Normal Physiology of Aging

With a few notable exceptions, the digestive system maintains normal functioning in older adults. To distinguish between the expected age-related alterations of the gut and symptoms attributable to pathologic conditions, the clinician must have an understanding of the normal physiology of aging. One must also appreciate the interactions between the gastrointestinal (GI) tract and long-standing exposures to environmental agents (e.g., medications, tobacco, alcohol) and chronic non-GI disease states (e.g., congestive heart failure, diabetes mellitus, chronic obstructive pulmonary disease [COPD], dementia, depression).⁵ With this knowledge, it will become apparent that most new GI complaints in otherwise healthy older adults are due to disease rather than to aging alone and therefore merit appropriate investigation and treatment.

Aging is not associated with a difference in the desire to eat or the hunger response prior to meal intake, but postprandial hunger and desire to eat are reduced.^6,7 One explanation may be that fasting and intraduodenal lipid-stimulated plasma concentrations of cholecystokinin (CCK), a physiologic satiety factor; leptin, a hormone that functions mainly as a signal of adiposity eliciting long-term satiety; and GLP-2, an incretin hormone mainly released by the L cells of the distal small intestine in response to nutrient ingestion, have been found to be higher in older than in younger men.^8–13 In addition, ghrelin, a growth hormone–releasing peptide from the stomach that functions as a potent stimulator of energy intake, is one-third lower in older adults.¹³ However, anorexia in older adults should not be attributed to advanced age alone. This symptom warrants evaluation to exclude a medical or psychological cause or a medication-induced adverse effect.⁶

Up to 40% of healthy older adults subjectively complain of dry mouth. Although baseline salivary flow probably decreases with aging, as noted with decreased salivary bicarbonate (involved in neutralization of refluxed acid), stimulated salivation is unchanged in healthy and edentulous geriatric patients.^14–18 Chewing power is diminished, probably because of decreased bulk of the muscles of mastication,^19,20 although perhaps attributable in part to preclinical manifestations of neurologic disease rather than to the normal aging process.¹⁸ Although many older patients are edentulous to some degree, better dental care has now enabled more of them to have intact teeth than in the past.^6,21,22

Gustatory and olfactory sensation tend to decrease with aging.^12,23 The ability to detect and discriminate among sweet, sour, salty, and bitter tastes deteriorates as one gets older.^6,12,23,24 Thresholds for salt and bitter taste show age-related elevations, whereas that for sweet taste appears stable.^6,25 Olfaction decreases dramatically following the fifth decade of life, frequently resulting in anosmia after the age of 90 years, when the olfactory threshold increases by about 50%, contributing to poor smell recognition.^6,12,26 Increasingly, chronic diseases observed during aging (Alzheimer or Parkinson diseases) may be responsible for such a decline, and recent studies have focused on the sensation of smell as a predictor of disease presentation.

Despite early data to the contrary, the physiologic function of the esophagus in otherwise healthy individuals is well preserved with increasing age, with the exception of very old patients.^27,28 Studies from the early 1960s introduced the concept of the term presbyesophagus, based on cineradiographic and manometric data,^29,30 but the term has been abandoned.³¹ Other studies study that excluded patients with diabetes or neuropathy found no increase in dysmotility in older men.³² Investigators have also found that minor alterations may occur in some octogenarians, including decreased pressure and delayed relaxation of the upper esophageal sphincter and reduction in the amplitude of esophageal contraction.^33,34 Furthermore, one study has shown that age-related changes of increased stiffness and reduced primary and secondary peristalsis in the human esophagus is associated with a deterioration of esophageal function beginning after the age of 40 years.³⁰ In addition, in a study comparing esophageal manometry and scintigraphic examinations of gastroesophageal reflux in groups of healthy volunteers ranging from 20 to 80 years of age, it was determined that although the number of reflux episodes per volunteer was similar in the various age groups, the duration of reflux episodes was longer in older volunteers. The older participants had impaired clearance of refluxed materials due to a high incidence of defective esophageal peristalsis.³⁵ Similarly, in another study, age was shown to correlate inversely with lower esophageal sphincter (LES) pressure and length, upper esophageal sphincter (UES) pressure and length, and peristaltic wave amplitude and velocity, suggesting that normal esophageal motility deteriorates with advancing age.³⁶ It was also noted that hiatal hernias are more common with increasing age and are found in up to 60% of patients older than 60 years.³⁷ Together, these findings may help explain the high prevalence of reflux symptoms in older adults.

