Fatty Liver Disease

I'm building better relationships with my coworkers, but right now its getting them to hang out with me on the weekends that is the trick.  I'm spending another Friday night inside and all this sitting around is making me think a lot about non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease, or NAFLD, is such a bizarre concept.  The disease is not fully understood and it tends to be highly under-diagnosed.  In the absence of viral hepatitis, alcohol and iron overload, high levels of triglycerides cause a build up of fatty deposits within the liver eventually leading to liver dysfunction.  A more specific, scientific definition would be macrovesicular hepatosteatosis occurring in the absence of alcohol consumption.  The estimated prevalence of the disease is anywhere from 15-33%.

NAFLD can lead to NASH can lead to cirrhosis of the liver.  The prevalence of NASH is between 5.7-17%.  NASH, or non-alcoholic steatohepatitis, is scarring and inflammation of the liver occurring secondary to large amounts of fat deposits in the liver.

As America gets bigger, so do obesity related complications and there have been increasingly more studies investigating the effects of obesity.  In more recent years, adipocytes (fat cells) have been more and more established as having endocrine functions, if not considered endocrine organs in and of themselves.  The cytokines and inflammatory mediators released from adipocytes are hypothesized to lead to NASH.  Adipocytes release leptin (causing fibrinogenesis), resistin (resulting in insulin resistance), angiotensin (vasoconstriction), TNF-alpha (death to hepatocytes and mitochondrial dysfunction), and decreased levels of adiponectin, which may be protective against insulin resistance.  Overgrowth of bacteria in the small intestines has also been implicated in the pathophysiology of NASH, but more research is needed.

Over 80% of patients with NAFLD meet the minimum criteria for metabolic syndrome and about 98% of NAFLD patients have insulin resistance.  In fact, NAFLD is becoming more established as the hepatic component of metabolic syndrome.

Metabolic syndrome is a disease state recognized by multiple organizations, but the definition may vary.  ATP III defines it as a patient meeting three of the five following criteria:  insulin resistance, elevated triglycerides, low HDL, hypertension, and/or a high waist circumference.  If you are really interested in diagnosing metabolic syndrome, feel free to reference the Grundy article at the end of this entry.  Waist circumference is used in place of BMI because visceral obesity is a better marker for obesity related complications and risk of NAFLD.  The metabolic syndrome diagnosis is a little bit edgy because each of the components need to be treated separately.  I like the concept because it gives recognition to obesity as a disease that affects many facets of the body but the diagnosis does not change how the patient would be treated.

Ok so let's get back to the liver.

Patients present with elevated aminotransferases not explained by the usual suspects.  They will often suffer from right upper quadrant discomfort, fatigue and malaise.  The physician may note hepatomegaly (enlarged liver), jaundice (caused by elevated bilirubin) and portal hypertension (caused when an inflamed and scarred liver impedes the flow of blood through the liver).

For the physician to make a diagnosis, he or she must first establish two things: that fatty liver disease is present and that it is unrelated to alcohol consumption.  The gold standard to establish the presence of fatty liver is a biopsy.  Realistically, biopsies are generally not the best option.  They are usually expensive and invasive.  They can potentially put the patient at risk of other complications.  A biopsy would only be performed if the results would change the course of treatment.  Otherwise, MRI, CT scan, and sonography can be used to show the presence of fatty liver.

Although non-alcoholic and alcoholic fatty liver disease may visually appear very similar, there are some major differences in presentation.  Aminotransferases are rarely highly elevated in the non-alcoholic disease; they are generally below 250 IU/L.  Additionally, the AST/ALT ratio in alcoholic liver disease is classically above 2.  In NAFLD, the ratio is less than 1.  Studies with NAFLD patients have excluded those with liver disease that could potentially be due to alcohol by excluding patients that consume greater than 2 drinks daily or greater than 4 drinks weekly.

The most common cause of mortality in patients with NAFLD is cardiovascular disease.  Patients with NASH are twice as likely to die of cardiovascular causes as the general population and NAFLD is being established as a CV risk factor independent of diabetes, hypertension, and hyperlipidemia.  A recent study published in the New England Journal of Medicine in 2010 provides a wonderful overview of cardiovascular considerations in patients with NAFLD.

Liver dysfunction is also a common complication of NAFLD, guessing that doesn't take rocket science.  About 15-25% of patients with NASH will progress to cirrhosis. The 10 year mortality for patients with cirrhosis secondary to NASH is about 30-40%.

