessels is sometimes a manifestation of infection or neoplasia.

In some older patients, especially those with systemic hypertension, small arteries and arterioles in portal tracts appear thickened and hyaline. Amyloidosis can give rise to thickening of arterial walls in the absence of sinusoidal deposits.

The arteriovenous malformations and telangiectases of hereditary haemorrhagic telangiectasia are sometimes found in the liver, with or without surrounding fibrosis.⁹ The presentation is as portal hypertension (accompanied by hepatic encephalopathy and nodular regeneration¹⁰^,¹¹), biliary disease (sometimes resembling primary sclerosing cholangitis or Caroli’s disease) or cardiac failure due to arteriovenous shunting.¹² Patients with liver involvement may have raised serum alkaline phosphatase levels without jaundice (‘anicteric cholestasis’), attributed to abnormal blood supply to the biliary tree.¹³ Severely damaged medium-sized bile ducts are occasionally seen histologically.

Infarcts of the liver result from arteritis, aneurysms, thrombosis, embolism or surgical ligation. They may complicate pregnancy or liver transplantation. Infarction can also follow occlusion of portal-vein branches,¹⁴ and may even be found in the absence of demonstrable vascular obstruction. The pathological features are as in other organs: there are well-defined zones of coagulative necrosis with congested and inflamed borders (Fig. 12.1). Portal tracts may survive within the infarcted areas. Coagulative necrosis of the centres of cirrhotic nodules following hypoperfusion is sometimes called nodular infarction.

Figure 12.1 Infarct.

The dead parenchyma to the right is intensely congested. Surviving liver tissue (left) is fatty. (Post-mortem liver, H&E.)

Shock, heart failure and heatstroke

Severe hypoperfusion of the hepatic parenchyma leads to necrosis, usually in perivenular regions (acinar zone 3) but also, additionally or alternatively, in mid-zonal regions (zone 2).¹⁵ Portal tracts and the periportal parenchyma typically remain normal. In contrast to the necrosis of acute hepatitis there is usually little or no inflammation, but in some patients neutrophils accumulate in limited numbers, particularly if the individual has received pressor support for 1 or more days.¹⁶ Affected areas may be congested, and contain large, ceroid-laden macrophages. There may be cholestasis and evidence of regenerative hyperplasia in the surviving parenchyma. The reticulin network shows regular condensation in the necrotic areas. Similar changes are seen in patients with heatstroke (Fig. 12.2). There may be steatosis in the surviving parenchyma. Inflammation ranges from absent in mild cases¹⁷ to severe when the damage is extensive.¹⁸ Systemic candidiasis is a complication.

Figure 12.2 Heatstroke.

There has been confluent necrosis in acinar zone 3. (Needle biopsy, H&E.)

(Section kindly provided by Professor Helmut Denk, Graz, Austria.)

One of the most important causes of this type of necrosis is heart failure with consequent hypoperfusion of the liver. The term ischaemic hepatitis is commonly used for the viral hepatitis-like clinical picture which may ensue.¹⁹ Congestive heart failure leads to sinusoidal dilatation (see Venous congestion and outflow obstruction).

The portal veins

Thrombosis of the main portal veins may result from infection (local or in the portal venous drainage area), cirrhosis,²⁰ liver transplantation, disorders of coagulation and venous outflow obstruction.²¹ Invasion by hepatocellular carcinoma is a common cause. In some patients no reason for the thrombosis can be discovered, but an underlying thrombophilic condition should always be excluded.²⁰ In the acute phase of pylephlebitis, septic thrombi may be seen in portal-vein branches in portal tracts (Fig. 12.3).

Figure 12.3 Pylephlebitis.

Thrombus with inflammatory cells, outlined by arrowheads, fills a portal-vein branch. The surrounding portal tract is also inflamed. (Wedge biopsy, H&E.)

Possible results of portal-vein thrombosis include diffuse or focal parenchymal atrophy, increase in the number of apoptotic hepatocytes,²² parenchymal nodularity (see Nodular regenerative hyperplasia, Ch. 11), and a mild degree of portal fibrosis. Focal atrophy, also known as Zahn’s infarction, is often found at the margins of tumour nodules. Occasionally portal venous obstruction leads to true infarction of the hepatic parenchyma.¹⁴ In many patients with thrombosis of the main portal veins the liver remains histologically normal.

Portal hypertension

Portal hypertension is most often the result of cirrhosis. Other causes include schistosomiasis, alcohol-related liver disease, non-alcoholic steatohepatitis, congenital hepatic fibrosis, the tropical splenomegaly syndrome, hepatic venous outflow obstruction and portal venous thrombosis. The last probably contributes to portal hypertension in polycythaemia and other haematological diseases.²³ In lymphoproliferative and myeloproliferative disorders, the portal infiltration may be a further pathogenetic factor.²⁴ The anatomical subdivision of portal hypertension into pre-hepatic, intra-hepatic and post-hepatic forms should be considered in conjunction with specific structural alterations in classifying the individual case.²⁵

There remains a somewhat ill-defined group of patients with portal hypertension not attributable to cirrhosis or to the other causes mentioned above (non-cirrhotic portal hypertension). In a few cases the condition is attributable to a toxin or toxins such as arsenic,²⁶ vinyl chloride²⁷^,²⁸ or cytotoxic drugs,²⁹ but in the majority no cause can be found. Several different labels have been used to describe aspects of this group (hepatoportal sclerosis, non-cirrhotic portal fibrosis, idiopathic portal hypertension). The term obliterative portal venopathy indicates that there may be demonstrable thrombosis or narrowing of portal-vein branches, but this is not always the case, and it is not clear whether the portal venous narrowing or occlusion is primary or secondary.