Most studies on gastric histology have found evidence of an increased prevalence of atrophic gastritis in people older than 60 years.^38,39 Consequently, it has been suggested that aging results in an overall decline in gastric acid output.^27,40,41 However, more recent data have demonstrated that gastric atrophy and hypochlorhydria are not normal processes of aging. Rather, Helicobacter pylori infestation, which is more common in older adults, not advancing age itself, appears to be the more likely cause of these histologic and acid secretory changes.^38,42–47 The literature remains conflicted over the issue of whether aging alone, rather than factors such as increased H. pylori infestation and decreased smoking, leads to altered pepsin secretion.^7,44,46 However, given recent trends, many older adult patients also retain their acid secretion ability in old age as a result of increased H. pylori treatment and cure. This can in turn raise the risk for reflux symptoms, given the peristaltic dysfunction associated with aging.⁴⁸ Data are scarce in relation to gastric motility, emptying, and gastroduodenal reflux and their relationship to gastric function and acid production. Intrinsic factor secretion is usually maintained into advanced age and is retained longer in the setting of gastric atrophy than acid or pepsin secretion.^49,50 Gastric prostaglandin synthesis, bicarbonate, and nonparietal fluid secretion may diminish, making older adults more prone to nonsteroidal inflammatory drug (NSAID)–induced mucosal damage.^6,7,12 Finally, most (but not all) studies have shown that gastric emptying of solids remains intact in older adults, although liquid emptying is prolonged.^51–56

Small bowel histology^57–59 and transit time^{12,55,60–62} do not appear to change with age in humans, although increased epithelial proliferation in response to cellular injury has been found in a rodent model.⁶³ Splanchnic blood flow is reduced in older adults.⁷ Small bowel absorptive capacity for most nutrients remains intact, but there are some exceptions, especially those due to effects of disease (e.g., chronic gastritis, bacterial overgrowth) and medications on micronutrient absorption.¹² However, the increase in small bowel bacterial overgrowth seen in older adults may be attributed to medications (slow gut transit), diseases such as diabetes, and mobility impairment, which lead to malnutrition and changes in gut immune function, and not to advancing age.⁶⁴ No change with aging was found in duodenal brush border membrane enzyme activity of glucose transport.⁶⁵ D-Xylose absorption testing remains normal after correction for renal impairment, except perhaps in octogenarians.^66,67 Jejunal lactase activity decreases with age, whereas that of other disaccharides remains relatively stable, declining only during the seventh decade.⁶⁸ Protein digestion and assimilation^27,69 and fat absorption remain normal with aging, although the latter has a more limited adaptive reserve capacity.^70–73 Absorption of fat-soluble vitamin A is increased in the older adult population,^12,49,74 whereas vitamin D absorption may be impaired,^49,75–77 and a reduction in vitamin D receptor concentration and responsiveness occurs.^6,21,75 Absorption of the water-soluble vitamins B₁ (thiamine),⁷⁸ B₁₂ (cyanocobalamin),^70,72,79 and C (ascorbic acid)⁸⁰ remains normal, whereas disparate data exist on folate absorption with aging.^81,82 Iron absorption is maintained in healthy older adults who are not hypochlorhydric,^83,84 but absorption of zinc^49,85 and calcium^49,86–88 declines with age.

