Hepatology 2009;49:306; Nejm 2002;346:1221

Epidem: The prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated between 10% and 24%. NAFLD is a spectrum of disease ranging from simple steatosis, to steatohepatitis, to advanced fibrosis and cirrhosis in the absence of substantial alcohol intake. Nonalcoholic steatohepatitis (NASH) is part of the spectrum of NAFLD that is found in 3% of lean pts and up to 20% of obese pts in Western countries. Obesity (especially central obesity), diabetes, and hyperlipidemia are commonly associated. However, the disease is notlimited to pts with these risk factors. A picture of steatosis with or without inflammation and fibrosis can be seen with starvation, TPN use, rapid weight loss, bariatric surgery, inherited metabolic defects, and a variety of drugs. These secondary causes of fatty liver disease all have unique clinical characteristics that are notfurther discussed here.

Pathophys: NASH is diagnosed when 3 criteria are met: (1) a liver bx shows macrovesicular fatty change and lobular or portal inflammation, with or without fibrosis; (2) there is convincing evidence of <40 gm per week of alcohol use (about 4 drinks per week, see p 250); and (3) there is no evidence of active infection with hep B or C or a secondary cause of steatosis (Hepatology 1990;11:74). Fatty liver (simple steatosis) is diagnosed when there is fatty change without inflammation or fibrosis. The pathogenesis of NAFLD is unknown. The accumulation of lipids in hepatocytes in association with insulin resistance appears to be an important first step. The progression from simple steatosis to steatosis with inflammation and fibrosis may be the result of oxidative stress on hepatocytes. Hepatic stellate cell activation, the inflammatory response, genetics, and other environmental factors have been identified as important factors in disease development (Curr Opin Gastroenterol 2009;25:230).

Sx: Most pts have no sx, but some may have fatigue or RUQ discomfort.

Si: Hepatomegaly is common. A minority present with signs of advanced liver disease (p 26).

Cmplc: Any of the complications of end-stage liver disease may occur (p 255).

Crs: The course of pts with NAFLD is notwell understood. Simple steatosis without fibrosis or inflammation typically has a benign course. Pts with NASH have an increased risk of death due to heart disease and liver disease. In a large series, 5% of pts with NASH at initial bx had progression to end-stage liver disease, including HCC at a median of 13.7 yr of follow-up (Hepatology 2006;44:865). In this series about 40% of pts had progression of their degree of fibrosis in follow-up. Since there is a higher than expected proportion of obese, diabetic pts with apparent cryptogenic cirrhosis, it has been postulated that NASH is an unrecognized cause of cryptogenic cirrhosis (Hepatology 1999;29:664).

Diff Dx: NASH is a consideration in pts with abnormal LFTs. The abnormal LFTs are usually found in the process of evaluating other medical problems. Other causes of abnormal LFTs and cirrhosis must be excluded (p 28). The most difficult differential point is that of alcoholic liver disease. A dx of NAFLD can only be made with liver bx. However, given the indolent nature of NAFLD and its lack of proven rx, many physicians forgo bx. It is assumed that pts with an unrevealing evaluation for other causes of abnormal LFTs have either simple steatosis (without inflammation) or NASH. Effective rx for NASH would make the distinction between simple steatosis and NASH more important.

Lab: ALT is usually greater than AST, and both are up to 2-3 × the normal values. NASH can be seen with normal transaminases. Alk phos is often mildly elevated. Bilirubin and PT are usually normal unless there is cirrhosis. Ferritin is elevated in more than half of pts but is generally <1000 ng/mL (GE 1994;107:1103). A variety of histopathologic changes have been described. Steatosis is seen mostly in zone 3 of the liver. Inflammation is usually mild and in the lobules without severe portal changes. Degenerating hepatocytes are present, and Mallory hyalin may be seen (as in alcoholic hepatitis). Fibrosis begins in sinusoids and may progress to cirrhosis. Predictors of fibrosis include age ≥50 yr, body mass index ≥28 kg/m², triglycerides ≥151 mg/dL, and ALT >2 × normal (GE 2000;118:1117). A variety of serum biomarkers to predict fibrosis, oxidative stress, and inflammation have been investigated, but no reliable method can be recommended for widespread use (Hepatology 2009;49:306).

X-ray: US may show increased echogenicity consistent with fat. CT or MRI may show evidence of fatty change. No study is adequately sensitive or specific for NASH.

