2614 PART 10 Disorders of the Gastrointestinal System

■ IMMUNOPATHOGENESIS

The weight of evidence suggests that the progressive liver injury in

patients with autoimmune hepatitis is the result of a cell-mediated

immunologic attack directed against liver cells in the setting of a loss

of, or failed, immunologic tolerance for self-liver antigens. In all likelihood, predisposition to autoimmunity is inherited, whereas the liver

specificity of this injury is triggered by environmental (e.g., chemical,

drug [e.g., minocycline], or viral) factors. For example, patients have

been described in whom apparently self-limited cases of acute hepatitis

A, B, or C led to autoimmune hepatitis, presumably because of genetic

susceptibility or predisposition. Evidence to support an autoimmune

pathogenesis in this type of hepatitis includes the following: (1) in the

liver, the histopathologic lesions are composed predominantly of cytotoxic T cells and plasma cells; (2) circulating autoantibodies (nuclear,

smooth muscle, thyroid, etc.; see below), rheumatoid factor, and hyperglobulinemia are common; (3) other autoimmune disorders—such as

autoimmune thyroiditis, rheumatoid arthritis, autoimmune hemolytic

anemia, ulcerative colitis, membranoproliferative glomerulonephritis, juvenile diabetes mellitus, vitiligo, celiac disease, and Sjögren’s

syndrome—occur with increased frequency in patients who have autoimmune hepatitis and in their relatives; (4) histocompatibility haplotypes associated with autoimmune diseases, such as HLA-B1, B8, DR3,

and DR4 as well as extended haplotype DRB1*

0301 and DRB1*

0401

alleles, are common in patients with autoimmune hepatitis; and (5) this

type of chronic hepatitis is responsive to glucocorticoid/immunosuppressive therapy, effective in a variety of autoimmune disorders.

Cellular immune mechanisms appear to be important in the pathogenesis of autoimmune hepatitis. In vitro studies have suggested that

in patients with this disorder, CD4+ T lymphocytes are capable of

becoming sensitized to hepatocyte membrane proteins and of destroying liver cells. Molecular mimicry by cross-reacting antigens that contain epitopes similar to liver antigens is postulated to activate these T

cells, which infiltrate, and result in injury to, the liver. Abnormalities

of immunoregulatory control over cytotoxic lymphocytes (impaired

regulatory CD4+CD25+ T-cell influences) may play a role as well.

Studies of genetic predisposition to autoimmune hepatitis demonstrate

that certain haplotypes are associated with the disorder, as enumerated above, as are polymorphisms in cytotoxic T lymphocyte antigens

(CTLA-4) and tumor necrosis factor α (TNFA*

2). The precise triggering factors, genetic influences, and cytotoxic and immunoregulatory

mechanisms involved in this type of liver injury remain incompletely

defined.

Intriguing clues into the pathogenesis of autoimmune hepatitis come

from the observation that circulating autoantibodies are prevalent in

patients with this disorder. Among the autoantibodies described in

these patients are antibodies to nuclei (so-called antinuclear antibodies

[ANAs], primarily in a homogeneous pattern) and smooth muscle

(so-called anti-smooth-muscle antibodies, directed at actin, vimentin,

and skeletin), antibodies to F-actin, anti-LKM (see below), antibodies

to “soluble liver antigen” (directed against a uracil-guanine-adenine

transfer RNA suppressor protein), antibodies to α-actinin, and antibodies to the liver-specific asialoglycoprotein receptor (or “hepatic

lectin”) and other hepatocyte membrane proteins. Although some of

these provide helpful diagnostic markers, their involvement in the

pathogenesis of autoimmune hepatitis has not been established.

Humoral immune mechanisms have been shown to play a role in the

extrahepatic manifestations of autoimmune and idiopathic hepatitis.

Arthralgias, arthritis, cutaneous vasculitis, and glomerulonephritis

occurring in patients with autoimmune hepatitis appear to be mediated

by the deposition of circulating immune complexes in affected tissue

vessels, followed by complement activation, inflammation, and tissue

injury. While specific viral antigen-antibody complexes can be identified in acute and chronic viral hepatitis, the nature of the immune

complexes in autoimmune hepatitis has not been defined.

■ CLINICAL FEATURES

Many of the clinical features of autoimmune hepatitis are similar to

those described for chronic viral hepatitis. The onset of disease may

be insidious or abrupt; the disease may present initially like, and be

confused with, acute viral hepatitis; a history of recurrent bouts of what

had been labeled acute hepatitis is not uncommon. In approximately a

quarter of patients, the diagnosis is made in the absence of symptoms,

based on abnormal liver laboratory tests. A subset of patients with

autoimmune hepatitis has distinct features. Such patients are predominantly young to middle-aged women with marked hyperglobulinemia

and high titer circulating ANAs. This is the group with positive lupus

erythematosus (LE) preparations (initially labeled lupoid hepatitis)

in whom other autoimmune features are common. Fatigue, malaise,

anorexia, amenorrhea, acne, arthralgias, and jaundice are common.

Occasionally, arthritis, maculopapular eruptions (including cutaneous

vasculitis), erythema nodosum, colitis, pleuritis, pericarditis, anemia, azotemia, and sicca syndrome (keratoconjunctivitis, xerostomia)

occur. In some patients, complications of cirrhosis, such as ascites and

edema (associated with portal hypertension and hypoalbuminemia),

encephalopathy, hypersplenism, coagulopathy, or variceal bleeding

may bring the patient to initial medical attention.

The course of autoimmune hepatitis may be variable. In patients

with mild disease or limited histologic lesions (e.g., piecemeal necrosis [inflammation and erosion of the limiting place of periportal

hepatocytes] without bridging), progression to cirrhosis is limited,

but, even in this subset, clinical monitoring is important to identify

progression; up to half left untreated can progress to cirrhosis over

the course of 15 years. In North America, cirrhosis at presentation

is more common in African Americans than in whites. In those with

severe symptomatic autoimmune hepatitis (aminotransferase levels

>10 times normal, marked hyperglobulinemia, “aggressive” histologic

lesions—bridging necrosis or multilobular collapse, cirrhosis), the

6-month mortality without therapy may be as high as 40%. Such severe

disease accounts for only 20% of cases; the natural history of milder

disease is variable, often accentuated by spontaneous remissions and

exacerbations. In a 10-year (2006–2016) national Dutch study, mortality in patients with autoimmune hepatitis was higher than that of the

general population only in patients with cirrhosis; for patients without

cirrhosis, survival was comparable to that of the general population.

Especially poor prognostic signs include the presence histologically of

multilobular collapse at the time of initial presentation and failure of

serum bilirubin to improve after 2 weeks of therapy. Death may result

from hepatic failure, hepatic coma, other complications of cirrhosis

(e.g., variceal hemorrhage), and intercurrent infection. In patients with

established cirrhosis, HCC may be a late complication (Chap. 82) but

occurs less frequently than in cirrhosis associated with viral hepatitis.

Laboratory features of autoimmune hepatitis are similar to those

seen in chronic viral hepatitis. Liver biochemical tests are invariably

abnormal but may not correlate with the clinical severity or histopathologic features in individual cases. Many patients with autoimmune hepatitis have normal serum bilirubin, alkaline phosphatase,

and globulin levels with only minimal aminotransferase elevations.

Serum AST and ALT levels are increased and fluctuate in the range

of 100−1000 units. In severe cases, the serum bilirubin level is moderately elevated (51−171 μmol/L [3−10 mg/dL]). Hypoalbuminemia

occurs in patients with very active or advanced disease. Serum alkaline

phosphatase levels may be moderately elevated or near normal. In

a small proportion of patients, marked elevations of alkaline phosphatase activity occur; in such patients, clinical and laboratory features

overlap with those of primary biliary cholangitis (Chap. 344). The

prothrombin time is often prolonged, particularly late in the disease or

during active phases.

Polyclonal hypergammaglobulinemia (>2.5 g/dL) is common in

autoimmune hepatitis, as is the presence of rheumatoid factor. As noted

above, circulating autoantibodies are also prevalent, most characteristically ANAs in a homogeneous staining pattern. Smooth-muscle antibodies are less specific, seen just as frequently in chronic viral hepatitis.

Because of the high levels of globulins achieved in the circulation of

some patients with autoimmune hepatitis, occasionally the globulins

may bind nonspecifically in solid-phase binding immunoassays for

viral antibodies. This has been recognized most commonly in tests for

antibodies to HCV, as noted above. In fact, studies of autoantibodies

in autoimmune hepatitis have led to the recognition of new categories

2615Chronic Hepatitis CHAPTER 341

of autoimmune hepatitis. Type I autoimmune hepatitis is the classic

syndrome prevalent in North America and northern Europe occurring

in young women, associated with marked hyperglobulinemia, lupoid

features, circulating ANAs, and HLA-DR3 or HLA-DR4 (especially

B8-DRB1*

03). Also associated with type I autoimmune hepatitis are

autoantibodies against actin and atypical perinuclear antineutrophilic

cytoplasmic antibodies (pANCA). Included in the spectrum of type I

autoimmune hepatitis is a subset of patients who lack ANA and antiLKM1 but who have circulating antibodies to soluble liver antigen.

Most of these patients are women and have clinical features similar

to, or perhaps more severe than, those of other patients with type I

autoimmune hepatitis.

Type II autoimmune hepatitis, often seen in children, more common

in Mediterranean populations, and linked to HLA-DRB1 and HLADQB1 haplotypes, is associated not with ANA but with anti-LKM.

Actually, anti-LKM represent a heterogeneous group of antibodies.

In type II autoimmune hepatitis, the antibody is anti-LKM1, directed

against cytochrome P450 2D6. This is the same anti-LKM seen in some

patients with chronic hepatitis C. Anti-LKM2 is seen in drug-induced

hepatitis, and anti-LKM3 (directed against uridine diphosphate glucuronyltransferases) is seen in patients with chronic hepatitis D. Another

autoantibody observed in type II autoimmune hepatitis is directed

against liver cytosol formiminotransferase cyclodeaminase (anti-liver

cytosol 1).

Liver biopsy abnormalities are similar to those described for chronic

viral hepatitis. Expanding portal tracts and extending beyond the plate

of periportal hepatocytes into the parenchyma (designated interface

hepatitis or piecemeal necrosis) is a mononuclear cell infiltrate that,

in autoimmune hepatitis, may include the presence of plasma cells.

Necroinflammatory activity characterizes the lobular parenchyma,

and evidence of hepatocellular regeneration is reflected by “rosette”

formation, the occurrence of thickened liver cell plates, and regenerative “pseudolobules.” Septal fibrosis, bridging fibrosis, and cirrhosis are

frequent. In patients with early autoimmune hepatitis presenting as an

acute-hepatitis-like illness, lobular and centrilobular (as opposed to the

more common periportal) necrosis has been reported. Bile duct injury

and granulomas are uncommon; however, a subgroup of patients

with autoimmune hepatitis has histologic, biochemical, and serologic

features overlapping those of primary biliary cholangitis (Chap. 344).

■ DIAGNOSTIC CRITERIA

An international group has suggested a set of criteria for establishing a diagnosis of autoimmune hepatitis. Exclusion of liver disease

caused by genetic disorders, viral hepatitis, drug hepatotoxicity, and

alcohol is linked with such inclusive diagnostic criteria as hyperglobulinemia, autoantibodies, and characteristic histologic features. This

international group has also suggested a comprehensive diagnostic

scoring system that, rarely required for typical cases, may be helpful

when typical features are not present. Factors that weigh in favor of

the diagnosis include female gender; predominant aminotransferase

elevation; presence and level of globulin elevation; presence of nuclear,

smooth-muscle, LKM1, and other autoantibodies; concurrent other

autoimmune diseases; characteristic histologic features (interface

hepatitis, plasma cells, rosettes); HLA-DR3 or DR4 markers; and

response to treatment (see below). A more simplified, more specific

scoring system relies on four variables: autoantibodies, serum IgG

level, typical or compatible histologic features, and absence of viral

hepatitis markers. Weighing against the diagnosis are predominant

alkaline phosphatase elevation, mitochondrial antibodies, markers of

viral hepatitis, history of hepatotoxic drugs or excessive alcohol, histologic evidence of bile duct injury, or such atypical histologic features as

fatty infiltration, iron overload, and viral inclusions.

