Tuesday, June 11, 2013

A Patient with an Unusual Skin Tone

I was working in my hepatology clinic when I saw on my schedule a new patient consult.  She was a 47 year old Caucasian woman who needed to be seen due to elevated liver enzymes.  She ended up being a referral from the rheumatology clinic, which made me think she probably had elevated liver enzymes from her medications, such as  Methotrexate.  But that thought was to be proven wrong.

Later on that morning I knocked on the exam door and went into introduce myself to the this new patient.  “Hi, I’m Sharon, I’m a physician assistant and I run the hepatology clinic here.  What’s brings you into this clinic?”

“Hi, I’m Dorothy, Dr. Andrews, my rheumatologist referred me over to you.  I’ve been told I have elevated liver enzymes.”

“Yes, I saw your liver enzyme numbers.  Usually elevated numbers can be caused by medications, viral diseases, fatty deposits in the liver and the like.  What medications are you on?”

“Well, Dr. Andrews has me on Nexium for my acid reflux, Norvasc for my raynaud’s disease, and Lisinopril for my blood pressure.  I’ve been on some prednisone in the past, but not now.   I take some Tylenol for my painful joints, I’ve been told not to take any Motrin or Aleve for them due to their potentially causing problems with my kidneys.”

“Were you ever on Methotreaxate?”

“Umm, that doesn’t ring a bell with me.”

 “I’ve looked at your endoscopy reports, you’ve had two of them done in the past five years by one of my attendings.  Both of them showed you have some pretty significant inflammation at the tail end of your swallowing tube, or what we call your esophagus.  How’s the Nexium working, are you having any symptoms at all?”

“The Nexium is fine.  I take it with my dinner meal, and since switching to an evening dose, I haven’t had anymore reflux symptoms.”

“Good.  Okay, well I see that you are being treated for scleroderma, or what we call systemic sclerosis.  How long have you had it and how extensive is it?”

“I was diagnosed with it 10 years ago when I presented with skin tightening over my fingers.  Since then I’ve had skin involvement on my forearms and face.  It hasn’t gone anywhere else.  Then of course, I’ve had lots of problems with my stomach and bowels because of it.  I had an episode of diarrhea there for a while, which they treated with antibiotics.  Dr. Andrews also keeps my blood pressure on the low end of normal.  He doesn’t want me to have any problems with my kidneys, or at least that’s what he’s told me.  I’ve also been seen by the dermatology service here and they treated me with their light therapy.  I had to go into their special cylinder they have and stay there for a few minutes each day.  But the light therapy worked, my skin felt better after that.”

“Well, I’m glad to hear that.  The light therapy you had is called PUVA, by the way.  So based on what you’ve told me you would be classified as having limited systemic sclerosis.  Looking at your face I see that you have little, tiny visible blood vessels on your skin surface.  Did you have those when you were diagnosed?”

“Yes, now that you mention it, I did.”

“How long has your skin been this dark tan to copper color?”

“Umm, probably shortly after I was diagnosed.”

“Do you have any other significant medical illness?”

“No, just my scleroderma.”

“Any previous surgeries?”


“How about allergies to medications?”

“Just penicillin.  I break out in hives with it.”

“Okay, well I think I got the rest of your medical information I need from reading through Dr. Andrews progress notes.  So let me explain what labs I’m going to be ordering, as well as the abdominal ultrasound, and then I’ll do your physical exam.  After that, I’ll schedule you to come back into clinic in about 10 days to 2 weeks for a follow up with me.”

“Umm, alright.”

I explained all of the blood work I was going to order (which would rule out the common forms of hepatitis: viral, iron overload, alcohol related, as well as auto-immune related (auto-immune related hepatitis, primary biliary cirrhosis {which is common with patients who have limited sclerosis} as well as primary sclerosing cholangitis.)   The ultrasound of her abdomen would show any fatty infiltrates in her liver, i.e. non-alcoholic steatohepatitis (inflammation in the liver due to fat). 

