Introduction

The liver is remarkable in its ability to preserve its function despite advanced age. Elderly patients are at an increased risk of more severe hepatic injury when exposed to hepatic insults. This increased risk is likely related to the liver’s age-related decrease in regenerative capacity. We will review the hepatic changes that are known to occur with aging and their pathologic consequences of liver disease in elderly patients (Table 90-1).

Liver Morphology

Liver volume significantly decreases with age, as shown in both postmortem and in vivo ultrasound studies. This decline, which can reach 40% of maximal healthy mass, occurs mostly after the sixth decade of life and is greater in men than in women. There is also a contemporaneous decrease in hepatic blood flow by approximately 35% to 40%. The cause of decreased blood flow is likely multifactorial—as a result of changes in cardiovascular output, diminished splanchnic blood flow, reduced portal vein blood flow, and increased resistance to portal flow. Hepatocytes accumulate lipofuscin with age while undergoing a decrease in the number of mitochondria, the concentration of smooth endoplasmic reticulum (SER), telomere length, and the activity of several liver microsomal enzymes.

Liver Function

Despite the observed changes in volume and blood flow, age-related changes to hepatic function are less evident in clinical practice (see Table 90-1). The capacity to sustain liver function during aging is reflected in the ability to successfully transplant livers from older deceased donors. Traditional liver chemistry tests, including serum aminotransferases, bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase, do not change with age. Likewise, there are no significant changes in coagulation factors. Serum albumin slightly decreases with age, but typically remains within the normal range. Serum cholesterol and triglycerides increase with age as there is a gradual decline in the metabolism of low-density lipoprotein (LDL) cholesterol.

There are age-related changes in the hepatic metabolism of certain medications, which is important since more than 30% of prescription drugs are prescribed to elderly men and women. The incidence of adverse drug reactions significantly increases with increasing age. Phase I drug metabolism relies on microsomal enzymes and results in metabolism by oxidation, reduction, demethylation, and hydrolysis. Phase II drug metabolism relies on cytosolic enzymes and results in metabolism by conjugation with several different polar ligands. Phase I reactions are usually catalyzed by the cytochrome P450 system in the hepatocyte SER. There is a significant decrease in the Phase I metabolism of several medications by as much as 50% with increasing age. Interestingly, medications that undergo Phase II metabolism remain unaffected by aging. The activity of Phase I metabolism is dependent on oxygen delivery. Thus, some of the age-related decreases in Phase I metabolism could be explained by decreased hepatic blood flow as well as by decreased SER concentration. Medications with known Phase I metabolism should be started at a low dose and titrated slowly in order to circumvent the problems associated with adverse drug reactions in the elderly patients.

Another important aspect of the effects of aging on hepatic function is the diminished ability of the liver to recover and regenerate in response to injury. There is an age-related proliferative decline in the rate at which partial living donor livers regenerate. Also, there is a higher mortality in elderly patients after partial hepatic resection. Lastly, the hepatotoxic effects of hepatitis viruses and medications like acetaminophen and isoniazid are more pronounced in the elderly.

Liver Diseases

Hepatitis A Virus

Hepatitis A virus (HAV) is an RNA virus within the picornavirus family (Table 90-2). It is spread via fecal–oral transmission. It is usually a self-limited infection consisting of fatigue, malaise, nausea, vomiting, anorexia, and fever in most adults. Acute HAV infection is diagnosed by the demonstration of HAV IgM antibodies within the serum in symptomatic patients. As the acute illness resolves, anti-HAV IgG antibodies develop conferring life-long immunity. With the development of improved sanitation, the proportion of adults lacking immunity to HAV has increased. At the same time, the severity of acute HAV infection increases with increasing age. Relative to younger patients, acute HAV infection in the elderly has a longer duration, is more severe, is associated with a higher rate of complications, and has a higher mortality rate. This higher mortality rate is owing to an increased incidence of fulminant hepatic failure in elderly patients with acute HAV infection. The increased incidence of fulminant hepatic failure is likely multifactorial because of comorbidities as well as the liver’s decreased regenerative capacity. There is a safe and effective vaccine for HAV. Although there are limited available guidelines for vaccinating nonimmune elderly patients, health-care providers of geriatric patients should be aware of the increased morbidity associated with HAV infections and should strongly consider screening and vaccinating elderly patients traveling to endemic areas, living in homes for the elderly, and especially bed-bound institutionalized patients requiring help with evacuation and disposal of excreta.

