Non-Alcoholic Fatty Liver Disease (Burns 3/25/2020)

Thanks to Dr. Autumn Burnes for being such a wonderful and flexible first presenter on our new Virtual Social Distancing Zoom Grand Rounds at SSRRH. It was really nice to take 45 minutes to think about something other than COVID-19. We had over 35 attendees. . .Thanks to everyone who tuned in!

The topic was Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH).

NAFLD: histologic evidence of an accumulation of fat in hepatocytes (steatosis)
NASH: the presence of NAFLD plus liver cell injury and death, and accumulation of inflammatory cells

Some shocking stats:

• 25% of US adults are affected by NAFLD 

  

  (NEJM 2017, https://www.nejm.org/doi/full/10.1056/NEJMra1503519)

• 5% have NASH
• NASH is among the top 3 indications for liver transplant and will likely surpass Hepatitis C and Alcohol cirrhosis in the coming years
• 70% of Type 2 diabetics have NAFLD (!!)

MOST COMMON risk factors include metabolic syndrome: abdominal obesity, impaired glucose tolerance/diabetes, hypertension, dyslipidemia

LESS COMMON risk factors include nutritional syndromes, drugs and toxins, inherited metabolic diseases, and pregnancy-related factors:

• TPN, rapid weight loss, jejunoileal bypass
• EtOH, corticosteroids, tamoxifen, amiodarone, methotrexate, industrial solvents
• Lipodystrophy, abetalipoproteinemia, Wilson's
• Acute fatty liver of pregnancy, HELLP 

NAFLD is a diagnosis of exclusion.

You should consider other causes of chronic liver disease, including (but not limited to): chronic viral hepatitis, hemachromatosis, autoimmune liver disease, alpha1antitrypsin deficinecy, Wilson's disease, drug induced liver disease)

NAFLD (by AASLD criteria):

1. Hepatic steatosis by imaging or histology [>5% hepatocytes, +ballooning/hepatocyte injury for NASH]
2. No significant alcohol consumption [>1 drink/day for F and 2 drinks/day M]
3. No competing etiologies for hepatic steatosis
4. No coexisting causes of chronic liver disease
5. Liver biopsy is gold standard

What is our primary care role ?

Consider using this AAFP approach to elevated liver enzymes in your primary care practice (this is a picture of Figure 1 from AAFP 2017 article, entire article can be found here: https://www.aafp.org/afp/2017/1201/p709.html)

(AAFP 2017)

It's frustrating and scary to not have much to offer patients who already have cirrhosis from NASH, so can we intervene sooner?

We don't have great tools to distinguish those who will go onto develop NASH from the large population that has NAFLD. But we know that risk of progression is multifactorial including genetic factors, epigenetic factors, and environmental (e.g. shift work, gut microbiome, toxins).

Here are two risk calculators (links should work):
NAFLD Fibrosis Score (Age, BMI, IGT/DM, AST, ALT, platelet count, albumin)
Fibrosis- 4 (Fib-4) Index for Liver Fibrosis (Age, AST, ALT, platelet count)

Routine screening for NASH is currently NOT recommended (by AASLD, USPSTF, or NICE guidelines) BUT we should have a high index of suspicion, particularly in our Type 2 diabetic patients, and we might consider either using the Fib-4 calculator to risk stratify OR send for elastography (specialized ultrasound).

However, for those of you who are looking for screening guidelines, here is a paradigm for HIGH risk patients:

There are evolving pharmacologic treatment options, including:

• Thiazolidinediones (pioglitazone), even in patients without diabetes  (some possible benefit in the PIVENS trial)
• GLP-1 agonists (very small study LEAN trial, too early to know)
• Vitamin E  (800 IU/day, recommended by AASLD only in biopsy-proven NASH)
• Keep taking statin if it is indicated (despite hepatotoxicity)
• (Metformin has NO benefit)

Mortality in NAFLD:

• Cardiovascular disease is the most common cause of death in patients with NAFLD, independent of other metabolic comorbidities. 
• we should treat CVD proactively
• Cancer
• Liver-related death
• Increased all-cause mortality

COVID-19 Update (Green 3/11/2020)

Great thanks to Dr. Gary Green, Infectious Disease specialist, for a well-attended Grand Rounds this week on COVID-19. Dr. Green's blend of  virology, epidemiology, and calm-ology left me feeling more confident and less panicky about our current situation with COVID-19. Hope you all feel the same!

