Updated: 03/13/08 01:44 PM
HOME HEAL EDUCATE RESEARCH DIRECTORY OUTREACH


Authors: W. Volwiler, R.A. Willson, A.M. Larson, and J.D. Ostrow
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U. Overview of Some Other Common Hepatic Diseases

  (This section is for general interest, you will not be tested on the details.)



Table 8
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Five Forms of Viral Hepatitis in Humans

  a. Hepatitis A (HAV):

HAV is an important cause of acute liver disease worldwide. It is caused by the hepatitis A virus, a 27 nm single-stranded RNA. The severity of the hepatitis caused by HAV is age related: among children, most infections are asymptomatic, but most adults become symptomatic and often jaundiced. The case fatality rate among reported cases is 0.2% to 0.4% due to fulminant hepatic failure.

This form of hepatitis is transmitted primarily by person-to-person contact, generally through fecal contamination and oral ingestion. Recently, cases of hepatitis A acquired via percutaneous transmission among intravenous drug users have been reported with increasing frequency. Common-source epidemics from contaminated food and water occur (i.e., restaurants), but are not common. They are, however, widely publicized. Hepatitis A remains a frequent infection among older children and young adults. On occasion, it may cause confusion as an intercurrent infection in a patient with another form of chronic liver disease (i.e., alcohol-induced, chronic hepatitis B). It may also cause worsening of chronic liver disease. Serologic testing for anti-HAV IgM provides rapid and accurate identification of this form of acute hepatitis (Figure 23). Acute hepatitis A does not develop a chronic carrier state or progress to chronic hepatitis/cirrhosis. There is no specific treatment for acute hepatitis A. Passive immunization for exposed patients exists and may prevent development of the disease. A vaccine for hepatitis A is effective in preventing this important cause of acute liver disease.

b. Hepatitis B (HBV):

HBV is a 42-nm double-stranded DNA virus with a long incubation period and generally insidious onset. The reported case fatality rate is 1%, due to fulminant hepatic failure.



HBV can lead to chronic hepatitis and carcinoma> 		  The virus may cause chronic infection. The likelihood of becoming chronically infected is inversely proportional with the age at which the infection occurs (i.e., 90% of infants, 6-10% of adults). This carrier state is central to the persistence and epidemiology of HBV. Worldwide, HBV infection is a major cause of acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma. The frequency of HBV infection and the patterns of its transmission vary markedly in different parts of the world. The disease is of low endemicity in the United States, occurring primarily in adulthood with only 0.2% to 0.9% of the population chronically infected. In China, Southeast Asia, and Africa, however, most HBV infection is acquired at birth, and 8% to 15% of the population is chronically infected.

Several serologic tests for HBV exist and interpretation may be complex. A typical serological pattern is illustrated in Figure 23. The risk of acquiring HBV from a blood transfusion has been almost completely eliminated with the advent of serological testing. Currently, IV drug abuse and sexual transmission remain the most common routes for acquiring HBV. Active and passive immunization is available for HBV, and the US Public Health Service has established new guidelines for an immunization program which should eventually lead to the control of HBV in this country. Potential treatment regimens continue to be explored to prevent the chronic sequelae of HBV. Interferon-alpha cures about 30% - 40% of patients.

The nucleoside analogues, lamivudine, adefovir, and entecavir have been FDA-approved and are as effective as interferon, with fewer side effects, but viral resistance can develop. Further drugs are in clinical trials (i.e. telbivudine).



Figure 23
Serological responses to Types A, B, and C Hepatitis

  c. Hepatitis C (HCV)

Hepatitis C virus (HCV) is an RNA virus of approximately 30-60 nm. The prevalence of HCV antibodies in the United States population is about 1.8%; however, it is higher in certain high-risk groups (i.e., IV drug users and hemophiliacs, 60% - 90%; dialysis patients, 28% - 30%). Nearly 4 million Americans carry antibody and 3 million are chronically infected with HCV. The predominant route of transmission is parenteral (IV drugs, transfusions, etc.) but transmission has been associated with other risk factors (rarely sexual) and postulated for others: sniffing cocaine, body/ear piercing, tattooing. As many as 10% of patients may have no identifiable risk factor. HCV shares epidemiological characteristics with those of HBV and multiple episodes of viral hepatitis may be observed in individuals at risk (i.e., HBV and HCV).