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The only treatment that has shown major benefit is weight loss.  Patients need to decrease fructose, carbohydrates, and saturated fats in their diets.  Moderate to high intensity excercise should also be emphasized for 30 minutes 3-5 times per week.  There have also been studies investigating sibutramine and orlistat in NAFLD.  Sibutramine caused a decrease in LFTs, but it is no longer on the market due to an increase in CV events.  As cardiovascular mortality is the greatest risk associated with NAFLD, the potential decrease in LFTs hardly seems worth the risk.  Orlistat did not show benefit in the trials that I investigated.  So patients, you are on your own.

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Patients also need to take care to avoid other medications or external factors that could further damage their liver.  Alcohol in any portion size is not recommended for patients with NAFLD, even though the disease was not caused by alcohol initially.

Vitamin E has been investigated in some trials.  Its anti-oxidant properties have been hypothesized to be beneficial in preventing further disease progression.  A daily dose of the RDA of vitamin E has very little risk of harm so could be recommended.  It is possible that other anti-oxidants, like vitamin C, may also be beneficial.

I previously mentioned that 98% of patients with NAFLD are also insulin resistant.  The pathophysiology of NAFLD has been closely linked to that of insulin resistance, therefore it was hypothesized that insulin sensitizing medications would also improve liver function.

Metformin.  The gold standard of care in type II diabetes unless you have an elevated serum creatine or don't like diarrhea.  The only available biguanide.  Early studies with smaller sample sizes showed benefit but later meta-analyses showed that there was no improvement in liver function tests with the use of metformin.  As type II diabetes is a common co-morbidity in this patient population, it still may be beneficial to many of the patients, but as a anti-hyperglycemic, not as a medication that would decrease liver damage.

Thiazolidinediones.  After six years of pharmacy school I am proud to say that I can actually pronounce the name of this medication class.  Through lies and bullshit of the pharmaceutical companies, the FDA has voted to keep GlaxoSmith Kline's rosiglitazone, Avandia, on the market.  Rosiglitazone did show benefit in reduction of LFTs in NAFLD along with pioglitazone, Actos.  However, rosiglitazone is associated with an increased risk of myocardial infarctions (heart attacks) and strokes.  I would never in a million years recommend rosiglitazone for any patient and it is insulting to patients and providers that the FDA allows it to stay on the market.

Pioglitazone came out with early mortality benefit data but it causes edema that can exacerbate heart failure and there has also been an increased risk of myocardial infarction associated with it.  I could say a lot more about the thiazolidinediones, cardiovascular disease and NAFLD, but I will conclude by saying that I would consider use of pioglitazone in patient with NAFLD.

The only thing left to do for patients with NAFLD is to monitor and treat other risk factors for cardiovascular disease.

The use of statins in this patient population has been somewhat controversial.  Most statins pass through the liver and can potentially cause increases in LFTs.  However, the beneficial modification of the lipid profile and decreased inflammation in the blood vessels has been hypothesized to be beneficial to liver disease caused by NAFL.  Although studies have not shown an improvement in liver function, they have shown that statins are safe and efficacious in reduction of LDL in these patients.  I would still recommend pravastatin or rosuvastatin which are more renal than other statins.

Angiotensin is implicated in the pathophysiology of NAFLD and NASH.  ACE inhibitors and angiotensin receptor blockers may be able to play a role in this disease state other than just causing blood pressure reduction.  I looked at a few small studies using losartan in patients with NAFLD.  Although the trials showed benefit, the sample sizes were very small and more trials are needed to prove a benefit.  I also would probably first consider an ACE inhibitor, for cost reasons only, even though no trials to my knowledge have been conducted in this patient population.

I really enjoyed reading about NAFLD and NASH, but unfortunately, the best advise a practitioner can give to the patient is to lose weight through diet and exercise and to decrease their other risk factors for cardiovascular disease.

References:

Ramesh S et al.  Evaluation and management of non-alcoholic steatohepatitis.  Journal of Hepatology 2005; 42:S2-S12.

American Gastroenterological Association medical position statement: nonalcoholic fatty liver disease.  Gastroenterology 2002; 123:1702-1704.

McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis.  Journal of Clinical Gastroenterology 2006; 40:S17-S29.

Grundy SM et al.  Diagnosis and management of metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement.  Circulation 2005; 112:2735-2752.

Targher G et al.  Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.  New England Journal of Medicine 2010; 363(14):1341-1350.

Promrat K et al.  Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.  Hepatology 2010; 51:121-129.

Sabuncu T et al.  The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis.  Romanian Journal of Gastroenterology 2003; 12(3):189-192.

Harrison SA.  Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial.  Hepatology 2009; 49:80-86.

Rakoski MO et al.  Meta-analysis: insulin sensitizers for the treatment of non-alcoholic steatohepatitis.  Alimentary Pharmacology and Therapeutics 2010; 32:1211-1221.