Several histologic changes have been demonstrated in the colon, including increased collagen deposition,⁷ atrophy of the muscularis propria, with an increase in the amount of fibrosis and elastin^27,89 and an increase in proliferating cells, especially at the superficial portions of the crypts.^63,90 Some studies have found that colonic transit time increases with aging to varying degrees,^73,91,92 perhaps due to the increase with age in the number of abnormally appearing myenteric ganglia in the human colon,⁹³ resulting in myenteric dysfunction, whereas others have not shown any change.^94,95 Prolonged transit time in older adults with constipation is due to factors associated with aging (e.g., comorbidity, immobilization, drugs) rather than to aging per se.⁹⁶ It is currently believed that colonic motility and the colon’s response to feeding are largely unaffected by healthy aging; however, conditions such as pelvic floor dysfunction and impaired rectal sensation and poor distention all contribute to impaired colonic function and altered bowel habits.

Anorectal physiologic changes have been well documented. Aging is associated with decreased resting anal sphincter pressure in men and women and decreased maximal sphincter pressure in women.^97–100 This may be due in part to age-related changes in muscle mass and contractility and in part to pudendal nerve damage associated with perineal descent in older women.^100–102 The closing pressure—that is, the difference between the maximum resting anal pressure and rectal pressure—also falls in older women.¹⁰² Maximum squeeze pressure declines with age, particularly in postmenopausal women,¹⁰ as does rectal wall elasticity.^103,104 An age-dependent increase in rectal pressure threshold producing an initial sensation of rectal filling has also been demonstrated.¹⁰⁵ The combined effects of reduced rectal compliance, sensation and perineal laxity may be the predisposing factors to fecal incontinence in older women.⁹⁹ Defecation dynamic studies in older women have shown a significant failure of rectal evacuation because of insufficient opening of the rectoanal angle and an increased degree of perineal descent compared with younger women.^96,106 Histologic¹⁰⁷ and endosonographic¹⁰⁸ studies on anorectal structure have revealed that the internal anal sphincter develops fibrofatty degeneration and increased thickness, respectively, with aging.

The pancreas undergoes minor histologic changes with aging.^27,109,110 There also appears to be a steady increase in the caliber of the main pancreatic duct, with other branches showing areas of focal dilation or stenosis, without any apparent disease or functional age-related changes^111,109 In fact, 69% of patients older than 70 years without pancreatic pathology have a so-called dilated duct when criteria developed for younger patients are applied.¹¹² However, any duct larger than 3 mm should be regarded as pathologic.¹¹³ High echogenicity of the pancreas is a normal finding on ultrasonography.^113,114 Aging reduces exocrine pancreatic flow rate and secretion of bicarbonate and enzymes, and the rate falls significantly with repeated stimulation.^{11,109,110,115,116} However, other studies have shown a lack of reduced pancreatic secretions with age, independent of disease and the effect of drugs.¹¹⁶ Given that a variable degree in functional reserve of different organ systems occurs in the aging process, it is not clearly known whether pancreatic insufficiency occurs as a sole consequence of aging.¹¹⁷

Anatomic studies on the liver reveal an age-related decrease in weight, both absolute and relative to body weight, as well as the number and size of hepatocytes.^118,119 Pseudocapillarization of the hepatic sinusoid (morphologic changes such as defenestration and thickening of the liver sinusoidal endothelial cell, increased numbers of fat-engorged, nonactivated stellate cells), lipofuscin accumulation, bile duct proliferation, fibrosis, and nonspecific reactive hepatitis are histologic changes more common in older adults.^119–121 The major functional changes in older adult patients are reduction in hepatic blood flow,^116,121 altered clearance of certain drugs, and delayed hepatic regeneration after injury.^121–124 The altered drug clearance is due to age-related reductions in phase I reactions (e.g., oxidation, hydrolysis, reduction), first-pass hepatic metabolism, and serum albumin–binding capacity. Phase II reactions (e.g., glucuronidation, sulfation), however, remain unaffected by aging.^{118,119,122,123} There are no age-specific alterations in conventional liver blood test results.¹²⁴

