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Nonalcoholic SteatoHepatitis (NASH) Pioglitazone Rx 2006 (NEJM)
Most NASH pts are obese, middle-aged women with asymptomatic hepatomegaly, diabetes, or hyperlipidmia who do not abuse alcohol. Lab findings typically show that the ALT level is equal to or > the AST level (the reverse in alcoholic hepatitis).
Although some pts develop cirrhosis, portal hypertension, & liver failure, most patients have a good prognosis. In some cases, the disease can be reversed with weight reduction.
Age: usually between 41-60 years. Predominantly female.
Commonly associated conditions: Obesity, diabetes, hyperlipidemia.
Symptoms: none in 48-100%; vague abdominal discomfort, RUQ abd. pain, fatigue or malaise.
Signs: hepatomegaly, rarely, stigmata of chronic liver disease or portal hypertension.
Lab. features:
2-3x increase in ALT & AST (ALT usually > AST, in contrast with
that seen in alcoholic hepatitis); Alkaline phosphatase levels are abnormal
in fewer than half of patients, and bilirubin levels are rarely elevated
; normal serum albumin, a prolonged prothrombin time is atypical; possible
elevation of serum ferritin levels.
DX of Steatohepatitis:
RX of Steatohepatitis:
Clinical Course:
Combining the results of Powell and colleagues (3),
Lee (10), and Bacon and colleagues
(15) gives a total of 28 patients. Of these,
1 (3%) improved, 15 (54%) remained unchanged, and 12 (43%) had histologic
progression during 1- to 7-year periods. Approximately 8% to 17% of patients
with NASH (3, 10) compared with 38% to 50% of patients
with alcoholic hepatitis (75, 76) progress to cirrhosis
after a similar follow-up period.
Prognosis is good in most patients. The precise role of weight reduction and ursodeoxycholic acid therapy in the favorable alteration of the natural history of this disorder needs to be addressed in large, well-controlled studies.
REF:
Review of Nonalcoholic Steatohepatitis by Sheth SG, Gordon FD, Chopra S
Annals
of Internal Medicine, 15 January 1997. 126:137-145.
Gastroenterology 1999 Jun;116(6):1413-9
Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.
Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ.
Department of Gastroenterology, Cleveland, Ohio, USA.
BACKGROUND & AIMS:
The spectrum of nonalcoholic fatty liver disease ranges from fatty liver
alone to nonalcoholic steatohepatitis. Most previous studies have short follow-up
and have not carefully delineated different histological types when determining
clinical outcomes. The aim of this study was to compare clinical characteristics
and outcomes of patients with different types of nonalcoholic fatty liver.
METHODS:
All liver biopsy specimens from 1979 to 1987 with fat accumulation were assessed
for inflammation, ballooning degeneration, Mallory hyaline, and fibrosis.
Biopsy specimens were also assessed for histological iron and hepatitis C
RNA. Outcomes were cirrhosis, mortality, and liver-related mortality.
RESULTS:
Of 772 liver biopsy specimens, complete data were available in 132 patients.
Fatty liver (type 1) did not differ from the other three types combined with
respect to gender, race, age, or obesity. Cirrhosis was more common
in the other types combined (22%) than fatty liver alone (4%; P </=
0.001). Overall mortality, histological iron, and hepatitis C did not differ
between groups. Most of the liver-related deaths were in type 4.
CONCLUSIONS:
The outcome of cirrhosis and liver-related death is not uniform across the
spectrum of nonalcoholic fatty liver. These poor outcomes are more frequent
in patients in whom biopsies show ballooning degeneration and Mallory hyaline
or fibrosis.
REVIEW
Nonalcoholic Steatohepatitis
Annals of Internal Medicine, 15 January 1997. 126:137-145.
Sunil G. Sheth, MD; Fredric D. Gordon, MD; and Sanjiv Chopra, MD
Nonalcoholic steatohepatitis is a distinct clinical entity in non-alcoholic ,characterized by
Patients with NASH are typically obese, middle-aged women with asymptomatic hepatomegaly who are diabetic or hyperlipidemic and present with an unrelated medical problem.
Elevated levels of free fatty acids in the liver are thought to be responsible for the development of steatohepatitis. Although NASH is most often a benign disease with an indolent course, patients with this condition occasionally develop cirrhosis, portal hypertension, and hepatic failure. In some cases, NASH may be reversed with weight reduction.
Prognosis is good in most patients. The precise role of weight reduction and ursodeoxycholic acid therapy in the favorable alteration of the natural history of this disorder needs to be addressed in large, well-controlled studies.
