Small Portal Veins

Obliteration of small portal veins (obliterative portal venopathy) may develop secondary to local inflammation, thrombosis, congestive portal venopathy, or toxic injury. Local inflammation is important in any disease with portal inflammation, including chronic hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, sarcoidosis, polyarteritis nodosa, and congenital hepatic fibrosis. Thrombosis may occur as a result of retrograde propagation of thrombi from hepatic veins or in response to sluggish and reversed blood flow, usually in cirrhotic livers. Also in cirrhotic livers, high intrahepatic pressure causes congestive venous injury. A variety of vasculotoxins, including azathioprine, cyclophosphamide, methotrexate, and arsenic, can cause endothelial injury and secondary luminal obliteration. In some geographic regions, schistosomiasis is the most frequent cause of portal vein disease and portal hypertension. The vascular changes in cirrhosis are discussed in Chapter 50.

Granulomas in sarcoidosis can cause phlebitis of small portal veins.¹¹ Medium-sized hepatic veins may also be affected. In most patients, granulomas in the portal tracts or associated portal fibrosis can cause presinusoidal resistance and portal hypertension but not cirrhosis.^12,13 NRH and portal vein thrombosis may occur.¹⁴

Pathologic Features

Left-sided cardiac failure or shock may lead to the development of sharply demarcated zones of coagulative necrosis (Fig. 51.7). Zone 3 is usually most susceptible to the effects of ischemia, giving rise to the term centrilobular necrosis. Rarely, isolated zone 2 necrosis is seen.³² Single-cell calcification may occur. Apoptotic bodies are usually observed in the zone between healthy and coagulated hepatocytes. Zone 1 necrosis is typical of diseases that produce intravascular fibrin deposition, such as toxemia of pregnancy and DIC. The fibrin in these conditions may be present in arterioles, portal venules, and zone 1 sinusoids. Regardless of cause, a reticulin stain can help identify areas of architectural collapse resulting from loss of hepatocytes.

In the liver, an infarct is defined as ischemic necrosis involving two or more contiguous and complete acini; both zone 1 and zone 2 must be involved. Infarcts occur when at least two of the following vessels are involved in the same unit of liver tissue: portal vein, hepatic vein, and hepatic artery (Fig. 51.8). In the presence of hypotension, lesser degrees of vascular obstruction are necessary to produce infarction. Often, no vascular obstruction can be identified.²¹

Differential Diagnosis

The differential diagnosis of zone 3 necrosis includes drug-induced injury, particularly with acetaminophen or cocaine. Amanita phalloides (mushroom) hepatotoxicity also shows zone 3 coagulative necrosis. Herpes virus infection results in necrosis that resembles infarcts except that the margins of necrosis do not follow the normal hepatic acinar landmarks and viral inclusions are usually visible. Atrophy and sinusoidal dilatation suggest underlying chronic passive congestion, as seen in patients with right-sided heart failure.³³ (see Hepatic Vein Disease). Livers with marked zone 3 atrophy and/or zone 3 necrosis, combined with zone 3 hemorrhage from retrograde congestion (as from right-sided heart failure), often have a gross appearance that resembles the cut surface of a nutmeg and is termed “nutmeg liver” (Fig. 51.9). The combination on microscopy of centrilobular necrosis from forward-flow ischemia with hemorrhage from retrograde congestion is termed centrilobular hemorrhagic necrosis.

Clinical Features

Peliosis may be minimal, asymptomatic, and grossly inapparent or severe in cases of cholestasis, liver failure, portal hypertension, development of a mass lesion, or spontaneous rupture. Calcifications may develop and can be seen radiologically.⁶⁰ Peliosis has been associated with exposure to a variety of drugs, including anabolic steroids, tamoxifen, corticosteroids, azathioprine, methotrexate, 6-thioguanine, 6-mercaptopurine, vinyl chloride, arsenic, and Thorotrast, and it may be seen in hairy cell leukemia.^61–63 Bartonella infection can cause bacillary peliosis, which occurs mainly in immunosuppressed patients.

