The Liver in Systemic Disease

Maureen M. Jonas

CYSTIC FIBROSIS

Cystic fibrosis (CF) is a genetic multisystem disorder that is discussed in greater detail in Chapter 512.

EPIDEMIOLOGY

Cystic fibrosis–associated liver disease is increasingly recognized as mortality from lung disease decreases. In many cases the course is benign and does not contribute significantly to morbidity or mortality. However, in a minority of cystic fibrosis (CF) patients, liver disease may directly affect survival. The incidence of CF liver disease appears to peak during adolescence and it is rare for liver disease to have its onset after 20 years of age. Symptomatic liver disease is observed in 20% to 50% of patients, and it can be the presenting or dominant feature of CF. Pathologic evidence of liver disease is found at autopsy in more than 75% of patients. Cirrhosis complicates CF in 1.4% of patients, with a peak frequency of 2.7% in those 16 to 20 years of age. Cirrhosis now accounts for virtually all nonpulmonary causes of death in patients with CF.¹

PATHOPHYSIOLOGY

Cystic fibrosis transmembrane regulator (CFTR) is a chloride channel on epithelial cells. In the liver, it is expressed on biliary tract cells, and is involved in chloride and water secretion into bile. There are no clear genotype associations with CF liver disease, although it is less common in those patients with pancreatic sufficiency. The factors that initiate, accentuate, and perpetuate the development of liver disease in patients with CF have not been identified. A 3:1 male preponderance of liver disease is seen in patients with CF.² One study has suggested an association with particular histocompatibility antigens, thus implicating a possible role for altered immune responses in patients with CF and liver disease.³ Another study demonstrated an association of a specific polymorphism of glutathione S-transferase with liver disease in CF patients.⁴ The variability in time of presentation, severity of liver disease, and rate of progression may be due to as yet unknown polymorphisms for other genes.

Although the precise pathogenetic effects of the CFTR defect in the liver are unknown, it results in the production of thick, tenacious secretions in the hepatobiliary system. Secretion of viscous bile results in impaired bile flow and consequent sludge and potential gallstone formation. Over time, these abnormalities in bile lead to persistent focal microscopic or macroscopic obstructions in the intrahepatic biliary tree causing chronic inflammation, bile duct proliferation, fibrosis with extension and coalescence. The resulting lesion is called focal biliary cirrhosis.

CLINICAL FEATURES

Several forms of liver disease are seen in patients with CF¹ (Table 423-1). Neonatal cholestasis occurs in 2% to 10% of affected infants, most commonly in those with meconium ileus, and may persist for several months. It is generally attributed to viscous bile with sludging. Hepatic steatosis is common, seen in up to 30% of patients, but its cause has not been clearly elucidated. Steatosis may be related to malnutrition, essential fatty acid deficiency, elevated cytokines, or the genetic defect itself. Focal biliary cirrhosis, a lesion virtually unique to CF as discussed above, is seen in up to 10% to 20% of individuals. This lesion occurs most often without signs or symptoms until portal hypertension and its complications ensue. Results of standard biochemical tests may be normal or nearly normal. Micronodular cirrhosis, typically with large regenerative nodules, is evident in only 2% to 5% of patients and may be multifactorial in etiology; it probably represents the end-stage of focal biliary cirrhosis. Patients with CF also have a high incidence of biliary tract disease, including hypoplastic gallbladders, gallstones and/or sludge, common bile duct strictures, common bile duct obstruction from severe pancreatic fibrosis, and a cholangiopathy indistinguishable from primary sclerosing cholangitis. Well-established biliary cirrhosis may present as hepatomegaly, splenomegaly, variceal bleeding, or abdominal pain or enlargement. The true incidence is undefined. End-stage CF-associated liver disease may be indistinguishable from other forms of severe liver disease.

Table 423-1. Types of Liver Disease in Cystic Fibrosis

DIAGNOSIS

The evaluation of liver disease in children with cystic fibrosis is dictated by the clinical presentation and may include sonography or other imaging modalities such as endoscopic retrograde cholangiopancreatography (ERCP). Other causes of liver disease should be excluded. Liver biopsy may be required to assure the correct diagnosis and to aid prognosis.