Although a cholecystographic study found that gallbladder emptying remained stable with increasing age, other studies have shown that gallbladder contraction in older adults may be less responsive to CCK.^125–127 Increases in the proportions of the phospholipid and cholesterol components of bile raise the lithogenicity index,^128,129 leading to an increased occurrence of gallstones in older adults.²⁷ Furthermore, the decline in bile salt synthesis, deconjugation of bile salt pigments, and increase in bactobilia are all speculated as being factors in the increased incidence of gallstone disease.¹³⁰ Choledocolithiasis is particularly common; in older adult patients who have undergone an emergency cholecystectomy, the incidence of bile duct stones approached 50%.¹³¹ Even in the absence of bile duct stones or other pathology, older adult patients generally have larger common bile duct diameters than younger patients.¹³²

Altered Manifestation of Adult Gastrointestinal Diseases

Although there are certain disorders that occur almost exclusively in older adults, most diseases afflicting older adults are those that affect younger adults as well. However, these illnesses may have typical features that must be recognized by clinicians and represent a formidable challenge. In older adults with an acute abdomen, the initial diagnostic impression has been found to be incorrect in up to two thirds of patients¹³³; the mortality in octogenarians is 70 times that in young adults.¹³⁴

Acute abdominal pain appears mute with age.^50,135 Theories explaining this phenomenon include increased endogenous opiate secretion, a decline in nerve conduction, and mental depression.¹³⁶ Pain localization is often atypical in older adult patients. Furthermore, age-dependent decline in immune function, along with a well-documented delay in pain perception, can give rise to an atypical or even absence of a febrile response, leukocytosis, and pain severity.¹³⁷ For example, in a study of acute appendicitis, 21% of patients older than 60 years presented with atypical pain distribution, whereas this occurred in only 3% of patients younger than 50 years.¹³⁸ Following appendectomy, morbidity and mortality in older adults carry a higher risk, up to 70% as compared to 1% in the general population.^139,140

The causes of acute abdominal pain differ as well. Acute cholecystitis, rather than nonspecific abdominal pain or acute appendicitis, was found to be the most common cause in one large survey.^134,135 In this series, 10% of patients older than 70 years were found to have a vascular cause for their pain, such as mesenteric ischemia, embolus, or infarction. Furthermore, retrospective studies have shown that in older adult patients with acute cholecystitis, over 60% of them did not present with the typical back or flank pain, and 5% had no pain at all. In addition, 40% denied nausea, over 50% were afebrile, and 41% had a normal white cell count. Overall, 13% of older adult patients had no fever, leukocytosis, or abnormal liver function test results.¹³⁵ A multicenter review has found that 25% of emergency patients older than 70 years had cancer (usually colorectal in Europe and North America, and hepatocellular in tropical regions)¹³⁴ as the cause of pain, whereas patients younger than 50 years had malignancy as the explanation in fewer than 1% of cases.¹⁴¹

Acute appendicitis may have few overt abdominal signs^142,143,135 and may therefore progress more frequently to gangrene and perforation.¹⁴³ Perforation rates range from 20% to 30% in the general population but increase to 50% to 70% in older adults.¹³⁵ Older adults account for 50% of all deaths from appendicitis.¹⁴⁴ Other intraabdominal inflammatory conditions, such as diverticulitis, may have rather nonspecific symptoms, including anorexia, altered mental status, low-grade or absence of fever, relatively little tenderness, and late-stage complications (e.g., hepatic abscess). Even biochemical abnormalities such as leukocytosis may be absent in a large number of cases.¹⁴⁴ Furthermore, perforation of a viscus may lack the typical dramatic manifestations.^48,136 Possible explanations for the paucity of tenderness in some cases include altered sensory perception, use of psychotropic drugs, and absence of chemical peritonitis if the patient is hypochlorhydric.⁵⁰ The site of perforation also differs with age. Colonic perforation is more common than perforated peptic ulcer disease or appendicitis, the two most common causes for generalized peritonitis in younger patients.¹³⁴

