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Beneficial Effects of Pentoxifylline on Hepatic Steatosis, Fibrosis and Necroinflammation in Patients With Non-alcoholic Steatohepatitis

From: http://www.medscape.com/viewarticle/559029_1
Discussion
"In the present study, we demonstrated significant histological improvement and normalization of aminotranferases at the end of 12 months of pentoxifylline treatment in patients with NASH.

NASH could progress to cirrhosis in up to 20-30% of patients.[2-4] No effective therapy for preventing disease progression or amelioration of this disease currently exists. The improvement in liver enzymes in the present study was associated with histological resolution of NASH. Sixty-seven percent of the patients in the present study had at least one grade improvement in Brunt's grading. Five of the six histological responders also had persistent normalization of their aminotransferases. Histological response was noted in steatosis, necroinflammation and fibrosis stage. Fibrosis could be down-staged in four out of six patients with baseline fibrosis. Most importantly, worsening of the fibrosis was observed in only one patient at the end of 12 months of treatment. Pentoxifylline thus could prove useful as an antifibrotic drug in NASH in addition to improving necroinflammation. However, in view of the small number of patients included in the study and because it was not a randomized controlled study, the possibility of sampling error in liver biopsy cannot be entirely excluded. Ratziu et al. recently found that histological lesions of NASH are unevenly distributed throughout the liver parenchyma, which might account for sampling error of liver leading to staging inaccuracies.[9] Although we agree to this theoretical possibility, the sustained biochemical improvement over the entire 12-month period and histological improvement in almost two-thirds of the patients is unlikely to be due to be a result of sampling error.....
In conclusion, pentoxifylline leads to a significant reduction in the AST and ALT levels in patients with NASH. This improvement correlates with histological resolution of steatosis, inflammation and fibrosis stage. Randomized controlled trials with long-term pentoxyfylline treatment with histological follow-up are justified."

Mike


9 Responses
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223152 tn?1346978371
Thanks -- now I will have to look for the CD b/c I can't get your station.  Ah, maybe the people in PA will smile today.

Think we should repost all the alcohol stuff on DD's new post?
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Avatar universal
I will put in a request right now.
I agree about the litter. I cannot believe the absolute disregard for forum decorum - that's rhyme and I sort of like it. Mike
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223152 tn?1346978371
You are right.  This side of the forum is getting "littered" as FL put it, with trash.  We do need to keep the focus of what this is for.  Can you imagine trying to read the archives anymore?  Boy, could I do some housekeeping over here.

I am amazed at your capacity for research.  You are a focused person!  Play something fun for me today (How about "A Touch of Gray")?
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Avatar universal
Thanks for that. Excessive drinking (whatever that really is) and HCV is definitely not smart. I was reading this forum today and it occurred to me that there should be something medical related over here, if only to make it seem like it's really the medical side. I hope you're happy and healthy this fine day. Mike
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223152 tn?1346978371
Good articles.  Here is another one on the impact of alcohol on hep C

http://www.medscape.com/viewarticle/488940_2

from the article:

Effect of Alcohol on Liver Fibrosis Progression
Over the past decade, several studies have shown that alcohol increases the progression of HCV to cirrhosis and HCC. Seef et al[32] reported that more than two thirds of deaths with end-stage liver disease secondary to non-A, non-B hepatitis occurred in alcoholic patients. The threshold level above which alcohol potentiates the progression of HCV disease is unknown. Approximately 10 g of alcohol is contained in 12 oz of regular beer, 5 oz of wine, or 1 oz of distilled spirits (80 proof). Excessive alcohol intake thought to potentiate the progression of chronic hepatitis C has been reported to be between 30 and 80 g/d in different studies. It has been shown that alcohol abuse accelerated the progression of hepatic injury in patients with HCV.[33-42] In 1997, Poynard et al showed that in patients with HCV who drank more than 50 g of alcohol per day there was a 34% increased rate of fibrosis as compared with those who drank less. In one study in which HCV was contracted via IVDU, it was noted that the relative risk of end-stage liver disease was 3.6 for persons drinking > 37 g/d and 1.57 for those drinking 13 to 37 g/d.[37] In another study in which risk of developing HCV cirrhosis was evaluated after blood transfusions, it was found that the risk of cirrhosis was fourfold higher in those who drank > 80 g/d.[38]

Unlike the case of heavy alcohol abuse, the effect of moderate amount of drinking and the progression of fibrosis in patients with HCV infection is not yet fully understood.[43] However a recent prospective study from France shows that both histological activity and fibrosis gradually increase with the amount of alcohol use and that even moderate alcohol consumption, as low as 31 to 50 g/d in men and 21 to 50 g/d in women, accelerates the histological lesions in chronic HCV patients.[44] In another retrospective study from Sweden, the effect of moderate alcohol consumption (< 40 g/d) on liver fibrosis progression in patients with HCV was analyzed.[45] Documented histological progression of liver disease was most likely among those who consumed a greater amount of alcohol (5.7 g/d) and had a higher drinking frequency (drinking days per year) of 34.5 as compared with those who drank less (2.6 g/d) and had a lower drinking frequency of 8.2.