Rx: (Hepatology 2009;49:306) Since NASH is associated with an increased risk of heart disease, it makes sense to emphasize the need to modify cardiac risk factors. Statins appear safe for treating hyperlipidemia in compensated liver disease (GE 2008;135:702). No safe, well-proven, and effective drug rx for NAFLD/NASH has been identified. Gradual weight loss and exercise have been advocated and appear to result in histologic and biochemical improvement (Hepatology 2004;39:1647). However, large well-conducted studies are lacking (Am J Med 2003;115:554), and weight loss is difficult to achieve. A reasonable recommendation would be to advise weight loss of 7-10% of body weight over 6-12 months using a balanced diet low in high-glycemic foods, low in saturated fat, and rich in fruits and vegetables. Moderate aerobic exercise of 30-45 min daily, 5-7 times weekly is appropriate. Bariatric surgery improves steatosis, fibrosis, and inflammation in the majority of pts who undergo this drastic intervention (Clin Gastroenterol Hepatol 2008;6:1396). A pilot study of ursodeoxycholic acid showed biochemical and histologic improvement at 1 yr (Hepatology 1996;23:1464), but a subsequent RCT showed no benefit (Hepatology 2004;39:770). Vitamin E has been used because of its antioxidant properties without
convincing evidence of benefit (Am J Gastro 2003;98:2348). Since the disease is associated with insulin resistance, attention has recently been on the use of insulin sensitizing drugs. Metformin may be helpful but the data are notconvincing (Cochrane Database Syst Rev 2007;CD005166). The thiazolidinediones (eg, pioglitazone, rosiglitazone) may be somewhat beneficial (GE 2008;135:100; Nejm 2006;355:2297), but concerns about safety and efficacy will need to be settled by large trials. Transplant has been used effectively to treat end-stage disease, though recurrence in the transplant is a risk (Transplantation 1996;62:1802). Screening and surveillance for HCC in cirrhotic pts is discussed on p 247.

Hepatology 2009;50:291; Am J Gastro 2001;96:3152

Epidem: There is a striking predominance in women (90%). Prevalence ranges from 5-392/1,000,000 (Semin Liver Dis 1997;17:13). Familial PBC is uncommon (1%) and seems to be related to maternally inherited factors (Gut 1995;36:615).

Pathophys: PBC is a destructive disease of small, interlobular bile ducts. It is an autoimmune disease. Almost all pts have antimitochondrial antibodies (AMAs). AMAs are directed against antigens on bile duct epithelial cells with similar antigenicity to the E2 subunit of pyruvate dehydrogenase (J Clin Invest 1993;91:2653). Immune destruction of bile ducts may be mediated in this way. A variety of infectious agents, including retroviruses, have been implicated as inciting antigenic stimuli in susceptible individuals (Am J Gastro 2004;99:2348). As bile ducts are destroyed, concentrations of hydrophobic bile acids and other hepatocellular toxins rise and cause further destruction. This causes recruitment of inflammatory cells, which produce cytokines that may promote fibrosis (Can J Gastroenterol 2000;14:43).

Sx: (Semin Liver Dis 1997;17:23) More than 60% of pts are asymptomatic at dx. Fatigue occurs in more than 60% of symptomatic pts and is a frustrating problem of unknown cause. Pruritus is the second most common sx and can be severe. Some pts will have RUQ pain that usually disappears in time. A minority will present with a complication of end-stage liver disease such as varices or ascites. Many pts have at least 1 other autoimmune disease such as thyroiditis, scleroderma, rheumatoid arthritis, the CREST syndrome, or Sjögren’s syndrome.

Si: (Can J Gastroenterol 2000;14:43) Findings vary with the stage of disease. In early disease, excoriations may be seen. Hepatomegaly is common (70%) and splenomegaly develops in about 35%. Jaundice, spider angiomata, and ascites are late manifestations. Xanthomas commonly occur around the eyes (xanthelasma) and less commonly occur on extremities. They disappear as disease progresses.

Crs: The rate of progression varies markedly among pts. UDCA rx has changed the natural history. In the pre-UDCA era, the 10-yr survival for asymptomatic pts was 50-70% and the median survival of symptomatic pts was 5-8 yr. Using a Markov model for 262 pts treated with UDCA, the 10-yr survival was 85% and the 20-yr survival was 66%. When the subgroups with stage 1 and 2 disease were examined, the 10-yr and 20-yr transplant-free survivals were 94% and 78%, respectively (similar to the control population) (GE 2005;128:297). Pts with AMA-negative PBC appear to have a course similar to AMA-positive pts (Hepatology 1997;25:1090).

