ALCOHOLIC HEPATITIS
DEFINITION
DEFINITION
Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol [217].
DIAGNOSTIC CONSIDERATIONS [217]
• Chronic alcohol intake usually exceeds 80 g/d in men and 30-40 g/d in women.
• Fatty liver is often asymptomatic.
• Alcoholic hepatitis may present as fever, right upper quadrant pain, tender hepatomegaly, and jaundice, but the patient may also be asymptomatic.
• AST is usually elevated but rarely above 300 units/L; AST is greater than ALT, usually by a factor of 2 or more.
• Often reversible but it is the most common precursor of cirrhosis in the United States.

EPIDEMIOLOGY
• Alcohol abuse is the most common cause of serious liver disease in Western societies. In the United States alone, alcoholic liver disease affects more than 2 million people (ie, approximately 1% of the population). The true prevalence of alcoholic hepatitis, especially of its milder forms, is unknown because patients may be asymptomatic and never seek medical attention.
• The prevalence appears to differ widely among different countries. In the Western Hemisphere, when liver biopsies were performed in people who drank moderate-to-heavy amounts of alcohol and were asymptomatic, the prevalence of alcoholic hepatitis was found to be approximately 25-30%.
Race: Although no genetic predilection is noted for any particular race, alcoholism and alcoholic liver disease are more common in minority groups, particularly among Native Americans. Likewise, since the 1960s, death rates of alcoholic hepatitis and cirrhosis have consistently been far greater for the nonwhite population than the white population. The nonwhite male rate of alcoholic hepatitis is 1.7 times the white male rate, 1.9 times the nonwhite female rate, and almost 4 times the white female rate.
Sex: Women are more susceptible than men to the adverse effects of alcohol. Women develop alcoholic hepatitis after a shorter period and smaller amounts of alcohol abuse than men, and alcoholic hepatitis progresses more rapidly in women than in men.
• The estimated minimum daily ethanol intake required for the development of cirrhosis is 40 g for men and 20 g for women older than 15-20 years. Furthermore, for patients who continue to drink after a diagnosis of alcoholic liver disease, the 5-year survival rate is approximately 30% for women compared with 70% for men.
• To date, no single factor can account for this increased female susceptibility to alcoholic liver damage. Lower gastric mucosal ADH content in women has been suggested to possibly lead to less first-pass clearance of alcohol in the stomach. A higher prevalence of autoantibodies has been found in the sera of alcoholic females compared with alcoholic males, but their clinical significance is questionable. Perhaps hormonal influences on the metabolism of alcohol or the higher prevalence of immunologic abnormalities is responsible for the differences described in the prevalence of alcoholic liver damage between men and women.
Age: Alcoholic hepatitis can develop at any age. However, its prevalence parallels the prevalence of ethanol abuse in the population, with a peak incidence in individuals aged 20-60 years.
CLINICAL FEATURES [221]
• The clinical presentation of alcoholic hepatitis is reflective of the inflammatory features characteristic of this disorder.
• Classically, alcoholic hepatitis presents with fever, jaundice, hepatomegaly, and, occasionally, signs of decompensated liver disease, such as ascites, portal hypertensive bleeding, and hepatic encephalopathy [222]
• However, patients with alcoholic hepatitis may be entirely asymptomatic.
• The comorbidity of infection and delirium tremens due to alcohol withdrawal needs to be considered in febrile patients.
• Peripheral stigmata of chronic liver disease should raise the suspicion of underlying cirrhosis.
• As many as 70% of patients with moderate or severe alcoholic hepatitis by laboratory parameters will have cirrhosis, if a biopsy is obtained.
• Heavy alcohol use is a prerequisite for the development of alcoholic hepatitis. The history is usually apparent; however, in some patients, alcohol use may be covert.
• Clues to the presence of alcoholism include a history of multiple motor vehicle accidents, convictions for driving while intoxicated, and poor interpersonal relationships. Alcoholism exhibits a genetic predisposition, and a history of alcoholism in a close relative may also indicate that a patient is at risk.
• A person who uses alcohol heavily may come to medical attention because of an intercurrent medical illness that produces altered mental status or persistent vomiting, which, in turn, triggers alcohol withdrawal symptoms. In such instances, the physician must be alert to the presence of a precipitating illness (eg, subdural hematoma, acute pancreatitis, gastrointestinal hemorrhage) and to the likelihood of alcohol withdrawal symptoms (eg, seizures, delirium tremens) in addition to the problems associated with alcoholic hepatitis.
DIFFRENTIAL DIOAGNOSIS [221]