Needle liver biopsies from patients with non-cirrhotic portal hypertension are often normal or show only non-specific changes. Abnormalities are more likely to be seen in operative wedge biopsies. Portal-vein branches are sometimes thickened and narrowed, unusually inconspicuous or replaced by multiple small, thin-walled channels. Their overall area is reduced, while portal tract lymphatics increase in number.³⁰ Dilated venules appear to herniate into the adjacent parenchyma³¹^,³² (Fig. 12.4). There may be portal fibrosis and enlargement, with or without inflammatory-cell infiltration (Fig. 12.5). Slender fibrous septa extending from the portal tracts give an appearance indistinguishable from incomplete septal cirrhosis.³³ These septa sometimes connect with bridge-like zones of necrosis.³¹ There may be randomly distributed thin-walled vessels in the lobules (‘megasinusoids’), and sclerosis or dilatation of efferent veins.³¹

Figure 12.4 Non-cirrhotic portal hypertension.

The portal-vein branches in the two portal tracts are widely dilated and appear to have herniated into the parenchyma. (Needle biopsy, H&E.)

(Section kindly provided by Professor Helmut Denk, Graz, Austria.)

Figure 12.5 Non-cirrhotic portal hypertension.

An enlarged, sclerotic portal tract contains arteries (a) and bile ducts (b), but portal-vein branches are inconspicuous. (Wedge biopsy, H&E.)

Diffuse or localised nodular hyperplasia of the parenchyma is commonly seen in these patients. There is thus overlap between hepatoportal sclerosis, nodular regenerative hyperplasia, incomplete septal cirrhosis ³³^,³⁴ and, rarely, partial nodular transformation.³⁵ Nodular regenerative hyperplasia, however, is also found in the absence of clinically evident portal hypertension.

In patients exposed to vinyl chloride monomer and other carcinogens there may be, in addition to the above features, perisinusoidal fibrosis and an increase in the number and size of sinusoidal cells.²⁷^,²⁸ Perisinusoidal fibrosis may also contribute to the portal hypertension which develops in some patients after renal transplantation.³⁶ Prolonged drug therapy has been suggested as a possible mechanism.

The hepatic sinusoids

The width of the sinusoids in liver biopsy specimens is very variable. It is influenced not only by the state of the patient’s circulation at the time of biopsy, but also by fixation and tissue processing. Slight variations in width are therefore of doubtful significance.

The amount of connective tissue in sinusoidal walls should also be assessed critically, since its appearance varies with section thickness. A definite increase in fibres is characteristic of chronic venous outflow obstruction and of steatohepatitis. In the former the pattern of fibrosis is usually linear (peri- or parasinusoidal fibrosis), while in steatohepatitis the fibrosis surrounds hepatocytes (pericellular fibrosis). Increased sinusoidal type IV collagen in diabetic hepatosclerosis ³⁷ is also in the differential diagnosis (see Ch. 7). Other causes and associations, some of them already mentioned above, include congenital syphilis, vinyl chloride toxicity, heroin addiction,³⁸ hypervitaminosis A,³⁹ diabetes,⁴⁰ renal transplantation, myeloid metaplasia⁴¹ and thrombocytopenic purpura.⁴² Endothelial cells lining the hepatic sinusoids sometimes contain iron-rich granules of uncertain significance, especially in viral hepatitis⁴³ and alcoholic liver disease. Immunoglobulin-containing eosinophilic granules have been reported, particularly in chronic hepatitis⁴⁴^,⁴⁵ (see Fig. 9.12).

Definite and regular dilatation of the sinusoidal network is associated with several conditions, the most important being venous outflow obstruction (see below). It has been reported in patients with tumours or granulomas, even when these did not involve the liver,⁴⁶ in Crohn’s disease,⁴⁷ in patients with anti-cardiolipin antibodies and features of the antiphospholipid syndrome,⁴⁸ haemophagocytic syndrome⁴⁹ and in heroin addicts.⁵⁰ Sinusoidal dilatation and congestion in the absence of venous outflow obstruction may also be seen with portal-vein thrombosis and congenital absence, rheumatoid arthritis, Still’s disease, and in wedge biopsies taken during abdominal surgery.⁵¹ Dilatation of periportal and mid-zonal sinusoids has been described in a small number of patients taking oral contraceptives⁵²^,⁵³ (Fig. 12.6). In some patients with renal cell carcinoma there is focal dilatation of mid-zonal sinusoids.⁵⁴

Figure 12.6 Sinusoidal dilatation.

Dilated periportal and midzonal sinsuoids are seen to the left, and a terminal hepatic venule to the right. The dilatation was attributed to an oral contraceptive steroid. (Needle biopsy, H&E.)

(Section kindly provided by Professor Hemming Poulsen, Copenhagen, Denmark.)

Peliosis hepatis

The borderline between regular diffuse dilatation and the focal dilatation known as peliosis hepatis is not always sharp.⁵⁴^,⁵⁵ In peliosis, blood-filled cysts are found in the parenchyma (Fig. 12.7), ranging in size from less than 1 to several millimetres in diameter. The endothelial lining is usually incomplete.⁵⁶ Peliosis is found in association with many different conditions and circumstances including wasting diseases, asphyxia,⁵⁷ neoplasia,⁵⁸ liver and renal transplantation,⁵⁹^,⁶⁰ drug therapy⁶¹^,⁶² and bacterial infection.⁶³ The lesion is often discovered incidentally, but rupture leading to haemoperitoneum has been reported.⁶³^,⁶⁴ Bacillary peliosis hepatis (see Ch. 15) is a different lesion, and is attributed to the bacteria which cause cutaneous bacillary angiomatosis in patients with AIDS. Their presence in silver preparations distinguishes the condition from simple peliosis.