Here's the down and dirty (recognizing that this is a dynamic situation-- it's very likely that information shared here will be out of date in a matter of days).

COVID-19 in our Community
As of 3/11/2020, Sonoma County has only three confirmed cases of COVID-19:

• 1 case of previously diagnosed COVID-19 transferred from Travis Air Force Base associated with the original Diamond Princess Cruise (Japan)
• 2 cases of COVID-19 associated with the Grand Princess Cruise (SF to Mexico)

As of this writing, there have been NO additional confirmed cases of COVID-19 in Sonoma County.

In fact, in the last two weeks, Dr. Green himself has tested 15 high risk symptomatic patients (high risk because of direct contacts to known COVID-19 cases and/or recent high risk travel history). All of these patients were symptomatic (i.e. cough, shortness of breath, fever) and all resulted NEGATIVE.

Dr. Green reassured us that currently, we have no evidence in Sonoma County of community transmission-- unlike many counties, including Santa Clara, San Francisco and Los Angeles. It doesn't mean we won't have community transmission in Sonoma County; we just don't yet.  

What Happened in Wuhan, China?

China "went through the wall first" explained Dr. Green--that is, because this novel Coronavirus originated in China, patients and healthcare workers have been literally on the front lines of a brand new disease. For this, they have suffered.

It has now been over three months since COVID-19 was first recognized, and we know a lot more about this virus than those brave healthcare workers-- many of whom gave their lives taking care of sick patients. 

China's experience is NOT necessarily our experience, but we can learn from them! 

• Chinese healthcare workers in Wuhan first recognized a string of strange respiratory cases and unusual pneumonias in early December 2019
• Just a few weeks later their scientists were able to identify a novel Coronavirus, and by January 7 the virus had been sequenced and shared with the world.
• Of note, SARS (2002-2003) and MERS (2012) were both novel Coronavirus outbreaks. Tons of Chinese research and prep done in response to these outbreaks are improving the global response to COVID-19.
• By Dr. Green's estimation, "this virus started in the right place"-- had such a virus emerged almost anywhere else in the world, we would not have been equipped to recognize it, identify it and study it so quickly. 

Healthcare Workers, what is our risk?
Of note, in China, over 3000 healthcare workers (HCW) have been infected with COVID-19, and at least 18 have died.  This scares many of us in the healthcare field. In one hospital, 29% of 138 confirmed cases were in HCW. This is likely because of inappropriate personal protective equipment (PPE) and underprepared infection control measures at the time COVID-19 was emerging. Also there was a tremendous strain on healthcare resources. Simultaneously, there was an abundance of community transmission in China due to insufficient infection control practices and large numbers of patients in crowded clinics in a crowded city.

(By the way, in the SARS epidemic, over 1/5 of confirmed cases were in healthcare workers).

In contrast, at Queen Mary Hospital in Hong Kong (a huge 1706-bed hospital) reported 42 COVID-19 confirmed cases. Of the 413 HCW who cared for confirmed cases, 11 had documented unprotected exposure. These HCW were all quarantined x 14 days. 

This is important: in this hospital, despite its massive size and the number of cases:

• No HCW becomes infected with COVID-19
• There were ZERO nosocomial transmission in the hospital

Dr. Green's take home: We can do this! We do this every year for flu and seasonal respiratory illness: wash your hands, don't come to work sick, use appropriate PPE and infection control practices when caring for sick patients. 

Flu vs. COVID-19: How worried should we be?

Dr. Green wants us to keep this in perspective. While COVID-19 is indeed a serious illness with global repercussions, the actual numbers of deaths (in the US and worldwide) are far lower than seasonal flu. And remember-- there have been no recorded pediatric deaths.

While initial studies from China were reporting a 2-3% mortality rates from COVID-19 those numbers now appear to be much much lower (on the order of ~0.6% from Korea). Initial reports were probably higher because China was really reporting a "case fatality" rate rather than a "mortality rate". While 0.6% is much higher than influenza mortality rates (typically ~0.1%), it is markedly lower than SARS, MERS or the Flu Pandemic of 1918.