Besides Dorothy having telangiectasias on her face, she had darkened course skin on her forearms, wrists and hands.  I could also see some small healed digital pits on her fingers.  Other than this her physical exam was unremarkable.  Later that day as I was writing my progress note, I notated that she was a pleasant, well informed Caucasian woman who did indeed fit the profile for having limited systemic sclerosis with CREST syndrome being present.  It would be interesting to see what her test results showed.

Scleroderma (Systemic Sclerosis) Risk Factors:

Black race has a higher prevalence over other races
Peak incidence occurs in the third or fourth decade of life
Etiology is unknown.

Systemic sclerosis is a disease where patient produce an excess of collagen fibers which results in fibrosis of the skin and internal organs.  It can also cause internal organ injury to the heart, lungs, GI, brain and kidneys.  Most patients also have muscular involvement.

Skin symptoms can include: itching, swelling, telangiectasia (micro small broken blood vessels), ulcers, fingernails that are pitting, hardened finger digits (calcinosis cutis).

GI symptoms (90% of patients have involvement) can include any part from the mouth to the anus: such as acid reflux, diarrhea, abdominal pain, GI bleeding, colic, bloating, malabsorption. 

Muscularskeletal involvement  can include myopathy (weakness of the muscle group or due to collagen deposition in the skeletal muscle), arthralgias (joint pain due to fibrosis of the overlying skin or inflammation of the joints). 

Pulmonary involvement will be either in the lung parenchyma (end result is interstitial  lung disease) or in the vasculature (which ends up in pulmonary hypertension).

Cardiac (heart) involvement can include:  scarring of the heart muscle, congestive heart failure, irregular heart rhythms, fluid in the pericardial sac, and/or microvascular disease.

Renal (kidney) (60-80% of patients with diffuse systemic sclerosis) can include:  increased protein in the urine, blood in the urine, high blood pressure, renal failure.

Vasculature (blood vessels): hypertension, Raynaud’s phenomenon (small blood vessel spasms), digital ulcers.

Patients who have sclerosis will have one of two kinds of sclerosis:  1) limited cutaneous sclerosis which has skin involvement of the distal extremities and face, or 2) patients will have diffuse systemic sclerosis which will involve skin proximal to the distal extremities (which can include chest, abdomen, shoulders, knees).

 Patients who have sclerosis can also be classified as having the CREST syndrome (this is usually found in patients who have limited systemic sclerosis)

C: Calcinosis cutis (hardening of the skin in the finger digits)
R: Raynaud’s phenomenon (vascular spasms which affect the hands)
E: Esophageal (swallowing tube) dysmotility (problems with moving food down the      
S:  Sclerodactyly (skin thickening over the finger digits)
T: Telangiectasia (micro small blood vessels on the surface of the skin which are              

Patients who have sclerosis can have any of the following antibodies found in their blood work:

Anti Scl-70
Anti U3-RNP
Anti PM Scl
Anti Th/To
ANA (95% of patients will be positive for this antibody)

The presence of a particular antibody will put them at risk for one type of organ disease over another.  For example, if the patient carries the Anti Scl 70 antibody this puts them at increased risk for lung involvement. 

Most patients who initially present with sclerosis will have the following symptoms:

Fatigue (76%)
Stiff joints (74%)
Loss of strength (68%)
Pain (67%)
Problems with sleeping (66%)
Problems with skin discoloration (47%)

Diagnosis of systemic sclerosis is done by the patient having tightness, thickening and/or swelling of the joints distal to the metacarpals.  Or they can have the typical skin changes seen in the hands: sclerodactyly, digital ulcers, or digital ulcers. 

Dorothy came back into the clinic towards the end of the following week.  Her lab results showed a positive ANA (which would be seen with her disease), but also a positive ASMA (anti-smooth muscle antibody) which could mean she had auto-immune hepatitis.  Her AMA titer was negative (and it would have been positive if  she had primary biliary cirrhosis).  Her AST and ALT were both elevated, above 200 each.  All of the rest of her blood work was negative. 