Schernthaner G et al.  Cardiovascular risk and thiazolidinediones- what do meta-analyses really tell us? Diabetes, Obesity and Metabolism 2010;12:1023-1035.

Ratziu V et al.  Therapeutic trials in nonalcoholic steatohepatitis: insulin sensitizers and related methodological issues.  Hepatology 2010; 52(6):2206-2215.

Shields WW et al.  The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): a pilot trial.  Therapeutic Advances in Gastroenterology 2009; 2(3):157-163.

Yokohama S et al.  Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatits.  Hepatology 2004; 40(5):1222-1225.

Favism

Favism.  G6PD deficiency.  Name derived from the hemolytic anemia a patient with G6PD deficiency will suffer after consuming fava beans.  My preceptor at my most recent rotation recently emailed me, asking if I would fill a prescription for the second generation antihistimine, meclizine, for a patient with G6PD deficiency.  Before I could answer, I had to take a few steps back and look at what exactly G6PD deficiency is.

G6PD, or glucose-6-phosphate dehydrogenase, is the rate limiting enzyme for a process that produces NADPH as a byproduct.  NADPH is a reducing agent used in the synthesis of fatty acids and cholesterol and is also utilized to protect cells from oxidative damage.

NADPH is essential to erythrocytes, which having no nucleus, during their 120 day lifecycle are unable to synthesize new proteins to repair cellular damages.  Erythrocytes rely heavily on reducing agents, like NADPH, to protect against oxidative damage.

Patients with G6PD deficiency have genetic mutations in the glucose-6-phosphate dehydrogenase enzyme.  The mutation in the enzyme determines the severity of the NADPH deficiency, and therefore the ability of erythrocytes to react to oxidative damage.  

Under conditions of oxidative stress when NADPH supplies are not sufficient to reduce the damage done to the cell, oxidized hemoglobin clumps together within the erythrocyte creating Heinz bodies, which are characteristic of G6PD deficiency.  This leads to hemolytic anemia, as the red cells burst and die.  

Symptoms of G6PD deficiency are brought on by oxidative stress; a variety of stressors can bring about hemolytic anemia.  Infections, diabetic ketoacidosis, fava beans, and some medications can bring on hemolytic anemia within days of exposure.  

Hemolytic anemia is often brought on by medications in patients with G6PD deficiency when glutathione reduces the medication in the liver during the metabolism process.  In order for the body to return glutathione to its usable state, the oxidized glutathione is reduced by NADPH.  When the mutant enzyme cannot keep up with replacing the NADPH stores, erythrocytes begin to suffer oxidative damage and anemia results, with the tell-tale Heinz bodies, dark urine, and often patients experience back-ache.

Unfortunately the medications that cause hemolytic anemia in this patient population are not structurally similar.  Additionally, many medications that are metabolized by glutathione reductase are safe, in therapeutic doses, for patients with G6PD deficiency to take, for example acetaminophen.

G6PD deficiency is genetic; prevalence varies among populations.  Persons of mediterranean, African, and middle eastern decent are more likely to have this deficiency.  A number of researchers have hypothesized that this enzyme mutation may have evolutionary survival benefits.  For example, like patients with an allele for sickle cell disease, recent studies have shown that patients with G6PD deficiency are less susceptible to malaria caused by Plasmodium falciparum.  

so...  Would I fill meclizine 25 mg for a patient with a salicylate allergy and G6PD deficiency?

Although metabolized in the liver, meclizine does not place patients with G6PD deficiency at risk of hemolytic anemia and is therefore safe to take.  Diphenhydramine, however, poses a low risk of hemolytic anemia.

Medications that put G6PD deficient patients at high risk of hemolytic anemia include: trimethoprim, dapsone, sulfa drugs like sulfamethoxazole, chloroquine, quinine, quinidine, ciprofloxacin, nitrofurantoin, primiquine, and probenecid.  This list is not all inclusive and other medications, like acetaminophen, diphenhydramine, and phenytoin pose a low risk of causing hemolytic anemia.

Patients with a G6PD deficiency can be referred to the G6PD Deficiency Favism Association’s website, available at http://www.g6pd.org for more information on their condition and for an extended list of medications to avoid.  

References:

Meisenberg G, Simmons WH, ed.  Principles of Medicinal Biochemistry.  2nd ed. Mosby-Elsevier, Philidelphia.  copyright 2006.

Beutler E.  G6PD deficiency.  Blood Journal 1994; 84: 3613-3636.

Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman’s: The Pharmacological Basis of Therapeutics.  11th ed.  New York: The McGraw-Hil Companies, Inc.; 2006.

DRUGDEX® System (electronic version). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com (cited 11/27/2010).

G6PD Deficiency Favism Association.  Available at http://www.g6pd.org (cited 11/27/2010).