See the slide below for the actual numbers, comparing (on the top) SARS, MERS and COVID-19 and (underneath the line) the 1918 flu pandemic and our current 2019-20 seasonal flu. Of note, in the US 136 children and over 20,000 people have died of influenza so far this season  (2018-2019, 80,000 people in the US died). Get your flu shot, please!

(sorry slide credit to Dr. Green, the formatting is a little off. First column=mortality rate, Second column= Ro; measure of infectivity (the higher the more infective), third column=case fatalities are actual counts of deaths)

What does COVID-19 actually look like?

While it does look a little like a common cold, there are a few things to note about COVID-19:

• This is primarily a virus of the LOWER respiratory tract (i.e. lungs), unlike most coronavirus infections, which are UPPER respiratory tract infections (i.e. head colds)
• This means that very few have rhinorrhea (aka a runny noses), ~4%
• Unlike influenza, which comes on abruptly, symptoms of COVID-19 seem to come on gradually over several days with worsening shortness of breath being a primary symptom after about 5 days of illness
• Fever is often present but often not very high 
• Cough is usually dry

We also know now that about 80% of people infected with COVID-19 have mild illness, 14% have severe and 5% have critical illness.

By far, the people most at risk are elderly with other chronic health conditions (especially cardio-pulmonary health conditions).

Who to test for COVID-19? (as of 3/8/2020)

Persons with symptoms (fever (T>100.3), cough, breathing difficulties or sore throat)

AND
Prioritize people who meet CDC criteria (https://www.cdc.gov/coronavirus/2019-ncov/travelers/index.html)

• any symptomatic person, including HCW with close contact with +COVID-19 patient in the last 14 days, including Grand Princess cruise ship passengers
• any symptomatic person who traveled to geographic area with CDC travel advisory 2/3 in the last 14 days of sx onset (China, Iran, Italy, Japan, South Korea)
• any person hospitalized with lower respiratory tract infection sx where an alternative etiology has not been identified

Don't test asymptomatic people!

US Healthcare system preparation:
Dr. Green assured us that even though we haven't experienced community transmission yet, COVID-19 will be coming to a community near you. Just like flu and RSV seasons. But this is going to be a long slog. We are just about the wrap up flu season, too bad, time to keep up the hard word. ,

Key goals for the US healthcare system per the CDC. These are our goals too in our local community!

1. Reduce morbidity and mortality
2. Minimize disease transmission
3. Protect healthcare personnel
4. Preserve our healthcare system functioning

So, healthcare workers, stay safe, wash your hands, wear PPE, don't come to work sick, and don't panic. 

A few extra super-interesting goodies:

On a vaccine: 

• During the 2002 SARS epidemic (which was also a novel coronavirus), there was a tremendous amount of work done to create a SARS vaccine. By the time the vaccine was ready, 20 months had passed, and the epidemic had died down. 
• However, the very substrate with which that vaccine was created is being used to fast-track a vaccine for COVID-19.
• That puts the world 20 months ahead of the game. 
• Look for vaccine trials for COVID-19 to start in the next couple months!

On antiviral medications: 

• During the SARS epidemic, it was noted that HIV+ patients on antiretrovirals (ARVs)-- particularly Kaletra-- did better than their counterparts, despite assumptions that they should be immunocompromised and do worse.
• This led to experimental use of ARVs for the SARS coronavirus
• Also, during the last Ebola outbreak, a new ARV was created (Remdemsivir), which didn't have great effect on Ebola but may work for coronavirus
• SO, in the US, China and other countries (and even locally) new and old ARVs are being used (experimentally) to treat people infected with COVID-19. So far with some good outcomes. So cool!

And finally, some additional resources

• Great map from Johns Hopkins with global data (but we can all agree that the black and red is a little overly dramatic, just what we don't need right now), Click here to go to live map: https://coronavirus.jhu.edu/map.html
• Local Sonoma County Department of Public Health website: https://socoemergency.org/emergency/novel-coronavirus/