■ DIFFERENTIAL DIAGNOSIS

Early during the course of chronic hepatitis, autoimmune hepatitis may

resemble typical acute viral hepatitis (Chap. 339). Without histologic

assessment, severe chronic hepatitis cannot be readily distinguished

based on clinical or biochemical criteria from mild chronic hepatitis.

In adolescence, Wilson’s disease (Chaps. 344 and 415) may present

with features of chronic hepatitis long before neurologic manifestations

become apparent and before the formation of Kayser-Fleischer rings

(copper deposition in Descemet’s membrane in the periphery of the

cornea). In this age group, serum ceruloplasmin and serum and urinary copper determinations plus measurement of liver copper levels

establish the correct diagnosis. Postnecrotic or cryptogenic cirrhosis

and primary biliary cholangitis (Chap. 344) share clinical features

with autoimmune hepatitis, and both alcoholic hepatitis (Chap. 342)

and nonalcoholic steatohepatitis (Chap. 343) may present with many

features common to autoimmune hepatitis; historic, biochemical, serologic, and histologic assessments are usually sufficient to allow these

entities to be distinguished from autoimmune hepatitis. Of course,

the distinction between autoimmune and chronic viral hepatitis is

not always straightforward, especially when viral antibodies occur

in patients with autoimmune disease or when autoantibodies occur

in patients with viral disease. Furthermore, the presence of extrahepatic features such as arthritis, cutaneous vasculitis, or pleuritis—not

to mention the presence of circulating autoantibodies—may cause

confusion with rheumatologic disorders such as rheumatoid arthritis

and systemic LE. The existence of clinical and biochemical features of

progressive necroinflammatory liver disease distinguishes chronic hepatitis from these other disorders, which are not associated with severe

liver disease. Rarely, hepatic venous outflow obstruction (Budd-Chiari

syndrome) may present with features suggestive of autoimmune hepatitis, but painful hepatomegaly, ascites, and vascular imaging provide

distinguishing diagnostic clues. Other diagnostic considerations would

include celiac disease and ischemic liver disease, which would be

readily distinguishable by clinical and laboratory features from autoimmune hepatitis.

In patients treated with immune checkpoint inhibitors for malignancy, the liver may be one of the autoimmune targets of therapy;

the syndrome resembles autoimmune hepatitis in clinical features

and response to glucocorticoid-based treatment. Finally, occasionally,

features of autoimmune hepatitis overlap with features of autoimmune

biliary disorders such as primary biliary cholangitis, primary sclerosing

cholangitis (Chaps. 344 and 346), or, even more rarely, mitochondrial

antibody-negative autoimmune cholangitis. Such overlap syndromes

are difficult to categorize, and often response to therapy may be the

distinguishing factor that establishes the diagnosis.

TREATMENT

Autoimmune Hepatitis

The mainstay of management in autoimmune hepatitis is glucocorticoid therapy. Several controlled clinical trials have documented

that such therapy leads to symptomatic, clinical, biochemical, and

histologic improvement as well as increased survival. A therapeutic

response can be expected in up to 80% of patients. Unfortunately,

therapy has not been shown in clinical trials to prevent ultimate

progression to cirrhosis; however, instances of reversal of fibrosis

and cirrhosis have been reported in patients responding to treatment, and rapid treatment responses within 1 year do translate into

a reduction in progression to cirrhosis. Although some advocate

the use of prednisolone (the hepatic metabolite of prednisone),

prednisone is just as effective and is favored by most authorities.

Therapy may be initiated at 20 mg/d, but a popular regimen in

the United States relies on an initiation dose of 60 mg/d. This high

dose is tapered successively over the course of a month down to

a maintenance level of 20 mg/d. An alternative, but equally effective, more appealing approach is to begin with half the prednisone

dose (30 mg/d) along with azathioprine (50 mg/d). With azathioprine maintained at 50 mg/d, the prednisone dose is tapered over

the course of a month down to a maintenance level of 10 mg/d.

The advantage of the combination approach is a reduction, over the

span of an 18-month course of therapy, in serious, life-threatening

complications of steroid therapy (e.g., cushingoid features, hypertension, diabetes, osteoporosis) from 66% down to <20%. Genetic

analysis for thiopurine S-methyltransferase allelic variants does not

2616 PART 10 Disorders of the Gastrointestinal System

correlate with azathioprine-associated cytopenias or efficacy and

is not assessed routinely in patients with autoimmune hepatitis.

In combination regimens, 6-mercaptopurine may be substituted

for its prodrug azathioprine, but this is rarely required. Azathioprine alone, however, is not effective in achieving remission, nor

is alternate-day glucocorticoid therapy. Limited experience with

budesonide in noncirrhotic patients suggests that this steroid side

effect−sparing drug may be effective; however, the few randomized

controlled trials of budesonide have not consistently shown efficacy. Although therapy has been shown to be effective for severe

autoimmune hepatitis (AST ≥10× the upper limit of normal or

≥5× the upper limit of normal in conjunction with serum globulin

greater than or equal to twice normal; bridging necrosis or multilobular necrosis on liver biopsy; presence of symptoms), therapy is

not indicated for mild forms of chronic hepatitis, and the efficacy

of therapy in mild or asymptomatic autoimmune hepatitis has not

been established.

Improvement of fatigue, anorexia, malaise, and jaundice tends

to occur within days to several weeks; biochemical improvement

occurs over the course of several weeks to months, with a fall in

serum bilirubin and globulin levels and an increase in serum albumin. Serum aminotransferase levels usually drop promptly, but

improvements in AST and ALT alone do not appear to be reliable

markers of recovery in individual patients; histologic improvement,

characterized by a decrease in mononuclear infiltration and in

hepatocellular necrosis, may be delayed for 6−24 months. Still, if

interpreted cautiously, aminotransferase levels are valuable indicators of relative disease activity, and, although recommended,

many authorities do not advocate for serial liver biopsies to assess

therapeutic success or to guide decisions to alter or stop therapy.

Rapidity of response is more common in older patients (≥69 years)

and those with HLA DBR1*

04; although rapid responders may

progress less slowly to cirrhosis and liver transplantation, they are

no less likely than slower responders to relapse after therapy. Therapy should continue for at least 12−18 months. After tapering and

cessation of therapy, the likelihood of relapse is at least 50%, even if

posttreatment histology has improved to show mild chronic hepatitis, and most patients require therapy at maintenance doses indefinitely. Continuing azathioprine alone (2 mg/kg body weight daily)

after cessation of prednisone therapy has been shown to reduce

the frequency of relapse. Long-term maintenance with low-dose

prednisone (≤10 mg daily) has also been shown to keep autoimmune hepatitis in check without the theoretical risk of azathioprine

marrow suppression and, in young women of child-bearing age,

teratogenicity; however, maintenance azathioprine is more effective

in preserving remission.

In medically refractory cases, an attempt should be made to

intensify treatment with high-dose glucocorticoid monotherapy

(60 mg daily) or combination glucocorticoid (30 mg daily) plus

high-dose azathioprine (150 mg daily) therapy. After a month,

doses of prednisone can be reduced by 10 mg a month, and doses

of azathioprine can be reduced by 50 mg a month toward ultimate,

conventional maintenance doses. Patients refractory to this regimen

may be treated with cyclosporine, tacrolimus, or mycophenolate

mofetil. Similarly, in exploratory studies, infusions of monoclonal antibodies directed at tumor necrosis factor (infliximab) and

against the B-lymphocyte antigen CD20 (rituximab) have been

reported to be of clinical benefit (improved aminotransferase levels,

immunoglobulin G levels, histologic inflammatory activity) as rescue therapy for refractory autoimmune hepatitis. To date, however,

only limited, often anecdotal, data in small numbers of patients

support these alternative approaches. If medical therapy fails, or

when chronic hepatitis progresses to cirrhosis and is associated

with life-threatening complications of liver decompensation, liver

transplantation is the only recourse (Chap. 345); in patients with

severe autoimmune hepatitis, failure of the bilirubin to improve

after 2 weeks of therapy should prompt early consideration of the

patient for liver transplantation. Recurrence of autoimmune hepatitis in the new liver occurs rarely in most experiences but in as many

as 35−40% of cases in others; nonetheless, 5-year patient and graft

survival exceed 80%.

Like all patients with chronic liver disease, patients with autoimmune hepatitis should be vaccinated against hepatitis A and

B, ideally before immunosuppressive therapy is begun, if practical. Patients with autoimmune hepatitis and cirrhosis should be

screened for HCC with ultrasound at 6-month intervals and for

gastroesophageal varices with upper gastrointestinal endoscopy at

intervals of 1–3 years, based on severity of liver disease.

■ FURTHER READING

AASLD/IDSA HCV Guidance Panel: Hepatitis C guidance 2019

update: American Association for the Study of Liver Diseases–

Infectious Diseases Society of America recommendations for testing,

managing, and treating hepatitis C virus infection. Hepatology

71:686, 2020. Updated regularly and available at http://www.hcvguidelines.org. Accessed April 20, 2020.

Bersoff-Matcha SJ et al: Hepatitis B virus reactivation associated

with direct-acting antiviral therapy for chronic hepatitis C virus: A

review of cases reported to the U.S. Food and Drug Administration

Adverse Event Reporting System. Ann Intern Med 166:792, 2017.

Bourliere M et al: Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med 376:2134, 2017.

Buti M et al: Tenofovir alafenamide versus tenofovir disproxil fumarate for the treatment of HBeAg-negative chronic hepatitis B virus

infection: A randomized, double-blind, phase 3 non-inferiority trial.

Lance Gastroenterol Hepatol 1:196, 2017.

Butt AA et al: Direct-acting antiviral therapy for HCV infection is

associated with a reduced risk of cardiovascular disease events. Gastroenterology 156:987, 2019.

Carbone M, Neuberger JM: Autoimmune liver disease, autoimmunity and liver transplantation. J Hepatol 60:210, 2014.

Carrat F et al: Clinical outcomes in patients with chronic hepatitis C

after direct-acting antiviral treatments: A prospective cohort study.

Lancet 393:1453, 2019.

Chan HLY et al: Tenofovir alafenamide versus tenofovir disproxil

fumarate for the treatment of HBeAg-positive chronic hepatitis B

virus infection: A randomized, double-blind, phase 3 non-inferiority

trial. Lancet Gastroenterol Hepatol 1:185, 2017.

European Association for the Study of the Liver: EASL 2017

clinical practice guidelines on the management of hepatitis B virus

infection. J Hepatol 67:370, 2017.

European Association for the Study of the Liver: EASL recommendations on treatment of hepatitis C 2018. J Hepatol 69:461, 2018.

European Association for the Study of the Liver: EASL recommendations on treatment of hepatitis C: Final update of the series. J

Hepatol 73:1170, 2020.

Forns X et al: Glecaprevir plus pibrentasvir for chronic hepatitis C

virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated

cirrhosis (EXPEDITION-1): A single-arm, open-label, multicentre

phase 3 trial. Lancet Infect Dis 17:1062, 2017.

Jacobson IM et al: American Gastroenterological Association Institute

clinical practice update-expert review: Care of patients who have

achieved a sustained virologic response after antiviral therapy for

chronic hepatitis C infection. Gastroenterology 152:1578, 2017.

Kwo PY et al: Glecaprevir and pibrentasvir yield high response rates in

patients with HCV genotype 1-6 without cirrhosis. J Hepatol 67:263,

2017.