Although the prevalence of NASH is not well-defined, it is reported worldwide and is detected in 1.2% to 9% of patients who have liver biopsy. In fact, the prevalence of NASH may be even higher in asymptomatic patients who do not consume substantial quantities of alcohol and in those who have negative results on serologic examinations for viral hepatitis. Thus, many patients with elevated plasma liver enzyme levels and negative results on noninvasive workup may have NASH.
Nonalcoholic steatohepatitis is seen most frequently in patients who are female, are morbidly obese, are diabetic, have had jejunal bypass surgery, or have been receiving certain medications. These patients have either no symptoms or vague abdominal discomfort. Levels of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are usually elevated. The diagnosis of NASH is confirmed by liver biopsy. The histologic features of the condition include macrovesicular fatty changes; parenchymal inflammation, fibrosis, or both; cirrhosis; and the presence of Mallory hyaline bodies (1-3). The pathogenesis of NASH is unclear, but various theories have implicated free fatty acids. Although NASH is generally considered to be a benign disease, it occasionally progresses to cirrhosis with a fatal outcome.
"Alcoholic hepatitis" is a well-defined term used to describe the
histologic pattern of liver injury that results from long-term consumption
of alcohol. The condition is characterized by cell damage that is often
distinguished by 1) the presence of Mallory hyaline bodies, an inflammatory
infiltrate predominantly comprising neutrophils with frequently associated
fatty degeneration (steatosis), and 2) fibrosis ranging from minimal perivascular
foci to dense scarring and fibrous septa (4, 5).
Nonalcoholic steatohepatitis is initially a perivenular injury but with
severe disease, the portal tracts may be involved, creating necrotic and
fibrotic bridges that can lead to cirrhosis (6). These
findings have also been described in patients who do not consume alcohol
or who consume it in amounts not known to cause substantial liver injury.
Powell and colleagues (3) proposed the following criteria for the diagnosis of NASH:
We believe that the diagnosis of NASH should not necessarily be ruled out in patients who have had infection antibodies to the hepatitis B virus. However, it should be ruled out for patients who are positive for hepatitis B surface antigen or antibodies to the hepatitis C virus.
The prevalence of NASH in the general population has not been defined. Among patients who have had liver biopsy, the prevalence is approximately 7% to 9% in western countries (1, 8) and 1.2% in Japan (9). Data from patients who have had liver biopsies show that alcoholic hepatitis is 10 to 15 times more common than NASH. These figures do not reflect the prevalence of these diseases in the general population (1, 10, 11).
Although NASH has been reported in persons in the second decade of life (12, 13), most cases occur in persons in the fifth and sixth decades of life (1, 9, 10, 14, 15). Cases occur more frequently in women (65% to 83%) (1, 3, 10, 14), although Bacon and colleagues (15) recently found a high preponderance of NASH in men (58%). It is not clear whether it is a hormonal effect or the higher prevalence of obesity in women that makes NASH more prevalent in women.
Obesity is the condition most often associated with NASH: In most studies, 69% to 100% of patients with NASH were also obese (1, 3, 10, 14, 16). However, Bacon and colleagues (15) reported a prevalence of obesity of 39%. Most patients with NASH are 10% to 40% heavier than ideal body weight (1, 2, 10, 14, 15). Nonalcoholic steatohepatitis has also been seen in obese patients who have had surgery for weight reduction. In fact, liver dysfunction occurs in 40% of obese patients who have had jejunal bypass surgery for weight reduction (17). In 2.2% to 6% of these patients, evidence of liver failure appears during the first 12 to 18 months, when weight loss is most rapid (18).
Non-insulin-dependent diabetes mellitus and elevated blood glucose values are noted in 34% to 75% of patients with NASH (1, 3, 10, 14, 16, 19), although Bacon and colleagues (15) reported a lower incidence (21%) and Baldridge and associates (12) found normal fasting blood glucose levels in 14 (100%) obese peripubertal children with NASH. In an autopsy study, Wanless and Lentz (2) found obesity, diabetes, or both to be present in 20 of 22 patients with steatohepatitis. They also noted a trend toward a higher prevalence of NASH in patients with type II diabetes requiring insulin.
In addition to obesity and non-insulin-dependent diabetes mellitus or hyperglycemia, Wanless and Lentz (2) found a substantially higher incidence of NASH in patients receiving intravenous glucose therapy in the last week of life and in obese patients who lost weight in the last month of life compared with obese patients who did not lose weight.