Studies vary regarding whether there is a higher prevalence of gastroesophageal reflux disease (GERD) in older adults,^145–148 but several studies have suggested that the frequency of GERD complications is significantly higher in older adults.^{145,146,149,150} Older adult patients have more intense abnormal acid contact time and advanced erosive disease.¹⁵⁰ Severe esophagitis is much more common in patients older than 65 years than in younger people.^149–151 Esophageal sensitivity seems to decrease with age,¹⁵² so very severe esophagitis may be associated with a relative paucity of symptoms. In fact, one study has shown that more than 75% do not experience acid regurgitation as an initial symptom.¹⁴⁵ Therefore, manifestations of GERD are more likely to be late-stage complications, such as bleeding from hemorrhagic esophagitis,¹⁵¹ dysphasia from a peptic stricture, or adenocarcinoma in the setting of a Barrett esophagus. Esophagitis accounts for a higher incidence of GI bleeding in persons older than 80 years.¹⁵⁰ GERD-induced chest pain may mimic or occur concomitantly with cardiac disease; thus, reflux must be excluded in any older adult patient with all but very typical angina.²⁸ Aspiration from occult GERD should be considered in older adult patients with recurrent pneumonia or exacerbations of underlying COPD.²⁸ Early endoscopy is indicated in all older adult patients with GERD, regardless of symptom severity.^145,146 The medical and surgical treatment of GERD in older adult patients follows the same principles as for young patients.¹⁴⁶ Proton pump inhibitors (PPIs) as a class are considered first-line treatment for GERD and erosive esophagitis in older adults,^145,153 although they may require a greater degree of acid suppression than younger patients to heal their esophagitis.¹⁴⁸ Also, with the advent of newer PPIs (e.g., pantoprazole), studies have shown good tolerability, even for long-term therapy due to minimal interactions with other drugs because of a lower affinity for cytochrome P450.¹⁵⁴ This is especially important in patients on clopidogrel, a prodrug that is metabolized to its active form by the same cytochrome p450 as most other PPIs and is used to prevent vascular events. Initial concern involved the potential to decrease efficacy; however, recent guidelines for the treatment of GERD have lessened any association.¹⁵⁰

Gastroduodenal ulcer disease has a several-fold greater incidence, hospitalization rate, and mortality in older adults,^155–157 with up to 90% of ulcer-related mortality in the United States occurring in patients older than 65 years.¹⁵⁷ This is due to an increase in injurious agents (e.g., H. pylori and NSAIDS, two factors that do not seem to act synergistically)^158,159 and to impaired defense mechanisms (e.g., lower levels of mucosal prostaglandins).^12,160 In fact, from 53% to 73% of older peptic ulcer patients are H. pylori–positive, yet eradication of the infection remains very low.¹⁶¹ There may be a paucity or distortion of classic burning epigastric pain, temporal features related to food intake, and typical patterns of radiation.⁵⁰ Pain was absent in one third of older hospitalized patients with peptic ulcer disease.¹⁶² As a result, older adult patients more frequently develop complications, such as bleeding or perforation. Giant benign ulcers of older adults can mimic malignancy by presenting with weight loss, anorexia, hypoalbuminemia, and anemia. Despite the increased morbidity and mortality of upper GI bleeding in older adults, endoscopic and clinical criteria have been reported that would allow for successful outpatient management.^{159,163–165}