Pathologic Features

The endothelial lining may be lost during lesion development, but it is usually regained in chronic lesions.⁶⁴ Severe peliosis is characterized by separation of the sinusoidal parenchyma from the portal tracts. The portal tracts appear similar to exfoliated branches of a tree in winter (Fig. 51.13). In Bartonella infection (discussed later), the organisms may be seen as a vague haze on hematoxylin and eosin (H&E)-stained sections but are well visualized with a Warthin-Starry stain.⁶⁵ Peliotic change to the sinusoidal vasculature may also be observed in various tumors, particularly hepatocellular adenoma, hepatocellular carcinoma, and angiosarcoma. Therefore, it is important to examine the surrounding liver and the endothelial lining for these lesions.

Peliosis may be mistaken for hemangioma. However, in the latter condition, the blood-filled spaces are lined by a robust vascular wall, and the portal tracts do not extend into the blood-filled cavities, as they do in peliosis.

Clinical Features

Patients with early disease exhibit tender hepatomegaly, ascites, rapid weight gain, and hepatic failure with elevated serum bilirubin.^85,89 The onset of this toxic syndrome can be diagnosed on clinical grounds, and percutaneous liver biopsy may be too risky a procedure given the potential of an evolving coagulopathy. If histologic diagnosis is needed to exclude other conditions, transjugular biopsy can provide a tissue sample and enable measurement of the hepatic venous pressure gradient.^90,91 A gradient greater than 10 mm Hg is considered highly specific for SOS in patients undergoing hematopoietic cell transplantation.

SOS occurs most commonly in patients being prepared for bone marrow transplantation with myeloablative doses of radiomimetic drugs and irradiation.^86,92 The drugs most often implicated are cyclophosphamide, busulfan, and gemtuzumab ozogamicin (Mylotarg⁹³). Occasionally, SOS develops in patients given low doses of other drugs and toxins, such as azathioprine, cysteamine, dacarbazine, dactinomycin, carmustine (BCNU), 6-mercaptopurine, 6-thioguanine, dimethylbusulfan, cytosine arabinoside, indicine-N-oxide, mustine (methchlorethamine hydrochloride), doxorubicin, urethane, vincristine, mitomycin-C, oxaliplatin,⁹⁴ etoposide, arsenic, Thorotrast, and intraarterial flurodeoxyuridine.^95–97 Patients who survive acute SOS usually recover completely, but the residual lesions of VOD may remain in the liver for a long period. Portal hypertension or cirrhosis is rare. If cirrhosis becomes clinically manifest, it is usually associated with the presence of other disease (e.g., chronic hepatitis C).⁹⁸

The initial description of “VOD” was in subjects exposed to pyrrolizidine alkaloids. These compounds are found in plants of the genera Senecio, Heliotropium, Crotalaria, and many others. Epidemics of pyrollizidine alkaloid toxicity occur mainly in arid climates, where toxin-containing plants may overgrow crops during periods of drought. Livestock may be affected when grazing, and humans may be affected by eating bread derived from these crops. Herbal medicines created from toxic plants, commonly called “bush tea,” can cause severe disease, especially in young children, and death may occur. Cirrhosis can occur in survivors of pyrrolizidine alkaloid–induced VOD.⁹⁹

SOS has also been observed in the use of oxaliplatin to treat colorectal cancer metastatic to liver. The underlying mechanism is thought to be toxic injury to the sinusoidal endothelial cells by oxaliplatin.⁹⁴

Pathologic Features

During the first 2 weeks of SOS, the liver exhibits marked diffuse hemorrhage.¹⁰⁰ In the early phase, cirrhosis that develops in survivors of pyrrolizidine toxicity is indistinguishable histologically from other causes of cirrhosis not related to SOS.⁹⁹

The early histologic changes, occurring as early as 1 week after cytoreductive or myeloablative therapy, include a widened and edematous subendothelial zone of the terminal hepatic venule that contains entrapped red blood cells, resulting in concentric narrowing of the venular lumina.¹⁰⁰ Clusters of debris from necrotic hepatocytes, dilated and destroyed sinusoids, and hemorrhage into the space of Disse can be seen surrounding the injured terminal hepatic venules (Fig. 51.14). The necrotic debris may also fill the venular lumina. In this early phase, the hepatic veins are often difficult to locate because of the degree of perivenous hemorrhage. Use of special stains, such as Masson trichrome or reticulin, may help demonstrate the presence and location of the hepatic veins. Examination of tissue under polarized light may also help identify collagen bundles that surround the hepatic veins.