Chronic hepatitis is common after infection with HCV   HCV accounts for approximately 20% of all cases of acute hepatitis in the US, and nearly for all cases (>90%) of non-A, non-B post-transfusion hepatitis. Eighty-five percent of patients develop chronic hepatitis. Chronic hepatitis is often silently progressive, with symptoms developing only after 10-20 years of disease. Approximately 10% - 40% of chronically infected patients will progress to cirrhosis after 18-20 years of infection, and of these, about 20% will develop hepatocellular carcinoma. HCV causes significant morbidity and mortality, and is the leading indication for liver transplantation in the United States today.

Risk of hepatitis C infection from blood transfusion ~1:100,000 units

Therapy of hepatitis C is difficult but improving 		  A serologic test (anti-HCV) provides identification of exposure to this virus and allows diagnosis of this important and common form of chronic viral hepatitis (Figure 23). Chronic HCV is more common (1.8%) than chronic HBV infection (0.1% of normal volunteer blood donors). Our ability to identify the virus in blood products has markedly improved the safety of the United States blood supply. Treatment is designed at virus eradication with prevention of sequelae of chronic infection. While treatment has been difficult, newer regimens (i.e. long-acting pegylated interferon and ribavirin) offer response rates up to 70%-80% in selected patients. There is currently no active or passive immunization for HCV.

  d. Hepatitis D (HDV)

HDV (formerly Delta virus) is a fairly recently identified and characterized hepatitis virus. It appears to be a small circular RNA virus, however, it is defective and requires the presence of HBV for its replication. This form of hepatitis affects only patients who are chronically infected with HBV (e.g., HBsAg positive). HDV is relatively rare in the United States, but is most commonly found among IV drug abusers, hemophiliacs, homosexuals, and patients from areas of the world where HDV infection is endemic (southern Europe, Middle East, south India, the Balkans, the Amazon basin).

In general, HDV is more severe than HBV alone. HDV may be acquired at the same time as HBV (co-infection) or it can occur spontaneously in a known HBV carrier (superinfection). Both forms may be associated with a severe or fulminant type of hepatitis; however, the spontaneous form of HDV appears to more commonly accelerate the progression of chronic HBV to cirrhosis. Potential treatment regimens for HDV follow those described for HBV (e.g. interferon, lamivudine, adefovir, , or entecavir). There is no active or passive immunization available for HDV.

e. Hepatits E (HEV)

HEV has fecal-oral transmission   HEV has been identified as the agent accounting for sporadic and major epidemics of viral hepatitis in under-developed countries (India, Pakistan, Mexico, Central Asia, Southeast Asia, North Africa) and travelers returning from these areas. This virus is serologically distinct from acute hepatitis A. HEV is a 32-34 nm single-stranded RNA virus.

Clinically, HEV resembles hepatitis A. It generally affects young adults and has a self-limited course. The mortality is very high (about 20% - 25%) in women in the last trimester of pregnancy. Chronic infection does not occur. Serological testing is available to identify HEV, but it is not yet routinely available. No passive or active immunization for HEV exists.

f. Potential Human Hepatitis Viruses:

With the advances in molecular biologic techniques, the nomenclature of the human hepatitis viruses will be expanded. Several potential human hepatitis viruses have been cloned and serologic assays are being developed.

g. Histopathology, Acute Hepatic Injury:

All forms of viral hepatitis have similar pathology. The initial lesion is an acute inflammation of the entire liver. The inflammatory infiltrate generally begins in the portal triads and consists of mononuclear cells (lymphocytes and monocytes). Occasional plasma cells and eosinophils may be seen. Neutrophils are usually absent. Random hepatocytes, singly or in clusters, undergo degeneration (necrosis). As the cellular necrosis evolves, the hepatocytes become smaller, deeply eosinophilic with pyknotic nuclei. When the pyknotic nucleus is extruded, the remaining cell is called an eosinophilic, acidophilic, or apoptotic body, a common histologic feature of acute viral hepatitis. Some hepatocytes become swollen and pale staining and are referred to as undergoing "ballooning" or "feathery" degeneration. Biliary canaliculi occasionally show inspissation of bile stained material. The reticulin framework generally remains well preserved and provides the scaffolding when the liver cells regenerate. In severe inflammation, the sinusoidal spaces are congested, and may give the impression of stromal hemorrhage (which may actually occur if inflammation is severe enough to destroy the reticulin framework). During recovery, inflammatory cells gradually disappear and Kupffer cells scavenge dead cells. Following inflammation, there is a marked stimulus for hepatocyte regeneration. Frequent mitoses are seen.

h. Variations in the clinical course of acute viral hepatitis (Fig. 24):

i. Normal convalescence:

Complete recovery usual in Hepatitis A, B and E, but not C.   Following hepatitis, the entire process may gradually heal. Liver cells no longer degenerate, bile canalicular plugging disappears, and the inflammatory collection diminishes in amount (with mononuclear cells remaining the longest within the portal triad zones). The liver returns to its original size, and hepatic biochemical functions become normal. This is by far the most frequent course in Hepatitis A, B, and E. Recovery occurs in only about 15%-20% of patients with Hepatitis C (Figure 24).



