Sandra D’Angelo - Clinical Correlations



Treatments for NASHA drug for NASH that may work…

Nonalcoholic steatohepatitis (NASH) is disease in which patients have features of alcoholic hepatitis on liver biopsy without aany prior history of significant alcohol consumption and negative hepatitis serologies. It is’s unclear how prevalent this disease is because most patients with liver function abnormalities do not undergo liver biopsy. In those that have had a liver biopsy, the prevalence is estimated to be 7-9%. It is most common in women, between the ages of 40-60 and often associated with the Metabolic syndrome;, obesity, type 2 diabetes mellitus, hyperlipidemia and hypertension. The pathogenesis of NASH has not been clearly defined; most theorize that the initial process is insulin resistance which later leads to hepatic steatosis.

Unfortunately, there is not enough data available to elucidate the natural history of NASH. Approximately 8-26 % of patients with NASH progress to cirrhosis. Most patients with NASH usually have abnormal liver function tests. Ultimately, a liver biopsy is necessary to confirm the diagnosis.

There aren’t many few treatment options available that have been proven effective in NASH. Refer to the table below for details. What’s new and exciting is the recent NEJM article entitled, “A Placebo controlled trial of Pioglitazone in subjects with Nonalcoholic Steatohepatitis.(NASH)” This proof-of-concept study looks at the role of pioglitazone in patients with NASH.

Fifty-five patients with diabetes or impaired glucose tolerance and liver biopsy confirminged NASH were randomly assigned to six months of either (a) a hypocaloric diet which meant a (a reduction of 500kcal per day in relation to calculated daily intake) plus+ pioglitazone 45mg daily or (b) a hypocaloric diet plus+ placebo. In order to assess assess for a treatment effectresponse, certain variables were analyzed both before and after treatment. These variables included hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test.

Results showed that those who received Ppioglitazones had significant metabolic and histologic improvements in subjects with nonalcoholic steatohepatitis compared to those who took placebo. Not Unsurprisingly, patients taking pioglitazone had improved glycemic control and glucose tolerance. Interestingly, they also had patients had significant improvements in transaminase levelsnormalized their AST/ALT, and decreased hepatic fat content on magnetic resonance spectrospcopy. and increased hepatic insulin sensitivity. Using magnetic resonance spectroscopy, patients in the Pioglitazone group also had decreased fat content. Inflammation and steatosis were also both significantly improved upon repeat liver biopsy among those taking pioglitazone was also reduced, however there was no reduction in fibrosis.

This study is promising for the future. As we know, Ppioglitazone increases hepatic insulin sensitivity and glucose clearance. This addresses the primary problem in NASH which is thought to be insulin resistance. It must be stressed that this was a proof of concept study. It is not surprising that the sample size was small and the results may not be generalized since the patients were such a well-defined group. In addition, the study period was only six months. This could also explain why there was not a significant reduction in fibrosis.

This certainly sets the groundwork for a larger and longer study with a longer study time period. In addition, one wouldwill hope for clearer endpoints, such as histologic improvement in hepatic fibrosis. For the time being, all we can offer is exercise, diet modification and better control of all aspects of the metabolic syndrome.

|TREATMENT |EFFECTS |

|Weight loss |Improvement in LFTS, histology, serum insulin, and quality of life |

|Vitamin E and C |decreases oxidative stress provides a rationale for its use in patients with NASH. |

| |A placebo-controlled trial involving 45 patients concluded that six months of treatment with a |

| |combination of vitamin E and C (1000 IU and 1000 mg, respectively) was associated with significant |

| |improvement in liver fibrosis. There was no benefit on necroinflammatory activity. |

| |Recent data suggests increase in mortality with vitamin E supplementation |

|Metformin |A controlled trial included 36 patients with NASH who were randomly assigned to a lipid and |

| |calorie-restricted diet with or without metformin for 6 months |

| |Improvement in necroinflammation was observed more frequently in patients in the metformin group but |

| |results did not achieve statistical significance |

|Pioglitazone |A pilot study included 18 nondiabetic patients with biopsy-proven NASH who were treated with |

| |pioglitazone (30 mg daily) for 48 weeks |

| |Serum ALT levels fell to normal in 72 percent of patients. Histologic features of steatosis, cellular |

| |injury, parenchymal inflammation, Mallory bodies, and fibrosis were significantly improved from |

| |baseline. Using strict criteria, histologic improvement was observed in two-thirds of patients |

|Rosiglitazone |An uncontrolled trial included 30 adults with histologically confirmed NASH who were treated with |

| |Rosiglitazone for 48 weeks |

| |All patients were overweight (BMI >25 kg/m(2)) including 23 percent who were severely obese. |

| |Paired biopsies before and after treatment were available in 26 patients. |

| |The mean global necroinflammatory score improved significantly; in ten patients (45 percent) the |

| |biopsies improved to an extent where they no longer met published criteria for NASH. There was also |

| |significant improvement is perisinusoidal fibrosis. Mean serum ALT levels showed corresponding |

| |improvement. |

|Probucol |a lipid lowering agent with antioxidant properties |

| |associated with a significant reduction in serum aminotransferases in a pilot, randomized controlled |

| |trial |

| |The effect on liver histology was not assessed. |

| |Probucol is not available in the United States. |

|Betaine |normal component of the metabolic cycle of methionine, which has a protective effect against steatosis |

| |in animal models |

| |A potential role in the treatment of NASH was suggested in a pilot study involving 10 adult patients |

| |Treatment for one year was associated with significant improvement in serum aminotransferase levels and|

| |liver histology. |

| |These results await confirmation in controlled trial |

|Ursodeoxycholic acid |potential benefit of ursodeoxycholic acid was suggested in a pilot study of 40 patients |

| |However, a subsequent larger controlled trial showed no benefit |

|Losartan |A pilot study of the angiotensin II receptor antagonist losartan in seven patients with NASH suggested |

| |a benefit on blood markers of hepatic fibrosis and serum aminotransferase levels |

| |Further studies are needed. |

|Pentoxifylline |inhibits production of TNF alfa, which has been hypothesized to contribute to the progression of NASH. |

| |Biochemical improvement was described in two pilot studies with a total 38 patients |

| |However, in one of the studies;9 of 20 patients dropped out due to side-effects (primarily nausea). |

|Orlistat |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. |

*Source: Uptodate.

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