Hyperlipidemia (hypertriglyceridemia, hypercholesterolemia, or both) is another common abnormality and has been reported in 20% to 81% of patients with NASH (1, 3, 10, 14-16, 19). In contrast with all other major studies, Bacon and colleagues (15) found that 14 of 33 patients with NASH had normal weight, blood sugar levels, and lipid levels.
Other conditions that are less commonly associated with NASH include extensive small-bowel resection (20); total parenteral nutrition (1, 21, 22); jejunal diverticulosis with bacterial overgrowth (23); gastroplasty for morbid obesity (24); biliopancreatic diversion (25); Weber-Christian disease (26); partial lipodystrophy that does not affect the face (27); abetalipoproteinemia (28); and therapy with such drugs as amiodarone (29), tamoxifen (30), perhexiline maleate (31), glucocorticoids (32), and synthetic estrogens (33) (Table 1).
The pathogenesis of NASH remains unclear. Steatosis is commonly encountered in protein-energy malnutrition, obesity, acute starvation, carbohydrate overload, and corticosteroid therapy, and there may be a common mechanism for the accumulation of triglycerides in the liver that is associated with these conditions (34).
The salient clinical and laboratory features of NASH are outlined in Table 2. A high proportion of patients (48% to 100%) have no symptoms of liver disease, and a small percentage (especially children [12, 13]) have vague abdominal discomfort or pain in the right upper quadrant (13, 15) or fatigue and malaise (10, 15). Most patients present because of other conditions (such as hypertension, gallstones, coronary artery disease, congestive heart failure, cancer, peripheral vascular disease, hypothyroidism, and gynecologic or psychiatric conditions) (10, 16) and are incidentally found to have abnormal liver function (10, 15). Significant alcohol consumption must be ruled out in all patients.
The most common finding at initial presentation is asymptomatic hepatomegaly (3, 10, 14, 15) without evidence of chronic liver disease (14). The most frequently noted abnormality is a two- to threefold elevation of levels of ALT and AST in plasma (3, 10, 12, 14, 15, 19). In two major studies (3, 15), levels of ALT were noted to be higher than levels of AST, a pattern that contrasts with that seen in alcoholic hepatitis. Van Ness and Diehl (60) found that 19% of patients (17 of 90) who had had liver biopsy for evaluation of chronically elevated plasma levels of ALT and AST in contrast to 7% to 9% of all patients who had had liver biopsies for other reasons, had nonalcoholic steatosis or steatonecrosis (1, 8). Alkaline phosphatase levels are abnormal in fewer than half of patients, and bilirubin levels are rarely elevated (10, 15). Serum albumin levels are almost always normal (10, 15), and a prolonged prothrombin time is atypical (although it was noted in 50% of patients in one series [1]).
Bacon and colleagues (15) identified abnormal results of iron tests (elevated levels of serum ferritin and transferrin saturation) in 18 of 31 patients. They reported elevations as great as fivefold in serum ferritin levels. None of the patients had histologic evidence of idiopathic genetic hemochromatosis.
Changes in fatty acids similar to those encountered with NASH can be caused by hepatitis C virus (61), and inflammation in NASH may be lymphocytic and periportal, thus mimicking the histologic changes seen in chronic hepatitis C infection. Chronic hepatitis C virus infection and possibly chronic hepatitis G virus infection (62) must be excluded in all patients with steatohepatitis. Ceruloplasmin levels, a1-antitrypsin levels, renal function test results, and electrolyte levels are usually normal in patients with NASH; tests for hepatitis B surface antigen are negative in these patients (15).
In patients who do not consume alcohol, liver biopsy specimens with histologic features similar to those seen in alcoholic hepatitis are the cornerstone of the diagnosis of NASH. In many studies (1, 3, 15), NASH has been diagnosed by the presence of fatty degeneration (steatosis) and lobular inflammation (hepatitis) only; hepatocyte degeneration, necrosis, fibrosis, cirrhosis, and Mallory hyaline bodies may not be present. Other studies (2, 10) have used a stricter definition for the histologic diagnosis of NASH, including steatohepatitis and hepatocyte ballooning or degeneration or hepatic fibrosis. The histologic features of NASH encompass a wide spectrum, from mild steatohepatitis to bridging fibrosis and cirrhosis.