• Viral hepatitis
• Hemochromatosis
• Acetaminophen toxicity
• Nonalcoholic steatohepatitis
INVESTIGATIONS
• CBC count
o A CBC count commonly reveals some degree of neutrophilic leukocytosis with bandemia. Usually, this is moderate; however, rarely, it is severe enough to provide a leukemoid picture.
o Alcohol is a direct marrow suppressant, and moderate anemia may be observed. In addition, alcohol use characteristically produces a moderate increase in mean corpuscular volume.
o Thrombocytosis may be observed as part of the inflammatory response; conversely, myelosuppression or portal hypertension with splenic sequestration may produce thrombocytopenia.
• A serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio greater than 2.0 helps differentiate ALD from other liver diseases with ratios of less than 2.0, such as nonalcoholic steatohepatitis and chronic viral hepatitis [223-225].
• Hepatic deficiency of pyridoxal-6-phosphate, a cofactor necessary for ALT enzymatic activity, is thought to cause the absence of ALT elevation in ALD [226]
• Of note, high values of serum AST and ALT (> 400 IU /L) should raise the suspicion of alternative diagnoses, such as acetaminophen toxicity, acute viral hepatitis, and ischemic liver injury.
• For the detection of hazardous alcohol consumption, routine laboratory testing (AST /ALT ratio, GGT, MCV) has sensitivities and specificities reported to be between 35 and 73% and 75 and 86%, respectively [227]
• Interestingly, the AST/ALT ratio and elevated GGT are more likely to occur in blacks and Mexican Americans than in whites [228]
• Although the clinical and laboratory features are fairly sensitive (79%) and specific (98%) for ALD [229], other diagnostic tests are helpful.
• Ultrasonography or computed tomography imaging may be useful in evaluating for evidence of cirrhosis and portal hypertension or ruling out alternative diagnoses, such as hepatic vein thrombosis, biliary obstruction, and malignancy.
• Liver function tests
o Common liver function tests include albumin level, prothrombin time (PT), and bilirubin level.
o Hypoalbuminemia occurs because of decreased hepatic synthetic function and coexisting PEM.
o Hyperbilirubinemia is typically a mixture of unconjugated and conjugated bilirubin, with the latter predominating. Bilirubinuria is normally present in patients who are icteric.
o Coagulopathy predominantly affects the extrinsic pathway of coagulation (measured by PT). It is usually unresponsive to vitamin K.
o The severity of hyperbilirubinemia and coagulopathy reflects the severity of alcoholic hepatitis and is of prognostic value.
• Electrolyte panel
o Electrolyte disorders may reflect effects of vomiting, portal hypertension with decreased circulating volume, alcoholic ketoacidosis, or respiratory alkalosis.
o Hypophosphatemia and hypomagnesemia are common consequences of coexistent malnutrition.
• Screening blood tests to exclude other conditions (appropriate in any patient with alcoholic hepatitis)
o Hepatitis B surface antigen detects hepatitis B.
o Anti–hepatitis C virus by enzyme-linked immunosorbent assay detects hepatitis C.
o Ferritin and transferrin saturation detect hemochromatosis.
o Marked elevation of aminotransferase levels should raise concern for viral hepatitis or drug hepatotoxicity. In particular, people who are alcoholics may develop severe liver necrosis from standard therapeutic doses of acetaminophen.
o Rapid deterioration of liver function should raise the possibility of hepatocellular carcinoma, which can be tested for by determination of alpha-fetoprotein levels.
o Jaundice with fever can be caused by gallstones producing cholangitis and is suggested by a disproportionate elevation of the alkaline phosphatase level.
• In suspected cases of alcoholic hepatitis, a liver biopsy may be needed if the diagnosis is in doubt, alternative diagnoses are suspected, or the decision to treat with corticosteroids or other pharmacotherapy is not straightforward [232]
• A percutaneous liver biopsy is often contraindicated because of the presence of coagulopathy, thrombocytopenia, and ascites. Transjugular liver biopsies may provide clinically useful information and can be performed safely in conjunction with transjugular portal venous pressure measurements [231]
• Characteristic features include neutrophilic infiltration and fibrosis (perivenular in distribution), hepatocyte necrosis, and Mallory bodies [230].
• These pathological findings may be indistinguishable from features seen in nonalcoholic steatohepatitis. The predominance of neutrophils in alcoholic hepatitis is unlike the typical mononuclear inflammation in chronic viral hepatitis.
TREATMENT
NON PHARMACOLOGICAL [217]
• Abstinence is the foundation of therapy for an alcohol problem.
• For patients with milder alcoholic hepatitis, a general diet containing 100 g/d of protein is appropriate.
• Provide supplemental multivitamins and minerals, including folate and thiamine.
• Salt restriction may be required in patients with ascites