Figure 24
Variations in the Course of Viral Hepatitis B and C in Caucasians




Massive loss of hepatocytes with collapse of residual structures 		  ii. Acute, fulminant, massive necrosis:

Fortunately, fulminant, frequently lethal, variant is relatively rare. Most of the hepatocytes undergo acute necrosis without regeneration. Sinusoids dilate and intralobular hemorrhage may occur. All residual structures, including their associated inflammatory cell collections collapse together. Occasional random islands of fairly normal hepatocytes may remain which are likely to include multinuclear giant hepatocytes. Although initially swollen, the liver can shrink to a very small size (often less than 1/3 normal) over a few weeks. The cut surface appears red and hemorrhagic.

iii. Submassive necrosis:

Severe massive or submassive necrosis may eventually result in permanent focal fibrosis. If the liver cell loss extends between adjacent central veins and portal triads, the corresponding collapse of the reticular structure of the liver leads to "bridging". This may have a more serious pathogenic course, and if sufficiently extensive may progress to cirrhosis.

iv. Chronic hepatitis:

Chronic Hepatitis common with HCV, but not a sequela of Hepatitis A or E   Occasionally, the acute hepatitis subsides but never totally heals and may even show intermittent acute relapses. Scattered focal liver cell death continues to occur, especially in the periportal region. Consequently, the border between the portal triads and lobular hepatocytes (terminal plate) becomes irregular and inflammatory cells and fibroblasts creep into the hepatocyte cords along the sinusoids (interface hepatitis or piecemeal necrosis). Regeneration is irregular and liver cell plates become two to three cells thick. Mononuclear inflammatory cells (small lymphocytes, plasma cells) abundantly infiltrate the portal triads and extend into the periportal region. An increase in the number of fibroblasts (derived from stellate cells) occurs in the portal areas. Tongues of fibrous tissue reach out from portal triads to penetrate among the hepatocytes and may bridge between portal triads leading to progressive cirrhosis.

i. Classification of chronic hepatitis

i. Medical treatment of chronic Hepatitis B:

The current nomenclature for chronic hepatitis entails the etiology (i.e., HBV, HCV) and the severity which is arbitrarily graded mild, moderate, or severe. Liver biopsies from patients with chronic viral hepatitis are scored on a scale of 0-4 for histologic inflammatory activity (grade) and fibrosis (stage) of the underlying chronic hepatitis ± cirrhosis.




IM or SubQ alfa-interferon for chronic HBV













Antiviral agents offer new promise 		  j. Therapy of chronic viral hepatitis

It is now possible to eliminate HBV replication and ameliorate the underlying liver disease in approximately 20% - 40% of Caucasian patients using alfa-interferon therapy. The pattern of clinical, biochemical, and serologic response to therapy is complex, most likely reflecting the heterogeneity of the pathogenesis of the liver disease in this setting. Alfa-interferon provided the first promise for an effective therapy of chronic HBV. Side effects limit its use and the sustained response rate is only approximately 20% - 40%. Clinical trials to date have examined alfa-interferon treatment of relatively mild to moderately severe chronic HBV liver disease. The role of alfa-interferon in patients with decompensated cirrhosis (i.e., ascites, edema, varices, encephalopathy) - the group that needs treatment most - has not been defined. These patients may actually worsen with therapy. It is currently recommended that these patients should be treated only in the context of controlled clinical trials or in medical centers with expertise in antiviral therapy. The nucleoside analogs, lamivudine, adefovir, and entecavir, have been FDA-approved and play an important role in the treatment of chronic hepatitis B. Importantly, they are oral agents, with limited side effects, and appear to be efficacious in both Caucasian and Asian patients, but viral resistance limits their long-term use. Other antiviral agents are currently being evaluated in clinical trials (telbivudine). The different genotypes of HBV have different susceptibilities to therapy.