The manifestation of celiac sprue differ considerably in older adults because features are generally more subtle than in young patients.^50,166 Only 25% of newly diagnosed older adult patients with celiac disease present primarily with diarrhea and weight loss.¹⁶⁷ Vague symptoms, including dyspepsia or an isolated folate or iron deficiency, may be the patient’s sole manifestation.^166,168,169 In one study, the mean delay to diagnosis in those aged 65 years and older was 17 years.¹⁷⁰ Irritable bowel syndrome was the most erroneous diagnosis made in older adult patients with presenting symptomatology.¹⁶⁹ Severe osteopenia and osteomalacia¹⁶⁶ and a bleeding diathesis due to hypoprothrombinemia are more common in older adults than in younger individuals.⁵⁰ Not uncommonly, the initial presentation in older adults may be a perforated viscus, given the multifocal and ulcerative lesions seen in the enteropathy-associated T cell lymphomas associated with celiac disease.¹⁶⁹ Small bowel lymphoma may be particularly common when celiac disease occurs in older adults,^170,171 specifically in patients who were diagnosed between 50 and 80 years of age.¹⁶⁹ Therefore, older adult patients with persistent symptoms, including weight loss, pain, and bleeding, despite strict adherence to a gluten-free diet, require careful evaluation to exclude GI malignancy.¹⁷²

Constipation is perceived by older adult patients to be straining during defecation rather than decreased bowel frequency,^173–175 and it may be manifested in unusual ways. Many older adult patients with constipation may meet diagnostic criteria for functional defecation disorders, such as rectal outlet delay. Excessive defecatory straining in older adult patients with underlying cerebrovascular disease or impaired baroreceptor reflexes can present as syncope or a transient ischemic attack. When unrelieved constipation progresses to fecal impaction, an overflow paradoxic diarrhea may occur, even in patients with relatively normal anal sphincter pressure. If the clinician does not recognize this and prescribes standard antidiarrheal therapy, the underlying impaction will only worsen and potentially lead to other serious complications, such as stercoral ulcers, volvulus, and bleeding.^174,175

New-onset Crohn disease in older adults is thought to account for almost one third of new cases.¹⁷⁶ Patients older than 60 years account for 10% to 30% of the total irritable bowel disease (IBD) population, with an equal male-to-female ratio. The incidence of IBD in older adults decreases with age, with a 65% occurrence between the ages of 60 to 70 years but only 10% in patients older than 80 years.¹⁷⁶ Misdiagnosis on initial presentation is more common in older adults, with an average delay of up to 6 years.^176,177 Crohn disease has been commonly reported to be limited to the colon more often than is in younger patients.¹⁷⁸ The colitis is more often left-sided in older adults, whereas proximal colonic involvement is more common in younger individuals.^179,180 However, the severity of disease is less severe in older adults, as exhibited by a lower incidence of fistula or stricture formation.¹⁷⁸ Older adult patients are less likely to have close relatives affected by Crohn disease and to have abdominal pain, weight loss, or anemia as a presenting symptom.¹⁷⁷ Crohn disease in older adults develops more rapidly, may be more severe on initial presentation, and is characterized by a shorter time interval between onset of symptoms and first resection.¹⁷⁷ Older adult patients with Crohn disease may suffer fewer relapses,⁵⁰ and their postoperative recurrence rate is lower than or equal to that of younger people.¹⁷⁸ However, in older adult patients who do have postoperative recurrence, it occurs more rapidly than in younger patients.¹⁷⁷ Whereas those few young Crohn disease patients who die do so because of their disease, death in older adult patients is usually due to unrelated causes.¹⁷⁸ Older adult patients are more prone to steroid-induced osteoporosis,¹⁷² but bisphosphonates prevent and effectively treat bone loss in these patients,¹⁸¹ and their use must be strongly considered in this setting. Extraintestinal manifestations were found to be similar in younger and older adults.