PHARMACOLOGICAL TREATMENT [217]
• Alcoholic hepatitis in its severe form is a life threatening condition.
• Patients may show a sudden and marked clinical deterioration during hospitalization, manifested by the development of ascites, encephalopathy, gastrointestinal bleeding or hepatorenal syndrome while the mortality in the acute phase has been estimated to be as high as 58%.
• Therefore, intensive clinical management must start from the admission, especially in patients who present with jaundice or have a DF >32 (a discriminant function defined by the patient's prothrombin time minus the control prothrombin time times 4.6 plus the total bilirubin in mg/dL). Ascites, encephalopathy and gastrointestinal bleeding are poor prognostic signs and require immediate attention and appropriate management. The mainstay of therapy is still based on abstinence and supportive care.
• Adequate volume replacement therapy preferably after monitoring through a central line, avoidance of diuretics as they may precipitate hepatorenal syndrome and the administration of vitamins including thiamine, folate pyridoxine and possibly vitamin K is the immediate course of action.
• Early institution of nutritional support by mouth or through a nasogastric tube (at least 25 kcal/kg/day) to assist liver function is recommended
• Early institution of broad spectrum antibiotics after blood, urine and ascitic cultures have been taken.
• Management of alcohol withdrawal with diazepam or chlordiazepoxide, titrated to vital signs and the level of arousal, is also of importance.
Corticosteroids
• American College of Gastroenterology recommended glucocorticoid treatment in patients with severe AH (DF > 32).
• The proposed treatment is prednisolone, 40 mg daily for 4 weeks followed by a taper. It has been estimated that seven patients need to be treated with corticosteroids to prevent one death.
• In addition, a recent study by Mathurin et al., showed that a fall in serum bilirubin levels at day 7 in severe AH (DF ≥ 32) patients treated with corticosteroids was an important predictive factor for improved survival at 6 months.
• However, whether corticosteroids should be discontinued in patients without a drop in serum bilirubin by day 7 needs validation from additional studies.
• In contrast, the efficacy of corticosteroids has not been adequately evaluated in patients with severe AH and concomitant pancreatitis, gastrointestinal bleeding, renal failure or active infection and therefore treatment is not recommended in these patient subgroups.
• Corticosteroid treatment is far from optimal in severe AH and it is not a widely accepted practice. Several clinicians are reluctant to use corticosteroids or reserve this treatment for carefully selected patients.
Pentoxifylline
• A recent study by Akriviades et al. produced promising results.These investigators conducted a prospective, randomised, double blind study of adequate size (101 patients) to test the efficacy of pentoxifylline (PTX) in severe AH (DF ≥ 32).
• They found that the patients who received 400 mg PTX three times daily for 4 weeks had a 40% reduction in mortality as compared to the placebo group (vitamin B12). The reduction in 4-week mortality was mainly attributed to the concomitant decrease in the incidence of hepatorenal syndrome by 65%-70%. Baseline serum TNF-α was elevated in both treatment and placebo groups and was decreased by PTX, especially in the subgroup of patients with the more severe form of disease.
• PTX was found safe with minor side effects from the gastrointestinal tract.
• These initial Results are encouraging and a randomised clinical trial is currently ongoing to help determine whether PTX has a role to play in the standard treatment of patients with severe AH.
Anti-TNF Therapy
• Based on this promising evidence suggesting a beneficial effect of TNF-α blockade, two research groups tested the efficacy of infliximab. The first published trial aimed to evaluate the tolerance and effectiveness of infliximab combined with steroids Twenty patients with biopsy proven severe AH (DF > 32) received prednisone 40 mg/day for 28 days and either a single infusion of infliximab (5 mg/kg IV) or placebo at study entry. Standard nutritional support and vitamin supplementation as well as prophylactic antibiotic therapy in patients with low-protein ascites were also given. Histology, plasma interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured at baseline and at day 10. Infliximab was well tolerated but it did not affect histology at day 10. In contrast, a significant reduction of cytokine levels at day 10 and of DF at day 28 was noted in the infliximab treatment arm compared with the prednisone alone group. The investigators concluded that this small randomised controlled study prompts for a larger-scale survival trial.
• It seems likely that low dose infliximab is safer than high dose.Future, carefully planned dose–response studies are needed to clarify the role of infliximab in severe alcoholic hepatitis.
• An alternative anti-TNF treatment using etanercept, was recently studied in patients with moderate or severe AH. In this open label pilot study, 13 patients with moderate or severe AH were targeted for a 2-week treatment period. The 30 day survival rate of patients receiving etanercept was 92% although 23% of patients had to discontinue due to adverse events including infection, hepatorenal decompensation and GI bleeding.

