Chapter 22 The liver in systemic disease
1 Abnormalities in liver biochemical tests are associated with many different systemic diseases. These abnormalities are generally incidental, but in some systemic diseases the liver may be severely compromised (Table 22.1).
2 In evaluating patients with systemic disease and liver dysfunction, the challenge for the clinician is to distinguish among hepatic manifestations of the systemic disease, liver toxicity from drugs used to treat that disease, and a coexisting primary liver disorder.
3 Liver involvement can occur in heart failure, connective tissue diseases, endocrine disorders, granulomatous diseases, lymphoma, hematologic diseases, systemic infections, gastrointestinal disorders including celiac disease and inflammatory bowel disease, and amyloidosis.
TABLE 22.1 The liver in systemic disease
| Disorder(s) | Hepatic manifestations | Liver biochemical test levels (most common abnormalities) |
|---|---|---|
| Cardiovascular | ||
| Heart failure | Vascular congestion; hepatomegaly | ↑Bil; ↑ALT; ↑PT |
| Ischemic hepatitis | Hepatocellular necrosis | ↑↑↑ALT; ↑Bil |
| Connective Tissue | ||
| Polymyalgia rheumatica and giant cell arteritis | Hepatocellular necrosis; portal inflammation | ↑ALP; ↑ALT |
| Rheumatoid arthritis; Felty’s syndrome; adult Still’s disease | Nonspecific: portal inflammatory infiltrates and fibrosis; drug hepatotoxicity | ↑ALP; ↑ALT |
| Systemic lupus erythematosus | Autoimmune hepatitis; autoimmune cholangiopathy; nodular regenerative hyperplasia; drug hepatotoxicity | ↑↑ALP; ↑Bil; ↑↑ALT |
| Systemic sclerosis; Sjogren’s syndrome | Budd–Chiari syndrome; antimitochondrial antibodies; primary biliary cirrhosis | ↑↑ALP; ↑Bil; (↑)ALT |
| Endocrine and Metabolic | ||
| Hyperthyroidism | Nonspecific inflammation and cholestasis | ↑ALP; ↑ALT; ↑GGTP |
| Type 2 diabetes mellitus | Steatosis; steatohepatitis | ↑ALT; ↑GGTP |
| Gastrointestinal and Nutritional | ||
| Celiac disease (see Table 22.3) | Elevated aminotransferase levels; association with primary biliary cirrhosis, autoimmune hepatitis, and PSC; jaundice | ↑ALT |
| Inflammatory bowel disease | Association with PSC, cholangiocarcinoma; hepatic steatosis; immunosuppressant medication hepatotoxicity; jaundice | ↑ALT |
| Anorexia | Steatosis; liver failure | ↑ALT |
| Obesity | Steatosis; steatohepatitis | ↑ALT; ↑GGTP |
| Granulomatous | ||
| Sarcoidosis | Epithelioid granulomas | ↑↑ALP; ↑ALT |
| Hematologic | ||
| Lymphomas, acute and chronic leukemias, myeloproliferative disorders (including myelofibrosis) | Hepatomegaly; infiltration; extrahepatic biliary obstruction | ↑ALP; ↑Bil |
| Sickle cell disease | Hemolysis; ischemia; pigment cholelithiasis | ↑↑Bil; ↑ALP; ↑ALT |
| Infections | ||
| Sepsis | Intrahepatic cholestasis; ischemic hepatitis; drug hepatotoxicity | ↑Bil; ↑ALP; ↑ALT |
| HIV infection | Hepatomegaly; coinfection with hepatitis B or C | ↑ALT |
| Tuberculosis | Caseating granulomas; drug hepatotoxicity | ↑ALT; ↑↑Bil; ↑ALP |
| Pneumonia | Nonspecific inflammatory changes | ↑↑Bil; ↑ALP |
| Amyloidosis | Infiltration; vascular congestion | ↑↑ALP; ↑ALT |
ALT, alanine aminotransferase; ALP, alkaline phosphatase; Bil, bilirubin; GGTP, gamma glutamyltranspeptidase; HIV, human immunodeficiency virus; PSC, primary sclerosing cholangitis.
Cardiac Disease (see Chapter 20)
heart failure
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 22.2).
3. Abnormal liver biochemical test results seen are a raised bilirubin level in 25% to 75% of patients and normal or mildly elevated serum aminotransferase levels. The alkaline phosphatase (ALP) 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. Long-standing hepatic congestion can result in extensive fibrosis, so-called cardiac cirrhosis. Treatment of the underlying heart failure normally leads to an improvement in both clinical and laboratory parameters of liver function.
TABLE 22.2 Symptoms and signs of hepatic congestion in 175 patients with acute or chronic right-sided heart failure
| 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 |
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.
Ischemic hepatitis and left-sided heart failure
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 test abnormalities. The cause of death is related to the cause of the ischemic injury to the liver, not to liver failure. Treatment should be directed to correcting the underlying disease process.
Connective Tissue Diseases
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 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.
Rheumatoid arthritis
1. Liver disease in rheumatoid arthritis (RA) is most commonly seen in patients with Felty’s 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 20). The pathogenesis of nodular regenerative hyperplasia has been proposed to be drug-induced or immune complex-induced obliteration of the portal venules.
Adult Still’s 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 abnormal liver enzymes are seen in 50% to 75%; nonsteroidal anti-inflammatory drug use may be a significant cofactor.
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. A few patients (approximately 5%) develop jaundice.