Liem KS et al: Limited sustained response after stopping nucleos(t)ide

analogues in patients with chronic hepatitis B: Results from a randomized controlled trial (Toronto STOP study). Gut 68:2206, 2019.

Lok ASG et al: Antiviral therapy for chronic hepatitis B viral infection

in adults: A systematic review and meta-analysis. Hepatology 63:284,

2016.

Loomba R, Liang TJ: Hepatitis B reactivation associated with immune

suppressive and biological modifier therapies: Current concepts,

management strategies, and future directions. Gastroenterology

152:1297, 2017.

2617Alcohol-Associated Liver Disease CHAPTER 342

Mcglynn EA et al: Assessing the safety of direct-acting antiviral agents

for hepatitis C. JAMA Open Network 2(6):e194765, 2019.

Papatheodoridis GV et al: Eight-year survival in chronic hepatitis

B patients under long-term entecavir or tenofovir is similar to the

general population. J Hepatol 68:1129, 2018.

Papatheodoridis GV et al: DARING-B: Discontinuation of effective

entecavir or tenofovir disoporxil fumarate long-term therapy before

HBsAg loss in non-cirrhotic HBeAg-negative chronic hepatitis B.

Antivir Ther 23:677, 2018.

Pawlotsky J-M et al: From non-A, non-B hepatitis to hepatitis C virus

cure. J Hepatol 62:S87, 2015.

Perrillo RP et al: American Gastroenterological Association Institute

technical review on prevention and treatment of hepatitis B virus

reactivation during immunosuppressive drug therapy. Gastroenterology 148:221, 2015.

Reddy KJ et al: American Gastroenterological Association Institute

guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology

148:215, 2015.

Rossi C et al: Sustained virologic response from interferon-based

hepatitis C regimens is associated with reduced risk of extrahepatic

manifestations. J Hepatol 71:1116, 2019.

Singal AG et al: AGA clinical practice update on interaction between

oral direct-acting antivirals for chronic hepatitis C infection and

hepatocellular carcinoma: Expert review. Gastroenterology 156:2149,

2019.

Singh S et al: Magnitude and kinetics of decrease in liver stiffness after

antiviral therapy in patients with chronic hepatitis C: A systematic

review and meta-analysis. Clin Gastroenterol Hepatol 16:27, 2018.

Spearman CW et al: Hepatitis C. Lancet 394:1451, 2019.

Tang LS et al: Chronic hepatitis B infection: A review. JAMA 319:1802,

2018.

Terrault N et al: Update on prevention, diagnosis, and treatment of

chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology

67:1560, 2018.

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342 Alcohol-Associated

Liver Disease

Bernd Schnabl

Alcohol-associated liver diseases (ALD) comprise a spectrum of diseases associated with chronic alcohol consumption ranging from

alcohol-associated fatty liver disease and steatohepatitis to more

advanced liver disease including fibrosis and cirrhosis. Acute alcoholic

hepatitis is an acute-on-chronic form of ALD that is associated with

liver failure and high mortality.

■ EPIDEMIOLOGY

Approximately 5.8% of adults in the United States have an alcohol use

disorder, defined as >2 drinks per day in women and >3 drinks per day

in men, or partake in binge drinking, defined as 4 drinks for women

and 5 drinks for men in ~2 h (1 drink equals ~14 g of ethanol, which

is 1 beer, 4 oz of wine, or 1 oz of 80% spirits). Prevalence of ALD correlates with the amount of alcohol consumption in different regions.

Prevalence of alcohol-associated fatty liver disease is 4.7% of the general

population in the United States, and 1.5% has stage 2 or greater fibrosis.

Liver cirrhosis is the eleventh leading cause of mortality worldwide,

causing 1.16 million deaths annually; 48% of cases of cirrhosis can be

attributed to alcohol. Among patients with alcohol use disorder, 18%

had fibrosis, 26% had cirrhosis, and 7% had acute alcoholic hepatitis

without underlying cirrhosis. In the European population, the annual

incidence rate for acute alcoholic hepatitis is between 24 and 27 per

million persons in women and between 46 and 65 per million persons

in men.

■ PATHOGENESIS

Alcohol in the form of ethanol is rapidly absorbed in the upper gastrointestinal tract and predominantly metabolized in the liver. Ethanol

reaches the liver through the portal vein, and the majority of ethanol

is oxidized via alcohol dehydrogenase 1 (ADH1) into acetaldehyde

in hepatocytes. Chronic alcohol consumption induces the expression

of a second ethanol-metabolizing enzyme, cytochrome P450 family

2 subfamily E member 1 (CYP2E1), which also converts ethanol into

acetaldehyde. In addition to the direct cellular toxic effects of acetaldehyde, metabolism of ethanol into acetaldehyde causes the generation of reactive oxygen species (ROS), resulting in further injury of

hepatocytes via lipid peroxidation and DNA damage. Acetaldehyde is

then oxidized into acetate via acetaldehyde dehydrogenase (ALDH).

Inherited deficiency of ALDH2 is common in Asian countries and

leads to acetaldehyde accumulation after alcohol consumption. These

individuals develop nausea and cutaneous flushing. Several mechanisms contribute to the development of hepatic steatosis related to

alcohol consumption. Acetate is converted into acetyl-coenzyme A

(CoA), which contributes to fatty acid and triglyceride synthesis.

Alcohol, in part through epigenetic changes, increases the expression

of genes involved in lipogenesis, while genes involved in fatty acid

transport and oxidation are suppressed. Alcohol also increases the ratio

of reduced nicotinamide adenine dinucleotide (NAD)/oxidized NAD

(NADH/NAD+) in hepatocytes, which further reduces mitochondrial

β-oxidation. Alcohol can increase fatty acid mobilization in adipose

tissue and the intestine, which will lead to hepatic accumulation of fatty

acids and increased hepatic steatosis. Overall, the net effect of these

processes contributes to fat accumulation in the liver.

■ RISK FACTORS FOR PROGRESSION OF ALD

Daily alcohol consumption or heavy drinking results in hepatic steatosis, but only 10–20% of such individuals will develop progressive liver

disease and cirrhosis. Therefore, other cofactors such as behavioral,

environmental, and genetic factors play important roles in progression

of ALD (Table 342-1). There is a dose-dependent increase, with regard

to the amount of alcohol consumed, in the likelihood of developing

liver cirrhosis. Women develop ALD at a lower daily alcohol intake.

Cigarette smoking is an independent risk factor for alcohol-associated

cirrhosis. The drinking pattern, in particular binge drinking and

excessive alcohol drinking outside meals, increases the risk of developing progressive ALD. Obesity and other chronic liver diseases such

as viral hepatitis, hemochromatosis, and nonalcoholic steatohepatitis

(NASH), are frequent cofactors contributing to progression of ALD.

Twin studies demonstrated a genetic predisposition to alcohol-associated liver cirrhosis that is independent from the genetic predisposition

to alcohol use disorder. Gene polymorphisms conferring increased

risk of alcohol-associated liver cirrhosis have been found in three

genes, patatin-like phospholipase domain-containing 3 (PNPLA3),

TABLE 342-1 Factors for Progression of Alcohol-Associated Liver

Disease

• Alcohol dose (>1 drink per day for women, >2 drinks per day for men)

• Drinking pattern (drinking without meal, binge drinking)

• Genetic factors, especially PNPLA3 polymorphism

• Female gender

• Smoking

• Increased body mass index and chronic liver diseases

• Intestinal microbiota

2618 PART 10 Disorders of the Gastrointestinal System

membrane bound O-acyltransferase domain-containing 7 (MBOAT7),

and transmembrane 6 superfamily member 2 (TM6SF2), although

the molecular mechanism is not well understood. A subset of patients

with alcohol use disorder develop changes in the gut microbiome and

increased intestinal permeability resulting in activation of hepatic

inflammation, hepatocyte death, and activation of fibrotic pathways.

Ongoing fibrosis due to continued alcohol consumption can result in

the development of cirrhosis with portal hypertension (Chap. 344).

■ CLINICAL FEATURES

The development of alcohol-associated steatosis, steatohepatitis, and

cirrhosis is most often clinically silent. Symptoms arise once the patient

with alcohol-associated liver cirrhosis decompensates or develops

alcoholic hepatitis (Table 342-2). Patients with alcoholic hepatitis have

been drinking heavily for typically >5 years and until at least 8 weeks

before onset of symptoms. They present with rapid onset of jaundice

(serum bilirubin >3 mg/dL), often accompanied by fever, malaise,

tender hepatomegaly, and clinical signs of hepatic decompensation,

such as ascites, bacterial infection, variceal bleeding, and hepatic

encephalopathy. Infections occur in 12–26% of patients with severe

alcoholic hepatitis at the time of admission. Alcoholic hepatitis is often

accompanied by systemic inflammatory response syndrome (SIRS) and

acute kidney injury (AKI) secondary to hepatorenal syndrome.

■ LABORATORY FINDINGS

Patients with simple hepatic steatosis can present with normal liver

function tests. Steatohepatitis is characterized by elevated levels of

aspartate aminotransferase (AST) and γ-glutamyl transferase (GGT).

Characteristic laboratory parameters for ALD include a ratio of AST

to alanine aminotransferase (ALT) of >1, and serum AST is rarely

>300 IU/L. Serum bilirubin and international normalized ratio (INR)

are typically normal. Elevated bilirubin and INR and low serum albumin and platelet count are common laboratory finings in patients with

cirrhosis. Patients with alcoholic hepatitis have AST and ALT elevations that do not exceed 400 IU/L, with AST/ALT ratio of >1.5 and

serum bilirubin >3 mg/dL.

■ DIAGNOSIS

The Alcohol Use Disorders Inventory Test (AUDIT) is a validated tool

for identifying patients with alcohol use disorder (Chap. 453). Diagnosis of ALD requires exclusion of other liver diseases in heavy drinkers.

Alcohol-associated steatosis can be diagnosed by simple ultrasound,

magnetic resonance imaging (MRI), or computed tomography (CT).

Noninvasive quantification of hepatic fat can be achieved with the

ultrasound technique of controlled attenuation parameter (CAP) or

with magnetic resonance proton density fat fraction (MR-PDFF). Liver

biopsy is rarely indicated for diagnosing alcohol-associated hepatic

steatosis or steatohepatitis. Liver biopsy typically shows hepatocytes

TABLE 342-2 Symptoms and Signs Associated with Alcohol-Associated

Cirrhosis and Alcoholic Hepatitis

• Tiredness

• Malnutrition and sarcopenia

• Abdomen: abdominal discomfort, hepatomegaly, splenomegaly, caput

medusae, ascites with weight gain, abdominal pain, and shortness of breath

• Skin: spider angioma, palmar erythema, jaundice, ecchymoses

• Eyes: icteric sclerae

• Hands: Dupuytren contracture

• Face: rhinophyma

• Reproductive system: gynecomastia, gonadal atrophy, loss of libido,

amenorrhea

• Neurologic:

• Peripheral neuropathy

• Alcohol withdrawal: tachycardia, agitation, tremor, seizures, delirium

• Hepatic encephalopathy: asterixis (flapping tremor), forgetfulness, inversion

of sleep/wake pattern, altered consciousness, confusion, lethargy, coma

• Wernicke-Korsakoff syndrome

with large lipid droplets (macrovesicular steatosis) around pericentral

veins (zone 3). Morphologic features of alcohol-associated steatohepatitis include hepatocyte injury and ballooning with Mallory-Denk

bodies, necrosis, and lobular inflammation with mononuclear and

neutrophilic granulocytes.