TREATMENT

Because the presumed underlying pathogenesis focuses on abnormal hyperviscid secretions with bile stasis with the intrahepatic accumulation of hydrophobic, hepatotoxic bile acids, there is a rationale to attempt to decrease the viscosity of bile or to displace hepatotoxic bile acids. Ursodeoxycholic acid (UDCA) has shown promise in studies of patients with CF-associated liver disease.⁵ UDCA therapy has been associated with an improvement in biochemical parameters and nutritional status. However, its long-term benefit, particularly in preventing cirrhosis, remains to be determined. Management of cystic fibrosis-related liver disease depends on the clinical manifestations and includes assessment of appropriate caloric intake and pancreatic enzyme supplementation. Infants with cholestasis or older patients with severe liver disease may require nutritional supplements in higher dosages because of the additional fat malabsorption associated with low intestinal luminal bile salt concentrations. Because taurine deficiency has been demonstrated in some patients with CF as a result of excessive losses, some experts recommend that supplemental taurine be provided to CF patients treated with UDCA but clinical trials show no significant effect of taurine supplementation. Other than the supportive role of nutritional management for chronic liver disease, no other specific dietary therapies are known.

Interventions for complications of cirrhosis and portal hypertension may be necessary such as sclerotherapy, band ligation or shunting. Liver transplantation may improve both pulmonary function and nutritional status in CF patients with end-stage liver disease.⁶ The optimal timing of transplantation is influenced by several factors, including the severity and expected progression of lung disease. Transplantation may not be indicated in patients whose primary manifestation of disease is portal hypertension and its consequences if they have intact hepatocellular function.⁷ In the minority who do require transplant, posttransplant medication doses must be carefully monitored; CF patients often need higher doses of drugs because of poor absorption and altered drug metabolism. In addition, outcomes are not favorable in adults, in whom survival times are affected by end-stage dysfunction in other organs.^8,9

HEART DISEASE

Hepatic dysfunction secondary to heart disease occurs in 2 typical settings. The first occurs when there is an acute decrease in cardiac output, such as in congestive heart failure or cardiogenic shock, the resultant injury is ischemic hepatopathy, which is typically manifested by very high aminotransferases. Serum bilirubin is less commonly elevated. In extreme examples, coagulopathy develops, indicating failure of hepatic synthetic function. In most instances, multiple organs, such as the kidneys, are also affected. In the majority of children, this injury is brief, with improvement over several days if the underlying hypotension resolves.

The more common type of hepatic injury due to underlying heart disease in the pediatric population is passive hepatic congestion. This occurs in patients with isolated right heart failure or other cardiac disease that is associated with persistently elevated right atrial pressure, such as mitral stenosis, constrictive pericarditis, or restrictive cardiomyopathy, or after repair of various types of congenital heart disease, such as hypoplastic left heart syndrome (HLHS). Passive hepatic congestion develops when elevated central venous pressure is transmitted back through the hepatic veins and into the sinusoids of the liver. The hepatic injury is called congestive hepatopathy and this, in turn, can lead to the development of “cardiac cirrhosis.” The most common type of repair for HLHS, the multistage Fontan procedure, is probably the most common cause of congestive hepatopathy in children. It has been associated with the entire spectrum of chronic liver injury due to passive congestion.⁹

CLINICAL FEATURES

Congestive hepatopathy is characterized clinically by abnormal aminotransferases, hepatomegaly, and ascites. Liver biopsy is associated with an increased risk of bleeding due to the higher venous pressures. When performed the histologic findings include damage to hepatocytes in zone 3, the area in proximity to the hepatic veins in each lobule, and then eventual fibrosis beginning in the pericentral region and extending until regenerative nodules typical of cirrhosis are formed. Even though cirrhosis is frequently the result, and mild coagulopathy is often present, hepatic function is typically well preserved and liver-related mortality is uncommon. Ultrasound most commonly demonstrates hepatomegaly and diffusely increased echogenicity. Doppler examination may show reversal of flow in the hepatic veins in extreme cases. The heterogeneous appearance of the liver on CT scan¹⁰ is the radiographic correlate of the “nutmeg liver” described on gross examination, due to areas of hemorrhage and necrosis around the central veins.

TREATMENT

Treatment for passive hepatic congestion should be aimed at decreasing right atrial pressure. Diuretics may be needed for the ascites. It has been noted that patients with hepatic congestion have altered drug metabolism, so increased susceptibility to drugs metabolized by the liver should be presumed. In addition, because many patients have undergone surgery for congenital heart disease, consideration should be given to looking for concomitant chronic viral hepatitis, especially in young adults who were treated before routine testing of blood for hepatitis C.

SICKLE CELL DISEASE

A group of disorders that can present with right upper quadrant abdominal pain and worsening jaundice with or without fever in a child with sickle cell disease are characterized as “sickle hepatopathy.”¹¹ The differential diagnosis of this presentation includes acute biliary tract disease, such as cholangitis or cholecystitis, a new viral hepatitis, and some disorders that are unique to the sickle cell patient, such as hepatic sequestration, acute sickle hepatic crisis, and sickle cell intrahepatic cholestasis.