As SOS evolves, hepatic stellate cells are activated, and collagen fibers are deposited in the sinusoidal spaces and hepatic venules. After several weeks, sinusoidal congestion and dropout (loss) of zone 3 hepatocytes develop, with sinusoidal fibrosis and intimal fibrosis of hepatic veins that are typically less than 200 µm in diameter (Fig. 51.15); this constitutes the “VOD” lesion. Bridging fibrosis connecting central veins can be seen in advanced stages.⁹¹ The degree of sinusoidal sclerosis and venous luminal narrowing is associated with the severity of the clinical signs and symptoms.^100,101

Differential Diagnosis

Although acute or chronic graft-versus-host disease (GVHD) needs to be considered in patients who have undergone hematopoietic stem cell (bone marrow) transplantation, the histologic patterns of injury are different from SOS. The injuries of GVHD center in the portal tracts, namely, bile duct damage and endotheliitis in acute GVHD and paucity of bile ducts in chronic GVHD.^101,102

Clinical Features

Patients with amyloidosis may have hepatomegaly, cholestasis, hepatic failure, ascites, or portal hypertension.^110,111 Other features include renal failure, nephrotic syndrome, and cardiomyopathy. Light chain deposition disease may also present with hepatomegaly, cholestasis, or hepatic failure.^112,113 Among patients with amyloidosis, those with hepatic involvement have significantly higher levels of alkaline phosphatase and C-reactive protein than those without hepatic amyloidosis.¹¹⁴

Pathologic Features

Amyloid is deposited in the matrix space or connective tissue of the portal tracts, or within the sinusoidal space of Disse, and within thickened vascular walls of arteries or veins. There is typically great variation in both the severity and the distribution of hepatic amyloid deposits (Fig. 51.16). Although arterial and sinusoidal deposits are most frequent, small globular deposits may occur in the portal tracts or parenchymal regions and may represent the initial stage of the sinusoidal pattern of involvement.^115–117 Bile ducts and peribiliary glands may show subepithelial deposits.^118,119 The pattern of distribution does not distinguish between AA and AL amyloidosis.¹⁰⁸ Apolipoprotein A1 amyloidosis usually shows interstitial deposits in the portal tracts.¹²⁰ In transthyretin amyloidosis, hepatic deposition is largely confined to nerves, so that clinical evidence of liver disease is usually absent.

In advanced cases with massive infiltration, the liver is enlarged and has a rubbery elastic consistency. Severe sinusoidal involvement impedes hepatocellular nutrition, leading to atrophy and dropout of hepatocytes, especially in zone 1.¹⁰⁸ Venous involvement may lead to accentuation of hepatocyte loss and condensation of amyloid into a confluent mass (amyloidoma). NRH may occur in patients with amyloidosis.¹²¹

Amyloid deposits are usually easily recognized on routine staining. Amyloid deposits stain weakly with eosin and with periodic acid–Schiff (PAS) stain with diastase digestion (d-PAS); they are usually positive with Congo red stain. Minimal involvement may be visualized with Congo red staining followed by examination under polarized light to detect apple-green birefringence. Thioflavin-T stain and an immunostain for the P component are more sensitive than Congo red at detecting small amounts of amyloid. Congophilia of AA amyloid is abolished by permanganate treatment. With regard to the differential diagnosis, light chain deposition disease may involve the sinusoidal spaces in a manner that resembles amyloid on H&E and d-PAS stains.¹¹² However, these deposits have a granular ultrastructure, whereas amyloid deposits are fibrillar.