Progression of alcohol-associated steatohepatitis to fibrosis can be

diagnosed using liver stiffness measurement by techniques such as

transient elastography (e.g., FibroScan). Liver stiffness <6 kPa indicates

normal liver, whereas cutoffs for each stage of alcohol-associated liver

fibrosis have been validated (>8 kPa indicates ≥F3 advanced fibrosis;

>12.5 kPa indicates F4 cirrhosis). Histology shows initially perivenular fibrosis with subsequent extension of collagen fibers into hepatic

lobules, described as septal fibrosis. Patients with cirrhosis show liver

nodularity on imaging with ultrasound, MRI, or CT scan. Radiologic

signs of portal hypertension include ascites, splenomegaly, and portalsystemic collateral vessels. Prognosis and risk of mortality are assessed

using Child-Pugh-Turcotte (CPT) or Model for End-Stage Liver Disease (MELD; or sodium-MELD) scores (Chap. 344).

In patients presenting with features suggestive of alcoholic hepatitis,

imaging is obtained to exclude biliary obstruction and hepatocellular

carcinoma (HCC). In addition, other causes of liver disease such as

viral hepatitis, Wilson’s disease, and severe autoimmune liver disease

should be ruled out. Histology shows macrovesicular steatosis, hepatocyte ballooning with Mallory-Denk bodies, megamitochondria,

neutrophil infiltration, bilirubinostasis, and chicken wire fibrosis. The

majority of patients with alcoholic hepatitis have underlying cirrhosis

(80%) (Chap. 344), and 10–20% of patients with a clinical diagnosis of

alcoholic hepatitis will have other liver diseases on biopsy. Therefore, in

the presence of potential confounding factors, including possible ischemic hepatitis (in the setting of, e.g., hypotension, massive gastrointestinal bleeding, recent cocaine use, septic shock), drug-induced liver

injury (DILI), autoimmune liver disease, uncertain alcohol use assessment, or atypical laboratory tests (AST <50 IU/L or >400 IU/L, AST/ALT

ratio <1.5), a transjugular liver biopsy is recommended to confirm the

diagnosis of alcoholic hepatitis. Infections need to be assessed routinely

with chest x-ray and blood, urine, and ascites cultures in patients presenting with alcoholic hepatitis.

TREATMENT

Alcohol-Associated Liver Disease (Fig. 342-1)

To date, the most effective therapy to reduce the progression of and

reverse ALD is prolonged alcohol abstinence. In particular, alcoholassociated hepatic steatosis and steatohepatitis are reversible with

cessation of alcohol consumption. Thus, treatment of the underlying alcohol use disorder is an integral part for therapy of ALD. There

are currently no approved drugs for treatment of alcohol-associated

steatosis and steatohepatitis with or without fibrosis.

Patients with alcohol-associated cirrhosis and ongoing alcohol

consumption are at risk for decompensation and development

of hepatic encephalopathy, ascites, variceal bleeding, hepatorenal

syndrome, and HCC (Chap. 344). Patients with cirrhosis should

undergo an upper gastrointestinal endoscopy to screen for varices.

HCC screening is recommended using ultrasonography every 6

months in patients with cirrhosis. Management of complications of

cirrhosis such as variceal bleeding, ascites, hepatic encephalopathy,

and HCC does not differ from patients with cirrhosis due to a different etiology (Chap. 344). Liver transplantation for patients with

alcohol-associated decompensated cirrhosis or HCC is a definitive

therapy and is currently the leading indication for liver transplantation in the United States. Liver transplantation evaluation should

be taken into consideration for patients with end-stage liver disease

(Chap. 345).

In patients diagnosed with alcoholic hepatitis, short-term mortality can be predicted using the Maddrey discriminant function

(MDF; calculated as 4.6 × [the prolongation of the prothrombin

time above control {seconds}] + serum bilirubin [mg/dL]), MELD

score (Chap. 344), or age-bilirubin-INR-creatinine (ABIC) score.

2619 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis CHAPTER 343

Patients with MDF <32 or MELD ≤20 are defined as having moderate alcoholic hepatitis. Currently, patients with moderate alcoholic

hepatitis are treated under a multidisciplinary team including an

alcohol use disorder specialist, dietitian for nutritional supplementation for patients with markedly reduced intake, and hepatologist

for managing liver disease complications. Enteral nutrition with a

goal of >21 kcal/kg and supplementation of micronutrients (in particular zinc) and vitamin supplementation (in particular vitamin B1

)

are recommended for patients with alcoholic hepatitis. Intravenous

albumin is preferred for volume expansion. MDF ≥32 or MELD

>20 identifies patients with severe alcoholic hepatitis and high

short-term mortality who will have a survival benefit with glucocorticoid treatment. Contraindications for glucocorticoid treatment

include uncontrolled infections or sepsis, AKI and hepatorenal syndrome, uncontrolled upper gastrointestinal bleeding, concomitant

diseases (including viral hepatitis, HCC, pancreatitis, DILI, active

tuberculosis, and HIV), multiorgan failure, and shock. Glucocorticoids can be used once infection, sepsis, and gastrointestinal bleeding are adequately controlled. Glucocorticoid use reduces the risk

of death in patients with severe alcoholic hepatitis within 28 days

of treatment but not in the following 6 months. Oral prednisolone,

40 mg/d for a total duration of 4 weeks, is preferred. For patients

unable to take oral medications, methylprednisolone, 32 mg/d IV,

is used. The combination of glucocorticoids with N-acetylcysteine

infusion might add short-term survival benefit at 1 month. Failure

of improvement of Lille score (≥0.45) after 7 days of glucocorticoid

treatment will determine patients with severe alcoholic hepatitis

who will unlikely benefit from continued treatment with glucocorticoids. Glucocorticoids should be stopped in nonresponders, and

early liver transplantation should be considered. Although shortterm prognosis is dependent on liver disease severity at the time

of presentation, long-term prognosis (>1 year) largely depends on

Alcoholic Hepatitis (AH)

Clinical diagnosis with

laboratory findings

Confounding

diagnostic

factors

TJ liver biopsy

7 days

Lille score <0.45

Continue prednisolone

for 28 days total

Stop prednisolone

Lille score ≥0.45

Severe AH

MDF ≥32

or MELD >20

Moderate AH

MDF <32

or MELD ≤20

- Alcohol

 abstinence

- Nutritional

 support

- If eligible, early liver transplantation (LT)

- If not eligible for LT: Supportive/palliative care

Contraindications

for corticosteroids

Oral prednisolone 40 mg/d

(unable to take oral medications:

methylprednisolone 32 mg/d IV)

FIGURE 342-1 Treatment algorithm for alcoholic hepatitis. In patients with a

clinical diagnosis of alcoholic hepatitis, confounding factors (see text) need to

be ruled out, if necessary, by transjugular (TJ) liver biopsy. Patients with severe

alcoholic hepatitis (AH), defined as Maddrey discriminant function (MDF) ≥32 or

Model for End-Stage Liver Disease (MELD) score >20, without contraindications

for glucocorticoids (see text) are candidates for such treatment. Nonresponders or

patients with contraindications for treatment should be considered for early liver

transplantation (LT) or supportive or palliative care, as clinically appropriate.

alcohol abstinence and underlying cirrhosis. Patients with severe

alcoholic hepatitis that is nonresponsive to medical therapy have

high 30-day mortality and are therefore unable to fulfill a minimum

of 6 months of alcohol abstinence, which is required in many centers for liver transplantation evaluation. Early liver transplantation

can be successfully performed in highly selected patients with an

excellent psychosocial profile (Chap. 345). If a nonresponder is

ineligible for early liver transplantation, supportive or palliative

care should be considered for patients with multiple-organ failure.

■ FURTHER READING

Crabb DW et al: Standard definitions and common data elements for

clinical trials in patients with alcoholic hepatitis: Recommendation

from the NIAAA Alcoholic Hepatitis Consortia. Gastroenterology

150:785, 2016.

Crabb DW et al: Diagnosis and treatment of alcohol-associated liver

diseases: 2019 practice guidance from the American Association for

the Study of Liver Diseases. Hepatology 71:306, 2020.

Louvet A et al: Corticosteroids reduce risk of death within 28 days for

patients with severe alcoholic hepatitis, compared with pentoxifylline

or placebo-a meta-analysis of individual data from controlled trials.

Gastroenterology 155:458, 2018.

Seitz HK et al: Alcoholic liver disease. Nat Rev Dis Primers 4:16, 2018.

Singal AK et al: ACG clinical guideline: Alcoholic liver disease. Am J

Gastroenterol 113:175, 2018.

343 Nonalcoholic Fatty Liver

Diseases and Nonalcoholic

Steatohepatitis

Manal F. Abdelmalek, Anna Mae Diehl

■ INCIDENCE, PREVALENCE,

AND NATURAL HISTORY

Nonalcoholic fatty liver disease (NAFLD) is the most common cause

of chronic liver disease in the United States, as well as worldwide. The

global prevalence of NAFLD is estimated to be as high as one billion.

In the United States, NAFLD is estimated to effect between 80 and

100 million individuals. NAFLD is strongly associated with insulin

resistance, overweight/obesity, and metabolic syndrome. However, it

can also occur in lean individuals and is particularly common in those

with a paucity of adipose depots (i.e., lipodystrophy). Ethnic/racial

factors also appear to influence liver fat accumulation; the documented

prevalence of NAFLD is lowest in African Americans (~25%), highest in Americans of Hispanic ancestry (~50%), and intermediate in

American whites (~33%).

NAFLD encompasses a spectrum of liver pathology with different

clinical prognoses (Fig. 343-1). The simple accumulation of triglyceride within hepatocytes (hepatic steatosis) is on the most clinically

benign extreme of the spectrum. On the opposite, most clinically

ominous extreme, are cirrhosis (Chap. 344) and primary liver cancer (Chap. 82). The risk of developing cirrhosis is extremely low in

individuals with isolated steatosis (nonalcoholic fatty liver [NAFL])

but increases as steatosis becomes complicated by liver-cell injury and

death and the accumulation of inflammatory cells (i.e., nonalcoholic

steatohepatitis [NASH]). At least a quarter of adults with NAFLD are

presumed to have NASH. NASH itself is also a heterogeneous condition; it can improve to steatosis or normal histology, remain relatively

stable for years, or cause progressive accumulation of fibrous scar that

eventuates in cirrhosis (stage 4 fibrosis). Advanced hepatic fibrosis is

the primary predictor of eventual liver-related morbidity and mortality

2620 PART 10 Disorders of the Gastrointestinal System

in NAFLD. Once NAFLD-related cirrhosis develops, the annual incidence of primary liver cancer can be as high as 1–2% per year.

Abdominal imaging is not able to determine which individuals

with NAFLD have associated liver-cell death and inflammation (i.e.,

NASH), and specific blood tests to diagnose NASH are not yet available. However, population-based studies that have used elevated serum

alanine aminotransferase (ALT) as a marker of liver injury indicate

that ~6–8% of American adults have serum ALT elevations that cannot

be explained by excessive alcohol consumption, other known causes

of fatty liver disease (Table 343-1), viral hepatitis, or drug-induced or

congenital liver diseases. Because the prevalence of such “cryptogenic”

Dynamic process

Healthy liver

A B

Steatosis (NAFL) Steatohepatitis (NASH) Cirrhosis

C D

FIGURE 343-1 Histopathologic spectrum of nonalcoholic fatty liver disease (NAFLD). NAFLD encompasses a dynamic spectrum of liver pathology. A. Healthy liver.

B. Simple steatosis (nonalcoholic fatty liver [NAFL]); arrow shows fatty hepatocyte. C. Nonalcoholic steatohepatitis (NASH); ballooned hepatocyte (arrow) near central vein

with adjacent blue-stained pericellular fibrosis (arrowheads). D. Cirrhosis with blue-stained bridging fibrosis surrounding micronodules of liver parenchyma.