Two studies from France have shown the impact of drinking on liver fibrosis progression in patients who are coinfected with HIV and HCV.[46,47] Drinking more than 50 to 80 g/d was associated with increased fibrosis progression and the risk of death from cirrhosis.

Most epidemiological studies have shown that the effects of alcohol and hepatitis C on liver disease progression are synergistic.[48-51] Corrao and Arico[36] demonstrated that the relative risk for developing cirrhosis in alcohol abusers not infected with HCV was 15 as compared with 9 in HCV-infected patients who did not drink. However, the risk in HCV-infected alcohol abusers was 147. In addition, the interaction between lifetime daily alcohol intake (LDAI) and HCV was additive at  50 g/d. However, one study showed that the effects of alcohol and HCV on cirrhosis were additive and not synergistic.[52]

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Avatar universal
Impact of Smoking on HCV Therapy
The impact of smoking on HCV treatment outcomes is unclear and is often questioned by patients. El-Zayadi[29] found that smokers have lower response rates to interferon-based therapy when compared with nonsmokers, and smoking can also foster the development of fibrosis. A study by Hezode and colleagues[30] showed that daily cannabis smoking was an independent predictor of fibrosis progression in patients with chronic hepatitis C. At the 2007 European Association for the Study of Liver Diseases, the same group of researchers found a strong association between daily cannabis use in chronic hepatitis C patients and steatosis severity.[31] Therefore, it is recommended that clinicians encourage patients to stop smoking and encourage smoking cessation classes or other modalities (eg, nicotine patch) to assist them in stopping.
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Avatar universal
Alcohol
Many patients with hepatitis C may have multiple mental health and drug abuse issues because of the interrelationships between risk of HCV transmission and these comorbidities. In a multicenter study, Anand and colleagues[24] screened 4061 HCV-infected veterans for psychiatric comorbidities and substance abuse and found that 78% of the sample had at least 1 substance abuse diagnosis and many also suffered from posttraumatic stress disorder. The researchers found that high-risk behaviors tended to be more common in individuals with past or recent alcohol use. In addition, once treatment was initiated, recent alcohol use was the only variable associated with early treatment discontinuation. However, patients that used alcohol and completed treatment had a comparable response to that of nondrinkers. By contrast, alcohol consumption of ≥ 30 g/day was associated with reduced response rates in patients receiving peginterferon plus ribavirin treatment in a study by Chang and colleagues.[25] According to data reviewed by Schiff,[26] alcohol use during treatment is associated with poor responses to HCV therapy. One study by Ohnishi and colleagues[27] showed a dose-response relationship between alcohol consumption and HCV RNA clearance. Whereas 27.7% of infrequent drinkers achieved SVR, none of those consuming 69 g/day or more without abstaining before therapy cleared the virus. In a similar study, Okazaki and colleagues[28] found that nondrinkers were significantly more likely to clear HCV (53.8%) than either those who drank > 70 g/day (12.5%) and those who maintained consumption to < 70 g/day (20.0%). Because the level of alcohol use at which the association with poor response appears is unclear, both Schiff[26] and the NIH guidelines[3] suggest that patients should abstain from alcohol completely during treatment. Patients should be encouraged to participate in support groups regularly during therapy to aid in their abstinence from alcohol. In addition, the clinician should maintain an open dialogue with the patient regarding alcohol use during treatment. Key management strategies for substance abuse in HCV patients are outlined in Table 6. To see a detailed discussion of substance abuse management in HCV, please follow this link to a challenging interactive case.
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Avatar universal
From the same article:

Mania
One challenge in identifying and managing psychiatric symptoms during therapy is that depressive and manic symptoms can be difficult to differentiate. Several studies have identified manic symptoms in patients undergoing interferon-based therapy.[22,23] In a prospective study, Castera and colleagues[23] found that 20% of patients receiving HCV therapy developed manic/hypomanic episodes during treatment, whereas an additional 23% developed major depression with manic features. Table 5 provides a guide for differentiating symptoms of depression vs dysphoric mania in hepatitis C patients.

Full mania is characterized by psychosis and involvement in dangerous or extremely risky behavior. Patients displaying these symptoms generally require hospitalization. In patients experiencing full mania, often hepatitis C therapy should be stopped immediately along with any antidepressants the patient may be taking, as antidepressants can exacerbate manic symptoms. It is important to note that treatment discontinuation can generally be avoided when adverse symptoms are detected early; the majority of psychiatric adverse events are preventable or treatable and with close screening, monitoring, and active management of these adverse effects, patients can have successful outcomes.