The diagnosis of amyloidosis is often established in biopsy specimens of the rectum, abdominal fat pad, labial salivary glands, or liver. Injection of radiolabeled serum amyloid P component, followed by scintigraphy, is a sensitive and specific method for establishing a diagnosis of both AA and AL amyloidosis. This method avoids the need for biopsy and demonstrates the entire distribution of amyloid deposits within the human body.¹¹⁹

Clinical Features

Symptomatic obstruction of all three hepatic veins (Budd-Chiari syndrome) typically manifests with painful hepatomegaly, ascites, fever, and liver failure. Gastrointestinal bleeding, jaundice, and hepatic encephalopathy are uncommon. Portal venous obstruction is a common manifestation when the disease is severe.^144–146 Increasingly, patients are discovered with minimal symptoms and with imaging studies that reveal involvement of only one or two of the main hepatic veins.¹⁴⁷ Thrombi in large hepatic veins often recanalize early in the course of the Budd-Chiari syndrome, so that some patients have cryptogenic cirrhosis and patent large hepatic veins on imaging studies at presentation. Obstruction of the vena cava is associated with dilated veins in the abdominal wall and chest and edema of the legs.¹⁴⁸ Serum transaminases, alkaline phosphatase, bilirubin, albumin, and prothrombin can be normal or increased. The protein level in ascitic fluid varies, but if it is higher than 3.0 g/dL, Budd-Chiari syndrome should be considered. However, the protein level can also be elevated in cardiac or pericardiac disease. Imaging studies such as ultrasonography with Doppler flow provide initial evidence of Budd-Chiari syndrome in most cases. Other imaging modalities include hepatic scintigraphy, computed tomography, and magnetic resonance imaging.¹³⁹ These modalities are most optimally used when the obstruction occurs in large hepatic veins.

The disease course is typically chronic, with less severe hepatic dysfunction compared with isolated hepatic vein disease.¹⁴⁹ Thrombosis typically recurs, leading to episodic worsening of disease. As a result of either sluggish blood flow or reversal of blood flow in the portal veins, thrombosis of the large portal veins occurs in 10% to 20% of patients with hepatic vein obstruction. Blood from the caudate lobe drains directly into the inferior vena cava via the inferior right hepatic vein. If this vein is spared from the thrombotic process, the caudate lobe may undergo segmental hyperplasia.¹⁵⁰ Caudate lobe hyperplasia or large regenerative nodules elsewhere in the liver may resemble a neoplasm clinically.¹⁴⁴ Long-standing Budd-Chiari syndrome has been shown to be a cause of hepatocellular carcinoma, especially in patients who have thrombotic involvement of the inferior vena cava.¹⁴⁹

Pathogenesis

Thrombosis is the most common cause of large hepatic vein obstruction. This condition may occur in an otherwise normal liver or in a liver with an obstructing lesion such as a neoplasm or cirrhosis. Amoebic abscess is an important cause of hepatic vein disease in developing countries. Sarcoidosis may involve medium- and large-sized hepatic veins. As indicated in Table 51.1, hypercoagulable states are often associated with hepatic vein thrombosis. Oral contraceptives and pregnancy are important stimuli of the coagulation cascade. Other predisposing factors include paroxysmal nocturnal hemoglobinuria, factor V Leiden, prothrombin G20210A, and protein C deficiency. Frequently, patients may have more than one risk factor, typically an underlying hypercoagulable state with an acute initiating event such as commencement of oral contraceptive use, pregnancy, trauma, or infection.¹⁵¹

Pathologic Features

The gross and microscopic features of Budd-Chiari syndrome are shown in Figure 51.19. At the macroscopic level, acute obstruction of all three hepatic veins causes massive hepatomegaly with prominent engorgement of the liver parenchyma. With time, the affected lobes become smaller, whereas unaffected regions undergo compensatory hypertrophy, a phenomenon that most frequently affects the caudate lobe.