ALT elevations increases with body mass index, it is presumed that

they are due to NASH. Hence, at any given point in time, NASH is

present in ~25% of individuals who have NAFLD (i.e., ~6–8% of the

general U.S. adult population has NASH). Smaller cross-sectional

studies in which liver biopsies have been performed on NASH patients

at tertiary referral centers consistently demonstrate advanced fibrosis

or cirrhosis in ~25% of those cohorts. By extrapolation, therefore,

TABLE 343-1 Alternative Causes of Hepatic Steatosis

• Alcoholic liver disease

• Hepatitis C (particularly genotype 3)

• Inborn errors of metabolism

• Abetalipoproteinemia

• Cholesterol ester storage disease

• Galactosemia

• Glycogen storage disease

• Hereditary fructose intolerance

• Homocystinuria

• Systemic carnitine deficiency

• Tyrosinemia

• Weber-Christian syndrome

• Wilson’s disease

• Wolman’s disease

• Medications (see Table 343-2)

• Miscellaneous

• Industrial exposure to petrochemical

• Inflammatory bowel disease

• Lipodystrophy

• Bacterial overgrowth

• Starvation

• Parenteral nutrition

• Surgical procedures

• Bilopancreatic diversion

• Extensive small-bowel resection

• Gastric bypass

• Jejunoileal bypass

• Reye’s syndrome

• Acute fatty liver of pregnancy

• HELLP syndrome (hemolytic anemia, elevated liver enzymes, low platelet

count)

TABLE 343-2 Medications Associated with Hepatic Steatosis

• Cytotoxic and cytostatic drugs

• 5-Fluorouraci

• l-Asparaginase

• Azacitidine

• Azaserine

• Bleomycin

• Methotrexate

• Puromycin

• Tetracycline

• Doxycycline

• Metals

• Antimony

• Barium salts

• Chromates

• Phosphorus

• Rare earths of low atomic number

• Thallium compounds

• Uranium compounds

• Other drugs and toxins

• Amiodarone

• 4,4’-Diethylaminoethoxyhexesterol

• Ethionine

• Ethyl bromide

• Estrogens

• Glucocorticoids

• Highly active antiretroviral therapy

• Hydralazine

• Hypoglycin

• Orotate

• Perhexiline maleate

• Safrole

• Tamoxifen

• Valproic acid

• Acetylsalicylic acid intoxication

• Apo-B inhibitors: Mipomersen and lomitapide

2621 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis CHAPTER 343

cirrhosis develops in ~6% of individuals with NAFLD (i.e., in ~1.5–2%

of the general U.S. population). The risk for advanced liver fibrosis is

highest in individuals with NASH who are aged >45–50 years and overweight/obese or afflicted with type 2 diabetes. Having a first-degree

relative with cryptogenic hepatitis or cirrhosis also increases the risk

for developing cirrhosis.

Heritable factors clearly impact susceptibility to hepatic steatosis,

NASH, liver fibrosis, and liver cancer. Genetic variants on or near

TM6SF2 or MBOAT7 (genes involved in lipid homeostasis) and

palatin-like phospholipase domain-containing 3 gene (PNPLA3, a gene

that encodes an enzyme involved in intracellular trafficking of lipids)

may increase the heritability of NAFLD. A recent meta-analysis showed

that PNPLA3 exerts a strong influence not only on hepatic fat accumulation but also on the severity of NASH and liver fibrosis. Indeed,

recent twin studies suggest that inheritance accounts for about half the

risk for developing cirrhosis. Epigenetic factors (i.e., heritable traits

that do not result from direct changes in DNA) may also influence

NAFLD pathogenesis and/or progression based on evidence that intrauterine exposures influence susceptibility to obesity and the metabolic

syndrome in adolescence. Studies of families with adult-onset obesity

have identified genome-wide epigenetic alterations that dysregulate

metabolic pathways controlling adiposity, insulin sensitivity, and tissue

generation or regeneration. Whether such epigenetic mechanisms

influence susceptibility to NASH and cirrhosis is being investigated.

NAFLD is currently the leading indication for liver transplantation

in the United States. Similar to cirrhosis caused by other liver diseases,

cirrhosis caused by NAFLD increases the risk for primary liver cancer.

Both hepatocellular carcinoma and intrahepatic cholangiocarcinoma

(ICC) have also been reported to occur in NAFLD patients without

cirrhosis, suggesting that NAFLD per se may be a premalignant condition. NAFLD, NASH, and NAFLD-related cirrhosis are not limited to

adults. All have been well documented in children. As in adults, obesity

and insulin resistance are the main risk factors for pediatric NAFLD.

Thus, the rising incidence and prevalence of childhood obesity suggests that NAFLD will be a major contributor to society’s burden of

liver disease in the future.

■ PATHOGENESIS

The mechanisms underlying the pathogenesis and progression of

NAFLD are not entirely clear. The best-understood mechanisms

pertain to hepatic steatosis. This is proven to result when hepatocyte

mechanisms for triglyceride synthesis (e.g., lipid uptake and de novo

lipogenesis) overwhelm mechanisms for triglyceride disposal (e.g.,

degradative metabolism and lipoprotein export), leading to accumulation of fat (i.e., triglyceride) within hepatocytes. Obesity stimulates hepatocyte triglyceride accumulation by altering the intestinal

microbiota to enhance both energy harvest from dietary sources and

intestinal permeability. Reduced intestinal barrier function increases

hepatic exposure to gut-derived products, which stimulate liver cells

to generate inflammatory mediators that inhibit insulin actions. Obese

adipose depots also produce excessive soluble factors (adipokines) that

inhibit tissue insulin sensitivity. Insulin resistance promotes hyperglycemia, which drives the pancreas to produce more insulin to maintain

glucose homeostasis. However, hyperinsulinemia also promotes lipid

uptake, fat synthesis, and fat storage. The net result is hepatic triglyceride accumulation (i.e., steatosis).

Triglyceride per se is not hepatotoxic. However, its precursors (e.g.,

fatty acids and diacylglycerols) and metabolic by-products (e.g., reactive oxygen species) may damage hepatocytes, leading to hepatocyte

lipotoxicity. Lipotoxicity also triggers the generation of other factors

(e.g., inflammatory cytokines, hormonal mediators) that deregulate

systems that normally maintain hepatocyte viability. The net result is

increased hepatocyte death. Dying hepatocytes, in turn, release various factors that trigger wound healing responses that aim to replace

(regenerate) lost hepatocytes. Such repair involves transient expansion

of other cell types, such as myofibroblasts and progenitor cells, that

make and degrade matrix, remodel the vasculature, and generate

replacement hepatocytes, as well as the recruitment of immune cells

that release factors that modulate liver injury and repair. NASH is

the morphologic manifestation of lipotoxicity and resultant wound

healing responses. Because the severity and duration of lipotoxic liver

injury dictate the intensity and duration of repair, the histologic features and outcomes of NASH are variable. Cirrhosis and liver cancer

are potential outcomes of chronic NASH. Cirrhosis results from futile

repair, i.e., progressive accumulation of wound healing cells, fibrous

matrix, and abnormal vasculature (scarring), rather than efficient

reconstruction/regeneration of healthy hepatic parenchyma. Primary

liver cancers develop when malignantly transformed liver cells escape

mechanisms that normally control regenerative growth. The mechanisms responsible for futile repair (cirrhosis) and liver carcinogenesis

are not well understood. Because normal liver regeneration is a very

complex process, there are multiple opportunities for deregulation

and, thus, pathogenic heterogeneity. To date, this heterogeneity has

confounded development of both diagnostic tests and treatments for

defective/deregulated liver repair (i.e., cirrhosis and cancer). Hence,

current strategies focus on circumventing misrepair by preventing and/

or reducing lipotoxic liver injury.

■ DIAGNOSIS

Diagnosing NAFLD requires demonstration of increased liver fat in

the absence of hazardous levels of alcohol consumption. Thresholds

for potentially dangerous alcohol ingestion have been set at more than

one drink per day in women and two drinks per day in men based on

epidemiologic evidence that the prevalence of serum aminotransferase

elevations increases when alcohol consumption habitually exceeds

these levels. In those studies, one drink was defined as having 10 g

of ethanol and, thus, is equivalent to one can of beer, 4 oz of wine,

or 1.5 oz (one shot) of distilled spirits. Other causes of liver fat accumulation (particularly exposure to certain drugs; Table 343-2) and

liver injury (e.g., viral hepatitis, autoimmune liver disease, iron or copper

overload, α1

 antitrypsin deficiency) must also be excluded. Thus, establishing the diagnosis of NAFLD does not require invasive testing: it can be

accomplished by history and physical examination, liver imaging (ultrasound is an acceptable first-line test; computed tomography [CT] or magnetic resonance imaging [MRI] enhances sensitivity for liver fat detection

but adds expense), and blood tests to exclude other liver diseases.

It is important to emphasize that, in individuals with NAFLD, the

liver may not be enlarged and serum aminotransferases and liver

function tests (e.g., bilirubin, albumin, prothrombin time) may be

completely normal. Because there is yet no one specific blood test for

NAFLD, confidence in the diagnosis of NAFLD is increased by identification of NAFLD risk factors. The latter include increased body mass

index, insulin resistance/type 2 diabetes mellitus, and other parameters

indicative of the metabolic syndrome (e.g., systemic hypertension,

dyslipidemia, hyperuricemia/gout, cardiovascular disease; Chap. 408)

in the patient or family members. Individuals who have, or have had,

pituitary or hypothalamic neoplasms and women with polycystic ovary

syndrome are also at increased risk for NAFLD. Hypothyroidism and

obstructive sleep apnea may also increase NAFLD, presumably by promoting obesity and/or exacerbating the metabolic syndrome.

Establishing the severity of NAFLD-related liver injury and related

scarring (i.e., staging NAFLD) is more difficult than simply diagnosing

NAFLD. Staging is critically important, however, because it is necessary

to define prognosis and thereby determine treatment recommendations. The goal of staging is to distinguish patients with NASH from

those with simple steatosis and to identify which of the NASH patients

have advanced fibrosis. The 10-year probability of developing liverrelated morbidity or mortality in steatosis is negligible, and hence, this

subgroup of NAFLD patients tends to be managed conservatively (see

below). In contrast, more intensive follow-up and therapy are justified

in NASH patients, and the subgroup with advanced fibrosis merits the

most intensive scrutiny and intervention because their 10-year risk of

liver-related morbidity and mortality is clearly increased.

Staging approaches can be separated into noninvasive testing

(i.e., blood testing, physical examination, and imaging) and invasive

approaches (i.e., liver biopsy). Blood test evidence of hepatic dysfunction (e.g., hyperbilirubinemia, hypoalbuminemia, prothrombin time

prolongation) or portal hypertension (e.g., thrombocytopenia) and

2622 PART 10 Disorders of the Gastrointestinal System

stigmata of portal hypertension on physical examination (e.g., spider

angiomata, palmar erythema, splenomegaly, ascites, clubbing, encephalopathy) suggest a diagnosis of advanced NAFLD. Liver biopsy has

been the gold standard for establishing the severity of liver injury and

fibrosis because it is both more sensitive and more specific than these

other tests for establishing NAFLD severity. Further, although invasive,

liver biopsy is seldom complicated by serious adverse sequelae such as

significant bleeding, pain, or inadvertent puncture of other organs and

thus is relatively safe. However, biopsy suffers from potential sampling

error unless tissue cores of 2 cm or longer are acquired. Also, examination of tissue at a single point in time is not reliable for determining

whether the pathologic processes are progressing or regressing. The

risk of serial liver biopsies within short time intervals is generally

deemed as unacceptable outside of research studies. These limitations of liver biopsy have stimulated efforts to develop noninvasive

approaches to stage NAFLD.

As is true for many other types of chronic liver disease, in NAFLD,

the levels of serum aminotransferases (aspartate aminotransferase

[AST] and ALT) do not reliably reflect the severity of liver cell injury,

extent of liver-cell death, or related liver inflammation and fibrosis.

