Saturday, February 17, 2018

CHIP, immune disorders, osteoarthritis, and hydroxychloroquine

A footnote in my post on Kateva’s liver disease linked to a NYT article on CHIP (clonal hematopoiesis of indeterminate potential). Wikipedia calls it “Clonal hematopoiesis”. To put it mildly, this is a hot research topic (wikipedia, lots of 2017 edits) …

Recently, several independent studies have confirmed the presence of malignancy-associated mutations in the blood of individuals who have no clinical signs of hematologic malignancy.[4][5][6] In combination, these studies have demonstrated the widespread incidence of clonal hematopoiesis in the healthy adult population and have stimulated further efforts to broaden our understanding of clonal hematopoiesis in health and disease.

Whenever we discover something new about human biology we round up all the diseases we don’t understand and look for a connection. The main focus now is on CHIP’s role in atherosclerotic heart disease, but I assume all the immune disorders are being CHIP tested. (I couldn’t find any articles on this today, which only makes me more suspicious :-).

If you’re going to look at mysterious CHIP disorders, I’d nominate the weird flavors of osteoarthritis. “Osteoarthritis” is an age related disorder (like CHIP), it’s very diverse, some of it has autoimmune type features — feels kind of CHIPpy. (As of Feb 2018 Google and Pubmed found nothing on “clonal hematopoiesis” osteoarthritis [2]. So you might have read it first here, except we know Google isn’t what it once was. Anyway, I’ve created an RSS feed for “clonal hematopoiesis” osteoarthritis — be interesting to see what that link shows in a few months.)

As long as I’m having fun with medical speculation, I’d like to throw in a mention to one of my favorite medications — hydroxychloroquine (HCQ). HCQ started life as a treatment for malaria, but it’s most commonly used for SLE and RA — autoimmune disorders. More recently it’s being explored as an adjunct to chemotherapy.

HCQ was thought to have something to do with Toll receptors (somewhat hot topic), but research on its oncology use focuses on how it interferes with lysosomal mediated autophagy. Autophagy (self-eating) is important for cells, it’s how they recycle their constituents to make new things. Some cells depend on this more than others. Retinal cells rely on autophagy and it’s probably not a coincidence that HCQ can cause retinal toxicity [1].

Cancer cells rely on autophagy too — they don’t have normal cooperative nutritional inputs. Which is why HCQ is being tested for cancer treatment.

Which brings me back to CHIP.  We think CHIP is a kind of premalignant age related disorder of the stem cells that form blood. We think HCQ might impair replication of disordered cells. We know HCQ works for some autoimmune disorders. We wonder about CHIP and oddball autoimmune disorders …

So it would be fun to see if HCQ inhibits CHIP.

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[1] Worryingly the process can continue even after the drug is stopped.

[2] Actually they both returned results, but they were nonsensical results. I miss when Google used to actually work. It was funny to get a false positive from PubMed, it’s usually reliable.

Notes on managing a canine biliary system clearance disorder (intrahepatic cholestatic liver disease).

I was doing a bit of personal research today that might be of interest to a few others, so sharing here.

Kateva, of fame,  is 12 years old. Since she was about 9 she’s had liver enzyme elevation on her routine vet exams. In early 2017 she had intermittent vomiting — which is not unusual among dogs. A month or two later she became jaundiced (yellow sclera) and very ill. She was found to have obstructive jaundice, likely chronic, with a very large gall bladder. Post cholecystectomy she developed pancreatitis. She had 3 paws in the grave when a combination of Emily’s diligent home nursing [6] and oral ursodiol (ursodeoxycholic acid - aka UCDA, Actigall) pulled her back. [1].

As best we can tell, without a liver biopsy (risk, $, uncertain benefit), Kateva has a disorder of hepatic bile clearance. These “intrahepatic cholestatic liver diseases” have been increasingly recognized in humans over the past few decades. The ones we’ve named include primary biliary cholangitis [2], primary sclerosing cholangitis, granulomatous liver disease, a host of rare genetic disorders and more familiar things like hepatitis. When one considers how tricky it is to produce bile and clear it through the liver into the bowels it’s likely there are many currently unrecognized varieties of bile clearance disorders.

Many of the intrahepatic bile excretion disorders respond to ursodiol. I recall use of it to dissolve gallstones in the 1980s (with laporoscopic surgery this became less valuable), it has been used in humans for primary biliary cirrhosis since 1996 [3]. Ursodiol has pretty clear short term benefit but we don’t know how much it changes longterm outcomes. Within a few years of use in humans it was tried in dogs and cats, this 2011 discussion is pretty good.

I liked this description of the mechanism of action …

Ursodiol … is a naturally occurring bile acid that is a minor fraction of the bile acid pool in humans, but a major fraction in bears and other hibernating animals.  Ursodeoxycholic acid is more water soluble (hydrophilic) than cholic or chenodeoxycholic acid and is less inherently toxic to cells.  When given orally, ursodeoxycholic acid becomes a major component of the bile acid pool, the proportion rising from <2% to as much as 65%.  By replacing the hydrophobic or more toxic bile acids with ursodiol, the toxic effects of cholestasis are ameliorated …  Ursodiol was approved for dissolution of gallstones in 1987 and as a therapy of primary biliary cirrhosis in 1996. 

Kateva had a good year but she’s slowing now. I think without the liver diseases she’d be early old age, but either the underlying liver disorder is worsening or she’s moved on to liver failure or a malignancy … or some other disorder. Old dogs, like old people, usually have a few things going on.

At her age both cost and the least-misery principle limit what we’re likely to inflict on her. Obeticholic acid (Ocaliva) is a new and fantastically expensive alternative to Ursodiol — too costly to consider given limited added benefit. Colchicine is used, but it probably doesn’t do much and it’s nasty to take. Investigational drugs are often prohibitively expensive but a veterinary formulation of budenoside (a steroid that disproportionately acts on the liver) and fenofibrate [5] might be affordable.

I wrote this post to help think about what we might do for Kat. I think we could push her ursodiol and, if we can get an affordable veterinary formulation, we might try the budenoside. Or we could spend money on things she might like better, like steak [7].

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[1] The surgery and ultrasound were costly, but the truly expensive parts were all the things that intersect with human medicine — lab tests, intravenous fluids, medications, and the like. For better or worse we had some resources, so the limit was her misery. We were close to that. The longterm ursediol trial was an informed hail mary pass by my wife and I with veterinarian support.

[2] Thought to be due to “environmental trigger(s) acting on a genetically susceptible individual”.  I’m sure everyone in this field is now wondering if PBC is a CHIP (clonal hematopoiesis of indeterminate potential) disorder. We really don’t know what causes it. Immune system dysfunction seems a contributor but it’s suspicious how ineffective immune suppressants have been. I wouldn’t be shocked if there were a genetic disorder in bile formation though.

[3] With veterinary compounding it’s not cheap, but more affordable than most specialty human medications.

[4] Ref removed, but consulted UpToDate often in this writing.

[5] Curiously fenofibrate drug information lists primary biliary cholangitis as a contraindication!

[6] Emily is an excellent physician, but she also has a knack for nursing.

[7] In the last few years I’ve done end-of-life management for two parents (mine), three gerbils (Kangaroo, Adric, and Pipsqueak), and now a dog. All of the considerations were very similar though budgets varied. The parents were the easiest decisions. The gerbil and dog decisions were much harder.