The manifestations of ulcerative colitis are generally the same in the young and the old, including extraintestinal manifestations.¹⁸⁰ In older adults, proctosigmoiditis is more common, with a lower incidence of proximal extension over time; pancolitis and the need for surgery are less common. Colectomy rates are lower in older adults with ulcerative colitis when compared to younger patients.¹⁷⁶

Therapy for inflammatory bowel disease in older adults can follow the same stepwise regimen as in the younger population. However, a clear distinction must be made between the fit older adult and the frail older adult. Studies have shown that the fit older adult can tolerate therapeutic modalities similar to those of the younger generation, with minimal additional risk or morbidity.¹⁸² However, it is imperative to take into account comorbidities, potential drug-drug interactions, and malignancy potential when considering therapy. Furthermore, a stepwise progression and “go slow” approach may be prudent in treatment of the older IBD patient.

The most common manifestation of gallstone disease in older adults are acute cholecystitis and cholangitis.⁵⁰ Biliary tract disease is the most common indication for surgical intervention in patients presenting with acute abdominal pain older than 55 years.¹³⁵ Cholecystitis in older adults may have nonspecific symptoms, including vague mental and physical disability.^135,183,184 Pain may be muted¹³⁵ or absent, even in the presence of gallbladder empyema, leading to a delay in hospitalization.¹⁸⁵ Typical features of cholangitis may be absent. Therefore, blood cultures are critical to exclude bacteremia as the sole evidence of an infected biliary tract, which can result in greater mortality in older adults.^186,187 Older adult patients who require an emergency cholecystectomy have a higher mortality rate than younger patients, but can do well with elective operations, aside from longer operative time and postoperative hospital stay.¹⁸⁸ Thus, surgery should not be denied to the healthy older adult patient with recurrent biliary colic based on age alone.^131,189 Minimally invasive procedures, such as endoscopic retrograde cholangiopancreatography and laparoscopic cholecystectomy, should be used whenever possible.¹³¹

The clinical course of liver disease in older adults is usually similar to that in younger adults, although complications are less well tolerated.^50,190 Chronic hepatitis C, along with alcoholic liver disease, has been emerging as the most common cause of chronic parenchymal liver disease in older adultsopulation.^124,191 The Centers for Disease Control and Prevention has recommended screening for hepatitis C virus (HCV) for all subjects born between 1945 and 1965, many of whom will be older than 60 years. This group represents 75% of all those infected with HCV in the United States.¹⁹² Viral hepatitis more commonly has a prolonged and cholestatic picture in older adults, although data are equivocal on whether they are more or less likely to suffer severe or fulminant hepatitis.¹¹⁹ Although the risk of death from fulminant liver failure from acute hepatitis A infection appears to increase with age,¹⁹¹ acute hepatitis B in older adult patients is usually a mild subclinical disease, and the risk of fulminant disease is not increased.¹⁹³ However, a higher risk for progressing to chronic infection exists for those who acquire the disease after 65 years of age.¹⁹¹ Advanced age at the onset of infection with HCV is associated with an increased mortality rate.¹⁹³ This is related to a more rapid rate of fibrosis, whose cause is unknown but is presumed to be related to the decline in immune function with age.¹⁹¹ When fulminant hepatic failure develops from any cause, advanced age is an adverse prognostic variable.¹²⁴ Certain conditions, including alcoholic liver disease, hemochromatosis, primary biliary cirrhosis, and hepatocellular carcinoma, are often seen in more advanced stages when they first present in older adult patients.¹¹⁹

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the United States and worldwide¹⁹⁴ and is seen with increasing prevalence in older adults.¹⁹⁵ However, studies have shown a lack of association with the metabolic syndrome, a clear distinction from the disease in adulthood.¹⁹⁵ In addition, the natural progression of NAFLD with associated liver complications is typically noted between the sixth and eight decades of life,¹⁹⁶ with progression to advanced fibrosis, cirrhosis, and mortality in older adult patients. Patient with NAFLD are at increased risk for hepatocellular carcinoma but this is likely limited to those with advanced fibrosis and cirrhosis.¹⁹⁷ Therefore, the diagnosis of cryptogenic cirrhosis in older adults may be directly related to the ever-rising epidemic of fatty liver in adulthood.