Thus, they are imperfect for determining which individuals with

NAFLD have NASH. This has prompted efforts to identify superior

markers of NASH and, particularly, liver fibrosis, because fibrosis stage

predicts eventual liver outcomes and mortality in NASH. Algorithms

that combine various laboratory tests (e.g., Enhanced Liver Fibrosis

[ELF] score, BARD score, AST to Platelet Ratio Index [APRI] score,

NAFLD fibrosis score, and Fibrosis-4 [FIB-4] score) are somewhat

helpful in separating NASH patients with advanced versus mild liver

fibrosis. The NAFLD fibrosis score (NFS) and FIB-4 score, two of

the most commonly employed noninvasive tests to assess severity of

hepatic fibrosis, can be calculated from a few readily available clinical variables (age, body mass index, glucose, platelet count, albumin,

AST, ALT) using published formulas that are readily accessed via an

online calculator. Both scores are helpful for gauging the severity of

NASH and liver fibrosis. Combining these tests with new imaging

approaches that permit noninvasive quantification of liver fat (e.g.,

MRI using proton density fat fraction [MRI-PDFF]) and liver stiffness,

a surrogate marker of liver fibrosis (e.g., magnetic resonance elastography [MRE], and transient elastography [FibroScan]), improves their

predictive power (Chap. 337). Transient elastography in particular

has become widely available and is relatively inexpensive. It is most

useful for excluding advanced liver fibrosis as cirrhosis is extremely

unlikely when the liver stiffness score is low. However, higher stiffness

scores must be interpreted with caution since several factors (obesity,

nonfasting state, hepatic inflammation, iron overload, and/or hepatic

congestion) decrease the specificity of the test. Increasingly, these new

serologic and imaging tools are being used serially or in combination

to monitor fibrosis progression and regression in NAFLD patients. As

a result, liver biopsy staging is becoming restricted to patients who

cannot be stratified reliably using these noninvasive assessments. Indeterminant or discordant results of noninvasive testing should prompt

referral to a liver specialist and consideration of liver biopsy.

■ CLINICAL FEATURES OF NAFLD

Most subjects with NAFLD are asymptomatic. The diagnosis is often

made when abnormal liver aminotransferases or features of fatty liver

are noted during an evaluation performed for other reasons. NAFLD

may also be diagnosed during the workup of vague right upper

quadrant abdominal pain, hepatomegaly, or an abnormal-appearing

liver at time of abdominal surgery. Obesity is present in 50–90% of subjects. Most patients with NAFLD also have other features of the metabolic syndrome (Chap. 408). Some have subtle stigmata of chronic liver

disease, such as spider angiomata, palmer erythema, or splenomegaly.

In a small minority of patients with advanced NAFLD, complications

of end-stage liver disease (e.g., jaundice, features of portal hypertension

such as ascites or variceal hemorrhage) may be the initial findings.

The association of NAFLD with obesity, diabetes, hypertriglyceridemia, hypertension, and cardiovascular disease is well known. Other

associations include chronic fatigue, mood alterations, obstructive

sleep apnea, thyroid dysfunction, polycystic ovary syndrome, and

chronic pain syndrome. NAFLD is an independent risk factor for metabolic syndrome (Chap. 408). Longitudinal studies suggest that patients

with NASH are at two- to threefold increased risk for the development

of metabolic syndrome. Similarly, studies have shown that patients

with NASH have a higher risk for the development of hypertension and

diabetes mellitus. The presence of NAFLD is also independently associated with endothelial dysfunction, increased carotid intimal thickness,

and the number of plaques in carotid and coronary arteries. Such data

indicate that NAFLD has many deleterious effects on health in general.

■ TREATMENT OF NAFLD

Treatment of NAFLD can be divided into three components: (1) specific

therapy of NAFLD-related liver disease; (2) treatment of NAFLDassociated comorbidities; and (3) treatment of the complications of

advanced NAFLD. The subsequent discussion focuses on specific

therapies for NAFLD, with some mention of their impact on major

NAFLD comorbidities (insulin resistance/diabetes, obesity, and dyslipidemia). Treatment of the complications of advanced NAFLD involves

management of the complications of cirrhosis and portal hypertension, including primary liver cancers. Approaches to accomplish these

objectives are similar to those used in other chronic liver diseases and

are covered elsewhere in the textbook (Chaps. 344 and 82).

At present, there are no U.S. Food and Drug Administration (FDA)–

approved therapies for the treatment of NAFLD. Thus, the current

approach to NAFLD management focuses on treatment to improve

the risk factors for NASH (i.e., obesity, insulin resistance, metabolic

syndrome, dyslipidemia). Based on our understanding of the natural history of NAFLD, only patients with NASH or hepatic fibrosis

are considered currently for targeted pharmacologic therapies. This

approach may change as our understanding of disease pathophysiology

improves and potential targets of therapy evolve.

Diet and Exercise Lifestyle changes and dietary modifications

that result in weight loss and/or improve insulin sensitivity are the primary treatments for NAFLD. Many studies indicate that loss of 3–5%

of body weight improves steatosis and that greater weight loss (i.e.,

≥7–10%) improves steatohepatitis and hepatic fibrosis. The benefits

of modifying dietary macronutrient contents (e.g., low-carbohydrate

vs low-fat diets, saturated vs unsaturated fat diets) generally parallel

changes in calorie consumption, suggesting that diet modifications

are mainly beneficial because they reduce energy intake and improve

obesity. However, a Mediterranean-type diet has been reported to

improve NASH and liver fibrosis independently of weight loss. Excluding foods and beverages high in added fructose and increasing coffee

consumption are also recommended because high-fructose diets have

been shown to exacerbate hepatic steatosis, steatohepatitis, and fibrosis, and consuming two or more cups of coffee per day is associated

with reduced risk of liver fibrosis. Changes in diet composition particularly merit consideration in lean individuals with NAFLD, although

available data are insufficient to determine if this improves their liver

histology. Modifying lifestyle to increase physical activity (i.e., energy

expenditure) complements dietary caloric restriction and, thus, expedites weight loss. Exercise also improves muscle insulin sensitivity,

which improves the metabolic syndrome independent of weight loss.

Both aerobic exercise and resistance training effectively reduce liver

fat. At least 30 min of moderate-intensity aerobic exercise or resistance

training five times per week is recommended. The choice of training

should be tailored to patients’ preferences and functional capacity to

enable long-term maintenance. Any activity is better than remaining

sedentary. Unfortunately, most NAFLD patients cannot sustain longterm compliance with diet and lifestyle modifications and, thus, fail

to maintain a healthier weight. Although pharmacologic therapies to

facilitate weight loss, such as orlistat, topiramate, phentermine, and

GLP-1 receptor agonists, are available, their role in the treatment of

NAFLD remains experimental.

Pharmacologic Therapies Several drug therapies have been

tried in both research and clinical settings. There are currently no

FDA-approved drugs for the treatment of NAFLD. Hence, at present,

2623 Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis CHAPTER 343

NAFLD patients without NASH or fibrosis should receive only counseling for healthy diet and physical activity. Consideration of additional

specific pharmacotherapy for liver disease is restricted to NAFLD

patients with more serious liver damage (i.e., NASH or liver fibrosis).

A number of large clinical trials designed to identify effective and safe

treatments for these conditions are in progress. Because NAFLD is

strongly associated with the metabolic syndrome and type 2 diabetes

(Chaps. 403 and 404), the efficacy of various insulin-sensitizing agents

has been examined. Metformin, an agent that mainly improves hepatic

insulin sensitivity, has been evaluated in several small, open-label

studies in adults and a recent larger, prospectively randomized trial

in children (dubbed the TONIC study). Although several of the adult

NASH studies suggested improvements in aminotransferases and, less

consistently, liver histology, metformin did not improve liver histology

in the TONIC study of children with NASH. Thus, it is not currently

recommended as a treatment for NASH. Thiazolidinediones (pioglitazone and rosiglitazone), drugs known to improve systemic insulin resistance, have been studied in adults with NASH. Both agents reduced

aminotransferases and improved some of the histologic features of

NASH in small, uncontrolled studies. A large, randomized, placebocontrolled clinical trial sponsored by the National Institutes of Health,

the PIVENS Study (Pioglitazone vs Vitamin E vs Placebo for the

Treatment of 247 Nondiabetic Adults with NASH), demonstrated

that resolution of histologic NASH occurred more often in subjects

treated with pioglitazone (30 mg/d) than with placebo for 18 months

(47 vs 21%, p = .001). However, many subjects in the pioglitazone group

gained weight, and liver fibrosis did not improve. Five-year follow-up of

subjects who were treated with rosiglitazone for up to 2 years demonstrated that extending treatment and follow-up duration did not further

improve NASH or liver fibrosis, and rosiglitazone has been associated

with increased long-term risk for cardiovascular mortality. Pioglitazone

may be safer than rosiglitazone, however, because in a recent large

meta-analysis it was associated with reduced overall morality, myocardial infarction, and stroke. Caution is still warranted, however, because

long-term use of thiazolidinediones has been associated with weight

gain, increased risk for bladder cancer, and bone fractures in women.

Incretin mimetics, drugs that act on the pancreas to optimize insulin

and glucagon release, have improved liver enzyme elevations. A small

pilot trial of daily injections of liraglutide and phase 2 studies of semaglutide demonstrated remission of NASH without worsening liver fibrosis. Agents that improve hyperglycemia by blocking renal reabsorption

of glucose, sodium glucose cotransporter (SGLT2) inhibitors, have been

observed to improve serum liver enzymes in diabetic patients with

and are also under formal evaluation as treatments for NASH. Both

incretin mimetics and SGLT2 inhibitors can be used in NASH patients

with type 2 diabetes or obesity (conditions for which the drugs have

an FDA-registered indication for use); however, they are not currently

approved specifically for the treatment of NASH.

Antioxidants have also been evaluated for the treatment of NAFLD

because oxidant stress is thought to contribute to the pathogenesis of

NASH. Vitamin E, an inexpensive yet potent antioxidant, has been

examined in several small pediatric and adult studies with varying

results. In all of those studies, vitamin E was well tolerated, and most

studies showed modest improvements in aminotransferase levels,

radiographic features of hepatic steatosis, and/or histologic features of

NASH. Vitamin E (800 IU/d) was compared to placebo in the PIVENS

and TONIC studies. In PIVENS, vitamin E was the only agent that

achieved the predetermined primary endpoint (i.e., improvement

in steatohepatitis without worsening of fibrosis). This endpoint was

met in 43% of patients in the vitamin E group (p = .001 vs placebo),

34% in the pioglitazone group (p = .04 vs placebo), and 19% in the

placebo group. Vitamin E also improved NASH histology in pediatric

patients with NASH (TONIC trial). However, recent population-based

studies suggest that chronic vitamin E therapy may increase the risk

for cardiovascular mortality, hemorrhagic stroke, and prostate cancer.

Thus, vitamin E should only be considered as a first-line pharmacotherapy for nondiabetic, noncirrhotic NASH patients who are at low

risk for cardiovascular disease or prostate cancer. Further studies are

needed before firm recommendations can be made regarding the

risk-to-benefit ratio and long-term therapeutic efficacy of vitamin

E in NASH. Ursodeoxycholic acid (a bile acid that improves certain

cholestatic liver diseases) and betaine (a metabolite of choline that

raises S-adenosylmethionine [SAM] levels and decreases cellular

oxidative damage) offer no histologic benefit over placebo in patients

with NASH. Experimental evidence to support the use of omega-3 fatty

acids in NAFLD exists; however, a recent large, multicenter, placebocontrolled study failed to demonstrate a histologic benefit.