Low long-term response with interferon alone

Combination therapy with pegylated interferon + Ribavirin. 		  ii. Medical treatment of chronic hepatitis C:

Alfa-interferon therapy has been extensively examined in chronic HCV infection. The results of many randomized controlled trials clearly demonstrate both safety and efficacy. Current treatment with long-acting (pegylated) interferon, allows once weekly dosing. Its use, in combination with Ribavirin, is the standard of care. This regimen will eradicate the virus in about 40%-50% of patients with HCV genotype 1 and 75%-85% of those infected with genotypes 2 or 3.




Liver transplantation, the court of last resort.













Limited by expense and shortage of donor livers. 		  iii. Liver transplantation:

Liver transplantation has proven to be a clinically appropriate therapeutic modality for selected patients with irreversible fulminant or chronic liver disease. In the relatively uncommon setting of fulminant liver failure, where mortality without treatment is up to 90%, liver transplantation can be life saving. Patients with chronic liver disease (i.e., viral, Wilson's disease, alcohol, etc.) not only have improved long-term survival, but also improved quality of life following liver transplantation. Chronic viral hepatitis is the leading indication for liver transplantation worldwide. The results of liver transplantation have been best in children in whom long-term survival of greater than 5 years may be as high as 85%-90%. In adults, the 5-year survival rates range from 80% to 90%, and are best with predominantly cholestatic liver disease (i.e., primary biliary cirrhosis). The results from liver transplantation are even more impressive when they are compared with the alternative of medical therapy for end stage chronic liver disease: medical therapy yields 1-year survival rates of only 0-30%. Although the results of liver transplantation are very good, a number of problems remain. These are predominantly related to the complications from immunosuppressive therapy in the post-transplant setting (i.e., infection, hypertension, and diabetes). Techniques for better organ preservation are continually evolving. Donor organ availability remains a major problem, and is the major reason why patients die waiting for an organ. The cost of liver transplantation is substantial: the price ranges from $100,000 to $250,000 or more in the United States (depending upon complications). The cost of medications after transplantation can run several thousand dollars a month.

2. Neoplasms of the Hepatobiliary Tract

  a. Primary malignant liver tumors

Hepatocellular vs cholangiocarcinoma









Risk factors 		  Primary neoplasms of the hepatobiliary tract are derived either from hepatocytes (hepatocellular carcinoma, HCC, or "hepatoma") or from the bile duct epithelium (cholangiocarcinoma). Both of these tumor types tend to invade locally. Distant metastases are uncommon, especially for cholangiocarcinoma. Hepatocellular carcinoma is one of the most common malignant tumors in some parts of the world, especially southeast Asia. In adults, HCC occurs frequently in association with cirrhosis of the liver. Major risk factors for HCC include metabolic liver diseases (hemochromatosis), environmental factors (aflatoxin), alcohol, hepatitis C virus infection (after cirrhosis has developed), and chronic hepatitis B viral infection (even before the development of cirrhosis).

i. Hepatocellular carcinoma:

Hepatocellular carcinoma (HCC) appears as irregular cords of cells, which resemble hepatocytes and form plates several cells thick. The included biliary canaliculi often contain bile. HCC is often multifocal and commonly invades and grows within the channels of the hepatic veins. HCC may extend into and occlude not only the hepatic venous outflow tract, but also the inferior vena cava. Tumor emboli may be delivered into the lungs, where metastases grow readily. HCC usually arises in cirrhotic livers and is initially manifested by worsening of the signs and symptoms of the cirrhosis, associated with a disproportionate increase in serum alkaline phosphatase. Later complaints are generally associated with rapid increase in tumor size, liver size, and abdominal girth. The swollen liver may cause right upper quadrant pain. Unless the tumor is small and localized to a single lobe of the liver, surgical removal is usually difficult and unrewarding.







Serum alpha-fetoprotein is a marker of HCC 		  Malignant hepatocytes may synthesize a variety of proteins (alpha-fetoprotein, erythropoietin, parathyroid-like hormone) not normally produced by the adult liver. Alpha-fetoprotein is a normal product of embryonic hepatocytes, but, in early infancy, it ceases to be produced in significant quantities. Rapidly regenerating hepatocytes (following acute liver injury), regenerating nodules in cirrhosis, and hepatoma cells may synthesize generous amounts of this protein. In adults with HCC, a high plasma level of alpha-fetoprotein can be demonstrated in 50% - 80% of patients. This, associated with a large liver mass and high alkaline phosphatase, is virtually diagnostic of HCC. The secreted erythropoietin may cause erythrocytosis and the parathyroid-like hormone may cause hypercalcemia.