Nutritional Therapy
• Patients with AH invariable have some degree of malnutrition and the severity of this protein-calorie malnutrition has been shown to closely correlate with mortality rate.
• Short course of steroids together with enteral nutrition is a good therapeutic option that needs further investigation by larger controlled trials.
Supportive Treatments With Potential Benefit
• The use of extracorporal liver support devices was developed to support patients with acute liver failure and was rarely used in patients with AH.
• Recent clinical studies on a new non-biological extracorporal liver device known as the molecular adsorbents recirculating system (MARS) suggest a promising role in the treatment of severe AH.[118,119]
• MARS treatment appears to be a promising therapeutic option for patients with severe AH and randomised controlled trials are required to determine its efficacy in this group of patients.
Liver transplantation
• If patient with alcohlic hepatitis has to undergo liver transplantation a 6-month period of abstinence is generally required before liver transplantation is considered, although this requirement has been questioned.
• Patients who have decompensated liver disease despite alcohol abstinence should be considered for liver transplantation. Quality of life and survival following liver transplantation for alcoholic liver disease are excellent.

FOLLOW UP
• If patient recovers follow up regularly asking about absteinance from alcohol
• Recommend periodic blood examination for ALT,AST, GGT and MCV to detect on going alcohlism
SURVEILLANCE
• If patient has alcoholic cirrhosis measure serum alpha fetoproteins and abdominal ultrasound every 6 – 12 months for HCC
PROGNOSIS [218]
• If patient has alcohlic hepatitis when the prothrombin time is short enough to permit liver biopsy (< 3 seconds above control), the 1-year mortality rate is 7%, rising to 20% if there is progressive prolongation of the prothrombin time during hospitalization. Individuals in whom the prothrombin time prohibits liver biopsy have a 42% mortality rate at 1 year
• Other unfavorable prognostic factors are a serum bilirubin greater than 10 mg/dL, hepatic encephalopathy, azotemia, lack of response to corticosteroid therapy, and possibly little steatosis on a liver biopsy specimen and reversal of portal blood flow by Doppler ultrasound
• If person recovers from acute alcohlic hepatitis the 3 year mortality is ten times greater than that of control individuals of comparable age.
• The most important prognostic consideration is continued excessive drinking

COUNCELLING
• Avoid alcohol strictly
• Food should contain adequate calories
• Proteins should be taken almost 100 gm/day
• Vitamins should be taken


NON ALCOHOLIC STEATOHEPATITIS (NASH)
DEFINITION
Nonalcoholic steatohepatitis (NASH) is the term used to describe the distinct clinical entity in which patients lack a history of significant alcohol consumption but have liver biopsy findings indistinguishable from alcoholic hepatitis [233, 234].