Many other pharmacotherapies that target dysregulated energy

homeostasis, lipotoxicity, cell death, and liver inflammation, processes

that are critically involved in the pathogenesis and/or progression of

NASH and liver fibrosis, are currently in clinical trials (e.g., probiotics,

farnesoid X receptor agonists, fibroblast growth factor agonists, antiapoptotic agents, anticytokine agents, dipeptidyl IV antagonists, PPAR

modulators, thyroid hormone receptor β-selective agonists, stearyl-CoA

desaturase-1 inhibitors, DGAT inhibitors, acyl-CoA carboxylase inhibitors, and direct modulators of liver fibrosis). Sufficient data do not yet

exist to justify their use as NASH treatments in clinical practice. Given

that liver disease outcomes in NASH patients are highly heterogeneous,

optimal treatment of NASH may need to be individualized by tailoring

therapy based on clinical or histologic phenotypes of NASH and/or

genetic susceptibility for disease progression.

Statins are an important class of agents to treat dyslipidemia and

decrease cardiovascular risk. There is no evidence to suggest that

statins cause liver failure in patients with any chronic liver disease,

including NAFLD. The incidence of liver enzyme elevations in NAFLD

patients taking statins is also no different than that of healthy controls

or patients with other chronic liver diseases. Moreover, several studies

have suggested that statins may improve aminotransferases and histology in patients with NASH. Yet there is continued reluctance to

use statins in patients with NAFLD. The lack of evidence that statins

harm the liver in NAFLD patients, combined with the increase risk for

cardiovascular morbidity and mortality in NAFLD patients, justifies

the use of statins to treat dyslipidemia in patients with NAFLD/NASH.

Bariatric Surgery Although interest in bariatric surgery as a

treatment for NAFLD exists, a recently published Cochrane review

concluded that lack of randomized clinical trials or adequate clinical

studies prevents definitive assessment of benefits and harms of bariatric surgery as a treatment for NASH. Most studies of bariatric surgery

have shown that bariatric surgery is generally safe in individuals with

well-compensated chronic liver disease and improves hepatic steatosis

and necroinflammation (i.e., features of NAFLD/NASH); however,

effects on hepatic fibrosis have been variable. Concern lingers because

some of the largest prospective studies suggest that hepatic fibrosis

might progress after bariatric surgery. Thus, the Cochrane review

deemed it premature to recommend bariatric surgery as a primary

treatment for NASH. This opinion was challenged by a recently study

that demonstrated that fibrosis stage had improved by 5 years after

surgery in about half the patients in one large bariatric surgery cohort.

However, most of those individuals had relatively mild fibrosis initially,

and thus, it is unclear if similar outcomes would occur in individuals

with more advanced liver disease. Indeed, there is general agreement that patients with NAFLD-related cirrhosis and, particularly,

those with portal hypertension should be excluded as candidates for

bariatric surgery. However, given growing evidence for the benefits of

bariatric surgery on metabolic syndrome complications in individuals

with refractory obesity, it is not contraindicated in otherwise eligible

patients with NAFLD or NASH.

Liver Transplantation Patients with NAFLD in whom end-stage

liver disease develops should be evaluated for liver transplantation

(Chap. 345). The outcomes of liver transplantation in well-selected

patients with NAFLD are generally good, but comorbid medical conditions associated with NAFLD, such as diabetes mellitus, obesity, and

cardiovascular disease, often limit transplant candidacy. NAFLD may

recur after liver transplantation. The risk factors for recurrent or de

novo NAFLD after liver transplantation are multifactorial and include

hypertriglyceridemia, obesity, diabetes mellitus, and immunosuppressive therapies, particularly glucocorticoids.

2624 PART 10 Disorders of the Gastrointestinal System

■ GLOBAL HEALTH CONSIDERATIONS

Obesity is an accelerating global disease. The worldwide prevalence

of obesity has more than doubled since 1980, and there are now >1

billion overweight adults, of whom at least 300 million are obese. In

the wake of the obesity epidemic follow numerous comorbidities,

including NAFLD. NAFLD is the most common liver disease identified

in Western countries and the fastest rising form of chronic liver disease

worldwide. The economic burden directly attributable to NAFLD is

already enormous (estimated direct medical costs of ~$103 billion/year

in the United States and €35 billion/year in the Europe-4 countries:

Germany, France, Italy, and United Kingdom) and predicted to increase

tenfold by the year 2025. Present understanding of NAFLD’s natural

history is based mainly on studies in whites who became overweight/

obese and developed the metabolic syndrome in adulthood. The

impact of the global childhood obesity epidemic on NAFLD pathogenesis/progression is unknown. Emerging evidence demonstrates that

advanced NAFLD, including cirrhosis and primary liver cancer, can

occur in children, prompting concerns that childhood-onset NAFLD

might follow a more aggressive course than typical adult-acquired

NAFLD. Some of the most populated parts of the world are in the

midst of industrial revolutions, and certain environmental pollutants

seem to exacerbate NAFLD. Some studies also suggest that the risk for

NASH and NAFLD-related cirrhosis may be higher in certain ethnic

groups such as Asians, Hispanics, and Native Americans, and lower in

others such as African Americans, compared with whites. Although

all of these variables confound efforts to predict the net impact of

this obesity-related liver disease on global health, it seems likely that

NAFLD will remain a major cause of chronic liver disease worldwide

for the foreseeable future.

■ FURTHER READING

Chalasani N et al: The diagnosis and management of nonalcoholic

fatty liver disease: Practice guidance from the American Association

for the Study of Liver Diseases. Hepatology 67:328, 2018.

Diehl AM, Day CSC: Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med 377:2063, 2017.

European Association for the Study of the Liver (EASL) et al:

EASL-EASD-EASO Clinical Practice Guidelines for the management

of non-alcoholic fatty liver disease. J Hepatol 64:1388, 2016.

Vos MB et al: NASPGHAN clinical practice guideline for the diagnosis

and treatment of nonalcoholic fatty liver disease in children: Recommendations from the Expert Committee on NAFLD (ECON) and the

North American Society of Pediatric Gastroenterology, Hepatology

and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr 64:319,

2017.

Cirrhosis is a condition that is defined histopathologically and has a

variety of clinical manifestations and complications, some of which

can be life-threatening. In the past, it has been thought that cirrhosis

was never reversible; however, it has become apparent that when the

underlying insult that has caused the cirrhosis has been removed, there

can be reversal of fibrosis. This is most apparent with the successful

treatment of chronic hepatitis C; however, reversal of fibrosis is also

seen in patients with hemochromatosis who have been successfully

treated and in patients with alcohol associate liver disease who have

discontinued alcohol use.

Regardless of the cause of cirrhosis, the pathologic features consist

of the development of fibrosis to the point that there is architectural

344 Cirrhosis and Its

Complications

Alex S. Befeler, Bruce R. Bacon

TABLE 344-1 Causes of Cirrhosis

Alcohol Cardiac cirrhosis

Chronic viral hepatitis Inherited metabolic liver disease

Hepatitis B Hemochromatosis

Hepatitis C Wilson’s disease

Autoimmune hepatitis α1

 Antitrypsin deficiency

Nonalcoholic steatohepatitis Cystic fibrosis

Biliary cirrhosis Cryptogenic cirrhosis

Primary biliary cholangitis

Primary sclerosing cholangitis

Autoimmune cholangiopathy

distortion with the formation of regenerative nodules. This results in a

decrease in hepatocellular mass, and thus function, and an alteration of

blood flow. The induction of fibrosis occurs with activation of hepatic

stellate cells, resulting in the formation of increased amounts of collagen and other components of the extracellular matrix.

Clinical features of cirrhosis are the result of pathologic changes

and mirror the severity of the liver disease. Most hepatic pathologists

provide an assessment of grading and staging when evaluating liver

biopsy samples. These grading and staging schemes vary between

disease states and have been developed for most conditions, including

chronic viral hepatitis, nonalcoholic fatty liver disease, and primary

biliary cholangitis. Advanced fibrosis usually includes bridging fibrosis

with nodularity designated as stage 3 and cirrhosis designated as stage 4.

Patients who have cirrhosis have varying degrees of liver function, and

clinicians need to differentiate between those who have stable, compensated cirrhosis and those who have decompensated cirrhosis. Patients

who have developed ascites, hepatic encephalopathy, or variceal bleeding are classified as decompensated. They should be considered for

liver transplantation, particularly if the decompensations are poorly

controlled. Many of the complications of cirrhosis will require specific

therapy. Portal hypertension is a significant complicating feature of

decompensated cirrhosis and is responsible for the development of

ascites and bleeding from esophagogastric varices, two complications

that signify decompensated cirrhosis. Loss of hepatocellular function

results in jaundice, coagulation disorders, and hypoalbuminemia and

contributes to the causes of portosystemic encephalopathy. The complications of cirrhosis are basically the same regardless of the etiology.

Nonetheless, it is useful to classify patients by the cause of their liver

disease (Table 344-1); patients can be divided into broad groups,

including those with alcohol-associated cirrhosis, cirrhosis due to

chronic viral hepatitis, biliary cirrhosis, nonalcoholic fatty liver disease,

and other, less common causes, such as cardiac cirrhosis, cryptogenic

cirrhosis, and other miscellaneous causes.

ALCOHOL-ASSOCIATED CIRRHOSIS

Excessive chronic alcohol use can cause several different types of

chronic liver disease, including alcohol-associated fatty liver, alcoholic hepatitis, and alcohol-associated cirrhosis. Furthermore, use of

excessive alcohol can contribute to liver damage in patients with other

liver diseases, such as hepatitis C, hemochromatosis, and fatty liver

disease related to obesity. Chronic alcohol use can produce fibrosis in

the absence of accompanying inflammation and/or necrosis. Fibrosis

can be centrilobular, pericellular, or periportal. When fibrosis reaches

a certain degree, there is disruption of the normal liver architecture

and replacement of liver cells by regenerative nodules. In alcoholassociated cirrhosis, the nodules are usually <3 mm in diameter; this

form of cirrhosis is referred to as micronodular. With cessation of alcohol use, larger nodules may form, resulting in a mixed micronodular

and macronodular cirrhosis.

Pathogenesis Alcohol is the most commonly used drug in the

United States, and >70% of adults drink alcohol each year. Twenty

percent have had a binge within the past month, and >7% of adults

regularly consume more than four or five drinks five or more times

a month. Unfortunately, >14 million adults in the United States meet

2625Cirrhosis and Its Complications CHAPTER 344

the diagnostic criteria for alcohol use disorder. In the United States,

chronic liver disease is the tenth most common cause of death in

adults, and alcohol-associated cirrhosis accounts for ~48% of deaths

due to cirrhosis.

Ethanol is mainly absorbed by the small intestine and, to a lesser

degree, through the stomach. Gastric alcohol dehydrogenase (ADH)

initiates alcohol metabolism. Three enzyme systems account for

metabolism of alcohol in the liver. These include cytosolic ADH, the

microsomal ethanol oxidizing system (MEOS) utilizing the inducible

cytochrome P450 CYP2E1, and peroxisomal catalase. Normally the

majority of ethanol oxidation occurs via ADH to form acetaldehyde,

which is a highly reactive molecule that may have multiple effects. The

MEOS pathway in chronic alcohol use causes induction of CYP2E1,

which leads to generation of reactive oxygen species and produces

more acetaldehyde. Ultimately, acetaldehyde is metabolized to acetate

by aldehyde dehydrogenase (ALDH). Intake of ethanol increases intracellular accumulation of triglycerides by increasing fatty acid uptake

and by reducing fatty acid oxidation and lipoprotein secretion. Protein

synthesis, glycosylation, and secretion are impaired. Oxidative damage

to hepatocyte membranes occurs due to the formation of reactive oxygen species; acetaldehyde is a highly reactive molecule that combines

with proteins and nucleic acids to form acetaldehyde adducts. These

adducts may interfere with specific enzyme activities, including microtubular formation and hepatic protein trafficking. With acetaldehydemediated hepatocyte damage, certain reactive oxygen species can result

in Kupffer cell activation. As a result, profibrogenic cytokines are produced that initiate and perpetuate stellate cell activation, with the resultant production of excess collagen and extracellular matrix. Connective

tissue appears in both periportal and pericentral zones and eventually

connects portal triads with central veins forming regenerative nodules.