Cmplc: Osteoporosis is the most common bone disorder. Steatorrhea and fat-soluble vitamin deficiency can be seen in advanced disease. Hypothyroidism is seen in 20% of pts. Rheumatoid arthritis (10%), scleroderma (4%), CREST syndrome, and SLE have been reported (Q J Med 1996;89:5). Up to 68% of pts have xerostomia or xerophthalmia and may have dysphagia (Dysphagia 1997;12:167). Any of the complications of end-stage liver disease may occur (p 255). Hepatobiliary malignancy is more common in PBC (RR = 46 in one referral series [Hepatology 1999;29:1396]), but malignancy is notas frequent as in other causes of cirrhosis (Am J Gastroenterol 1997;92:676). Varices are seen earlier in the course of PBC than with other liver diseases, because the portal HTN is partially presinusoidal and synthetic function may be relatively well preserved.

Diff Dx: PBC is usually considered in the evaluation of an asymptomatic pt with elevated alk phos or when a pt presents with evidence of chronic liver disease such as ascites or bleeding from varices. Some cases of PBC are detected because of autoantibody testing done for other reasons in pts with normal LFTs. This group often evolves into typical PBC (Lancet 1996;348:1399). The diff dx generally includes the other causes of abnormal LFTs or cirrhosis (p 28). The chief points of confusion are sclerosing cholangitis (p 233), which produces similar LFT abnormalities, drug-induced cholestasis, sarcoidosis, and autoimmune hepatitis. When the liver bx shows bile duct lesions suggestive of PBC, but the AMA is negative and the ANA and ASMA are positive, it is difficult to confidently make a dx. These pts are said by some experts to have an overlap syndrome called autoimmune cholangitis that may respond to steroids like autoimmune hepatitis (Gut 1997;40:440). Autoimmune hepatitis can follow an initial dx of PBC. To make a dx of PBC, biliary obstruction must be excluded with imaging studies, especially if the AMA is negative.

Lab: AMA is 95% sensitive and 98% specific for PBC. AMAs are directed against a family of dehydrogenase enzymes, chiefly pyruvate dehydrogenase (Semin Liver Dis 1997;17:61). The major autoantigen, located on the inner mitochondrial membrane, is the E2 component of pyruvate dehydrogenase (J Hepatol 1986;2:123). Levels do notcorrelate with disease severity. Elevation of alk phos is the most notable laboratory abnormality in early-stage disease. The GGTP and 5’NT are elevated in a parallel fashion. ALT/AST are usually <5 × normal. Bilirubin and PT become elevated as disease progresses. Most pts have elevated cholesterol. Since the elevation is in the HDL fraction of cholesterol, the risk for heart disease is low (Hepatology 1992;15:858). ANA and antithyroid antibodies are common. Many other autoantibodies have been reported. Elevations of IgM and polyclonal IgG are seen.

Four pathologic stages are recognized on liver bx. In stage I, inflammatory cells surround a bile duct with evidence of duct epithelial degeneration. In some cases a frankly necrotic duct can be seen in a granuloma (the florid duct lesion). In stage II, fibrosis develops in the portal zones, and inflammation extends into the lobules. In stage III, fibrosis joins portal triads. Stage IV shows established cirrhosis.

X-ray: Obstruction of the bile ducts should be excluded with US or CT scan. ERCP/MRCP would be reserved for cases in which PSC (p 233) was a serious consideration.

Endoscopy: Endoscopy should be performed in pts with advanced disease to identify and treat varices (p 255).

Curr Opin Gastroenterol 2008;24:377; Am J Gastro 2002;97:528

Epidem: About 70% of pts with primary sclerosing cholangitis (PSC) are men. About 75% of pts have IBD. The majority of the IBD pts have UC (85%), but some have Crohn’s. The estimated prevalence is 1-15/100,000 with wide geographic variation (Scand J Gastroenterol 1998;33:99).

Pathophys: PSC is characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. PSC is defined by the presence of bile duct strictures on cholangiography, by cholestatic LFT abnormalities, and by the absence of diseases that could give a similar picture (see Diff Dx). Immune mechanisms are thought to be important in the pathogenesis, especially since the disease is associated with IBD, autoantibodies and immunoglobulin elevations are present, and inflammation is T-cell mediated. Infectious and toxic etiologies have been considered and rejected. Though PSC causes obliteration of larger bile ducts than PBC, the end result is the same: cholestasis that causes progressive parenchymal destruction.

Sx: Most pts come to dx because of abnormal LFTs, sometimes detected in evaluation of their associated IBD. These pts are usually asymptomatic. Fatigue, pruritus, jaundice, night sweats, and weight loss may occur as disease progresses. An important minority of pts experience attacks of fever, RUQ pain, and worsened LFTs in a picture that mimics bacterial cholangitis.