Risk factors 		  ii. Cholangiocarcinoma:

Cholangiocarcinoma shows a geographic variation as well, although not as much as HCC. Cholangiocarcinoma occurs more commonly in older individuals (average age at presentation ~ 60 years), and is rare before age 40. Cholangiocarcinoma coexists with cirrhosis less commonly than does HCC. Major risk factors include long-standing ulcerative colitis, Crohn's disease, primary sclerosing cholangitis, developmental abnormalities of the bile ducts, intrahepatic cholelithiasis, and chronic liver fluke infestation. There is no known relationship with chronic hepatitis B or C infection.

Biliary duct and gallbladder carcinoma





Fibrous stroma is characteristic 		  The tumors arise equally from the gallbladder and the biliary ducts. There is an increased incidence arising in gallbladders which contain stones. For the biliary ducts, the chief sites of origin are: a) the papilla of Vater; b) the junction of the cystic and common hepatic ducts; and c) the bifurcation of the two main intrahepatic ducts. Cholangiocarcinomas are adenocarcinomas that typically grow in tubular elements (resembling bile ducts) embedded in abundant fibrous stroma. The cells vary from tall columnar to short cuboidal and usually grow in great disarray, but may show a glandular organization. Sometimes, when the sclerosis is intense, it is difficult to identify the few neoplastic cells.

Early rise in serum alkaline phosphatase





Do not produce alpha-fetoprotein 		  Cholangiocarcinomas grow slowly, and are initially manifested by a prolonged, progressive, marked elevation of the serum alkaline phosphatase, without symptoms. Pruritus and jaundice do not appear until the obstruction of the bile flow is more marked. Dilatation of the intra- and extrahepatic biliary radicles occurs proximal to (above) the malignant obstruction. Jaundice occurs more commonly than in HCC, but cholangiocarcinomas do not produce alpha-fetoprotein.

Cholangiocarcinomas of the papilla are sometimes associated with intermittent common bile duct obstruction because of fluctuations of tissue edema around the tumor and its periodic sloughing of necrotic portions into the gut lumen. Metastases occur by lymphatic spread. Surgical removal of the tumor is the treatment of choice if technically feasible, but often the tumor is too large by the time it is detected. The results of radiation therapy and cancer chemotherapy are poor, so they are usually treated palliatively by endoscopic stent placement.

b. Secondary (metastatic) tumors of the liver

Metastases to liver more common than primary tumors   The incidence of secondary tumors of the liver far exceeds the incidence of primary hepatobiliary neoplasms. The large blood flow to the liver, including its exclusive portal venous drainage from the gastrointestinal organs, is the most likely explanations for this. Breast, lung, and particularly colon, pancreas, and stomach, are the most frequent sources of hepatic metastases.

Usually multiple









An elevated alkaline phosphatase is the earliest abnormal laboratory finding 		  Metastatic tumors in the liver usually form multiple (less often solitary) well circumscribed nodules of varied size, differing in color, texture, and firmness from the surrounding hepatic parenchyma. These nodules tend to displace and compress the parenchyma. On microscopic examination, tongues of tumor tissue are frequently seen infiltrating into the surrounding hepatic tissue, where they elicit a reaction of acute and chronic inflammatory cells. With expansive growth, the large nodules may compromise the blood supply to themselves or the surrounding parenchyma; local infarction results. A newly elevated serum alkaline phosphatase is often the only clue to the presence of metastases. They are generally easily visualized on abdominal ultrasonography.

Leukemic and lymphomatous infiltrates may be deposited along sinusoidal channels, especially in the regions of the portal triads. Such metastases are widely infiltrative rather than circumscribed and nodular.

3. Infection of the Liver

Multiple routes for bacteria to the liver   a. Bacterial infection in the liver may arrive by hepatic arterial, portal venous, or biliary routes. The abundant blood supply received by the liver makes it a frequent site of the localization of bacterial growth in systemic sepsis. In systemic bacteremias, arterial dissemination may lead to localized single or multiple liver abscesses of varying size. As with other multifocal, space-occupying lesions in the liver, the most common laboratory abnormality is an elevated alkaline phosphatase. Severe sepsis in areas of the abdomen drained by the portal venous system may allow portal dissemination of bacteria to the liver with secondary hepatic abscesses and, rarely, septic portal thrombophlebitis.

Hepatic granulomas: tuberculosis, fungi



Elevated alkaline phosphatase typical 		  b. Granulomas. The liver is a common site for growth of tubercle bacilli and fungi. In these conditions, small inflammatory granulomas are randomly scattered throughout the organ, often without particular relationship to lobular zones. Alkaline phosphatase elevation is again characteristic and often the only abnormal liver function test.