Hepatocyte loss occurs, and with increased collagen production and

deposition, together with continuing hepatocyte destruction, the liver

contracts and shrinks in size. This process generally takes from years

to decades to occur and requires repeated insults.

Clinical Features The diagnosis of alcohol associate liver disease

requires an accurate history regarding both amount and duration of

alcohol consumption. Patients with alcohol associate liver disease can

present with nonspecific symptoms such as vague right upper quadrant

abdominal pain, fever, nausea and vomiting, diarrhea, anorexia, and

malaise. Alternatively, they may present with more specific complications

of chronic liver disease, including ascites, edema, upper gastrointestinal

(GI) hemorrhage, jaundice, or encephalopathy. Many cases present incidentally at the time of autopsy or elective surgery. The abrupt onset of

any of these complications may be the first event prompting the patient to

seek medical attention. Other patients may be identified in the course of

an evaluation of routine laboratory studies that are found to be abnormal.

On physical examination, the liver and spleen may be enlarged, with the

liver edge being firm and nodular. Other frequent findings include scleral

icterus, palmar erythema (Fig. 344-1), spider angiomas (Fig. 344-2),

parotid gland enlargement, digital clubbing, muscle wasting, edema, and

ascites. Men may have decreased body hair and gynecomastia as well

as testicular atrophy, which may be a consequence of hormonal abnormalities or a direct toxic effect of alcohol on the testes. In women with

advanced alcohol-associated cirrhosis, menstrual irregularities usually

occur including amenorrhea. These changes are often reversible following

cessation of alcohol ingestion.

Laboratory tests may be completely normal in patients with early

compensated alcohol-associated cirrhosis. Alternatively, in advanced

liver disease, many abnormalities usually are present. Patients may be

anemic from chronic GI blood loss, nutritional deficiencies, or hypersplenism or as a direct suppressive effect of alcohol on the bone marrow.

A unique form of hemolytic anemia (with spur cells and acanthocytes)

called Zieve’s syndrome can occur in patients with severe alcoholic hepatitis. Platelet counts are often reduced early in the disease, reflective of

portal hypertension with hypersplenism. Serum total bilirubin can be

normal or elevated with advanced disease. Prothrombin times are often

prolonged and usually do not respond to administration of parenteral

vitamin K. Serum sodium levels are usually normal unless patients have

ascites and then can be depressed, largely due to ingestion of excess free

water. Serum alanine and aspartate aminotransferases (ALT, AST) are

typically elevated, particularly in patients who continue to drink, with

AST levels being higher than ALT levels, usually by a 2:1 ratio.

Diagnosis Patients who have any of the above-mentioned clinical

features, physical examination findings, or laboratory studies should be

considered to have alcohol associate liver disease. The diagnosis, however, requires accurate knowledge that the patient is continuing to use

or has recently stopped alcohol. Furthermore, other forms of chronic

liver disease (e.g., chronic viral hepatitis or metabolic or autoimmune

liver diseases) must be considered or ruled out, or if present, an estimate of relative causality along with the alcohol use should be determined. Liver biopsy can be helpful to confirm a diagnosis but generally

is not performed unless there is a suspicion of an alternative diagnosis.

In patients who have had complications of cirrhosis and who

continue to drink, there is a <50% 5-year survival. In contrast, in

patients who are able to remain abstinent, the prognosis is significantly

improved, particularly when they have resolution of liver complications; however, some individuals who remain abstinent do not improve

and liver transplantation is a viable option.

TREATMENT

Alcohol-Associated Cirrhosis and Alcoholic Hepatitis

Abstinence is the cornerstone of therapy for patients with alcohol

associate liver disease. In addition, patients require good nutrition

and long-term medical supervision to manage underlying complications that may develop. Complications such as the development of

FIGURE 344-1 Palmar erythema. This figure shows palmar erythema in a patient with

alcohol-associated cirrhosis. The erythema is peripheral over the palm with central pallor.

FIGURE 344-2 Spider angioma. This figure shows a spider angioma in a patient with

hepatitis C cirrhosis. With release of central compression, the arteriole fills from the

center and spreads out peripherally.

2626 PART 10 Disorders of the Gastrointestinal System

ascites and edema, variceal hemorrhage, or portosystemic encephalopathy all require specific management and treatment. Liver transplantation can be an effective long-term treatment in those who

have been deemed a low enough risk for alcohol relapse and do not

respond to other treatments.

Glucocorticoids are occasionally used in patients with severe

alcoholic hepatitis in the absence of infection. Short-term survival

has been shown to be improved in certain studies and meta-analysis,

although 6-month survival is more dependent on abstinence. Treatment is restricted to patients with a discriminant function (DF)

value of >32. The DF is calculated as the serum total bilirubin plus

the difference in the patient’s prothrombin time compared to upper

limit of control (in seconds) multiplied by 4.6. Failure to improve

total bilirubin after 7 days predicts treatment failure, and glucocorticoids can be stopped; otherwise, they are continued for 28 days.

There is modest evidence that intravenous N-acetylcysteine plus

glucocorticoids may have survival benefit in alcoholic hepatitis if

the DF is >32. Other therapies including oral pentoxifylline, parenterally administered inhibitors of tumor necrosis factor (TNF) α

such as infliximab or etanercept, anabolic steroids, propylthiouracil,

antioxidants, colchicine, and penicillamine have not shown clearcut benefits and are not recommended. A variety of nutritional

therapies have been tried, both parenteral and enteral feedings;

however, there is no clear evidence of improved survival. There

is evidence that persons who consume >21.5 kcal/kg body weight

per day have better survival, so achieving better caloric intake is

recommended. Finally, in highly selected patients with good social

support structure who fail other treatments for alcoholic hepatitis,

early liver transplant can be an effective treatment.

The cornerstone to treatment is cessation of alcohol use. Recent

experience with medications that reduce craving for alcohol, such

as acamprosate calcium and baclofen, have been favorable. Patients

may take other necessary medications even in the presence of cirrhosis. Acetaminophen use is often discouraged in patients with

liver disease; however, if no more than 2 g of acetaminophen per

day are consumed, there generally are no problems unless there is

active alcohol use.

■ CIRRHOSIS DUE TO CHRONIC VIRAL

HEPATITIS B OR C

Of patients exposed to the hepatitis C virus (HCV), ~80% develop

chronic hepatitis C, and of those, ~20–30% will develop cirrhosis over

20–30 years. Many of these patients have had concomitant alcohol

use, and the true incidence of cirrhosis due to hepatitis C alone is

unknown. It is expected that an even higher percentage will go on to

develop cirrhosis over longer periods of time. In the United States,

~5–6 million people have been exposed to HCV, and ~4–5 million are

chronically viremic. Worldwide, ~170 million individuals have hepatitis C, with some areas of the world (e.g., Egypt) having up to 15%

of the population infected. HCV is a noncytopathic virus, and liver

damage is probably immune-mediated. Progression of liver disease

due to chronic hepatitis C is characterized by portal-based fibrosis with

bridging fibrosis and nodularity developing, ultimately culminating in

the development of cirrhosis. In cirrhosis due to chronic hepatitis C,

the liver is small and shrunken with characteristic features of a mixed

micro- and macronodular cirrhosis seen on liver biopsy. In addition

to the increased fibrosis that is seen in cirrhosis due to hepatitis C, an

inflammatory infiltrate is found in portal areas with interface hepatitis

and occasionally some lobular hepatocellular injury and inflammation.

In patients with HCV genotype 3, steatosis is often present.

Similar findings are seen in patients with cirrhosis due to chronic

hepatitis B. Of adult patients exposed to hepatitis B, ~5% develop

chronic hepatitis B, and ~20% of those patients will go on to develop

cirrhosis. Special stains for hepatitis B core (HBc) and hepatitis B

surface (HBs) antigen will be positive, and ground-glass hepatocytes

signifying HBs antigen (HBsAg) may be present. In the United States,

there are ~2 million carriers of hepatitis B, whereas in other parts

of the world where hepatitis B virus (HBV) is endemic (i.e., Asia,

Southeast Asia, sub-Saharan Africa), up to 15% of the population

may be infected, having acquired the infection vertically at the time of

birth. Thus, >300–400 million individuals are thought to have hepatitis

B worldwide. Approximately 25% of these individuals may ultimately

develop cirrhosis.

Clinical Features and Diagnosis Patients with cirrhosis due to

either chronic hepatitis C or B can present with the usual symptoms

and signs of chronic liver disease. Fatigue, malaise, vague right upper

quadrant pain, and laboratory abnormalities are frequent presenting

features. Diagnosis requires a thorough laboratory evaluation, including quantitative HCV RNA testing and analysis for HCV genotype, or

hepatitis B serologies to include HBsAg, anti-HBs, HBeAg (hepatitis B

e antigen), anti-HBe, and quantitative HBV DNA levels.

TREATMENT

Cirrhosis due to Chronic Viral Hepatitis B or C

Management of complications of cirrhosis revolves around specific

therapy for treatment of whatever complications occur (e.g., esophageal variceal hemorrhage, development of ascites and edema, or

encephalopathy). In patients with chronic hepatitis B, numerous

studies have shown beneficial effects of antiviral therapy, which is

effective at viral suppression, as evidenced by reducing aminotransferase levels and HBV DNA levels and improving histology by

reducing inflammation and fibrosis. Several clinical trials and case

series have demonstrated that patients with decompensated liver

disease can become compensated with the use of antiviral therapy

directed against hepatitis B. Currently available therapy includes

lamivudine, adefovir, telbivudine, entecavir, and tenofovir, with the

latter two being preferred because of reduced risk of viral resistance.

Interferon α can also be used for treating hepatitis B, but it should

not be used in cirrhotics (see Chap. 341).

Treatment of patients with cirrhosis due to hepatitis C used to be

more difficult because the side effects of pegylated interferon and

ribavirin therapy were difficult to manage. Over the past several

years, interferon-based regimens have been replaced by directacting antiviral protocols that are highly successful (>95% cure

rate), well tolerated, and usually of short duration (8–12 weeks), but

costly. These medications have truly revolutionized the treatment of

hepatitis C (see Chap. 341).

CIRRHOSIS FROM AUTOIMMUNE

HEPATITIS AND NONALCOHOLIC FATTY

LIVER DISEASE

Other causes of posthepatitic cirrhosis include autoimmune hepatitis

(AIH) and cirrhosis due to nonalcoholic steatohepatitis. Many patients

with AIH present with cirrhosis that is already established. Typically,

these patients will not benefit from immunosuppressive therapy with

glucocorticoids or azathioprine because the AIH is “burned out.” In

this situation, liver biopsy does not show a significant inflammatory

infiltrate. Diagnosis in this setting requires positive autoimmune

markers such as antinuclear antibody (ANA) or anti-smooth-muscle

antibody (ASMA). When patients with AIH present with cirrhosis and

active inflammation accompanied by elevated liver enzymes, there can

be considerable benefit from the use of immunosuppressive therapy.

Patients with nonalcoholic steatohepatitis are increasingly being

found to have progressed to cirrhosis. With the epidemic of obesity

that continues in Western countries, more and more patients are

identified with nonalcoholic fatty liver disease (Chap. 343). Of these,

a significant subset has nonalcoholic steatohepatitis and can progress

to increased fibrosis and cirrhosis. Over the past several years, it has

been increasingly recognized that many patients who were thought to

have cryptogenic cirrhosis in fact have nonalcoholic steatohepatitis.

As their cirrhosis progresses, they become catabolic and then lose the

telltale signs of steatosis seen on biopsy. Management of complications

of cirrhosis due to either AIH or nonalcoholic steatohepatitis is similar

to that for other forms of cirrhosis.