Nonalcoholic steatohepatitis has generally been thought of as a stable disease. Lee (10) followed 39 patients clinically for an average of 3.8 years. During this period, only 1 patient developed hepatic failure. The patient was an obese, diabetic woman who had cirrhosis on biopsy. She developed increasing jaundice, ascites, and encephalopathy and died of gastrointestinal bleeding 1.6 years after diagnosis. Ten of 39 patients died because of an underlying medical condition that was not related to liver disease. Three of the 5 patients with cirrhosis died, and 2 remained stable. Follow-up biopsies done in 13 patients over an average of 3.5 years showed no increase in fibrosis or substantial change in morphology in 8 patients. Five patients had a progression of fibrosis during 1.7 to 6.1 years, and 2 developed cirrhosis. No progression of fibrosis was reported by Falchuk and colleagues (74) in 2 of 5 patients who had biopsies repeated after 1 year.
Powell and colleagues (3) repeated biopsies in 13 of 42 patients over a 1- to 9-year period. In 6 patients, no morphologic changes were noted. Two patients who had had active cirrhosis or marked fibrosis showed inactive cirrhosis or marked fibrosis. Three patients who had initially had fatty inflammation developed fibrosis during 1-, 2-, and 6-year periods. One patient had loss of inflammation and fibrosis at 6 years, and another progressed from fibrosis to cirrhosis during the same period. The patient who had had cirrhosis on initial biopsy developed hepatocellular cancer after 6 years. Bacon and colleagues (15) documented no histologic progression in 1 patient at 4 years and progression from bridging fibrosis to cirrhosis in 1 patient after 7 years.
Combining the results of Powell and colleagues (3), Lee (10), and Bacon and colleagues (15) gives a total of 28 patients. Of these, 1 (3%) improved, 15 (54%) remained unchanged, and 12 (43%) had histologic progression during 1- to 7-year periods. Approximately 8% to 17% of patients with NASH (3, 10) compared with 38% to 50% of patients with alcoholic hepatitis (75, 76) progress to cirrhosis after a similar follow-up period.
Cirrhosis related to obesity is present in 0.3% of the general population at autopsy and 1.8% of obese patients at autopsy. Cirrhosis related to obesity comprises approximately 12% of all cases of cirrhosis (2). In addition to cirrhosis related to obesity, evolution to cirrhosis after jejunal bypass has also been clearly established (77, 78).
Propst and colleagues (8) compared survival rates of patients with alcoholic hepatitis with those of patients with NASH using Kaplan-Meier survival curves. They found that the 5-and 10-year probabilities of survival were 38% and 15% for alcoholic hepatitis and 67% and 59% for NASH. They also reported that patients with NASH did not have a lower life expectancy than age- and sex-matched controls from the normal population.
The effect of weight loss is variable, and it is interesting to note that although the histologic lesion of steatohepatitis deteriorates after rapid weight loss (79), improvement occurs after gradual weight reduction (80).
Although patients with NASH generally have an indolent course, nearly half develop progressive fibrosis and as many as one sixth develop cirrhosis. No clinical, laboratory, or histologic features can predict progression or distinguish patients with or without worsening liver disease.
The clinician's ability to predict the nature of the pathologic process that causes chronic elevations of plasma levels of ALT and AST without examining liver biopsy specimens remains imperfect. Van Ness and Diehl (60) showed that the predictive value of a diagnosis of nonalcoholic fatty liver before biopsy was only 56% for NASH compared with 86% for alcoholic liver disease.
In patients with abnormal liver function, extensive evaluations should be done to determine the cause of the abnormality. An accurate history often suggests alcoholic liver disease or drug-related abnormality. Laboratory testing, including serologic tests for viral hepatitis; iron studies; and measurements of ceruloplasmin levels, levels and phenotype of a-antitrypsin, and antimitochondrial and antinuclear antibodies, should be done for potentially treatable causes of chronic liver diseases. Such radiologic studies as liver ultrasonography and Doppler ultrasonography of hepatic and portal vessels are also appropriate. Ultrasonography in NASH often shows a hyperechoic texture or a bright liver (81) because of diffuse fatty infiltration. However, this finding is not specific and cannot be used to diagnose NASH. If none of the above tests are definitive, then a liver biopsy is recommended to confirm or rule out NASH, especially if the patient has the typical clinical features described earlier.