At the microscopic level, centrizonal sinusoidal congestion and dilatation, atrophy and dropout of hepatocytes, and perivenular fibrosis are seen. Large- and medium-sized hepatic veins show intimal fibrosis, often in the form of multiple layers, suggesting recurrent thrombosis. Most veins achieve some degree of recanalization with the formation of multiple luminal channels or delicate webs. Secondary thrombosis of small and large portal veins may be observed as well. The type of parenchymal injury that occurs in cases of pure hepatic vein obstruction typically leads to a characteristic venocentric pattern of septation, termed reverse nodularity. The reason is that hepatocyte necrosis occurs mainly near the obstructed hepatic veins, which results in a central vein–to–central vein pattern of necrosis and, subsequently, fibrosis. The portal tracts are seldom incorporated into the fibrous septa.

When secondary portal vein thrombosis occurs, venoportal septa may develop, leading ultimately to a “venoportal” pattern of cirrhosis. By way of context, venoportal cirrhosis is the type seen in the cirrhosis that develops in the setting of chronic hepatitis.

Regions of liver only mildly affected by venous outflow obstruction may develop a pattern of atrophy and compensatory hyperplasia that can be mistaken for NRH. Indeed, large regenerative nodules in better-vascularized areas of the liver are detected in more than 50% of cases of hepatic vein thrombosis. Although the nodules are usually few in number and typically 1 to 2 cm in diameter, in some livers they may be numerous and can reach several centimeters in maximum diameter. Clinically and radiologically, these nodules may be misinterpreted as neoplasms or as FNH.

Liver biopsies are helpful for diagnosing hepatic vein outflow obstruction. A wedged hepatic venous pressure measurement may also be obtained.⁹¹ A biopsy is sometimes used to determine the severity of the disease, including the presence of necrosis and fibrosis.¹²⁷ Biopsies obtained via the transvenous route may detect thrombotic material sampled from the lumen of the hepatic vein. Regional variation in pathologic features may lead to spurious conclusions. Therefore, biopsies taken for this purpose should be obtained from two sites.

Differential Diagnosis

Budd-Chiari syndrome should be suspected when one sees severe congestion or hemorrhage within the liver cell plates, recent thrombi within hepatic veins of any size, or intimal fibrous thickening of hepatic veins larger than 100 µm in diameter. Integration of the clinical history and imaging studies with the histologic findings is important to establish a correct diagnosis.

In settings of acute or chronic obstruction to hepatic venous outflow, the differential diagnosis for Budd-Chiari syndrome includes SOS (after bone marrow transplantation or after exposure to pyrrolizidine alkaloids), pericarditis, and congestive heart disease. The pathologic features of congestive heart failure, constrictive pericarditis, and chronic SOS may be quite similar to those caused by large hepatic vein thrombosis. Oxaliplatin-based systemic neoadjuvant chemotherapy in patients with metastatic colorectal cancer can cause injury to the hepatic microvasculature that leads to sinusoidal obstruction; this injury is manifested by perisinusoidal fibrosis that may mimic Budd-Chiari syndrome.^94,154 Some other forms of drug-induced injury manifest with thrombi within small-sized hepatic veins.¹⁵⁵

Care must be taken to examine whether any of the following are present: vasculitis, neoplasm, granulomas (Fig. 51.20), sickled red cells, intraparenchymal abscess, or infectious agents, such as amebae or fungi. The presence of extramedullary hematopoiesis may suggest a myeloproliferative disease. Most hypercoagulable states require laboratory tests for diagnosis. Bone marrow culture may reveal the presence of a subclinical myeloproliferative disease if red blood cell colonies form, in vitro, without exogenous erythropoietin stimulation. Protein S and C deficiencies are difficult to diagnose because hepatic failure may result in a decrease of the serum levels of these proteins. Genetic tests are available for some types of anomalies of the coagulation cascade.