Hepatitis B Virus

Hepatitis B virus (HBV) is a DNA virus within the hepadnavirus family. HBV is a blood-borne pathogen. The complete virion, or dane particle, is composed of the DNA enclosed within a nucleocapsid surrounded by surface coat. Acute infection is associated with mild constitutional symptoms like anorexia, fatigue, and right upper quadrant discomfort. Approximately 30% of infected adults will develop jaundice. Less than 5% of acute HBV infections arising de novo in adults living in the United States will lead to chronic infections. Acute HBV infection is relatively rare in elderly adults, as the primary risk factors associated with transmission are intravenous drug use and high-risk sexual behavior. There is an increased risk of becoming a chronic HBV carrier with increasing age, which is possibly related to an age-related decline in cellular immunity. Similar to HAV, acute HBV infection has an age-related increase in mortality associated with fulminant hepatic failure. Chronic HBV infection is a risk factor for hepatocellular carcinoma, and this risk increases with age. With regards to therapy, the incidence of adverse reactions to interferon is increased in elderly patients and its use should be approached with caution. On the other hand, the recently approved antiviral agents such as entecavir, adefovir, and telbivudine are safe to use irrespective of age. Lastly, there is a significant age-related decreased antibody response rate after immunization with the HBV vaccine. The HBV vaccine is delivered in a series of three injections. Elderly patients might require a fourth injection in order to improve immunogenic HBV vaccine response.

Hepatitis C Virus

Hepatitis C virus (HCV) is an RNA virus within the flaviviridae family. It is a blood-borne pathogen, and currently intravenous drug use is the major risk factor associated with disease transmission. Most elderly patients with HCV likely acquired the infection 20 to 40 years ago as a result of exposure to unscreened blood or blood products. Approximately 170 million people are infected with HCV worldwide. HCV is the most common cause of viral-induced acute hepatitis in elderly patients. Acute HCV infection in a person not abusing illicit drugs should prompt a search for a source such as an infected medical professional involved in phlebotomy, surgery, or dental care. Acute infection in the elderly usually consists of mild nonspecific symptoms including fever, abdominal discomfort, fatigue, and possible jaundice. Chronic HCV infection develops in 50% to 80% of infected individuals with the subsequent development of cirrhosis in a significant proportion of these patients. The prevalence of chronic HCV infection is increasing in the elderly population. Chronic HCV-related cirrhosis is associated with the development of hepatocellular carcinoma, and this risk is increased significantly with age. Also, the severity of liver disease among patients with chronic HCV infection is worse with increasing age. Similarly, the progression to cirrhosis is faster in older patients, and the serum HCV viral load is significantly higher when compared to younger adults. Any patient who received blood or blood products prior to 1992 should be screened for HCV. Elderly patients initiating therapy with ribavirin and interferon should be truly assessed carefully with attention to comorbidities given the known age-related adverse effects with antiviral therapies.

Drug-Induced Liver Damage

Older patients consume the largest portion of both prescription and over-the-counter medications. Both age and polypharmacy are risk factors for drug-induced hepatotoxicity. Elderly patients often have altered pharmacokinetics and pharmacodynamics caused by changes in renal, hepatic, cardiovascular, and pulmonary function and decreased body mass. Drug-induced liver toxicity occurs more frequently in elderly patients and tends to be more severe. Clinically, drug-induced hepatotoxicity presents with nonspecific symptoms or subclinically, reflected only in serum laboratory abnormalities. Some medications have a well-recognized increased risk of liver toxicity with age. For example, isoniazid frequently causes some evidence of liver toxicity in patients older than 50 years, yet, rarely causes liver damage in patients younger than 20 years. Health care providers taking care of elderly patients should be aware of this increased risk of drug-induced hepatotoxicity and should be vigilant in assessing for hepatic inflammation.

Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC) is a disease characterized by an immune-mediated destruction of the intralobular biliary system. It is predominantly regarded as a disease affecting middle aged women; however, greater than one-third of patients with PBC are older than 65 years. Cholestatic features predominate with pruritus presenting as an early symptom. Antimitochondrial antibodies are present in the serum and are a hallmark of the disease. Elderly patients diagnosed with PBC likely have long-standing and slowly progressive disease. Symptomatic elderly patients with PBC are associated with a poor prognosis. Compared to younger adults, the liver-related mortality is greater in patients diagnosed with PBC who are older than 65 years. Treatment should be focused on symptom management of pruritus and malabsorption. Ursodeoxycholic acid slows the progression of the disease. Liver transplantation remains the ultimate therapy and should be considered in well-selected geriatric patients.

Autoimmune Hepatitis

Autoimmune hepatitis is a condition of unknown etiology leading to chronic hepatic inflammation and destruction, with resultant cirrhosis. It has a bimodal onset, with a second peak of presentation in persons in their sixth decade or older. Elderly patients may present with clinically less aggressive disease. In this regard, the disease may go initially unrecognized in the geriatric population. Liver biopsy is essential for making the diagnosis. Autoimmune hepatitis generally responds well to immunosuppressive therapy. Elderly patients receiving chronic therapy with corticosteroids need to be monitored closely for serious side effects such as osteoporosis, glucose intolerance, and cataract formation. Prognosis is likely similar between elderly patients and younger adults.

Hepatocellular Carcinoma

In western Europe and North America, hepatocellular carcinoma (HCC) usually occurs in older patients. Major risk factors for the development of HCC include chronic hepatic inflammation and cirrhosis. Presentation and diagnosis of HCC in elderly patients are associated with a significantly worse prognosis when compared to younger adults. This is likely related to the advanced stage of liver disease and tumor within this patient population. Treatment of carefully selected geriatric patients by surgical resection, liver transplantation, or by anticancer therapies such as chemoembolization or radiofrequency ablation appears to be associated with a similar morbidity and mortality as compared to younger patients. Thus, age should not be a contraindication for therapy for HCC in the appropriate elderly patient.

Transplantation

Liver transplantation is the ultimate therapy for patients with end-stage liver disease. The number of transplants completed in the United States continues to increase. Alcohol-related liver disease and chronic hepatitis C are the two most common reasons for end-stage liver disease within the elderly population. Unfortunately, there is a growing discrepancy between the patients waiting for a liver transplantation and available donors. This discrepancy will continue to worsen as the population of elderly patients with cirrhosis continues to grow. As a result of this disparity, patients are forced to wait longer periods of time on the transplant recipient list prior to transplantation. Pretransplant evaluation of elderly patients should take into account age-related comorbidities, specifically, cardiovascular disease, osteoporosis, and malignancy. Despite the need for a thorough pretransplant evaluation, advanced age is not a contraindication for liver transplantation. Unfortunately, age is an independent risk factor for perioperative mortality, largely because of nonhepatic causes. Similarly, elderly transplant recipients have a worse postoperative long-term survival. Owing to the risks associated with liver transplantation, geriatric patients should be carefully selected by a multidisciplinary team noting significant comorbid conditions. Post-transplant care should entail continued management of cardiovascular risk factors, assessment and treatment for osteoporosis, and vigilant surveillance for malignancy.

Cholelithiasis

Table 90-3 outlines the risk factors associated with gallstone formation. Age is a major factor, although the reasons for this are unclear. By the ninth decade of life, the prevalence of gallstones is 38% in women and 22% in men. In men older than 90 years, the incidence increases to 31%. The prevalence of gallstones in the U.S. population increases by 1% per year in women and by 0.5% per year in men after age 15. Native Americans are predisposed to gallstone formation at an earlier age. At age 50, the prevalence of gallstones in Native Americans is 80% in women and 70% in men. The increase in risk in women is related to increased biliary cholesterol excretion by estrogen. Approximately 500 000 people in the United States develop symptomatic gallstones each year.