Management
No proven therapy for NASH exists. Because obesity is the condition most commonly associated with NASH, weight loss is frequently advocated. However, weight loss is difficult to evaluate because obese patients with NASH rarely achieve or maintain sustained reductions in weight. Moreover, the effect of weight loss on liver disease is not consistent (11, 79, 80, 82, 83). Eriksson and colleagues (11) studied three patients with histologic features of NASH who were 50% to 60% overweight. The patients all responded with normalization of biochemical values, and two had normalization of histologic changes (liver biopsy was not repeated in the third patient) after weight reduction of 9% to 28%, although the patients still exceeded ideal body weight. Abdelmalek and colleagues (83) reported a patient with abnormal liver function and mild steatohepatitis. The patient was empirically treated with ursodeoxycholic acid for 1 year and had complete biochemical normalization of liver test results despite a weight gain of 2.72 kg (6 pounds). A repeated liver biopsy showed only mild, patchy portal hepatitis and periportal fibrosis without necrosis or fatty changes. The patient discontinued therapy with ursodeoxycholic acid on her own and developed abnormal liver function after 1 year; however, normal function returned after therapy with ursodeoxycholic acid was reinstituted.
Ursodeoxycholic acid has both lipid-altering properties and direct cytoprotective effects (84) that may have caused the improvement in this patient. Laurin and colleagues (85) recently studied the role of ursodeoxycholic acid and clofibrate therapy in the treatment of patients with NASH. Twenty-four patients received ursodeoxycholic acid, 13 to 15 mg/kg of body weight per day, and 16 patients with hypertriglyceridemia received clofibrate, 2 g/d. Both groups received treatment for 1 year. Despite its lipid-lowering properties, clofibrate was not found to be beneficial in the treatment of NASH. In contrast, ursodeoxycholic acid therapy significantly reduced plasma levels of ALT, alkaline phosphatase levels, g-glutamyltransferase levels, and hepatic steatosis. Randomized, controlled trials are required to validate the effect of ursodeoxycholic acid therapy in patients with NASH.
Nonalcoholic steatohepatitis is a distinct clinical entity that is occasionally encountered in adults and children. It forms an important differential diagnosis for asymptomatic patients with chronically elevated plasma levels of AST and ALT, especially if obesity, diabetes, or hyperlipidemia are present. Diagnosis is confirmed by liver biopsy that shows variable histologic features, ranging from mild steatohepatitis to severe fibrosis and cirrhosis. Although NASH is usually a benign condition with an indolent course, nearly half of cases progress, and as many as one sixth of patients with NASH develop cirrhosis. No definite therapy for NASH exists, although weight reduction or ursodeoxycholic acid therapy may result in improvement.
Current Author Addresses: Dr. Sheth: Department of Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215.
Treatment of Nonalcoholic Fatty Liver: Present
and Emerging Therapies
[Sem
Liver Disease 21(1):81-88, 2001] from Medscape.com site
Paul Angulo, M.D., and Keith D. Lindor, M.D., Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota
When Should Patients with NAFL be Treated?
The decision whether to treat an individual patient with NAFL should be primarily dictated by knowing the potential risk of progression to end-stage liver disease. However, because no prospective, longitudinal clinical studies have been performed, the clinical course of this condition remains unknown, and hence treatment recommendations remain speculative.
An attempt at gradual weight loss as well as a concerted effort to maintain appropriate control of serum glucose and lipid levels is a useful first step in the management of NAFL patients. Perhaps this, along with appropriate exclusion of other liver disease, may be the only treatment recommendation for NAFL patients with pure steatosis and no evidence of inflammation or fibrosis, who seem to have the best prognosis[3,4] within the spectrum of NAFL. NAFL patients with steatohepatitis, particularly those with fibrosis on liver biopsy, may have a worse prognosis; they should be monitored closely, have a greater effort made for adequate metabolic control, and be offered enrollment in well-controlled clinical trials evaluating the potential benefit of promising medications. For the NAFL patients with cirrhotic stage and decompensated disease, liver transplantation is a potential life-extending therapeutic alternative.
Table 1. Causes of Nonalcoholic Fatty Liver Disease
Nutritional:
Obesity
Type 2 diabetes mellitus
Protein-calorie malnutrition
Starvation
Total parenteral nutrition
Rapid weight loss
Drugs:
Corticosteroids
Estrogens
Salicylates
Calcium channel blockers
Amiodarone
Tamoxifen
Tetracycline
Chloroquine
Perhexiline maleate
Metabolic/ Genetics:
Wilson's disease
Lipodystrophy
Dysbetalipoproteinemia
Weber-Christian disease
Wolman's disease
Cholesterol ester storage
Others:
Environmental hepatotoxins
Inflammatory bowel disease
HIV* infection
Small bowel diverticulosis
REVIEW: Nonalcoholic Fatty Liver Disease - P. Angulo
NEJM April 18,
2002;346:1221-1231