Sarcoidosis   Sarcoidosis produces a similar clinical and pathological picture.

Amebiasis   Amebiasis, due to infection with parasitic ameba (E. histolytica) may produce focal liver abscesses of varying size and numbers. Single very large abscesses involving the right lobe of the liver are frequent.

4. Disorders of Hepatic Circulation
(other than portal hypertension)

Factors determining hepatic blood flow   Liver blood flow is dependent upon a) cardiac output, b) the tone and patency of the splanchnic vasculature, c) sinusoidal tone and patency, and d) the hepatic venous return via the inferior vena cava to the right atrium.

Causes of increased splanchnic arterial resistance   Portal venous inflow to the liver is reduced whenever splanchnic venous dilation, and/or vasoconstriction of the splanchnic arterioles, occurs. Such significant increases in splanchnic arterial resistance occur in response to: elevation of body temperature, sudden assumption of upright posture, peripheral arterial hypotension, and the direct actions of vasoconstrictive drugs (such as vasopressin and ergot derivatives).

Ischemic necrosis most affects zone 3 (centrilobular) hepatocytes   Diffuse ischemic liver necrosis most often results when portal venous inflow is severely decreased, most commonly due to shock in association with massive hemorrhage, complications of surgery, or severe acute myocardial damage. The centrilobular (zone 3) hepatocytes are most severely affected. Although jaundice is often present, milder degrees of this syndrome are manifested by transient, isolated, striking elevations of serum AST and ALT levels.

When the ischemia results from impaired hepatic venous outflow combined with hypoxia, the centrilobular zone exhibits hemorrhage as well as necrosis. Causes of this syndrome include severe cor pulmonale (right-sided heart failure secondary to chronic lung disease) and acute hepatic venous occlusions (acute Budd-Chiari syndrome).

a. Arterial insufficiency


Arterial blood supply generally crucial to liver survival 		  Anoxic liver cell death occurs rapidly in the absence of arterial blood supply. The cirrhotic patient is more sensitive to arterial insufficiency because of the already distorted vascular anatomy. The hepatic arterial system is protected by a variety of available collateral sources, including branches of the phrenic, right gastric, gastroduodenal arteries. The sufficiency of these extrahepatic collateral vessels varies widely among individuals. In some, it is possible even to ligate the main hepatic artery without fatal necrosis. Collaterals between intrahepatic arterial segments are only spottily available. Extensive anoxic death of hepatocytes engenders a fulminant toxic illness with high fever, high white blood cell count, and profound metabolic hepatic failure with encephalopathy and jaundice. With less severe or more distal arterial occlusion, the infarction may be localized to specific, wedge-shaped segments of the liver, and only jaundice and elevation of serum transaminases may be seen.

b. Venous congestion

May be localized in large vessels or diffuse throughout hepatic veins.




May be secondary to right-sided heart failure.



Acute vs. Chronic Budd-Chiari syndrome. 		  Congestion of the liver may likewise be uniformly diffuse or localized to specific segments when there is occlusion of hepatic vein branches. The latter set of conditions may evolve from neoplastic occlusion (especially with hepatoma), local thrombosis, or endophlebitis (veno-occlusive disease). Generalized hepatic congestion results from interference with venous return to the heart from the entire liver and may be due to obstruction of the main hepatic vein, obstruction of the inferior vena cava between liver and heart, or right ventricular failure due to pulmonary hypertension or tricuspid valve insufficiency). Acute, complete hepatic venous obstruction (acute Budd-Chiari syndrome) leads to hepatic cell necrosis with proportionate hepatic metabolic failure. Congestion and edema of the liver rapidly causes organ swelling with stretching of Glisson's capsule, often causing right upper abdominal pain and tenderness. Partial, long-standing interference of hepatic venous outflow (e.g., due to hepatoma or renal cell carcinoma) yields sinusoidal dilation, hepatic cell atrophy and eventual stellate fibrosis, all mainly centrilobular. Only very rarely does this scarring extend to connect the central vein areas of adjacent lobules ("bridging") and evolve into congestive ("cardiac") fibrosis of the liver. Liver lymphatics become extremely engorged and carry massively increased volumes of plasma-rich fluid. The engorged sub-capsular hepatic lymphatics weep fluid directly from the liver surface into the peritoneal cavity in increased amounts, contributing to ascitic fluid collections.

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