Kastrup EK, Spenard PL, Tra PN, Williams AL, Wickersham RM, Schwalm AJ, et al., editors.  Drug Facts and Comparisons.  2010 ed. St. Louis: Wolters Kluwer Health; 2009.

Blood and Chocolate

Theobroma cacao.  Food of the Gods. Xocoatl.

Origins of chocolate are traced back to before the Aztecs, who believed chocolate had divine properties and had even used cacao beans as currency.  Before sacrifices to the gods, victims were given chocolate to drink and when the Spanish arrived, mistaking Cortes for the snake god, Quetzalcoatl, Montezuma served them chocolate.

The legend of Quetzalcoatl has since been immortalized in Downtown San Jose’s Cesar Chavez park.  My brother was patient enough to pose for me next to it on my last trip home.

Chocolate has since been adopted by cultures and civilizations throughout the world, and while we may not still be feeding it to our victims before sacrifice, our love of chocolate has driven intrigue and research into closer examination of its delicious properties.  

In vogue today is the effects of chocolate on blood pressure.  Chemical components in dark chocolate have been shown to have preventative effects on stroke and trials have consistently shown that consumption of cocoa daily can lower systolic blood pressure up to 4.5 mmHg. 

Why do we care about high blood pressure? High blood pressure is treated to prevent a heart attack or stroke and to prevent other complications, like heart or kidney failure.

A review of the literature by Desch et al was published at the beginning of the year in the American Journal of Hypertension.  Desch sites that interest in the effects of chocolate on blood pressure originated from observation of the Kuna indians, who consumed large amounts of chocolate and who had low rates of high blood pressure.  Closer examination revealed that chocolate contains a lot of plant flavanols, which have been previously shown to have beneficial effects on blood pressure. 

If chocolate is to be recommended for blood pressure, it needs to be eaten daily to keep blood pressure consistently down.  Additionally, the 4.5 mmHg drop seen is not going to be enough for the majority of patients diagnosed with hypertension; traditional medications and other lifestyle modifications will be needed.  Not to be forgotten either, is that this is the era of obesity; when scientists are seriously considering putting statins into fast food orders, is encouraging increased consumption of dark chocolate to treat blood pressure really the answer?

Another interesting area regarding hypertension treatment is that every patient really is a unique and beautiful snowflake, meaning high blood pressure is driven through different mechanisms in different patients, especially patients of different ethnic backgrounds.  

Umscheild et al site that while African-American patients are more likely to have a better understanding and awareness of hypertension, they are less likely to have controlled blood pressure despite treatment.  African-Americans are also significantly more likely to have strokes and kidney failure, compared with the rest of the population.  Umscheild’s research on disparity published in January 2010 showed that providers were just as likely to intensify blood pressure therapy for African-Americans as they were for other patients, indicating that there is another reason for disparity than negligence in the health care system.

Most concerning to me is the increasing amount of evidence showing that fluctuations in blood pressure place patients at risk of cardiovascular events.  An analysis by Rothwell et al published in the Lancet in March 2010 found that fluctuations in blood pressure between office visits was a predictor of cardiovascular events and stroke independent of mean blood pressure.

I can hardly remember to take my multivitamin daily; how many patients with high blood pressure are unable to successfully adopt taking their blood pressure medications daily into their routine?  For patients with high blood pressure who don’t feel sick and are now told that they will have to take a daily (or twice daily) pill for the rest of their life to treat a risk that is poorly understood by the patient, it must be difficult to work up the motivation to take as directed.  

Evidence from trials like Rothwell's really show where a pharmacist can step up to play a role in reducing risk.  For patients consistently late in filling prescription for blood pressure medications, pharmacists have the opportunity to talk to the patient about risks, help them to better understand the benefit of taking the medication, and the risks associated with non-compliance.  

One last final shout out to Mr. Ghirardelli, who arrived in San Francisco, CA during the gold rush and discovered that he could make more money selling hot chocolate to crusty miners than actually panning for gold.  His chocolate remains awesome and delicious to this day.

References:

Bensen A.  A brief history of chocolate.  Smithsonian.com 2008.

Shah ZA et al.  The flavanol (-)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway.  Journal of Cerebral Blood Flow & Metabolism 2010.

Desch S et al.  Effect of cocoa products on blood pressure: systematic review and meta-analysis.  American Journal of Hypertension 2010;23(1):97-103.

O'Riordan M.  The "MacStatin": Fast food with some ketchup, salt, and a statin to go.  theheart.org 2010.

Umscheild CA et al.  Racial disparities in hypertension control, but not treatment intensification.  American Journal of Hypertension 2010;23(1):54-61.

Rothwell PM et al.  Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension.  The Lancet 2010;375:895-905.