Hepatic sequestration is the rapid accumulation of sickled red blood cells in the liver that causes massive hepatomegaly and a falling hematocrit. Treatment with exchange transfusion usually results in improvement, as in other types of acute sequestration syndromes.

Acute sickle hepatic crisis results from hypoxic hepatocyte injury due to intrasinusoidal sickling. This disorder is manifested by modest increases in aminotransferases (about 5–10 times normal) and serum bilirubin values of approximately 15 mg/dl. Treatment with intravenous fluid and analgesics is usually associated with resolution of symptoms in 1 to 2 weeks.

Sickle cell intrahepatic cholestasis may have a similar presentation at the onset, but is characterized by higher ALT values (usually greater than 1000 IU/L) and very high bilirubin levels because of hemolysis, cholestasis, and the concomitant renal failure, which is commonly noted. The hypoxic injury to hepatocytes is so severe that liver failure may develop. Exchange transfusion may be of some benefit.¹² In contrast to sequestration and acute hepatic crisis, sickle cell intrahepatic cholestasis carries a significant mortality rate.¹³

Chronic liver disease in patients with sickle cell disease may be due to chronic viral hepatitis or hepatic iron overload from numerous blood transfusions. In addition, sickling may lead to thrombosis within the hepatic veins, causing Budd-Chiari syndrome.

HEMATOPOIETIC STEM CELL TRANSPLANTATION

Liver complications of hematopoietic stem cell transplantation are discussed in Chapter 133.

ENDOCRINE DISORDERS

THYROID DISEASE

There is an important relationship between the liver and thyroid function. The liver is the major site of thyroid hormone metabolism and production of thyroid binding proteins. Thyroid hormones are important for normal hepatic function, such as conjugation of bilirubin.

Abnormalities in liver-related biochemical tests are common in patients with hyperthyroidism.¹⁴ These include elevated aminotransferases, alkaline phosphatase and even mild hyperbilirubinemia. Hepatic injury is attributed to ischemia, because hepatic oxygen consumption is increased in the absence of compensatory increase in hepatic blood flow. Most patients have mild self-limited hepatitis that resolves with restoration of euthyroidism, but hepatic failure has been reported in patients with severe thyrotoxicosis.

Drugs used to treat hyperthyroidism may cause mild, transient changes in aminotransferases in a dose-related pattern. Propylthiouracil may cause an idiosyncratic severe hepatic injury after weeks to months, which is more common in women younger than 30 years; this has been associated with liver failure¹⁶ and death or need for liver transplantation. A cholestatic pattern of hepatic injury is noted in some patients, particularly women over age 50, from methimazole and carbimazole.¹⁴ There are no specific recommendations regarding monitoring of patients receiving these drugs, so awareness of these potential toxicities is important.

The most common hepatic finding in hypothyroidism is cholestatic jaundice,¹⁵ because the production and flow of bile are affected. Hypercholesterolemia results from impairment of bile salt excretion into bile. In severe hypothyroidism (myxedema), rightsided heart failure may be associated with ascites. Again, these abnormalities usually resolve with thyroid hormone replacement.

NEONATAL HEPATITIS ASSOCIATED WITH HYPOPITUITARISM

Infants with hypopituitarism may present with cholestatic liver disease. Associated findings include hypoglycemia, microphallus, and optic nerve hypoplasia with wandering nystagmus. Liver biopsy reveals giant-cell hepatitis, indistinguishable from idiopathic neonatal hepatitis. The pathogenesis of this disorder is unclear. The prognosis of the liver disease is excellent if recognized promptly with appropriate management of the endocrine deficiencies.

HUMAN IMMUNODEFICIENCY VIRUS INFECTION

Liver disease frequently contributes to the morbidity and mortality of human immunodeficiency virus (HIV) infection in both adults and children, but the etiologies are somewhat different. In adults, coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is responsible for much of the observed hepatic injury, but these infections are much less common in children with HIV. Drug hepatotoxicity plays an important role in both adults and children. In children with HIV, a frequent cause of liver disease is opportunistic infections, causing either hepatitis or HIV cholangiopathy.