Obliteration of small hepatic veins and congestion of the liver parenchyma are frequent findings in cirrhosis of any cause. Ironically, the long-standing venocentric cirrhosis caused by hepatic vein thrombosis may show little or no congestion, possibly because of the perivenous scarring or the parenchymal regeneration that occurs. As a result, accurate histologic differentiation of hepatic vein thrombosis from other types of cirrhosis often requires large enough tissue samples to allow for an evaluation of the large hepatic veins. In any case, histologic evaluation can be difficult, because a liver with severe cirrhosis of any etiology often shows intimal thickening of medium- and large-sized hepatic veins due to congestive venopathy or thrombosis.¹⁵⁶

Pathologic Features

Large regenerative nodules are composed of hepatocytes that range from completely normal to markedly reactive in appearance. The nodules are supplied by portal tracts that contain arteries and ducts, either with or without portal veins. Lobar hyperplasia in Budd-Chiari syndrome, primary sclerosing cholangitis, and biliary atresia are physiologically similar to large regenerative nodules but are delimited, in part, by the hepatic capsule. Marked regenerative activity, particularly in the presence of cholestasis, may be difficult to distinguish from dysplasia. However, regenerative nodules show cells with a low nucleus-to-cytoplasm ratio, hepatocyte plates that are usually less than two cells thick, absence of atypical mitoses, and retention of reticulin that are usually associated with portal structures. Regenerative nodules that occur in the absence of a portal vein may be confused with FNH.

Clinical Features

FNH is the most frequent type of large regenerative nodule, and it is the most common benign solid liver lesion, occurring in approximately 3% of the adult population. Ninety percent of patients are women of child-bearing age, two thirds of whom have a history of oral contraceptive use. FNH also occurs in children and in the elderly. Although they usually are an incidental finding, the lesions can cause pain and in rare instances can hemorrhage. Hepatic hemangioma coexists in 20% of patients. A variety of systemic vascular anomalies have been found in association with FNH, including absence of portal vein, dystrophic systemic arteries (often with spontaneous rupture), and vascular anomalies in the brain.¹⁶⁷ Astrocytoma and meningioma have also been reported in patients with FNH. Hepatic imaging studies characteristically show increased arterial flow involving a large artery, centripetal flow, and prolonged opacification.

Pathogenesis

Early observers reported that FNH resembles cirrhosis and therefore may represent a reaction to tissue injury.^168,169 The nodularity of FNH is thought to be a manifestation of hepatocellular hyperplasia in response to increased arterial blood flow.^170,171 The cells in FNH have been shown to be polyclonal.¹⁷² The consistent presence of a single large feeding artery led to the suggestion that FNH may represent a hyperplastic response to the effects of altered blood flow from a large anomalous artery.¹⁷³ However, the presence of arteriovenous shunts in FNH indicates that the artery may be a secondary phenomenon and that the loss of portal veins and ducts characteristic of this lesion may also occur secondary to shunts.¹⁷⁴

Pathologic Features

FNH nodules range from a few millimeters to larger than 5 cm, occasionally occupying an entire lobe of the liver (Fig. 51.22). Although in most cases of FNH they are solitary, approximately 20% occur as multiple lesions. Grossly, the lesion is well demarcated and not encapsulated. The cut surface shows a central, star-shaped scar with radiating septa. Microscopically, thick fibrous septa are invariably present within a nodule of hyperplasic hepatocytes arranged in cords as much as two cells thick; they are revealed by a reticulin stain. A bile ductular reaction is present on the border between the fibrous septa and parenchyma; this is demonstrated by a cytokeratin 7 (CK7) stain. Many thick-walled arteries are also present within the fibrous septa. Inflammatory infiltrates of mononuclear cells are also present in the fibrous septa. Changes of chronic cholestasis with cholate stasis and accumulation of copper (demonstrated by the rhodanine stain) or copper-binding protein (demonstrated by the Victoria blue stain) are also very common.¹⁷⁵ In equivocal cases when the typical features such as fibrous septa, ductular reaction, and thick-walled arteries are lacking, glutamine synthetase stain showing characteristic broad and anastomosing regions mimicking a “maplike” pattern is diagnostic.¹⁷⁶ FNH-like nodules that contain portal veins or bile ducts may represent large regenerative nodules as a precursor to FNH.¹⁷⁷