Mike
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Avatar universal
From: Clinical Care:
http://clinicaloptions.com/Hepatitis/Management%20Series/
Advanced%20HCV%20Management/Modules/Overcoming%20Barriers/Pages/
Page%201.aspx

Depression
Psychiatric disorders may complicate tolerance or adherence to interferon-based antiviral treatment, as found by Ho and colleagues[15] in their study of the veteran population. In this study, 33 patients received 6 months of standard interferon alfa. Of the 19 individuals who had psychiatric disorders before starting HCV therapy, 68% discontinued treatment or had dose reductions due to adverse events compared with 20% of those with no psychiatric disorder at baseline. In addition, a study performed by Raison and colleagues[16] showed that baseline depressive symptoms significantly predicted on-treatment depressive symptom severity in 162 patients treated with peginterferon alfa-2b plus weight-based ribavirin (P < .0001) (Figure 2). Together, results from these studies indicate the importance of identifying depressive symptoms before initiating therapy and appropriately managing them to increase opportunity for treatment success.

It is important to identify these patients at baseline because studies show that patients with psychiatric disorders can successfully complete treatment when managed with proper medications and closely monitored.[13,17] One key management tool for psychiatric comorbidties is the incorporation of a mental healthcare professional into the team of clinicians managing the hepatitis C patient. This allows for more rapid recognition of psychiatric symptoms and optimal management strategies. In addition, there are several tools available, both self-reported and physician administered, to measure depression and anxiety at baseline and throughout treatment. The following are the most commonly used scales in the setting of hepatitis C.

Self-Report Scales

    * Beck Depression Inventory
    * CES-D (click here to download a copy of the CES-D screening tool for use in your practice)
    * Hospital Anxiety and Depression Scale
    * Zung Self-Rating Depression Scale

Clinician Rating Scales

    * Hamilton Depression Scale
    * Montgomery-Åsberg Depression Scale

Each scale can be used to identify symptoms before initiating therapy. In addition, serial depression symptom scores can be used to detect changes in severity of depressive symptoms throughout treatment. It should be noted that although these scales measure depressive symptoms, the Diagnostic and Statistical Manual of Mental Disorders criteria or structured clinical interview for depression must be used to confirm if major depression is present. In addition, suicidal ideation should be screened for through direct questioning of the patient.

Many nonpharmacologic measures can be considered for managing or preventing mild depression, such as support groups, exercise, stress reduction techniques, and psychotherapy. These methods can be used before initiating HCV therapy and continued throughout treatment. Some patients may benefit from treatment with antidepressant medications before HCV therapy. Few studies have been performed evaluating the use of pretreatment with antidepressants in the HCV therapy setting. However, data in the malignant melanoma population suggest that this strategy may be useful in some patients. Musselman and colleagues[18] evaluated 40 malignant melanoma patients receiving interferon therapy. Before initiating treatment, 20 patients were randomized to receive 14 weeks of paroxetine (2 weeks before initiating interferon and 12 weeks into the treatment regimen). Among patients not receiving paroxetine, 45% developed major depression compared with 11% of those receiving the paroxetine treatment, suggesting that antidepressant therapy reduced the risk of depression development on treatment. In a more recent publication, Raison and colleagues[19] have shown similar results in the setting of hepatitis C. The investigators randomized 61 patients to receive paroxetine pretreatment (n = 28) 2 weeks before starting HCV therapy and for 24 weeks during treatment with interferon alfa plus ribavirin. The remaining 33 patients did not receive antidepressant therapy. As measured by the Montgomery-Åsberg Depression Rating Scale, patients receiving paroxetine pretreatment had lower rates of mild to severe depression during HCV treatment when compared with the placebo group (P = .02). In total, 26.7% of those receiving placebo developed depressive symptoms considered to be moderate or severe, whereas 8.7% of those assigned to receive paroxetine pretreatment met these criteria.

No formal guidelines regarding prophylactic antidepressant use in HCV have been developed. However, Raison and colleagues[20] have developed a set of criteria to determine which patients would be the best candidates for this approach (Table 4).

When managing depressive symptoms, selective serotonin reuptake inhibitors, such as citalopram, paroxetine, sertraline, or fluoxetine, are commonly used in this setting. One should note that it may take up to 14 days for this class of drugs to become fully effective. If the patient has not responded after 2-3 weeks, either dose increases or switching or adding a second antidepressant can be considered. It is important that patients be counseled to alert their healthcare provider if suicidal ideation develops during therapy. The patient should be specifically queried to determine if they have a desire, plan, and means of committing suicide. If so, the patient requires immediate cessation of antiviral therapy, immediate intervention, and possible psychiatric hospitalization. No robust estimates of suicide rates during interferon-based treatment have been reported; however, treatment with interferon plus ribavirin has been reported to be associated with suicidal thoughts, suicide attempts, and successfully completed suicides. The relative risk associated with treatment is unknown, and therefore, patients should be monitored closely to determine any significant changes in behavior.[21] It is important to note that suicidal behavior may occur suddenly and without warning and that depression screening tools are not necessarily predictive of suicide. Therefore, suicidal ideation must be queried directly. To see a detailed discussion of depression management in HCV, please follow this link to a challenging interactive case.

Mike
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