Newborns may acquire either HIV or HBV or both infections from coinfected mothers, but perinatal transmission of HBV may be prevented with appropriate use of passive and active immunization. Horizontal transmission of HBV to children with HIV, from household contacts, is another mechanism of coinfection. Adolescents with HIV are at risk for HBV infection through sexual activity or injection drug use. Risk is higher for men to who have sex with men. Studies of HBV coinfection in HIV-infected youth in the United States and Canada demonstrated prevalences of 19% and 16%, respectively. In adults, the risks of chronicity and progression of chronic HBV to cirrhosis are greater if HIV precedes HBV acquisition. In one study, liver-related mortality was three times higher in coinfected patients compared to those with HIV alone.¹⁷

The diagnosis of HBV in HIV-infected children is the same as in any child, the detection of hepatitis B surface antigen in serum. If this persists longer than 3 to 6 months, chronic HBV is confirmed. Indications for treatment are the same as in monoinfected children: evidence of ongoing viral replication (HBV DNA or HBeAg), persistent elevation of ALT, and chronic hepatitis on liver biopsy. Therapeutic decisions are challenging, and must take into consideration whether treatment is being provided for HIV, HBV, or both, because indications for treatment of each infection may not be synchronous. Although combination therapies are recommended in adults because of these concerns,¹⁸ there are no data from studies in children with HIV and HBV coinfection. It is important to continue HBV therapy when initiating or changing highly active antiretroviral therapy (HAART), because HBV flares can be difficult to distinguish from drug hepatotoxicity.

The prevalence of HCV infection among HIV-infected children was 1.5% in a large trial-related cohort.¹⁹ Diagnosis of HCV infection in children with HIV may require direct viral detection with molecular assays (eg, PCR), because HCV antibody may not develop in some of these children. There is no clear evidence that HCV infection in HIV-coinfected children follows a more rapid course, although HCV is certainly a cause for significant liver disease in adults with HIV.²⁰ There are some data to suggest that treatment for HCV during the early stages of HIV infection, with control of HIV viremia and normal or near-normal CD4 counts, is more likely to be effective. Although no therapies are specifically licensed for HCV infection in children with HIV, the combination of peginterferon and ribavirin, as is standard in adults, should be considered.

Drug hepatotoxicity is common in patients with HIV infection. In one study, risk for hepatotoxicity from antiretroviral therapy was increased 7-fold in patients older than 40 years, and 10-fold in those with CD4 counts of less than 310 cells/ml.²² HCV coinfection was a significant risk as well.²² HIV-infected patients are exposed to many drugs other than antiretrovirals that may be hepatotoxic, such as antibiotics, antifungals, antivirals, and so forth,²³ making decisions regarding medication selection and discontinuation difficult.

Forms of sclerosing cholangitis occur in the settings of certain known underlying disorders,²⁴ including primary and secondary immunodeficiencies. In HIV infection, this is called AIDS cholangiopathy, because it is an AIDS-defining illness, usually owing to an opportunistic infection, associated with high morbidity and even mortality. Cryptosporidium is the most common identifiable pathogen in the biliary tract in patients with AIDS cholangiopathy,²⁵ but other organisms such as cytomegalovirus, microsporidium, Campylobacter species, giardia, and Candida albicans have been implicated in some cases. Cholangiography demonstrates characteristic findings of intrahepatic bile duct dilatation and strictures or isolated common bile duct enlargement due to papillary stenosis. Although the latter may respond to endoscopic dilatation, the diffuse cholangiopathy often has a protracted course, with poor response to antimicrobial agents. Prognosis has been associated with degree of immune impairment and CD4 counts, and has been improved since the availability of HAART.²⁶

OTHER IMMUNOLOGIC DISORDERS

Liver involvement is also frequent in as many as 25% of patients with immunodeficiency syndromes other than HIV including those with severe combined immunodeficiency, hyper IgM syndrome, and common variable immunodeficiency.²⁷ Patients present with elevated liver enzymes; many have splenomegaly and/or hepatomegaly. The majority of the patients with chronic liver disease have sclerosing cholangitis but some have nonspecific mild inflammation and fibrosis. Limited experience with liver transplantation in these patients is not encouraging, because infectious complications have resulted in death. Therefore, liver transplantation should be considered in these patients only within the context of plans for immune reconstitution.

OTHER SYSTEMIC INFLAMMATORY DISORDERS

Liver involvement occurs in association with a large variety of vasculitic disorders (including Kawasaki syndrome), systemic juvenile rheumatoid arthritis (JRA), systemic lupus erythematosis, and macrophage activation syndromes. Liver disease in those conditions presents as a chronic a cholestatic syndrome, fatty infiltration, organomegaly, or the liver can be involved with primary inflammation, scarring and/or parenchymal collapse. Liver disease also occurs in celiac disease. Liver disease usually improves with treatment of the primary disorder.

REFERENCES

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