Differential Diagnosis

Clinically and pathologically, FNH should be distinguished from hepatic adenoma (see Chapter 55). This is not usually difficult, unless one is evaluating only biopsy specimens. Adenomas are more uniform in appearance, without alternating areas of hepatocyte hyperplasia and atrophy. Adenomas also have less periarterial collagen than FNH. Most adenomas do not contain bile ducts or ductules, although a telangiectatic variant may contain these structures.¹⁶⁸ FNH exhibits neither hemorrhage nor malignant transformation, unlike hepatocellular adenoma.

Definition

Hepatoportal sclerosis denotes a condition consisting of portal hypertension, splenomegaly, and anemia (caused by hypersplenism) in a patient without cirrhosis but with dense portal tract fibrosis and obliteration of portal veins.¹⁸⁴ By definition, parasites, myeloproliferative disease, and radiographic evidence of occlusion of the major hepatic and portal veins are excluded. However, some studies also describe IPH as a condition that results from thrombosis of the intrahepatic portal veins¹⁹⁰ and hepatoportal sclerosis as an “abnormality of intrahepatic portal veins with portal fibrosis and nodular regeneration.”¹⁹¹ Thus, confusion persists regarding the definition of this condition. To create further confusion, dense portal tract fibrosis also may be the residuum of regressed cirrhosis (discussed in Chapter 50) or a remnant lesion of intrahepatic portal vein thrombosis (discussed earlier in this chapter).

The underlying etiology of hepatoportal sclerosis remains unclear. Factors such as infection, autoimmunity, and hypercoagulopathy have been suggested based on epidemiologic or experimental studies.^192–198 The key issue remains whether portal tract sclerosis can arise de novo and generate “true” hepatoportal sclerosis.

Chronic exposure to arsenic, which may occur after years of arsenic ingestion at concentrations of 0.01 mg/kg/day, does, in fact, result in a “true” hepatoportal sclerosis.¹⁹⁹ For example Nevens and co-workers²⁰⁰ described eight patients who had been treated for psoriasis and had received arsenic-containing Fowler solution. The total arsenic intake varied from 4 to 16 g, and the interval between treatment and the onset of portal hypertension ranged from 2 to 16 years. Datta and colleagues²⁰¹ reported the development of noncirrhotic portal hypertension in nine patients from northern India, all of whom had consumed high levels of arsenic from contaminated drinking water, adulterated opium, or indigenous medicines. The hypothesis has been advanced that arsenic can cause hepatoportal sclerosis by inducing chronic damage to the intrahepatic portal veins; whether this involves bone fide thrombosis of these veins is not known.

Other conditions associated with noncirrhotic portal hypertension in which the reported histologic lesion is “hepatoportal sclerosis” include latent or overt myeloproliferative syndromes,²⁰² a variety of prothrombotic states,²⁰¹ human immunodeficiency virus (HIV) infection,²⁰³ and the rare Adams-Oliver syndrome.¹⁹¹ In Japan, a role for immunologic abnormalities has also been suggested.¹⁸⁴

Clinical Features

Clinically, hepatoportal sclerosis is manifested by portal hypertension, splenomegaly, and pancytopenia resulting from hypersplenism. Aside from splenomegaly, anemia, and noncirrhotic portal hypertension,¹⁸⁴ patients usually have normal or near-normal serum transaminases, bilirubin, and alkaline phosphatase levels. Hepatic function is intact. Esophageal varices are often demonstrable by endoscopy or radiography, and the hepatic veins are patent. The extrahepatic portal vein is patent, usually with the formation of collateral vessels. There may be normal or slightly elevated wedge hepatic venous pressure. Not all of these radiographic studies need to be performed to invoke the diagnosis, nor is a liver biopsy (percutaneous or transjugular) always necessary. Nevertheless, by definition, associated clinical evidence of portal hypertension should be unequivocal.