Non-alcoholic fatty liver disease (NAFLD) is the term used to describe the alcohol-like liver injury that occurs in the absence of alcohol abuse. It embraces a range of histological abnormalities including simple steatosis or fatty liver, non-alcoholic steatohepatitis (NASH) and NAFLD induced cirrhosis [235].

DIAGNOSTIC CONSIDERATIONS
The following criteria have been proposed for the diagnosis of NASH [234,235]:
• A liver biopsy showing moderate to gross macrovesicular fatty change with inflammation (lobular or portal) and with or without Mallory bodies, fibrosis, or cirrhosis. It is possible that portal fibrosis alone may represent a variant of NASH.
• Convincing evidence of negligible alcohol consumption (less than 40 g of ethanol per week) including a detailed history obtained by three physicians independently and interrogation of family members and local medical practitioners. Random blood assays for ethanol estimation should be negative. If performed, assays for the presence of desialylated transferrin in serum, a marker of alcohol consumption, should also be negative.
• Absence of serologic evidence of infection with hepatitis B or hepatitis C.

In clinical practice, a meticulous history by three physicians is not usually practical; therefore this is not mandatory for the diagnosis. In addition, patients with past infection with hepatitis B virus infection should not necessarily be excluded. On the other hand, patients positive for hepatitis B surface antigen or hepatitis C virus antibody or HCV-RNA should be excluded.

EPIDEMIOLOGY
The prevalence of NASH in the general population is not well defined. Among patients who have had liver biopsies, NASH is seen in approximately 7 to 9 percent in Western countries [234,236] and 1.2 percent in Japan [237].
Sex:
• As many as 75% of patients in initial reported studies were females.
• In more recent studies, 50% of patients are females.
Age:
• Fatty liver occurs in all age groups.
• The majority of cases occur between the ages of 40 and 60 [234,237], although there have been reports in children over age 10.
• NASH is the third most common cause of chronic liver disease in adults in the United States (after hepatitis C and alcohol). It is now probably the leading reason for mild elevations of transaminases.
CAUSES
Although the etiology of NASH is unknown, it is frequently associated with:

• Obesity has been reported in 69 to 100 percent of cases. Most patients are 10 to 40 percent above ideal body weight [237].
• NASH also occurs in obese patients who have undergone surgery for weight reduction; it usually develops during the first 12 to 18 months, the period in which weight loss is most rapid [238].
• Type 2 diabetes, a frequent complication of obesity, has been described in 34 to 75 percent of patients with NASH [239].
• Hyperlipidemia (hypertriglyceridemia and/or hypercholesterolemia), which is frequently associated with both obesity and type 2 diabetes, has been reported in 20 to 80 percent of patients with NASH
• Metabolic disorders — total parenteral nutrition, rapid weight loss, acute starvation, and intravenous glucose therapy in the last week before death [240].
• Abdominal surgery — extensive small bowel resection, gastroplasty for morbid obesity, biliopancreatic diversion, and jejunal bypass.
• Drugs or toxins — amiodarone, tamoxifen, perhexilene maleate, glucocorticoids, highly active retroviral therapy, synthetic estrogens, and certain pesticides.
• Miscellaneous — Wilson's disease, Weber-Christian disease, partial lipodystrophy of the face sparing type, abetalipoproteinemia, and jejunal diverticulosis with bacterial overgrowth.


CLINICAL FEATURES
SYMPTOMS
• Patients are usually asymptomatic
• Patient might feel mild right upper quadrant discomfort
• Patient may have features of the metabolic syndrome such as high BMI (> 25kg/m2), hypertension, dyslipidaemia and impaired glucose tolerance/type 2 diabetes.

SIGNS
• Hepatomegaly is present in around 50%
• Acanthosis nigricans may be present in children.
• Splenomegaly and stigmata of portal hypertension (eg, ascites, edema, spider angiomas, varices, gynecomastia, menstrual disorders) may occur in patients with cirrhosis.


