The Liver in Systemic Disease

Heart Failure

The liver may become congested secondary to right-sided heart failure; the following clinical, laboratory, and pathologic features related to the liver may be seen:

• 1.

  A dull ache in the right upper quadrant

• 2.

  Hepatomegaly is noted in 50% of cases and is associated with splenomegaly or ascites in 10% to 20%. Other signs of right-sided heart failure include raised jugular venous pressure and peripheral edema ( Table 24.2 ).

  TABLE 24.2

  Symptoms and Signs of Hepatic Congestion in 175 Patients With Acute or Chronic Right-Sided Heart Failure

  Adapted from Richman SM, Delman AJ, Grob D. Alterations in indices of liver function in congestive heart failure with particular reference to serum enzymes. Am J Med. 1961;30:211–225.

  	Acute Heart Failure (%)	Chronic Heart Failure (%)
  Any hepatomegaly (>11 cm span)	99	95
  Marked hepatomegaly (>5 cm below right costal margin)	57	49
  Peripheral edema	77	71
  Pleural effusion	25	17
  Splenomegaly	20	22
  Ascites	7	20

• 3.

  Abnormal liver biochemical test results include a raised bilirubin level in 25% to 75% of patients and normal or mildly elevated serum aminotransferase levels. The serum alkaline phosphatase (ALP) level is usually (but not always) normal. Up to 75% of patients have a prolonged prothrombin time (PT).

• 4.

  Histopathologic examination shows an enlarged purplish liver with the cut surface having alternating patches of congested centrilobular regions and pale, less involved areas, the so-called nutmeg appearance.

• 5.

  Microscopically, the central veins and centrilobular sinusoids are dilated and engorged with blood; inflammation is not observed. Longstanding hepatic congestion can result in extensive fibrosis, so-called cardiac cirrhosis. Treatment of the underlying heart failure normally leads to improvement in both clinical and laboratory parameters of liver function.

Ischemic Hepatitis and Left-Sided Heart Failure

Hepatic damage associated with acute left ventricular failure is frequently termed ischemic (or hypoxic) hepatitis. It usually occurs in the setting of an acute myocardial infarction or cardiogenic shock but can result from an abrupt, severe decrease in cardiac output from any cause, vasoactive drugs (e.g., cocaine, ergotamine overdose), or severe hypoxemia.

• 1.

  The major manifestations are biochemical: Elevated serum levels of aspartate and alanine aminotransferase (AST, ALT) and lactate dehydrogenase (LDH) (predominantly hepatic fraction) to 25 or more times the upper limits. Values peak within 1 to 3 days of the inciting event and rapidly return to near normal, usually within 7 to 10 days. Serum bilirubin and ALP levels are generally normal or only mildly elevated. Liver failure and hepatic encephalopathy can occur.

• 2.

  Mortality rates in patients with ischemic hepatitis are high (40% to 50% in some series) but do not correlate with the degree of liver biochemical test abnormalities. The cause of death is related to the cause of the ischemic injury to the liver and not to liver failure. Treatment should be directed to correcting the underlying disease process.

Immunoglobulin G4-Related Disease

• 1.

  Immunoglobulin G4–related disease (IgG4-RD) is a multisystem fibroinflammatory condition associated with type 1 autoimmune pancreatitis, which affects 60% of patients with IgG4-RD and is also associated with sialadenitis, tubulointerstitial nephritis, dacryoadenitis, and periaortitis.

• 2.

  Sclerosing cholangitis occurs in 13% of patients with IgG4-RD, usually in association with autoimmune pancreatitis, and typically presents with obstructive jaundice.

• 3.

  Imaging appearances resemble other pancreaticobiliary diseases such as primary sclerosing cholangitis (PSC), cholangiocarcinoma, or pancreatic cancer. Elevated serum IgG4 values (or an IgG4 to IgG1 ratio of >0.24) can discriminate IgG4-RD from other pancreaticobiliary diseases.

• 4.

  The disorder is typically responsive to high-dose oral glucocorticoids. Relapse may be treated with immunomodulators and consideration of the monoclonal CD20 antibody rituximab.

Polymyalgia Rheumatica and Giant Cell Arteritis

• 1.

  Abnormalities in liver biochemical tests may be seen in both polymyalgia rheumatica and giant cell arteritis. Elevation of serum ALP levels occurs in approximately 30% of patients; elevated serum aminotransferase levels may also be observed.

• 2.

  Liver biopsy specimens demonstrate focal hepatocellular necrosis, portal inflammation, and scattered small epithelioid granulomas.

• 3.

  The liver abnormalities usually do not cause clinical problems and resolve within a few weeks of the initiation of glucocorticoid therapy.

Rheumatoid Arthritis

• 1.

  Liver disease in rheumatoid arthritis (RA) is most commonly seen in patients with Felty syndrome (splenomegaly and neutropenia in the setting of RA). These patients frequently have hepatomegaly, and approximately 25% have elevated serum aminotransferase and ALP levels. Liver biopsy findings are usually nonspecific: Infiltration of portal areas with lymphocytes and plasma cells and mild portal fibrosis.

• 2.

  Some patients with RA develop nodular regenerative hyperplasia with atrophy and formation of regenerative nodules that may result in portal hypertension, ascites, and variceal hemorrhage (see Chapter 22 ). The pathogenesis of nodular regenerative hyperplasia has been proposed to be drug-induced or immune complex–induced obliteration of the portal venules.

• 3.

  Hepatotoxicity can be associated with salicylates, gold, and methotrexate.

Adult Still Disease

• 1.

  This multisystem inflammatory disorder of unknown origin is characterized by spiking fever, evanescent rash, arthritis, and multiorgan involvement.

• 2.

  Liver abnormalities, including hepatomegaly and elevated liver enzyme levels, are seen in 50% to 75% of patients; nonsteroidal antiinflammatory drug use may be a cofactor.

• 3.

  After consideration of the possible contribution of medications to hepatic dysfunction, treatment of the underlying disorder with antiinflammatory drugs, immunosuppressant medications, or biologic agents is indicated.

Systemic Lupus Erythematosus

• 1.

  Liver biochemical test abnormalities are common in systemic lupus erythematosus (SLE), but clinically significant liver disease is uncommon.

• 2.

  Frequent abnormalities include elevated ALT and ALP levels, normally less than four times the upper limit of normal. In a few patients (approximately 5%), jaundice develops.

• 3.

  Causes of liver biochemical abnormalities in SLE are as follows:

  • ▪

    Steatosis (most common finding on liver biopsy specimens)

  • ▪

    Autoimmune hepatitis, as a result of either SLE itself or coexistent classic autoimmune hepatitis (see Chapter 7 )

  • ▪

    Autoimmune cholangiopathy, with a greater increase in the ALP level than the ALT level

  • ▪

    Nodular regenerative hyperplasia (may be seen in all connective tissue diseases)

  • ▪

    Coexistent viral hepatitis (In one study, 11% of patients with SLE were positive for hepatitis C viral RNA.)

  • ▪

    Budd-Chiari syndrome, particularly in patients with antiphospholipid syndrome (see Chapter 21 )

  • ▪

    Drugs, especially methotrexate and salicylates

• 4.

  Drugs suspected of causing abnormal liver biochemical test levels, particularly salicylates, should be withdrawn. Otherwise, the treatment of liver dysfunction in SLE depends on the cause. Most abnormal liver biochemical test results do not represent clinically significant liver disease.