Assuming that other conditions are excluded, the prognosis for patients with hepatoportal sclerosis is generally good, particularly if bleeding from esophageal varices can be managed conservatively. Massive bleeding caused by varices is the most common cause of death. Therefore, in severe cases, mitigation of variceal bleeding is critical, either endoscopically or surgically.

Pathologic Features

The pathologic changes of hepatoportal sclerosis are attributable to persistent circulatory insufficiency of the portal venous system.²⁰⁴ Macroscopically, the liver may be normal in size or mildly atrophic, with an irregular undulating and finely wrinkled surface contour.¹⁸⁴ Surface features of atrophy are not uniformly distributed, and there may be distinct disproportionality in the sizes of the liver lobes. Definite nodule formation is uncommon. On cut surface of a resected or autopsied liver, the trunk of the portal vein and major intrahepatic portal vein branches may be dilated and may show thickening of the muscular wall. Fibrosis of portal tracts may extend throughout the corpus of the liver, commonly forming spikes or wedges. Conspicuous phlebosclerosis and perivascular fibrosis in the portal tracts may be present, along with newly formed thrombi. The distribution of hepatic veins may be irregular, and they may be sclerosed or obliterated in atrophic regions.

The cardinal pathologic features of IPH are attributed to compromise of the intrahepatic terminal portal radicles with significant fibrosis of the portal tracts and atrophy of the hepatic parenchyma resulting from insufficient perfusion from the portal system.¹⁸⁴ Microscopically, the primary features are marked portal fibrosis, obliteration of intrahepatic terminal portal vein radicles, and a variable degree of parenchymal atrophy (Fig. 51.25). The lobular architecture is maintained, but occasional portal-to-portal or portal-to-central bridging septa may be present.^135,203 Some cases show extensive ischemic changes in the parenchyma. Portal veins, when identified, exhibit thickening and sclerosis of the wall, with a reduction in luminal diameter and muscular hypertrophy or fibrosis. In many portal tracts, portal vein radicles are completely obliterated by fibroelastosis. These changes are best demonstrated with an elastin stain. In other portal tracts, organized thrombi with recanalization may be present. The bile ducts may show concentric periductal fibrosis. Marked dilatation of the sinusoids may also be present, resulting in “megasinusoids,” which are believed to result from portal hypertension. When one is examining the portal tracts of livers with this condition, hepatic arteries and bile ducts serve as valuable anatomic landmarks. Portal veins usually exhibit much larger diameter than the hepatic arteries. However, in hepatoportal sclerosis, the calibers of affected portal veins are similar to those of the hepatic arteries or even smaller. Although thrombosis of the portal veins is a known phenomenon, it is very rare, accounting for only as much as 3% in reported series.²⁰⁵

The hepatic parenchyma between affected portal tracts is atrophic, with shrunken hepatocytes and dilated sinusoids. Abnormally dilated blood vessels may be seen connecting residual portal veins to sinusoids. It is thought that increased portal pressure may aggravate the formation of these abnormal vessels,²⁰⁵ which appear to serve as collaterals formed in response to the blockage of the portal blood flow.²⁰⁶ In affected regions, phlebosclerosis and occlusion of the terminal hepatic venules or major branches of the hepatic veins may also be present; this condition is considered to be a result of the persistent insufficiency of the portal blood supply. The hepatic parenchyma commonly shows vague nodularity with hyperplasia but without surrounding fibrous septa. Collagen deposition within the sinusoidal spaces that surround the hepatocytes in a patchy fashion may occasionally be seen. However, hepatoportal sclerosis does not evolve to cirrhosis.

Differential Diagnosis

To establish a diagnosis of hepatoportal sclerosis, cirrhosis, especially highly regressed cirrhosis, should be excluded, along with overt extrahepatic portal vein thrombosis, hepatic vein thrombosis, and the presence of intrabiliary parasites and schistosomiasis. This disorder remains a diagnosis of exclusion. Only then can reassurance of a benign clinical course be conveyed to the patient.