DIFFRENTIAL DIAGNOSIS

The differential diagnosis is broad. The diagnosis of steatohepatitis requires the exclusion of many factors [241]
Alcoholic Fatty Liver
Alcoholic Hepatitis
Alcoholism
Alpha1-Antitrypsin Deficiency
Autoimmune Hepatitis
Celiac Sprue
Cirrhosis
Drug-Induced Hepatotoxicity
Hemochromatosis
Hepatitis A
Hepatitis B
Hepatitis C
Hepatitis D
Hepatitis E
Hepatitis, Viral
Hyperthyroidism
Hypothyroidism
Isoniazid Hepatotoxicity
Malabsorption
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
Protein-Losing Enteropathy
Vitamin A Toxicity
Wilson Disease
Acute fatty liver of pregnancy

INVESTIGATIONS [242]

• No laboratory studies can help definitively establish a diagnosis of NASH.
• Aminotransferases
o The only abnormality may be an elevated aspartate aminotransferase (AST) or ALT level. These levels may be elevated as much as 10-fold. However, the AST and ALT levels may be normal in some patients with fatty liver or NASH.
o In the absence of cirrhosis, an AST-to-ALT ratio of greater than 2 suggests alcohol use, whereas a ratio of less than 1 may occur in patients with NASH.
• Alkaline phosphatase
o This level can be elevated in some patients with NASH.
o Usually, it is less than 2- to 3-times normal.
• Lipids
o Hyperlipidemia may be present.
o Increased triglycerides are common in children.
• Iron studies
o Elevations in serum ferritin, iron, and/or decreased transferrin saturation may occur in patients with NASH.
o Although iron overload occurs in a small proportion of patients with NASH, these patients have more severe disease. An iron index score may be ordered on a liver biopsy specimen to evaluate for phlebotomy. Hemochromatosis gene testing is recommended when the ferritin is significantly elevated.
• Viral serological markers: Before the diagnosis of NASH can be made, viral markers should be tested and viral infection excluded.
• If patient has NAFLD random blood assays for ethanol estimation should be negative.
• If performed, assays for the presence of desialylated transferrin in serum, a marker of alcohol consumption, should also be negative
• Autoimmune markers, such as antinuclear antibody (ANA) and anti–smooth muscle antibody (ASMA), are often slightly elevated in NASH.
o Positive antibodies are associated with more severe fibrosis levels.
o In the appropriate clinical setting, serum protein electrophoresis (SPEP) and anti–liver-kidney antibody may lead to a diagnosis of autoimmune liver disease.
• Fasting insulin and glucose levels will alert the clinician to potential glucose intolerance and may lead to more effective therapies.
• Ultrasound
o The liver is hyperechogenic or bright.
o Steatosis is detected only when substantial (30% or more) fatty change is present.
• Computed tomography
o The mean CT (Hounsfield unit) number is lower in the liver than in the spleen.
o CT scans may be used to monitor the course of the disease on successive scans.
o Focal fatty lesions may be identified by dual-energy CT scans that demonstrate increased attenuation with increasing energy and no change in normals.
• Magnetic resonance imaging
o MRI may be useful for excluding fatty infiltration. Phase-contrast imaging correlates with the quantitative assessment of fatty infiltration across the entire range of liver disease.
o Loss of intensity on T1-weighted images may be useful in identifying focal fat.
• Noninvasive studies, such as ultrasound, CT scan, and MRI, may identify the presence of a fatty liver. However, these imaging techniques cannot distinguish between benign steatosis and steatohepatitis. Benign steatosis may be focal or diffuse, whereas steatohepatitis is usually diffuse.
• Liver biopsy
o Liver biopsy should be performed in patients suspected of having NASH who have any of the following clinical and laboratory features: Peripheral stigmata of chronic liver disease, splenomegaly, cytopenia, abnormal iron studies, diabetes and/or significant obesity in an individual over the age of 45
o A liver biopsy and histopathologic examination are required to establish the diagnosis.
o The diagnosis should be considered in all patients with unexplained elevations in serum aminotransferases (eg, with findings negative for viral markers or autoantibodies or with no history of alcohol use).