Her abdominal ultrasound did not show any fatty infiltrates, although it was mildly enlarged.  I explained all of this to Dorothy, and advised her that her lab results required that we acquire a fine needle biopsy of her liver tissue to see what was going on microscopically.  This would then tell us whether auto-immune hepatitis was indeed present.

Dorothy agreed, so I set her up with the interventional radiologists.  She came back to see me two weeks after her biopsy.

“Dorothy, your liver biopsy shows that you have auto-immune hepatitis going on.  You already have one auto-immune disease, in other words your sclerosis, so it’s not uncommon to eventually come down with a second auto-immune disease.  I was actually expecting your results to come back with primary biliary cirrhosis, but when your AMA titer was negative, this was ruled out.”

“I see. So what can I do about this?”

“Well for you, it should be rather simple.  I’ve already talked with Dr. Andrews and he has agreed that I can start you on a short course of low dose prednisone while I’m slowly increasing a medication called Imuran.  Imuran is a chronic long term medication we use to suppress a person’s immune system.  In your case we will be suppressing it so that it doesn’t continue its attack on your liver.  You’ll probably also find that it will help out with your sclerosis, seeing that it is a medication that is used there.”

“Oh, alright, that sounds simple.”

“Yes, we try to keep things as simple as possible.”

Treatment of Systemic Sclerosis is based on which organ system(s) are involved.  Patients who have this disease need to be seen by the various specialists (cardiologist, pulmonologist, nephrologist, etc). 

Skin:  Anti-histamines are used for pruritis (itchy) skin, UVA light therapy, calcium channel blockers (Raynaud’s).

GI tract: proton pump inhibitors for acid reflux (esophageal symptoms), endoscopy and laser treatment for those who have gastric antral venous ectasia, rotating extended use of antibiotics for those who have bacterial overgrowth, surgery for those who have small bowel bleeding from numerous small vessel disease. 

Renal:  angiotension converting enzyme medications for hypertension (high blood pressure) or impending renal failure, hemodialysis (acute renal failure)
Pulmonary: for those with interstitial lung disease (parenchymal disease) are treated with cyclophosphamide and/or systemic steroids.  They can be maintained on chronic long acting steroids such as imuran. 

For those who have pulmonary hypertension they can be treated with endothelin receptor antagonist (bosentan) along with a vasodilatory agent (sildenafil) and/or prostacyclin analogue (such as iloprost). 

Patients are also eventually on oxygen supplementation.

Cardiac:  patients are treated with congestive heart failure medications which include blood pressure medications (ACE inhibitors, ARBs, calcium channel blockers, etc), digoxin, coumadin/xarelto for irregular heart rhythms), pacemakers, etc.

Overall treatment of the systemic sclerosis is usually done with oral steroids (although patients have to be watched for renal disease), Imuran (chronic long term steroid), methotrexate (immune suppressive medication).

With the new field of monoclonal antibodies, a monoclonal is being looked at investigationally to see whether it has any effect in patients with systemic sclerosis.  The monoclonal is named TGF beta 1.  This monoclonal blocks endothelial growth factor.

Dorothy came back into the clinic several times over the next few months as I tapered her prednisone and increased her Imuran.  At her four month visit her liver enzymes were normal and she was on full dose Imuran without any side effects.  So I started seeing her every three months for a visit and she never had any problems to speak of.  Her liver enzymes stayed normal the whole time.  Her sclerosis was mildly better with her on the Imuran, so Dr. Andrews and I decided to leave her at the current dose schedule.
Long term complications from this disease includes:

Heart failure
Lung failure (from pulmonary hypertension or parenchymal involvement)
Kidney failure (sclerosis renal crisis)
Cancer (5 fold increase for patients to have lung cancer).

Mortality in increased in patients who have sclerosis, for any patient’s age matched group, patients with sclerosis have a 5-8 times higher mortality (if they have diffuse disease).  If they have limited disease their mortality is 2x  higher.  There is a 10% mortality at 5 years and 18% at 10 years for those patients with diffuse sclerosis.  Patients generally succumb to a pulmonary complication. 

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