TREATMENT
There is no proven effective therapy for NASH. Attempts should be made to modify potential risk factors such as obesity, hyperlipidemia, and poor diabetic control. Weight reduction should be gradual, since rapid weight loss has been associated with worsening of liver disease

NON PHARMACOLOGICAL THERAPY

• If patient of NASH are overweight (body mass index >25 kg/m2) they should be considered for a weight loss program. A target of 10% of baseline weight is often used as an initial goal of weight loss. Weight loss should proceed at a rate of 1–2 lb/wk.
• If patient has NASH dietary recommendations generally include both caloric restriction and a decrease in saturated fats as well as total fats to <30% or less of total calories. Although there are no data to support or refute the value of decreasing saturated fats and increasing the fiber content of diet on NASH, it is thought that these interventions may be of value. However, further research is needed to substantiate this opinion.
• Diet modifications are usually accompanied by a recommendation to exercise regularly. Both intermittent as well as daily exercise can help achieve weight loss and improve insulin sensitivity

PHARMACOLOGICAL THERAPY

• If patient of NAFLD is diabetic hemoglobin A1c should ideally be brought to <7%. However, the impact of this on NASH is not established



• Vitamin E and C decreases oxidative stress provides a rationale for its use in patients with NASH but cannot be recommended.

• Hypoglycemic agents

Several hypoglycemic agents continue to be studied. These drugs improve insulin sensitivity so can improve NASH

1. Metformin
2. Pioglitazone

3. Rosiglitazone

• Probucol — Probucol (a lipid lowering agent with antioxidant properties) was associated with a significant reduction in serum aminotransferases in a pilot, randomized controlled trial
• Betaine — Betaine is a normal component of the metabolic cycle of methionine, which has a protective effect against steatosis in animal models. Studies in humans are ongoing
• Ursodeoxycholic acid — A potential benefit of ursodeoxycholic acid was suggested in a pilot study of 40 patients. However, a subsequent larger controlled trial showed no benefit.
• Losartan — Angiotensin II is involved in the pathogenesis of hepatic fibrosis and enhances iron deposition and insulin resistance. Further studies are needed.
• Pentoxifylline — Pentoxifylline inhibits production of TNF alfa, which has been hypothesized to contribute to the progression of NASH.
• Orlistat — Orlistat is a gastrointestinal lipase inhibitor used in the treatment of obesity and type 2 diabetes mellitus. A pilot randomized controlled trial in patients with NASH found a significant reduction in fatty liver as assessed by ultrasound. Serum aminotransferases also declined to a greater extent with orlistat than placebo.


FOLLOW UP
• In patients who are obese and are diagnosed as having NASH, schedule a liver biopsy in six months to one year, and instruct patients to lose 10 to 15 pounds. A liver biopsy can be deferred if liver function tests normalize following weight loss.
• Patients with NASH should be seen regularly by a primary care physician who may be able to detect disease progression through physical examination findings (eg, spider telangiectasia, palmar erythema, splenomegaly), laboratory findings (eg, decreasing platelets, elevated bilirubin, decreasing albumin), patient complaints (eg, encephalopathy, ascites, fatigue), or incidental imaging study findings (eg, cirrhotic liver, splenomegaly, varices, ascites) every 1 -2 years.
• Patient with NASH who are diabetic should be monitored for HbA1c every 3 months till patient achieve a goal of < 7% then every 6 months
• Patient with dyslipidemia should have lipid profiles checked every 6 weeks till patient has stable controlled profiles than yearly.

SURVEILLANCE
• Patient should be followed up for development of chronic liver disease. Data from three other studies in which a total of 28 patients underwent repeat liver biopsy found that only one patient improved, 15 (54 percent) remained unchanged and 12 (43 percent) had histologic progression over follow-up of one to seven years [243-245]. Another report described the outcome of 132 patients with NASH followed for up to 18 years [246]. Progression to cirrhosis was much more likely in patients whose initial biopsies demonstrated ballooning degeneration and Mallory hyaline or fibrosis than patients with steatosis alone (26 versus 4 percent).


PROGNOSIS [247]
• Steatosis may be reversible with weight loss.
• Long-term natural history studies of patients with NAFLD who undergo repeat biopsies have shown that 30% progress, 30% remain stable, and 30% improve over a 3-year period without pharmacologic intervention.
• Abnormal glucose tolerance testing is an independent risk factor for progression of NASH.

COUNCELLING
• Lose weight if overweight
• Control diabetes
• Control dyslipidemias
• Advise regular exercise